How do NSAIDs cause ulcer disease?

Size: px
Start display at page:

Download "How do NSAIDs cause ulcer disease?"

Transcription

1 BaillieÁ re's Clinical Gastroenterology Vol. 14, No. 1, pp. 147±159, 2000 doi: /bega , available online at on 11 How do NSAIDs cause ulcer disease? John L. Wallace PhD Professor Department of Pharmacology and Therapeutics, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada Gastroduodenal ulceration and bleeding are the major limitations to the use of non-steroidal anti-in ammatory drugs (NSAIDs). The development of safer NSAIDs or of e ective therapies for the prevention of the adverse e ects of existing NSAIDs requires a better understanding of the pathogenesis of NSAID-induced ulcer disease. NSAIDs can cause damage to the gastroduodenal mucosa via several mechanisms, including the topical irritant e ect of these drugs on the epithelium, impairment of the barrier properties of the mucosa, suppression of gastric prostaglandin synthesis, reduction of gastric mucosal blood ow and interference with the repair of super cial injury. The presence of acid in the lumen of the stomach also contributes to the pathogenesis of NSAID-induced ulcers and bleeding, by impairing the restitution process, interfering with haemostasis and inactivating several growth factors that are important in mucosal defence and repair. In recent years, a fuller understanding of the pathogenesis of NSAID-induced ulcer disease has facilitated some new, very promising approaches to the development of stomach-sparing NSAIDs. Key words: ulcer; non-steroidal anti-in ammatory drug; acid; neutrophils; cyclo-oxygenase; nitric oxide. The ability of non-steroidal anti-in ammatory drugs (NSAIDs) to cause ulceration and bleeding in the upper gastrointestinal tract was rst documented by the endoscopic study of Douthwaite and Lintott in In that study, the investigators demonstrated the ability of aspirin to damage the stomach. In the years that followed, more potent NSAIDs, such as indomethacin, phenylbutazone and the fenamates, were brought to market. Shortly thereafter, case reports of melaena associated with the use of aspirin and the newer NSAIDs began to appear in the literature, and in the 1960s and 70s, case-control studies began to document the gastrointestinal toxicity of this class of drug. In recent years, the upper gastrointestinal tract damage caused by NSAIDs has been referred to as an `epidemic' by a number of investigators. 2,3 This is in part attributable to the widespread use of these drugs, particularly by patients with osteoarthritis and rheumatoid arthritis. The world market for NSAIDs is approximately $8 billion. The cost of treating NSAID-related gastrointestinal adverse e ects almost certainly exceeds this amount (the annual cost of treating NSAID gastropathy in rheumatoid arthritis patients in the USA, for example, having been reported to exceed $4 billion). 4 Developing anti-in ammatory drugs that do not produce ulceration or bleeding in the gastrointestinal tract, or developing prophylactic therapies that substantially /00/ $35.00/00 *c 2000 Harcourt Publishers Ltd.

2 148 J.L.Wallace reduce the toxicity of existing NSAIDs, depends upon clearly understanding the pathogenesis of NSAID-induced ulceration. In this chapter, the mechanisms by which NSAIDs damage the mucosa, interfere with repair and promote bleeding will be reviewed. In general, the properties of NSAIDs that contribute to ulcerogenesis can be divided into two categories: (1) topical irritancy, and (2) the suppression of prostaglandin synthase activity. In addition, the presence in the stomach and duodenum of acid and, in some cases, Helicobacter pylori (H. pylori), may contribute to the ability of NSAIDs to damage the mucosa. TOPICAL IRRITATION OF THE MUCOSA Studies in the 1960s by Davenport suggested that aspirin could directly damage the gastric epithelium. 5 The breaking of the `barrier' permitted the back-di usion of acid into the mucosa, which eventually led to the rupture of mucosal blood vessels. These topical irritant properties were subsequently found to be predominantly associated with those NSAIDs with a carboxylic acid residue. The unionized forms of these drugs can enter epithelial cells in the stomach and duodenum. Once in the neutral intracellular environment, the drugs are converted to an ionized state and cannot di use out. This has been referred to as `ion trapping'. 6 As the drug accumulates within the epithelial cell, the osmotic movement of water into the cell results in swelling of the epithelial cell, eventually to the point of lysis. 6,7 Another mechanism by which NSAIDs could damage the gastroduodenal epithelium is via the uncoupling of oxidative phosphorylation in the epithelial cells. 7,8 Various NSAIDs have been shown to uncouple mitochondrial respiration 7,8, leading to a depletion of ATP and therefore a reduced ability to regulate normal cellular functions, such as the maintenance of intracellular ph. The ability of NSAIDs to uncouple oxidative phosphorylation also appears to be related to some extent to acidic moieties (such as carboxylic acid residues), since substitution at these sites interferes with the ability of these compounds to act as uncouplers. 8 The theory that NSAIDs cause topical injury by virtue of their e ects on mitochondrial respiration has been challenged, mainly based on the observation that gastric and duodenal ulcers are observed following the parenteral or rectal administration of NSAIDs 9,10. Erosions and ulcers can also be produced in experimental circumstances in which NSAIDs are administered parenterally. 11 It is also di cult to comprehend how the uncoupling of oxidative phosphorylation would occur in gastrointestinal epithelial cells but not in the numerous other cells with which an NSAID would have contact subsequent to its absorption. On the other hand, the small intestine would be repeatedly exposed to NSAIDs that are excreted in bile and recycled enterohepatically, so it is conceivable that the uncoupling of oxidative phosphorylation is an important component of the pathogenesis of NSAID-induced enteropathy. A third mechanism that could account for the topical irritant properties of NSAIDs is 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 primary barrier to acid-induced damage in the stomach. 12,13 They demonstrated that the surface of the stomach is hydrophobic and that this hydrophobicity can be reduced by various pharmacological agents. For example, NSAIDs were shown to associate with the surface-active phospholipids within the mucus gel layer, thereby reducing its hydrophobic properties. 13±15 These investigators further demonstrated that the mucus gel layer in the stomach of rats and mice given NSAIDs was converted from a

3 Pathogenesis of NSAID ulceration 149 non-wettable to a wettable state. This e ect was found to persist for several weeks or months after the cessation of NSAID administration. 12,14 Attempts have been made to produce NSAIDs with reduced topical irritant e ects. These include formulations in slow-release or enteric coated tablets, as well as the 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 prodrugs is comparable to that seen with standard NSAIDs. 16±18 This is taken as evidence that the topical irritant properties of NSAIDs are not paramount in terms of their ability to induce frank ulceration in the stomach. However, one cannot completely exclude this possibility. Most NSAIDs are excreted in bile. Even with parenteral administration of the NSAID, therefore, a re ux of duodenal contents into the stomach would result in the topical exposure of the gastric mucosa to these drugs. E orts have recently been made to develop gastrointestinally safe NSAIDs on the basis of a reduced ability to interfere with the surface-active phospholipid layer in the gastrointestinal mucus. Lichtenberger et al proposed that pre-associating NSAIDs with zwitterionic phospholipids prior to their administration should reduce the ability of the NSAIDs to associate the phospholipids in the mucus gel, and should therefore reduce their ulcerogenicity. 12 They demonstrated this to be the case by pre-associating aspirin and other NSAIDs with dipalmitoyl-phosphatidylcholine (DPPC) and demonstrating that the complex produced signi cantly less damage in the gastrointestinal tract than did the parent drug. 14 Importantly, the pre-association of aspirin with DPPC did not interfere with the e ectiveness of the aspirin to reduce fever or in ammation. 19 Similar e ects could be obtained with other NSAIDs. 14,19 SUPPRESSION OF PROSTAGLANDIN SYNTHESIS Vane's discovery in 1971 that NSAIDs inhibit prostaglandin synthesis 20 led directly to the discovery of the ability of minute quantities of exogenous prostaglandins to protect the gastrointestinal tract from injury induced by topical irritants and NSAIDs. 21 This in turn led to extensive research into the roles of prostaglandins in mucosal defence. There is substantial evidence that the ability of an NSAID to cause gastric damage correlates well with its ability to suppress gastric prostaglandin synthesis 22±25 ; agents that are weak inhibitors of gastric prostaglandin synthesis are less ulcerogenic. 24,25 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. 22±24 Why does the suppression of gastric prostaglandin synthesis lead to mucosal injury? As mentioned above, it is now clear that prostaglandins play a central role in modulating mucosal defence. Endogenous prostaglandins are involved in the regulation of mucus and bicarbonate secretion by the gastric and duodenal epithelium, mucosal blood ow, epithelial cell proliferation, epithelial restitution and mucosal immunocyte function. 26 This is not to say that prostaglandins are the only endogenous substances regulating these components of mucosal defence; indeed, nitric oxide appears to perform many of the same functions as the prostaglandins in this respect. 26 Thus, the inhibition of prostaglandin synthesis alone may not result in the formation of gastric erosions or ulcers. For example, mice in which the gene for cyclo-oxygenase-1 was disrupted exhibited negligible levels of gastric prostaglandin synthesis yet did not spontaneously develop gastric erosions or ulcers. 27 Of course, one would, in such a situation, anticipate that adaptation of the stomach to the chronic absence of prostaglandins would occur (i.e. there might be an enhanced production of other

4 150 J.L.Wallace gastroprotective substances). On the other hand, the suppression of mucosal prostaglandin synthesis, while not necessarily resulting in ulcer formation, will reduce the ability of the gastric mucosa to defend itself against luminal irritants. This has been demonstrated very clearly in experimental animals. Doses of NSAIDs that substantially reduced mucosal prostaglandin synthesis did not cause overt gastric injury but did greatly increase the susceptibility of the gastric mucosa to damage induced by irritants (e.g. bile salts). 28 In terms of the pathogenesis of ulcer disease, is there one component of mucosal defence that is more important than others with respect to its impairment by NSAIDs? This question has not yet been completely answered. The fact that gastric ulcers can be induced by parenterally administered NSAIDs 9±11, and that this damage can be produced independently of the presence of luminal acid 29,30, suggests that the impairment of mucus and/or bicarbonate secretion may be of lesser signi cance. While prostaglandins are extremely potent inhibitors of mast cell degranulation 31,andmast cells are capable of releasing a variety of mediators (e.g. leukotriene C 4 and plateletactivating factor) that can contribute to mucosal injury 32,33, the e ects of NSAIDs on mast cells do not seem to be crucial to the pathogenesis of mucosal injury. This latter conclusion is based on the observation that rats in which mucosal mast cells have been depleted by chemical means, or mice that are genetically de cient of mast cells, exhibit similar susceptibility to NSAID-induced gastric injury as do their respective controls. 34 The rate of epithelial turnover has been shown to be reduced by NSAIDs and could contribute to the pathogenesis of ulcer disease. 35 However, it is unlikely that this e ect is the principal one that leads to the development of an ulcer. The component of mucosal defence that appears to be most profoundly altered by NSAIDs is the gastric microcirculatory response to injury. When the mucosa is exposed to an irritant, or when super cial epithelial injury occurs, mucosal blood ow substantially increases. This is probably a response aimed at removing any toxins or bacterial products that enter the lamina propria, neutralizing back-di using acid and contributing to the formation of a microenvironment at the surface of the mucosa that is conducive to repair. 36 As described in greater detail below NSAIDs can reduce gastric mucosal blood ow and profoundly alter the behaviour of neutrophils owing through the gastric microcirculation. EFFECTS ON THE MICROCIRCULATION The ability of NSAIDs to reduce gastric mucosal blood ow has been recognized for several decades. 37±39 Prostaglandins of the E and I series are potent vasodilators that are continuously produced by the vascular endothelium, so the inhibition of their synthesis by an NSAID leads to a reduction in vascular tone. Several lines of evidence have suggested that damage to the vascular endothelium is an early event following the administration of NSAIDs to experimental animals. 40,41 Endothelial injury is also an early event in the pathogenesis of gastrointestinal damage associated with ischaemia± reperfusion 42, in which neutrophils have been demonstrated to play a critical role as mediators of endothelial injury. 43 This observation led us to examine the possible role of the neutrophil in the pathogenesis of experimental NSAID gastropathy (Figure 1). Our studies and those of others demonstrated that NSAID administration to rats resulted in a rapid and signi cant increase in the number of neutrophils adhering to the vascular endothelium in both gastric and mesenteric venules. 25,44±46 This e ect was typically seen within 15±60 minutes after the administration of an NSAID, consistent

5 Pathogenesis of NSAID ulceration 151 Figure 1. Role of changes in the gastric microcirculation in the pathogenesis of NSAID-induced ulceration. NSAIDs suppress prostaglandin (PG) synthesis, and cause an increase in the liberation of leukotriene (LT) B 4 and tumour necrosis factor (TNF). The net result is an increase in expression of various adhesion molecules, leading to neutrophil adherence to the vascular endothelium. with the period of time required for the suppression of prostaglandin synthesis by these drugs. 47 Subsequent studies demonstrated that this adherence was dependent on the expression of the b 2 -integrins (CD11/CD18) on the neutrophil and intercellular adhesion molecule-1 (ICAM-1) on the vascular endothelium. 46 Such adherence could also be demonstrated to occur in vitro using isolated human neutrophils and endothelial cells from human umbilical vein. 48 Furthermore, the upregulation of ICAM-1 on the vascular endothelium in the gastric microcirculation was shown to occur within 15±30 minutes of the administration of an NSAID to rats, and this could be prevented by the administration of exogenous prostaglandins. 49 Of course, the fact that neutrophils adhere to the vascular endothelium following NSAID administration does not necessarily mean that these cells contribute to the endothelial injury of the mucosal tissue injury that can be induced by NSAIDs. To test this hypothesis, a number of studies were carried out. First, we demonstrated that depleting circulating neutrophils in the rat, either with an anti-neutrophil serum or with methotrexate, greatly reduced the severity of the gastric damage induced by indomethacin or naproxen. 50 Importantly, the induction of neutropenia also prevented

6 152 J.L.Wallace the damage to the vascular endothelium induced by the NSAIDs. 50 Second, we 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. 41,46 Third, we found that administration of prostaglandins at doses previously shown to prevent gastric injury prevented NSAID-induced leukocyte adherence. 44,45 Further evidence for a link between neutrophil adherence and NSAID-induced gastric injury came from studies of arthritic rats. 51 These animals, like humans with rheumatoid arthritis, exhibit an increased susceptibility to NSAID-induced gastric damage. Interestingly, these rats also exhibited an increased level of neutrophil adherence to the vascular endothelium. This appeared to be due to an increase in expression of ICAM-1 on the vascular endothelium of arthritic rats, since pre-treatment with an antibody against ICAM-1 reduced leukocyte adherence and the susceptibility to NSAID-induced gastric damage to levels seen in healthy controls. 51 These studies suggest that, in response to the suppression of prostaglandin synthesis by NSAIDs, there is a rapid upregulation of expression of ICAM-1 on the vascular endothelium and possibly an upregulation of b 2 -integrin expression on circulating neutrophils, resulting in an increased adherence of neutrophils to the endothelium. This begs the question of whether the enhanced adhesion molecule expression is purely a consequence of the reduction of prostaglandin synthesis, or whether there is another chemical signal produced in response to diminished prostaglandin synthesis that triggers the events leading to neutrophil adherence. Santucci et al suggested that tumour necrosis factor-a (TNFa) might be the key signal for NSAID-induced neutrophil adherence within the gastric microcirculation. 52 The release of TNFa from macrophages and mast cells has been shown to be suppressed by prostaglandins 31,53,andTNFa is a well-characterized stimulus for adhesion molecule expression. 54 Santucci et al demonstrated that the levels of TNFa in the plasma of rats signi cantly increased following the administration of indomethacin, this being accompanied by a parallel accumulation of neutrophils within the gastric microcirculation and the development of gastric injury. 52 Furthermore, pre-treatment with a TNFa synthesis inhibitor, pentoxifylline, dose-dependently reduced neutrophil accumulation in the gastric microcirculation and gastric damage. 52 These results have been con rmed and extended by Appleyard et al using a number of structurally unrelated inhibitors of TNFa synthesis and an anti-tnfa antibody. 55 Another group of mediators that might contribute to the increase in neutrophil adherence following NSAID administration is the leukotrienes. Like prostaglandins, leukotrienes are derived from arachidonic acid. They have been shown to be capable of altering the susceptibility of the gastric mucosa to injury 44,56±58, at least in part through stimulatory e ects on neutrophil adherence to the vascular endothelium. 44 Inhibitors of leukotriene synthesis and leukotriene receptor antagonists have been shown to exert some protective e ects in experimental models of NSAID-induced gastric damage. 56±58 There is also evidence of an elevated leukotriene B 4 production following NSAID administration to laboratory animals 44 and man 59, and inhibitors of leukotriene synthesis and a leukotriene B 4 receptor antagonist have been shown to prevent NSAID-induced neutrophil adherence to the vascular endothelium both in vivo 44 and in vitro. 48 Evidence for a role for neutrophils in the pathogenesis of gastric ulceration in humans has recently been provided. 60 Patients taking NSAID therapy who had signi cant numbers of neutrophils within the gastric mucosa were approximately six times more likely to develop an ulcer over the course of 24 weeks than were patients who

7 Pathogenesis of NSAID ulceration 153 did not have signi cant numbers of neutrophils in their gastric mucosa. It is also noteworthy that, in a clinical trial examining the potential bene t of famotidine for the prevention of NSAID-related gastroduodenal ulcers, Taha et al observed that an increased peripheral white cell count was a signi cant risk factor for ulcer development. 61 They suggested that this observation was consistent with the hypothesis that NSAID-induced gastropathy was mediated, at least partially, by neutrophils. How would the adherence of neutrophils to the vascular endothelium contribute to the formation of gastroduodenal ulcers? First, the adherence of neutrophils to the vascular endothelium is accompanied by an activation of these cells, leading to the release of proteases (e.g. elastase and collagenase) and oxygen-derived free radicals (e.g. superoxide anions). These substances may mediate much of the endothelial and epithelial injury caused by NSAIDs. This is supported by observations that the severity of NSAID-induced mucosal injury can be markedly diminished by compounds that scavenge oxygen-derived free radicals 62,63 and by inhibitors of neutrophil-derived proteases. 64,65 Second, neutrophil adherence to the endothelium, and the subsequent recruitment of other elements of blood (e.g. platelets), could produce an obstruction of the capillaries, thereby reducing gastric mucosal blood ow. In this respect, it should be noted that the well-characterized ability of NSAIDs to reduce gastric blood ow 37±39 has been shown to occur subsequent to the appearance of `white thrombi' in the gastric microcirculation. 38 INHIBITION OF RESTITUTION Damage to the gastric epithelium probably occurs on a daily basis but does not usually lead to deeper mucosal injury because of the ability of rapid (i.e. within minutes) repair to occur via the process of restitution. This process involves the rapid migration of healthy cells from the gastric pits to re-establish an intact epithelial barrier. 66 The cells move along the denuded basement membrane, which acts as a template and has been shown to be crucial to the restitution process. 66±69 The basement membrane can be damaged by acid, leading to an inhibition of restitution and the progression of necrosis to deeper layers of the mucosa. 47,70,71 This does not, however, occur in normal circumstances because of the formation over sites of injury (i.e. exposed basement membrane) of a microenvironment in which the ph is maintained at near neutral, eveninthepresenceofasigni cantacidloadinthelumen. 47,70 A `mucoid cap' consisting of mucus, cellular debris and plasma proteins (particularly brin) forms within seconds of gastric epithelial injury, trapping the plasma that leaks from the underlying microcirculation. 70 It is this plasma which accounts for the near-neutral ph within the protective mucoid cap, since even a very brief cessation of mucosal blood ow results in a rapid decrease in the ph within the mucoid cap, which in turn results in the formation of haemorrhagic erosions. 41 As discussed above, NSAIDs can decrease mucosal blood ow. Thus, NSAIDs can cause gastric injury by interfering with the appropriate function of the mucoid cap and therefore the process of restitution. Indeed, we observed that, following the systemic administration of an NSAID to an animal in which super cial epithelial injury had been induced, the ph within the mucoid cap that had formed over the sites of epithelial damage began to decline in parallel with the inhibition of prostaglandin synthesis. 41 Within minutes thereafter, the formation of haemorrhagic erosions was clearly evident. This e ect could be prevented through the luminal delivery of exogenous prostaglandins, as could the formation of haemorrhagic erosions. 41

8 154 J.L.Wallace REPAIR OF ULCERS In addition to causing ulcer formation, NSAIDs can delay the healing of pre-existing ulcers and promote their bleeding. 72,73 Thee ectsonulcerhealingareprobably related, once again, to the ability of NSAIDs to suppress prostaglandin synthesis. In normal gastric mucosa, prostaglandin synthesis occurs mainly via the cyclo-oxygenase-1 isoform. However, at a site of ulceration, and particularly around the ulcer margin, cyclo-oxygenase-2 appears to be the primary contributor to prostaglandin synthesis. Studies in mice and rats initially demonstrated the marked upregulation of cyclooxygenase-2 in ulcerated gastric tissue 74,75, and this has recently been con rmed in humans. 76 Moreover, the treatment of rats or mice with selective inhibitors of cyclooxygenase-2 results in a signi cant delay of ulcer healing. 74,75 These observations, and reports of selective cyclo-oxygenase-2 inhibitors exacerbating intestinal in ammation and ulceration 77, suggest that caution should be exercised in regarding the new cyclooxygenase-2 inhibitors as gastrointestinally safe. 78,79 The ability of NSAIDs to promote the bleeding of pre-existing ulcers is most probably related to their inhibitory e ects on platelet aggregation. 80,81 The inhibition of platelet aggregation by NSAIDs occurs as a consequence of the inhibition of thromboxane synthesis. It should be noted that, unlike other NSAIDs, aspirin produces an irreversible inhibition of thromboxane synthesis in the platelet. Thus, even the low doses of aspirin used for the prophylaxis of myocardial infarction and stroke can signi cantly increase the risk of gastrointestinal bleeding. 82±84 ROLE OF ACID The observation that NSAID-induced ulcers can develop in achlorhydric individuals 29,30 has contributed to a widely held belief that acid is not involved in the pathogenesis of these lesions. Further reinforcing this hypothesis are several studies demonstrating that treatment with histamine H 2 -receptor antagonists did not reduce the incidence of NSAID-induced ulceration. 85±87 However, many of these types of studies have demonstrated that H 2 -antagonists and proton pump inhibitors can prevent NSAID-induced gastric lesions, but not the formation of the clinically more signi cant ulcers, as well as ulcer complications. Recently, however, Taha et al reported that a high dose of famotidine (40 mg twice daily) was e ective in preventing NSAID-induced ulcers 61,andHawkeyetal 88 demonstrated that omeprazole could signi cantly reduce the incidence of NSAID-induced ulceration. These studies suggested that a profound suppression of acid secretion, as is produced by omeprazole or by a high dose of famotidine, was necessary in order to have a signi cant impact on the incidence of NSAID-induced ulcers. Acid may contribute to NSAID-induced ulcer formation in several ways. First, acid can exacerbate damage to the gastric mucosa induced by other agents. For example, acid can convert regions of ethanol-induced vascular congestion in the mucosa to actively bleeding erosions. 66 Second, acid will contribute to ulcer formation by interfering with haemostasis. Platelet aggregation, for example, is inhibited at a ph of less than Third, as outlined above, acid can convert super cial injury to deeper mucosal necrosis by interfering with the process of restitution. Fourth, acid can inactivate several growth factors (e.g. broblast growth factor) that are important for the maintenance of mucosal integrity and for the repair of super cial injury, since these growth factors are acid-labile. 90

9 Pathogenesis of NSAID ulceration 155 It is important to note that NSAIDs can increase gastric acid secretion, although it is not clear whether such e ects have any impact on ulcer formation or healing. Prostaglandins exert inhibitory e ects on parietal cells 91, so the inhibition of their synthesis by NSAIDs can result in an increase in gastric acid secretion. 92 SUMMARY A great deal has been learned about the pathogenesis of NSAID-induced gastric injury over the past two decades. As a result, several new NSAIDs, which will have greatly reduced gastrointestinal toxicity relative to current drugs, are in the process of being introduced to the marketplace. For example, selective inhibitors of cyclo-oxygenase-2, which will spare the major form of cyclo-oxygenase in the gastrointestinal tract, produce substantially less injury to the stomach than do the current NSAIDs that inhibit both cyclo-oxygenase-1 and Whether or not these agents prove to be as e ective for the treatment of the full range of in ammatory conditions currently treated with NSAIDs remains to be seen, and some experimental studies suggest that this may not be the case. 94,95 Nitric oxide-releasing NSAIDs represent another approach to reducing the adverse e ects of this class of drug. 96 The design of these new NSAIDs would not have been possible had it not been for an increased understanding of the pathogenesis of NSAID-induced ulceration. Acknowledgements Dr Wallace is a Medical Research Council of Canada Senior Scientist and an Alberta Heritage Foundation for Medical Research Senior Scientist. REFERENCES 1. Douthwaite AH & Lintott SAM. Gastroscopic observation of the e ect of aspirin and certain other substances on the stomach. Lancet 1938; 2: 1222± Gabriel SE & Bombardier C. NSAID induced ulcers. An emerging epidemic? Journal of Rheumatology 1990; 17: 1±4. 3. Singh G, Ramey DR, Morfeld D et al. Gastrointestinal tract complications of nonsteroidal antiin ammatory drug treatment in rheumatoid arthritis. A prospective observation cohort study. Archives of Internal Medicine 1996; 156: 1530± Bloom BS. Direct medical costs of disease and gastrointestinal side e ects during treatment of arthritis. American Journal of Medicine 1988; 83 (supplement 2A): 20± Davenport HW. Gastric mucosal hemorrhage in dogs. E ects of acid, aspirin, and alcohol. Gastroenterology 1969; 56: 439± Fromm D. How do non-steroidal anti-in ammatory drugs a ects gastric mucosal defenses? Clinical and Investigative Medicine 1987; 10: 251± Somasundaram S, Hayllar H, Ra S et al. The biochemical basis of non-steroidal anti-in ammatory druginduced damage to the gastrointestinal tract: a review and a hypothesis. Scandinavian Journal of Gastroenterology 1995; 30: 289± Mahmud T, Wrigglesworth JM, Scott DL & Bjarnason I. Mitochondrial function and modi cation of NSAID carboxyl moiety. In ammopharmacology 1996; 42: 189± Estes LL, Fuhs DW, Heaton AH & Butwinick CS. Gastric ulcer perforation, associated with the use of injectable ketorolac. Annals of Pharmacotherapy 1993; 27: 42± Henry D, Dobson A & Turner C. Variability in the risk of major gastrointestinal complications from nonaspirin nonsteroidal anti-in ammatory drugs. Gastroenterology 1993; 10: 1078±1088.

10 156 J.L.Wallace 11. Wallace JL & McKnight GW. Characterization of a simple animal model for nonsteroidal antiin ammatory drug induced antral ulcer. Canadian Journal of Physiology and Pharmacology 1993; 71: 447±452. *12. Lichtenberger LM. The hydrophobic barrier properties of gastrointestinal mucus. Annual Review of Physiology 1995; 57: 565± Goddard PJ, Hills BA & Lichtenberger LM. Does aspirin damage canine gastric mucosa by reducing its hydrophobicity? American Journal of Physiology 1987; 252: G421±G Lichtenberger LM, Wang ZM, Romero JJ et al. Non-steroidal anti-in ammatory drugs (NSAIDs) associate with zwitterionic phospholipids: insight into the mechanism and reversal of NSAID-induced gastrointestinal injury. Nature Medicine 1995; 1: 154± Lichtenberger LM, Wang ZM, Giraud MN et al. E ect of naproxen on gastric mucosal hydrophobicity. Gastroenterology 1995; 108: A Graham DY, Smith JL, Holmes GI & Davies RO. Nonsteroidal anti-in ammatory e ect of sulindac sulfoxide and sul de on gastric mucosa. Clinical Pharmacology and Therapeutics 1985; 38: 65± Carson JL, Strom BL, Soper KA et al. The relative gastrointestinal toxicity of the nonsteroidal antiin ammatory drugs. Archives of Internal Medicine 1987; 147: 1054± Hawthorne AB, Mahida YR, Cole AT & Hawkey CJ. Aspirin-induced gastric mucosal damage: prevention by enteric-coating and relation to prostaglandin synthesis. British Journal of Clinical Pharmacology 1991; 32: 77± Lichtenberger LM, Ulloa C, Vanous AL et al. Zwitterionic phospholipids enhance aspirin's therapeutic activity,asdemonstratedinrodentmodelsystems.journal of Pharmacology and Experimental Therapeutics 1996; 277: 1221± Vane JR. Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nature 1971; 231: 232±235. *21. Robert A, Schultz JR, Nezamis JE & Lancaster C. Gastric antisecretory and antiulcer properties of PGE 2, 15-methyl PGE 2, and 16,16-dimethyl PGE 2. Gastroenterology 1976; 70: 359± Lanza FL. A review of gastric ulcer and gastroduodenal injury in normal volunteers receiving aspirin and other nonsteroidal anti-in ammatory drugs. Scandinavian Journal of Gastroenterology 1989; 24 (supplement 163): 24± Rainsford KD & Willis C. Relationship of gastric mucosal damage induced in pigs by antiin ammatory drugs to their e ects on prostaglandin production. Digestive Diseases and Sciences 1982; 27: 624± Whittle BJR. Temporal relationship between cyclooxygenase inhibition, as measured by prostacyclin biosynthesis, and the gastrointestinal damage induced by indomethacin in the rat. Gastroenterology 1981; 80: 94± Wallace JL, McCa erty D-M, Carter L et al. Tissue-selective inhibition of prostaglandin synthesis in rat by tepoxalin: anti-in ammatory without gastropathy. Gastroenterology 1993; 105: 1630± Wallace JL & Tigley AW. New insights into prostaglandins and mucosal defence. Alimentary Pharmacology and Therapeutics 1995; 9: 227± Langenbach R, Morham SG, Tiano HF et al. Prostaglandin synthase 1 gene disruption in mice reduces arachidonic acid-induced in ammation and indomethacin-induced gastric ulceration. Cell 1995; 83: 483± Whittle BJR. Mechanisms underlying gastric mucosal damage induced by indomethacin and bile salts, and the actions of prostaglandins. British Journal of Pharmacology 1977; 60: 455± Rashid F & To olon EP. Misoprostol healed a benign nonsteroidal antiin ammatory drug-induced gastric ulcer in a patient with pentagastrin-fast achlorhydria. Journal of Clinical Gastroenterology 1993; 16: 219± Janssen M, Dijkmans BAC, Vanderbroucke JP et al. Achlorhydria does not protect against benign upper gastrointestinal ulcers during NSAID use. Digestive Diseases and Sciences 1994; 39: 362± Hogaboam CM, Bissonnette EY, Chin BC et al. Prostaglandins inhibit in ammatory mediator release from rat mast cells. Gastroenterology 1993; 104: 122± Rioux KP & Wallace JL. Mast cell activation increases gastric mucosal injury through peptido-leukotriene release. American Journal of Physiology 1994; 266: G863±G Rosam AC, Wallace JL & Whittle BJR. Potent ulcerogenic actions of platelet-activating factor on the stomach. Nature 1986; 319: 54± Rioux KP & Wallace JL. Mast cells do not contribute to NSAID-induced gastric mucosal injury in rodents. Alimentary Pharmacology and Therapeutics 1996; 10: 173± Eastwood GL & Quimby GF. E ect of chronic aspirin ingestion on epithelial proliferation in rat fundus, antrum, and duodenum. Gastroenterology 1982; 82: 852± Wallace JL & Granger DN. The cellular and molecular basis for gastroduodenal mucosal defense. FASEB Journal 1996; 10: 731±740.

11 Pathogenesis of NSAID ulceration Ashley SW, Sonnenschein LA & Cheung LY. Focal gastric mucosal blood ow at the site of aspirininduced ulceration. American Journal of Surgery 1985; 149: 53± Kitahora T & Guth PH. E ect of aspirin plus hydrochloric acid on the gastric mucosal microcirculation. Gastroenterology 1987; 93: 810± Gana TJ, Huhlewych R & Koo J. Focal gastric mucosal blood ow in aspirin-induced ulceration. Annals of Surgery 1987; 205: 399± Rainsford KD. Microvascular injury during gastric damage by anti-in ammatory drugs in pigs and rats. Agents and Actions 1983; 13: 457±460. *41. Wallace JL, Keenan CM & Granger DN. Gastric ulceration induced by nonsteroidal anti-in ammatory drugs is a neutrophil-dependent process. American Journal of Physiology 1990; 259: G462±G Granger DN, Kvietys PR & Perry MA. Leukocyte-endothelial cell adhesion caused by ischemia and reperfusion. Canadian Journal of Physiology and Pharmacology 1993; 71: 67± Hernandez LA, Grisham MB, Twohig B et al. Granulocytes: the culprit in ischemic damage to the intestine. American Journal of Physiology 1987; 253: H669±H Asako H, Kubes P, Wallace JL et al. Indomethacin-induced leukocyte adhesion in mesenteric venules: role of lipoxygenase products. American Journal of Physiology 1992; 262: G903±G Asako H, Kubes P, Wallace JL et al. Modulation of leukocyte adhesion to rat mesenteric venules by aspirin and salicylate. Gastroenterology 1992; 103: 146± Wallace JL, McKnight W, Miyasaka M et al. Role of endothelial adhesion molecules in NSAID-induced gastric mucosal injury. American Journal of Physiology 1993; 265: G993±G Wallace JL & McKnight GW. The mucoid cap over super cial gastric damage in the rat. A highph microenvironment dissipated by nonsteroidal antiin ammatory drugs and endothelin. Gastroenterology 1990; 99: 295± Yoshida N, Takemura T, Granger DN et al. Molecular determinants of aspirin-induced neutrophil adherence to endothelial cells. Gastroenterology 1993; 105: 715± Andrews FJ, Malcontenti-Wilson C & O'Brien PE. E ect of nonsteroidal anti-in ammatory drugs on LFA- 1 and ICAM-1 expression in gastric mucosa. American Journal of Physiology 1994; 266: G657±G Wallace JL, Arfors K-E & McKnight GW. A monoclonal antibody against the CD18 leukocyte adhesion molecule prevents indomethacin-induced gastric damage in the rabbit. Gastroenterology 1991; 100: 878± McCa erty DM, Granger DN & Wallace JL. Indomethacin-induced gastric injury and leukocyte adherence in arthritic versus healthy rats. Gastroenterology 1995; 109: 1173±1180. *52. Santucci L, Fiorucci S, Giansanti M et al. Pentoxifylline prevents indomethacin induced acute gastric mucosal damage in rats: role of tumour necrosis factor alpha. Gut 1994; 35: 909± Kunkel SL, Wiggins RC, Chensue SW & Larrick J. Regulation of macrophage tumor necrosis factor production by prostaglandin E2. Biochemical and Biophysics Research Communications 1986; 137: 404± Rothlein R, Czajkowski M, O'Neill MM et al. Induction of intercellular adhesion molecule 1 on primary and continuous cell lines by pro-in ammatory cytokines. Regulation by pharmacologic agents and neutralizing antibodies. Journal of Immunology 1988; 141: 1665± Appleyard CB, McCa erty DM, Tigley AW et al. Tumour necrosis factor mediation of NSAID-induced gastric damage: role of leukocyte adherence. American Journal of Physiology 1996; 270: G42±G Rainsford KD. The e ects of 5-lipoxygenase inhibitors and leukotriene antagonists on the development of gastric lesions induced by nonsteroidal antiin ammatory drugs in mice. Agents and Actions 1987; 21: 316± Pihan G, Rogers C & Szabo S. Vascular injury in acute gastric mucosal damage: mediatory role of leukotrienes. Digestive Diseases and Sciences 1988; 33: 625± Vaananen PM, Keenan CM, Grisham MB & Wallace JL. A pharmacological investigation of the role of leukotrienes in the pathogenesis of experimental NSAID-gastropathy. In ammation 1992; 16: 227± Hudson N, Balsitis M, Everitt S & Hawkey CJ. Enhanced gastric mucosal leukotriene B 4 synthesis in patients taking non-steroidal anti-in ammatory drugs. Gut 1993; 34: 742± Taha AS, Dahill S, Morran C et al. Neutrophils, Helicobacter pylori, and nonsteroidal anti-in ammatory drug ulcers. Gastroenterology 1999; 116: 254± Taha AS, Hudson N, Hawkey CJ et al. Famotidine for the prevention of gastric and duodenal ulcers caused by nonsteroidal antiin ammatory drugs. New England Journal of Medicine 1996; 334: 1435± Del Soldato P, Foschi D, Benoni G & Scarpignato C. Oxygen free radicals interact with indomethacin to cause gastrointestinal injury. Agents and Actions 1985; 17: 484± Vaananen PM, Meddings JB & Wallace JL. Role of oxygen-derived free radicals in indomethacin-induced gastric injury. American Journal of Physiology 1991; 261: G470±G Yoshida N, Cepinskas G, Granger DN et al. Aspirin-induced, neutrophil-mediated injury to vascular endothelium. In ammation 1995; 19: 297±312.

12 158 J.L.Wallace 65. Murakami K, Okajima K, Harada N et al. Plaunotol prevents indomethacin-induced gastric mucosal injury in rats by inhibiting neutrophil activation. Alimentary Pharmacology and Therapeutics 1999; 13: 521± Morris GP & Wallace JL. The roles of ethanol and of acid in the production of gastric mucosal erosions in rats. Virchows Archives B (Cell Pathology) 1981; 38: 23± Svanes K, Ito S, Takeuchi K & Silen W. Restitution of the surface epithelium of the in vitro frog gastric mucosa after damage with hyperosmolar sodium chloride. Gastroenterology 1982; 82: 1409±1426. *68. Lacy ER & Ito S. Rapid epithelial restitution of the rat gastric mucosa after ethanol injury. Laboratory Investigation 1984; 51: 573± Moore R, Carlson S & Madara JL. Rapid barrier restitution in an in vitro model of intestinal epithelial injury. Laboratory Investigation 1989; 60: 237± Wallace JL & Whittle BJR. Role of mucus in repair of gastric epithelial damage in the rat. Inhibition of epithelial recovery by mucolytic agents. Gastroenterology 1986; 91: 603± Black BA, Morris GP & Wallace JL. E ects of acid on the basal lamina of the rat stomach and duodenum. Virchows Archives B (Cell Pathology) 1985; 50: 109± Armstrong CP & Blower AL. Non-steroidal anti-in ammatory drugs and life threatening complications of peptic ulceration. Gut 1997; 28: 527± Stadler P, Armstrong D, Margalith D et al. Diclofenac delays healing of gastroduodenal mucosal lesions. Double-blind, placebo-controlled endoscopic study in healthy volunteers. Digestive Diseases and Sciences 1991; 36: 594±600. *74. Mizuno H, Sakamoto C & Matsuda K. Induction of cyclooxygenase-2 in gastric mucosal lesions and its inhibition by the speci c antagonist delays healing in mice. Gastroenterology 1997; 112: 387± Schmassmann A, Peskar BM, Stettler C et al. E ects of inhibition of prostaglandin endoperoxide synthase-2 in chronic gastro-intestinal ulcer models in rats. British Journal of Pharmacology 1998; 123: 795± Jackson LM, Wu KC, Mahida YR et al. Cyclooxygenase (COX)-1 and -2 in normal, in amed and ulcerated human gastric mucosa. Gut 1999; (in press). 77. Reuter BK, Asfaha S, Buret A et al. Exacerbation of in ammation-associated colonic injury in rat through inhibition of cyclooxygenase-2. Journal of Clinical Investigation 1996; 98: 2076± Wallace JL. Selective COX-2 inhibitors: is the water becoming muddy? Trends in Pharmacological Sciences 1999; 20: 4± Wallace JL, McKnight W & Bak A. Selective inhibitors of COX-2: are they really e ective? Are they really GI-safe? Journal of Clinical Gastroenterology 1998; 27: S28±S Prichard PJ, Kitchingman GK, Walt RP et al. Human gastric mucosal bleeding induced by low dose aspirin, but not warfarin. British Medical Journal 1989; 298: 493± Hawkey CJ, Hawthorne AB, Hudson N et al. Separation of the impairment of haemostasis by aspirin from mucosal injury in the human stomach. Clinical Science 1991; 81: 565± The SALT Collaborative Group. Swedish Aspirin Low-Dose Trial (SALT) of 75 mg aspirin as secondary prophylaxis after cerebrovascular ischaemic events. Lancet 1991; 338: 1345± Meade TW, Roderick PJ, Brennan PJ et al. Extracranial bleeding and other symptoms due to low dose aspirin and low intensity oral anticoagulation. Thrombosis and Haemostasis 1992; 68: 1± Cryer B, Luk G & Feldman M. E ects of very low doses of aspirin (ASA) on gastric, duodenal & rectal prostaglandins (PGs) & mucosal injury. Gastroenterology 1995; 108: A Agrawal NM. Epidemiology and prevention of non-steroidal anti-in ammatory drug e ects in the gastrointestinal tract. British Journal of Rheumatology 1995; 34 (supplement 1): 5± Koch M, Capurso L, Dezi A et al. Prevention of NSAID-induced gastroduodenal mucosal injury: metaanalysis of clinical trials with misoprostol and H2-receptor antagonists. Digestive Diseases 1995; 13 (supplement 1): 62± Simon TJ, Berger ML, Hoover ME et al. A dose-ranging study of famotidine in prevention of gastroduodenal lesions associated with non-steroidal anti-in ammatory drugs (NSAIDs): results of a US multicenter trial. American Journal of Gastroenterology 1994; 89: 1644 (abstract). *88. Hawkey CJ, Karrasch JA, Szczepanski L et al. Omeprazole compared with misoprostol for ulcers associated with nonsteroidal antiin ammatory drugs. New England Journal of Medicine 1998; 338: 727± GreenFW,KaplanMM,CurtisLE&LevinePH.E ectofacidandpepsinonbloodcoagulationand platelet aggregation: a possible contributor to prolonged gastroduodenal mucosal hemorrhage. Gastroenterology 1978; 74: 38± Szabo S, Folkman J, Vattay P et al. Accelerated healing of duodenal ulcers by oral administration of a basic broblast growth factor in rats. Gastroenterology 1994; 106: 1106± Soll AH. Mechanisms of action of antisecretory drugs: studies on isolated canine fundic mucosal cells. Scandinavian Journal of Gastroenterology 1986; 21: 1±6.

13 Pathogenesis of NSAID ulceration Ligumsky M, Goto Y & Yamada T. Prostaglandins mediate inhibition of gastric acid secretion by somatostatin in the rat. Science 1983; 219: 301±303. *93. Xie W, Robertson DL & Simmons DL. Mitogen-inducible prostaglandin G/H synthase: a new target for nonsteroidal antiin ammatory drugs. Drug Development Research 1992; 25: 249±265. *94. Wallace JL, Bak A, McKnight W et al. Cyclooxygenase-1 contributes to in ammatory responses in rats and mice: implications for GI toxicity. Gastroenterology 1998; 115: 101± Wallace JL, Chapman K & McKnight W. Limited anti-in ammatory e cacy of cyclooxygenase-2 inhibition in carrageenan-airpouch in ammation. British Journal of Pharmacology 1999; 126: 1200± Wallace JL, Elliott SN, Del Soldato P et al. Gastrointestinal sparing anti-in ammatory drugs: the development of nitric oxide-releasing NSAIDs. Drug Development Research 1997; 42: 144±149.

Protection of human gastric mucosa against aspirinðenteric coating or dose reduction?

Protection of human gastric mucosa against aspirinðenteric coating or dose reduction? Aliment Pharmacol Ther 1999; 13: 187±193. Protection of human gastric mucosa against aspirinðenteric coating or dose reduction? A. T. COLE*, N. HUDSON*, L. C. W. LIEW*, F. E. MURRAY*, C. J. HAWKEY* & S.

More information

ulcer healing role 118 Bicarbonate, prostaglandins in duodenal cytoprotection 235, 236

ulcer healing role 118 Bicarbonate, prostaglandins in duodenal cytoprotection 235, 236 Subject Index Actin cellular forms 48, 49 epidermal growth factor, cytoskeletal change induction in mucosal repair 22, 23 wound repair 64, 65 polyamine effects on cytoskeleton 49 51 S-Adenosylmethionine

More information

Phospholipid Association Reduces the Gastric Mucosal Toxicity of Aspirin in Human Subjects

Phospholipid Association Reduces the Gastric Mucosal Toxicity of Aspirin in Human Subjects THE AMERICAN JOURNAL OF GASTROENTEROLOGY Vol. 94, No. 7, 1999 1999 by Am. Coll. of Gastroenterology ISSN 0002-9270/99/$20.00 Published by Elsevier Science Inc. PII S0002-9270(99)00267-1 Phospholipid Association

More information

D DAVID PUBLISHING. 1. Introduction. Maher Mbarki 1, Helen Sklyarova 1, Krystyna Aksentiychuk 1, Ihor Tumak 2 and Eugene Sklyarov 1

D DAVID PUBLISHING. 1. Introduction. Maher Mbarki 1, Helen Sklyarova 1, Krystyna Aksentiychuk 1, Ihor Tumak 2 and Eugene Sklyarov 1 Journal of Pharmacy and Pharmacology (2016) 32-36 doi: 10.17265/232-2150/2016.0.011 D DAVID PUBLISHING Plasma Levels of Leukotriene B and Prostaglandin E2 Correlation with Endoscopic Changes after NSAID

More information

Cyclooxygenase 2 implications on maintenance of gastric mucosal integrity and ulcer healing: controversial issues and perspectives

Cyclooxygenase 2 implications on maintenance of gastric mucosal integrity and ulcer healing: controversial issues and perspectives Gut 2001;49:443 453 443 Review Cyclooxygenase 2 implications on maintenance of gastric mucosal integrity and ulcer healing: controversial issues and perspectives Summary Cyclooxygenase (COX), the key enzyme

More information

NSAIDs: Side Effects and Guidelines

NSAIDs: Side Effects and Guidelines NSAIDs: Side Effects and James J Hale FY1 Department of Anaesthetics Introduction The non-steroidal anti-inflammatory drugs (NSAIDs) are a diverse group of drugs that have analgesic, antipyretic and anti-inflammatory

More information

Non-steroidal anti-inflammatory drugs and gastrointestinal damage problems and solutions

Non-steroidal anti-inflammatory drugs and gastrointestinal damage problems and solutions 82 University of Glasgow and Department of Gastroenterology, Royal Infirmary, Glasgow Correspondence to: Professor R I Russell, 28 Ralston Road, Bearsden, Glasgow G61 3BA rirla@aol.com Submitted 26 October

More information

Original Article. Abstract. Introduction

Original Article. Abstract. Introduction Original Article Frequency of NSAID Induced Peptic Ulcer Disease Saeed Hamid, Javed Yakoob, Wasim Jafri, Shanul Islam, Shahab Abid, Muhammad Islam Section of Gastroenterology, Department of Medicine, Aga

More information

Name: Class: "Pharmacology NSAIDS (1) Lecture

Name: Class: Pharmacology NSAIDS (1) Lecture I Name: Class: "Pharmacology NSAIDS (1) Lecture د. احمد الزهيري Inflammation is triggered by the release of chemical mediators from injured tissues and migrating cells. The specific mediators vary with

More information

Gastrointestinal Safety of Coxibs and Outcomes Studies: What s the Verdict?

Gastrointestinal Safety of Coxibs and Outcomes Studies: What s the Verdict? Vol. 23 No. 4S April 2002 Journal of Pain and Symptom Management S5 Proceedings from the Symposium The Evolution of Anti-Inflammatory Treatments in Arthritis: Current and Future Perspectives Gastrointestinal

More information

LOW DOSE ASPIRIN CARDIOVASCULAR DISEASE FOR PROPHYLAXIS OF FOR BACKGROUND USE ONLY NOT TO BE USED IN DETAILING

LOW DOSE ASPIRIN CARDIOVASCULAR DISEASE FOR PROPHYLAXIS OF FOR BACKGROUND USE ONLY NOT TO BE USED IN DETAILING LOW DOSE ASPIRIN FOR PROPHYLAXIS OF CARDIOVASCULAR DISEASE FOR BACKGROUND USE ONLY NOT TO BE USED IN DETAILING Use of Low Dose Aspirin to Treat and Prevent Cardiovascular Disease In recent decades, aspirin

More information

A. Incorrect! Histamine is a secretagogue for stomach acid, but this is not the only correct answer.

A. Incorrect! Histamine is a secretagogue for stomach acid, but this is not the only correct answer. Pharmacology - Problem Drill 21: Drugs Used To Treat GI Disorders No. 1 of 10 1. Endogenous secretagogues for stomach acid include: #01 (A) Histamine (B) Gastrin (C) PGE1 (D) A and B (E) A, B and C Histamine

More information

GASTROINTESTINAL AND ANTIEMETIC DRUGS. Submitted by: Shaema M. Ali

GASTROINTESTINAL AND ANTIEMETIC DRUGS. Submitted by: Shaema M. Ali GASTROINTESTINAL AND ANTIEMETIC DRUGS Submitted by: Shaema M. Ali GASTROINTESTINAL AND ANTIEMETIC DRUGS by: Shaema M. Ali There are four common medical conditions involving the GI system 1) peptic ulcers

More information

Review Article. NSAID Gastropathy: An Update on Prevention. Introduction. Risk Factors. Kam-Chuen Lai

Review Article. NSAID Gastropathy: An Update on Prevention. Introduction. Risk Factors. Kam-Chuen Lai Review Article NSAID Gastropathy: An Update on Prevention Kam-Chuen Lai Abstract: Keywords: Adverse reactions to non-steroidal anti-inflammatory drugs (NSAIDs) are common. Upper gastrointestinal complications

More information

Mitigating GI Risks Associated with the Use of NSAIDs

Mitigating GI Risks Associated with the Use of NSAIDs bs_bs_banner Pain Medicine 2013; 14: S18 S22 Wiley Periodicals, Inc. Mitigating GI Risks Associated with the Use of NSAIDs Mahnaz Momeni, MD,* and James D. Katz, MD Departments of *Rheumatology, Medicine,

More information

NONSTEROIDAL ANTI- INFLAMMATORY DRUGS

NONSTEROIDAL ANTI- INFLAMMATORY DRUGS NONSTEROIDAL ANTI- INFLAMMATORY DRUGS MRS. M.M. HAS A 3 YR. HX OF PROGRESSIVE RIGHT HIP PAIN. THE PAIN INCREASES WITH WEIGHT BEARING ACTIVITY. PT. HAS BEEN ON ACETAMINOPHEN WITHOUT RELIEF. PERTINENT LABS

More information

The Gastrointestinal Barrier

The Gastrointestinal Barrier The Gastrointestinal Barrier The gastrointestinal mucosa forms a barrier between the body and a lumenal environment which not only contains nutrients, but is laden with potentially hostile microorganisms

More information

EICOSANOID METABOLISM

EICOSANOID METABOLISM 1 EICOSANOID METABOLISM EICOSANOIDS C20 polyunsaturated fatty acids e.g. Arachidonic acid Eicosanoids physiologically, pathologically and pharmacologically active compounds PG Prostaglandins TX - Thromboxanes

More information

Attribution: University of Michigan Medical School, Department of Microbiology and Immunology

Attribution: University of Michigan Medical School, Department of Microbiology and Immunology Attribution: University of Michigan Medical School, Department of Microbiology and Immunology License: Unless otherwise noted, this material is made available under the terms of the Creative Commons Attribution

More information

Cell-Derived Inflammatory Mediators

Cell-Derived Inflammatory Mediators Cell-Derived Inflammatory Mediators Introduction about chemical mediators in inflammation Mediators may be Cellular mediators cell-produced or cell-secreted derived from circulating inactive precursors,

More information

Enhanced gastric mucosal bleeding with doses of aspirin used for prophylaxis and its reduction by ranitidine

Enhanced gastric mucosal bleeding with doses of aspirin used for prophylaxis and its reduction by ranitidine Br. J. clin. Pharmac. (1989), 28, 581-585 Enhanced gastric mucosal bleeding with doses of aspirin used for prophylaxis and its reduction by ranitidine G. K. KITCHINGMAN, P. J. PRICHARD, T. K. DANESHMEND,

More information

Review Article. Safety Profile of Nonsteroidal Antiflammatory Drugs (NSAID) Safety Profile of NSAID

Review Article. Safety Profile of Nonsteroidal Antiflammatory Drugs (NSAID) Safety Profile of NSAID Safety Profile of Nonsteroidal Antiflammatory Drugs (NSAID) R. Stoilov: University Hospital St Ivan Rilski, Clinic of Rheumatology Contact: Rumen Stoilov, Clinic of Rheumatology, University Hospital St

More information

The New England Journal of Medicine

The New England Journal of Medicine NITROVASODILATORS, LOW-DOSE ASIRIN, OTHER NONSTEROIDAL ANTIINFLAMMATORY DRUGS, AND THE RISK OF UER GASTROINTESTINAL BLEEDING ANGEL LANAS, M.D., EDUARDO BAJADOR, M.D., EDRO SERRANO, M.D., JAVIER FUENTES,

More information

5. Which component of the duodenal contents entering the stomach causes the most severe changes to gastric mucosa:

5. Which component of the duodenal contents entering the stomach causes the most severe changes to gastric mucosa: Gastro-intestinal disorders 1. Which are the most common causes of chronic gastritis? 1. Toxic substances 2. Chronic stress 3. Alimentary factors 4. Endogenous noxious stimuli 5. Genetic factors 2. Chronic

More information

SELECTED ABSTRACTS. Figure. Risk Stratification Matrix A CLINICIAN S GUIDE TO THE SELECTION OF NSAID THERAPY

SELECTED ABSTRACTS. Figure. Risk Stratification Matrix A CLINICIAN S GUIDE TO THE SELECTION OF NSAID THERAPY SELECTED ABSTRACTS A CLINICIAN S GUIDE TO THE SELECTION OF NSAID THERAPY The authors of this article present a 4-quadrant matrix based on 2 key clinical parameters: risk for adverse gastrointestinal (GI)

More information

- Mohammad Sinnokrot. -Ensherah Mokheemer. - Malik Al-Zohlof. 1 P a g e

- Mohammad Sinnokrot. -Ensherah Mokheemer. - Malik Al-Zohlof. 1 P a g e -1 - Mohammad Sinnokrot -Ensherah Mokheemer - Malik Al-Zohlof 1 P a g e Introduction Two of the most important problems you will face as a doctor are coagulation and bleeding, normally they are in balance,

More information

NSAID gastropathy and enteropathy: distinct pathogenesis likely necessitates distinct prevention strategies

NSAID gastropathy and enteropathy: distinct pathogenesis likely necessitates distinct prevention strategies REVIEWbph_1509 67..74 BJP British Journal of Pharmacology DOI:10.1111/j.1476-5381.2011.01509.x www.brjpharmacol.org NSAID gastropathy and enteropathy: distinct pathogenesis likely necessitates distinct

More information

Non-steroidal anti-inflammatory drugs: who should receive prophylaxis?

Non-steroidal anti-inflammatory drugs: who should receive prophylaxis? Aliment Pharmacol Ther 2004; 20 (Suppl. 2): 59 64. Non-steroidal anti-inflammatory drugs: who should receive prophylaxis? C. J. HAWKEY Wolfson Digestive Diseases Centre, Institute of Clinical Research,

More information

NSAID-Induced Gastrointestinal Damage

NSAID-Induced Gastrointestinal Damage GASTROENTEROLOGY BOARD REVIEW MANUAL STATEMENT OF EDITORIAL PURPOSE The Hospital Physician Gastroenterology Board Review Manual is a study guide for fellows and practicing physicians preparing for board

More information

Effective management of gastrointestinal PROCEEDINGS EVALUATING THE APPROACHES TO SAFE AND EFFECTIVE ANALGESIA FOR OLDER PATIENTS WITH ARTHRITIS *

Effective management of gastrointestinal PROCEEDINGS EVALUATING THE APPROACHES TO SAFE AND EFFECTIVE ANALGESIA FOR OLDER PATIENTS WITH ARTHRITIS * EVALUATING THE APPROACHES TO SAFE AND EFFECTIVE ANALGESIA FOR OLDER PATIENTS WITH ARTHRITIS * David A. Peura, MD, FACP, FACG ABSTRACT *This article is based on a presentation given by Dr Peura at the PRI-MED

More information

Non-Steroidal Anti- Inflammatory Drugs. ATPE 410 Chapter 6

Non-Steroidal Anti- Inflammatory Drugs. ATPE 410 Chapter 6 Non-Steroidal Anti- Inflammatory Drugs ATPE 410 Chapter 6 Inflammatory Process A normal, beneficial process that begins immediately after injury to facilitate repair and return the tissue to normal function

More information

The usual dose is 40 mg daily with amoxycillin 1.5 g (750 mg b.d.) for 2 weeks. Up to 2 g/day of amoxycillin has been used in clinical trials.

The usual dose is 40 mg daily with amoxycillin 1.5 g (750 mg b.d.) for 2 weeks. Up to 2 g/day of amoxycillin has been used in clinical trials. Name Gasec - 2 Gastrocaps Composition Gasec-20 Gastrocaps Each Gastrocaps contains: Omeprazole 20 mg (in the form of enteric-coated pellets) Properties, effects Proton Pump Inhibitor Omeprazole belongs

More information

Prevalence of gastroduodenal lesions in chronic nonsteroidal anti-inflammatory drug users presenting with dyspepsia at the Kenyatta National Hospital

Prevalence of gastroduodenal lesions in chronic nonsteroidal anti-inflammatory drug users presenting with dyspepsia at the Kenyatta National Hospital Research Article Department of Clinical Medicine and Therapeutics, University of Nairobi, Kenya Corresponding author: Dr. G O Oyoo. Email: geomondi@hotmail. com Prevalence of gastroduodenal lesions in

More information

Ibuprofen versus other non-steroidal anti-in ammatory drugs: use in general practice and patient perception

Ibuprofen versus other non-steroidal anti-in ammatory drugs: use in general practice and patient perception Aliment Pharmacol Ther 2000; 14: 187±191. Ibuprofen versus other non-steroidal anti-in ammatory drugs: use in general practice and patient perception C. J. HAWKEY 1,D.J.E.CULLEN 1,9,G.PEARSON 1,S.HOLMES

More information

ETIOPATHOGENICAL ASPECTS OF NONSTEROIDAL ANTI- INFLAMMATORY DRUGS IN ELDERLY Mihaela Bursova¹, Gabriela Lilios², Maria Suta³, Gh.

ETIOPATHOGENICAL ASPECTS OF NONSTEROIDAL ANTI- INFLAMMATORY DRUGS IN ELDERLY Mihaela Bursova¹, Gabriela Lilios², Maria Suta³, Gh. ETIOPATHOGENICAL ASPECTS OF NONSTEROIDAL ANTI- INFLAMMATORY DRUGS IN ELDERLY Mihaela Bursova¹, Gabriela Lilios², Maria Suta³, Gh. Taralunga² 1.CLINICAL EMERGENCY COUNTY HOSPITAL CONSTANŢA, GERIATRICS DEPARTAMENT

More information

ASPIRIN. Session Two of TIP Assignment

ASPIRIN. Session Two of TIP Assignment ASPIRIN Session Two of TIP Assignment History Behind Aspirin Development 2 Pain relief is something that has been sought after since the ancient Greeks and Egyptians used bark and dried leaves of the poplar

More information

What is Bandolier? Balance benefits and harms

What is Bandolier? Balance benefits and harms What is Bandolier? The first issue of Bandolier, an independent journal about evidence-based healthcare, written by Oxford scientists, (RAM AND HJM) was printed in February 1994. It has appeared monthly

More information

-Mohammad Ashraf. -Anas Raed. -Alia Shatnawi. 1 P a g e

-Mohammad Ashraf. -Anas Raed. -Alia Shatnawi. 1 P a g e -1 -Mohammad Ashraf -Anas Raed -Alia Shatnawi 1 P a g e Dr. Alia started the lecture by talking about subjects we are going to cover through this course; you can refer to the record if you are interested.

More information

Ibuprofen. Ibuprofen and Paracetamol: prescribing overview. Ibuprofen indications CYCLO-OXYGENASE (COX I) CYCLO-OXEGENASE (COX II) INFLAMMATORY PAIN

Ibuprofen. Ibuprofen and Paracetamol: prescribing overview. Ibuprofen indications CYCLO-OXYGENASE (COX I) CYCLO-OXEGENASE (COX II) INFLAMMATORY PAIN Ibuprofen Ibuprofen and Paracetamol: prescribing overview Sarah Holloway Macmillan CNS in palliative care NSAID Non-selective COX inhibitor Oral bioavailability: 90% Onset of action: 20-30 mins (can take

More information

In 1971, Sir John Vane proposed that nonsteroidal

In 1971, Sir John Vane proposed that nonsteroidal Non-steroidal antiinflammatory drugs: facts and fallacies This article serves to review NSAIDs, their mechanism of action and adverse effects, as well as to establish the therapeutic position of the new-generation

More information

Omeprazole and sucralfate in the treatment of NSAID-induced gastric and duodenal ulcer

Omeprazole and sucralfate in the treatment of NSAID-induced gastric and duodenal ulcer Aliment Pharmacol Ther 1998; 12: 355±360. Omeprazole and sucralfate in the treatment of NSAID-induced gastric and duodenal ulcer G. BIANCHI PORRO, M. LAZZARONI, G. MANZIONNA & M. PETRILLO Gastrointestinal

More information

GI Pharmacology. Dr. Alia Shatanawi 5/4/2018

GI Pharmacology. Dr. Alia Shatanawi 5/4/2018 GI Pharmacology Dr. Alia Shatanawi 5/4/2018 Drugs Used in Gastrointestinal Diseases Drugs used in Peptic Ulcer Diseases. Drugs Stimulating Gastrointestinal Motility &Laxatives. Antidiarrheal Agents. Drugs

More information

Anti-inflammatory drugs

Anti-inflammatory drugs Anti-inflammatory drugs 1 Inflammatory process 1. stimulus (cut) 2. Initial local vasoconstriction( blood loss) 3. vasodilation, local immune/inflammatory reaction (heat, redness) 4. swelling and pain

More information

Case 4: Peptic Ulcer Disease. Requejo, April Salandanan, Geralyn Talingting, Vennessa Tanay, Arvie

Case 4: Peptic Ulcer Disease. Requejo, April Salandanan, Geralyn Talingting, Vennessa Tanay, Arvie Case 4: Peptic Ulcer Disease Requejo, April Salandanan, Geralyn Talingting, Vennessa Tanay, Arvie Case 4: PUD Problem List: 1. Peptic Ulcer Disease SOAP Note: S Patient is complaining of abdominal pain

More information

Prostaglandins And Other Biologically Active Lipids

Prostaglandins And Other Biologically Active Lipids Prostaglandins And Other Biologically Active Lipids W. M. Grogan, Ph.D. OBJECTIVES After studying the material of this lecture, the student will: 1. Draw the structure of a prostaglandin, name the fatty

More information

MUSCULOSKELETAL PHARMACOLOGY. A story of the inflamed

MUSCULOSKELETAL PHARMACOLOGY. A story of the inflamed MUSCULOSKELETAL PHARMACOLOGY A story of the inflamed 1 INFLAMMATION Pathophysiology Inflammation Reaction to tissue injury Caused by release of chemical mediators Leads to a vascular response Fluid and

More information

Database of Abstracts of Reviews of Effects (DARE) Produced by the Centre for Reviews and Dissemination Copyright 2017 University of York.

Database of Abstracts of Reviews of Effects (DARE) Produced by the Centre for Reviews and Dissemination Copyright 2017 University of York. A comparison of the cost-effectiveness of five strategies for the prevention of non-steroidal anti-inflammatory drug-induced gastrointestinal toxicity: a systematic review with economic modelling Brown

More information

Impact of Asthma in the U.S. per Year. Asthma Epidemiology and Pathophysiology. Risk Factors for Asthma. Childhood Asthma Costs of Asthma

Impact of Asthma in the U.S. per Year. Asthma Epidemiology and Pathophysiology. Risk Factors for Asthma. Childhood Asthma Costs of Asthma American Association for Respiratory Care Asthma Educator Certification Prep Course Asthma Epidemiology and Pathophysiology Robert C. Cohn, MD, FAARC MetroHealth Medical Center Cleveland, OH Impact of

More information

INFLAMMATION & REPAIR

INFLAMMATION & REPAIR INFLAMMATION & REPAIR Lecture 7 Chemical Mediators of Inflammation Winter 2013 Chelsea Martin Special thanks to Drs. Hanna and Forzan Course Outline i. Inflammation: Introduction and generalities (lecture

More information

Is ranitidine therapy sufficient for healing peptic ulcers associated with non-steroidal anti-inflammatory drug use?

Is ranitidine therapy sufficient for healing peptic ulcers associated with non-steroidal anti-inflammatory drug use? ORIGINAL PAPER doi: 10.1111/j.1742-1241.2006.01147.x Is ranitidine therapy sufficient for healing peptic ulcers associated with non-steroidal anti-inflammatory drug use? N. D. YEOMANS, 1 *L-ESVEDBERG,

More information

The cardioprotective benefits of ... REPORTS... Gastrointestinal Safety of Low-Dose Aspirin. Byron Cryer, MD

The cardioprotective benefits of ... REPORTS... Gastrointestinal Safety of Low-Dose Aspirin. Byron Cryer, MD ... REPORTS... Gastrointestinal Safety of Low-Dose Aspirin Byron Cryer, MD Abstract The cardioprotective benefits of aspirin support the use of low-dose regimens for primary and secondary prevention of

More information

Gastro-oesophageal reflux disease and peptic ulcer disease. By: Dr. Singanamala Suman Assistant Professor Department of Pharm.D

Gastro-oesophageal reflux disease and peptic ulcer disease. By: Dr. Singanamala Suman Assistant Professor Department of Pharm.D Gastro-oesophageal reflux disease and peptic ulcer disease By: Dr. Singanamala Suman Assistant Professor Department of Pharm.D Gastro-oesophageal reflux disease and peptic ulcer disease Learning objectives:

More information

Cyclooxygenase-2 Expression in Gastric Antral Mucosa Before and After Eradication of Helicobacter pylori Infection

Cyclooxygenase-2 Expression in Gastric Antral Mucosa Before and After Eradication of Helicobacter pylori Infection THE AMERICAN JOURNAL OF GASTROENTEROLOGY Vol. 94, No. 5, 1999 1999 by Am. Coll. of Gastroenterology ISSN 0002-9270/99/$20.00 Published by Elsevier Science Inc. PII S0002-9270(99)00126-4 Cyclooxygenase-2

More information

CHAPTER 18. PEPTIC ULCER DISEASE, SELF-ASSESSMENT QUESTIONS. 1. Which of the following is not a common cause of peptic ulcer disease (PUD)?

CHAPTER 18. PEPTIC ULCER DISEASE, SELF-ASSESSMENT QUESTIONS. 1. Which of the following is not a common cause of peptic ulcer disease (PUD)? CHAPTER 18. PEPTIC ULCER DISEASE, SELF-ASSESSMENT QUESTIONS 1. Which of the following is not a common cause of peptic ulcer disease (PUD)? A. Chronic alcohol ingestion B. Nonsteroidal antiinflammatory

More information

AVERTING RISKS ASSOCIATED WITH UTILISING SMALL ANIMAL NSAIDS

AVERTING RISKS ASSOCIATED WITH UTILISING SMALL ANIMAL NSAIDS Vet Times The website for the veterinary profession https://www.vettimes.co.uk AVERTING RISKS ASSOCIATED WITH UTILISING SMALL ANIMAL NSAIDS Author : Catherine F Le Bars Categories : Vets Date : April 6,

More information

Understandings, Applications & Skills

Understandings, Applications & Skills D.2 Digestion Understandings, Applications & Skills Statement D.2.U1 Nervous and hormonal mechanisms control the secretion of digestive juices. D.2.U2 Exocrine glands secrete to the surface of the body

More information

A HISTOLOGICAL STUDY OF THE EFFECTS OF NONSTEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDs) ON THE GASTRIC AND DUODENAL MUCOSA

A HISTOLOGICAL STUDY OF THE EFFECTS OF NONSTEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDs) ON THE GASTRIC AND DUODENAL MUCOSA A HISTOLOGICAL STUDY OF THE EFFECTS OF NONSTEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDs) ON THE GASTRIC AND DUODENAL MUCOSA Abstract Pages with reference to book, From 287 To 290 Naheed Moghal, N.A. Jafarey

More information

(b) Stomach s function 1. Dilution of food materials 2. Acidification of food (absorption of dietary Fe in small intestine) 3. Partial chemical digest

(b) Stomach s function 1. Dilution of food materials 2. Acidification of food (absorption of dietary Fe in small intestine) 3. Partial chemical digest (1) General features a) Stomach is widened portion of gut-tube: between tubular and spherical; Note arranged of smooth muscle tissue in muscularis externa. 1 (b) Stomach s function 1. Dilution of food

More information

ORIGINAL ARTICLE. Abstract

ORIGINAL ARTICLE. Abstract ORIGINAL ARTICLE Prescription of Nonsteroidal Anti-inflammatory Drugs and Co-prescribed Drugs for Mucosal Protection: Analysis of the Present Status Based on Questionnaires Obtained from Orthopedists in

More information

ASPIRIN AND VASCULAR DISEASE

ASPIRIN AND VASCULAR DISEASE ASPIRIN AND VASCULAR DISEASE SUMMARY Aspirin is an effective antiplatelet agent for patients with cardiovascular and cerebrovascular disease. Incidence of adverse effects and drug interactions increases

More information

Index. B Biotransformation, 112 Blood pressure, 72, 75 77

Index. B Biotransformation, 112 Blood pressure, 72, 75 77 Index A Acute gout, treatment, 41 Adenomatous polyposis coli (APC), 224 Adenomatous polyp prevention on Vioxx (APPROVe), 250 Ankylosing spondylitis (AS), 40 41 Antiplatelet therapy, 138 Antithrombotic

More information

Advent of Novel Phosphatidylcholine-Associated Nonsteroidal Anti-Inflammatory Drugs with Improved Gastrointestinal Safety

Advent of Novel Phosphatidylcholine-Associated Nonsteroidal Anti-Inflammatory Drugs with Improved Gastrointestinal Safety Gut and Liver, Vol. 7, No. 1, January 2013, pp. 7-15 review Advent of Novel Phosphatidylcholine-Associated Nonsteroidal Anti-Inflammatory Drugs with Improved Gastrointestinal Safety Yun Jeong Lim*,, Elizabeth

More information

1) Mononuclear phagocytes : 2) Regarding acute inflammation : 3) The epithelioid cells of follicular granulomas are :

1) Mononuclear phagocytes : 2) Regarding acute inflammation : 3) The epithelioid cells of follicular granulomas are : Pathology Second 1) Mononuclear phagocytes : - Are the predominant cells in three day old wounds - Are common in liver, spleen and pancreasd - Produce fibroblast growth factor - Secrete interferon-g -

More information

Complementary studies of the gastrointestinal safety of the cyclo-oxygenase-2-selective inhibitor etoricoxib

Complementary studies of the gastrointestinal safety of the cyclo-oxygenase-2-selective inhibitor etoricoxib Aliment Pharmacol Ther 2003; 17: 201 210. doi: 10.1046/j.0269-2813.2003.01407.x Complementary studies of the gastrointestinal safety of the cyclo-oxygenase-2-selective inhibitor etoricoxib R. H. HUNT*,

More information

A Cost-Effective Disease Management Approach to Minimizing NSAID-Related GI Mucosal Injury

A Cost-Effective Disease Management Approach to Minimizing NSAID-Related GI Mucosal Injury A Cost-Effective Disease Management Approach to Minimizing NSAID-Related GI Mucosal Injury A. Mark Fendrick, MD Summary Nonsteroidal anti-inflammatory drugs (NSAIDs) are prescribed often in the U.S., particularly

More information

Duodenal Ulcer / Duodenitis

Duodenal Ulcer / Duodenitis Duodenal Ulcer / Duodenitis Endoscopy Department Patient information leaflet You will only be given this leaflet if you have been diagnosed with duodenitis and/or a duodenal ulcer. The information below

More information

NOTOPAIN CAPLETS. Diclofenac Sodium + Paracetamol. Composition. Each tablet contains: Diclofenac Sodium BP 50mg Paracetamol BP 500mg.

NOTOPAIN CAPLETS. Diclofenac Sodium + Paracetamol. Composition. Each tablet contains: Diclofenac Sodium BP 50mg Paracetamol BP 500mg. NOTOPAIN CAPLETS Diclofenac Sodium + Paracetamol Composition Each tablet contains: Diclofenac Sodium BP 50mg Paracetamol BP 500mg Pharmacology Phamacodynamics Diclofenac relieves pain and inflammation

More information

GASTRODUODENAL damage can be seen on endoscopy

GASTRODUODENAL damage can be seen on endoscopy Vol. 334 No. 22 TO PREVENT GASTRIC AND DUODENAL ULCERS CAUSED BY NSAIDS 43 FOR THE PREVENTION OF GASTRIC AND DUODENAL ULCERS CAUSED BY NONSTEROIDAL ANTIINFLAMMATORY DRUGS ALI S. TAHA, PH.D., NICHOLAS HUDSON,

More information

Gastric ulcer Duodenal ulcer Pancreatitis Ileus. Barbora Konečná

Gastric ulcer Duodenal ulcer Pancreatitis Ileus. Barbora Konečná Gastric ulcer Duodenal ulcer Pancreatitis Ileus Barbora Konečná basa.konecna@gmail.com Peptic ulcers of stomach and duodenum (PUD) Ulcers are chronic, often solitary lesions, that occur in any part of

More information

Gastrointestinal side-effects of traditional non-steroidal anti-inflammatory drugs and new formulations

Gastrointestinal side-effects of traditional non-steroidal anti-inflammatory drugs and new formulations Aliment Pharmacol Ther 2004; 20 (Suppl. 2): 48 58. Gastrointestinal side-effects of traditional non-steroidal anti-inflammatory drugs and new formulations M. LAZZARONI & G. BIANCHI PORRO Gastroenterology

More information

: Overview of EFA metabolism

: Overview of EFA metabolism Figure 1 gives an overview of the metabolic fate of the EFAs when consumed in the diet. The n-6 and n-3 PUFAs when consumed in the form of dietary triglyceride from various food sources undergoes digestion

More information

A bleeding ulcer: What can the GP do? Gastrointestinal bleeding is a relatively common. How is UGI bleeding manifested? Who is at risk?

A bleeding ulcer: What can the GP do? Gastrointestinal bleeding is a relatively common. How is UGI bleeding manifested? Who is at risk? Focus on CME at the University of British Columbia A bleeding ulcer: What can the GP do? By Robert Enns, MD, FRCP Gastrointestinal bleeding is a relatively common disorder affecting thousands of Canadians

More information

Bleeds in Cardiovascular Disease

Bleeds in Cardiovascular Disease Preventing Gastrointestinal Bleeds in Cardiovascular Disease Patients t on Aspirin i Joel C. Marrs, Pharm.D., BCPS Clinical Assistant Professor OSU/OHSU College of Pharmacy Pharmacy Practice IX (PHAR 766)

More information

taurocholate-induced gastric mucosal damage in the rat

taurocholate-induced gastric mucosal damage in the rat Gut, 1985, 26, 77-775 Effect of cimetidine and omeprazole on aspirin- and taurocholate-induced gastric mucosal damage in the rat R J UTLEY, A S M SALIM, AND D C CARTER From the University Department of

More information

Peptic ulcer disease. Nomin-Erdene. D SOM-531

Peptic ulcer disease. Nomin-Erdene. D SOM-531 Peptic ulcer disease Nomin-Erdene. D SOM-531 Learning objectives Stomach gross anatomy PUD Epidemiology Pathogenesis Clinical manifestation Diagnosing Treatment Complicated ulcer disease Surgical procedures

More information

Effect of glutamine on the intestinal permeability changes induced by indomethacin in humans

Effect of glutamine on the intestinal permeability changes induced by indomethacin in humans Aliment Pharmacol Ther 1999; 13: 679±685. Effect of glutamine on the intestinal permeability changes induced by indomethacin in humans E. DEN HOND, M. PEETERS, M. HIELE, V. BULTEEL, Y. GHOOS & P. RUTGEERTS

More information

Disease causing organisms Resistance Immunity

Disease causing organisms Resistance Immunity Part 1 Disease causing organisms Resistance Immunity Bacteria Most common pathogens Anthrax Cholera Staphylococcus epidermidis bacteria Bacterial diseases Tuberculosis Cholera Bubonic Plague Tetanus Effects

More information

PHM142 Lecture 4: Platelets + Endothelial Cells

PHM142 Lecture 4: Platelets + Endothelial Cells PHM142 Lecture 4: Platelets + Endothelial Cells 1 Hematopoiesis 2 Platelets Critical in clotting - activated by subendothelial matrix proteins (e.g. collagen, fibronectin, von Willebrand factor) and thrombin

More information

Innate vs Adaptive Response

Innate vs Adaptive Response General Immunology Innate vs Adaptive Response Innate- non-specific (4 types of barriers) anatomic- ato mechanical ca (skin), ph, mucous, normal flora Physiologic- temperature, ph, chemicals (lysozyme,

More information

Gastrointestinal Safety and Anti-Inflammatory Effects of a Hydrogen Sulfide Releasing Diclofenac Derivative in the Rat

Gastrointestinal Safety and Anti-Inflammatory Effects of a Hydrogen Sulfide Releasing Diclofenac Derivative in the Rat GASTROENTEROLOGY 2007;132:261 271 Gastrointestinal Safety and Anti-Inflammatory Effects of a Hydrogen Sulfide Releasing Diclofenac Derivative in the Rat JOHN L. WALLACE,* GIUSEPPE CALIENDO, VINCENZO SANTAGADA,

More information

Analgesics. Munir Gharaibeh, MD, PhD, MHPE Faculty of Medicine The University of Jordan March, 2014

Analgesics. Munir Gharaibeh, MD, PhD, MHPE Faculty of Medicine The University of Jordan March, 2014 Analgesics Munir Gharaibeh, MD, PhD, MHPE Faculty of Medicine The University of Jordan March, 2014 Mar-14 Munir Gharaibeh, MD, PhD, MHPE 2 Feature Comparison of Analgesics Narcotic (Opioids) Nonnarcotic

More information

Aspirin-Induced Gastric Mucosal Injury: Lessons Learned From Animal Models

Aspirin-Induced Gastric Mucosal Injury: Lessons Learned From Animal Models GASTROENTEROLOGY 1989;96:606-14 Aspirin-Induced Gastric Mucosal Injury: Lessons Learned From Animal Models GORDON KAUFFMAN Department of Surgery. Milton S. Hershey Medical Center. Pennsylvania State University.

More information

KK College of Nursing Peptic Ulcer Badil D ass Dass, Lecturer 25th July, 2011

KK College of Nursing Peptic Ulcer Badil D ass Dass, Lecturer 25th July, 2011 KK College of Nursing Peptic Ulcer Badil Dass, Lecturer 25 th July, 2011 Objectives: By the end of this lecture, the students t will be able to: Define peptic pp ulcer Describe the etiology and pathology

More information

Figure 13-1: Antiplatelet Action of Aspirin (Modified After Taneja et.al 2004) ASPIRIN RESISTANCE

Figure 13-1: Antiplatelet Action of Aspirin (Modified After Taneja et.al 2004) ASPIRIN RESISTANCE CHAPTER 13 ASPIRIN Action Aspirin Resistance Aspirin Dose Therapeutic Efficacy - Secondary prevention - Acute coronary syndromes - Primary prevention Limitations and Side Effects Aspirin Aspirin should

More information

A. Correct! Nociceptors are pain receptors stimulated by harmful stimuli, resulting in the sensation of pain.

A. Correct! Nociceptors are pain receptors stimulated by harmful stimuli, resulting in the sensation of pain. Pharmacology - Problem Drill 19: Anti-Inflammatory and Analgesic Drugs No. 1 of 10 1. are pain receptors stimulated by harmful stimuli, resulting in the sensation of pain. #01 (A) Nociceptors (B) Histamines

More information

Pharmacology - Problem Drill 11: Vasoactive Agents

Pharmacology - Problem Drill 11: Vasoactive Agents Pharmacology - Problem Drill 11: Vasoactive Agents Question No. 1 of 10 1. Vascular smooth muscle contraction is triggered by a rise in. Question #01 (A) Luminal calcium (B) Extracellular calcium (C) Intracellular

More information

ph Dependent Drug Delivery System: Review

ph Dependent Drug Delivery System: Review ph Dependent Drug Delivery System: Review Korake.S.P. SVERI s College of Pharmacy (Poly.), Pandharpur The ph-dependent CTDDS exploit the generally accepted view that ph of the human GIT increases progressively

More information

INFLAMMATION. 5. Which are the main phases of inflammation in their "sequence": 1. Initiation, promotion, progression.

INFLAMMATION. 5. Which are the main phases of inflammation in their sequence: 1. Initiation, promotion, progression. INFLAMMATION 1. What is inflammation: 1. Selective anti-infective pathological reaction. 2. Pathological process, typical for vascularized tissues. 3. Self-sustained pathological condition. 4. Disease

More information

We are IntechOpen, the world s leading publisher of Open Access books Built by scientists, for scientists. International authors and editors

We are IntechOpen, the world s leading publisher of Open Access books Built by scientists, for scientists. International authors and editors We are IntechOpen, the world s leading publisher of Open Access books Built by scientists, for scientists 4,100 116,000 120M Open access books available International authors and editors Downloads Our

More information

SPECIAL REPORT. Aspirin and Risk of Gastroduodenal Complications

SPECIAL REPORT. Aspirin and Risk of Gastroduodenal Complications CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2009;7:725 735 SPECIAL REPORT Proton Pump Inhibitors for Gastroduodenal Damage Related to Nonsteroidal Anti-inflammatory Drugs or Aspirin: Twelve Important Questions

More information

PHARMACOTHERAPEUTIC ANALYSIS OF NON- STEROIDAL ANTI-INFLAMMATORY DRUGS PRESCRIBED AT RHEUMATOLOGY / ORTHOPEDIC CLINICS. Waleed M.

PHARMACOTHERAPEUTIC ANALYSIS OF NON- STEROIDAL ANTI-INFLAMMATORY DRUGS PRESCRIBED AT RHEUMATOLOGY / ORTHOPEDIC CLINICS. Waleed M. J. Al Azhar University-Gaza 2003,Vol. 6, 2 P.47-56 PHARMACOTHERAPEUTIC ANALYSIS OF NON- STEROIDAL ANTI-INFLAMMATORY DRUGS PRESCRIBED AT RHEUMATOLOGY / ORTHOPEDIC CLINICS. Waleed M. Sweileh An-Najah National

More information

Ali Jaber, Ph.D. MS in Pharmacy MS in Pharmaceutical Chemistry

Ali Jaber, Ph.D. MS in Pharmacy MS in Pharmaceutical Chemistry Nonsteroidal antiinflammatory drugs (NSAID) Ali Jaber, Ph.D. MS in Pharmacy MS in Pharmaceutical Chemistry The inflammatory response occurs in vascularised tissues in response to injury. It is part of

More information

Digestive System Module 4: The Stomach *

Digestive System Module 4: The Stomach * OpenStax-CNX module: m49286 1 Digestive System Module 4: The * Donna Browne Based on The by OpenStax This work is produced by OpenStax-CNX and licensed under the Creative Commons Attribution License 4.0

More information

Objectives By the end of lecture the student should:

Objectives By the end of lecture the student should: Objectives By the end of lecture the student should: Illustrate α oxidation of fatty acids. Understand ω oxidation of fatty acids. List sources and fates of active acetate. Discuss eicosanoids. 2- α Oxidation

More information

Have COX-2 inhibitors influenced the co-prescription of anti-ulcer drugs with NSAIDs?

Have COX-2 inhibitors influenced the co-prescription of anti-ulcer drugs with NSAIDs? et al. DOI:10.1111/j.1365-2125.2003.02012.x British Journal of Clinical Pharmacology Have COX-2 inhibitors influenced the co-prescription of anti-ulcer drugs with NSAIDs? Mary Teeling, Kathleen Bennett

More information

OPERATIVE TREATMENT OF ULCER DISEASE

OPERATIVE TREATMENT OF ULCER DISEASE Página 1 de 8 Copyright 2001 Lippincott Williams & Wilkins Greenfield, Lazar J., Mulholland, Michael W., Oldham, Keith T., Zelenock, Gerald B., Lillemoe, Keith D. Surgery: Scientific Principles & Practice,

More information

NON STEROIDAL ANTI INFLAMMATORY NSAID

NON STEROIDAL ANTI INFLAMMATORY NSAID NON STEROIDAL ANTI INFLAMMATORY DRUGS NSAID inflammation Normal, protective response to tissue injury 1-physical trauma 2-noxious chemical 3-microbial agent NSAIDs act by inhibiting the synth. Of prostaglandins

More information

prostaglandins on alkali secretion by rabbit gastric

prostaglandins on alkali secretion by rabbit gastric Gut, 1983, 24, 784-789 Effects of non-steroidal anti-inflammatory drugs and prostaglandins on alkali secretion by rabbit gastric fundus in vitro W D W REES, L C GIBBONS, AND L A TURNBERG From the University

More information

Medical Virology Immunology. Dr. Sameer Naji, MB, BCh, PhD (UK) Head of Basic Medical Sciences Dept. Faculty of Medicine The Hashemite University

Medical Virology Immunology. Dr. Sameer Naji, MB, BCh, PhD (UK) Head of Basic Medical Sciences Dept. Faculty of Medicine The Hashemite University Medical Virology Immunology Dr. Sameer Naji, MB, BCh, PhD (UK) Head of Basic Medical Sciences Dept. Faculty of Medicine The Hashemite University Human blood cells Phases of immune responses Microbe Naïve

More information