• Share
  • Email
  • Embed
  • Like
  • Private Content
NON-STEROIDAL ANTI INFLAMMATORY DRUGS AND GASTROINTESTINAL TOXICITY
 

NON-STEROIDAL ANTI INFLAMMATORY DRUGS AND GASTROINTESTINAL TOXICITY

on

  • 632 views

Non-steroidal anti inflammatory drugs (NSAIDs) because of their high efficacy as both anti-inflammatory and analgesic agents, are one of the most commonly prescribed drugs world-wide. They are used in ...

Non-steroidal anti inflammatory drugs (NSAIDs) because of their high efficacy as both anti-inflammatory and analgesic agents, are one of the most commonly prescribed drugs world-wide. They are used in treatment of many commonly occurring disorders such as chronic arthropathies, headache and low back pain. Their widespread and uncontrolled use is promoted by their over the counter availability. This acts as a double edge sword. One of the most common adverse effects that add largely to its morbidity and mortality
is the gastrointestinal tract damage.

Statistics

Views

Total Views
632
Views on SlideShare
632
Embed Views
0

Actions

Likes
0
Downloads
8
Comments
0

0 Embeds 0

No embeds

Accessibility

Categories

Upload Details

Uploaded via as Adobe PDF

Usage Rights

© All Rights Reserved

Report content

Flagged as inappropriate Flag as inappropriate
Flag as inappropriate

Select your reason for flagging this presentation as inappropriate.

Cancel
  • Full Name Full Name Comment goes here.
    Are you sure you want to
    Your message goes here
    Processing…
Post Comment
Edit your comment

    NON-STEROIDAL ANTI INFLAMMATORY DRUGS AND GASTROINTESTINAL TOXICITY NON-STEROIDAL ANTI INFLAMMATORY DRUGS AND GASTROINTESTINAL TOXICITY Document Transcript

    • NON-STEROIDAL ANTI INFLAMMATORY DRUGS AND GASTROINTESTINAL TOXICITY.
    • Review Article NON-STEROIDAL ANTI INFLAMMATORY DRUGS AND GASTROINTESTINAL TOXICITY Divij Mehta* and DK Bhargava** *Registrar, **Senior Consultant,Department of Gastroenterology and Hepatology, Indraprastha Apollo Hospitals, Sarita Vihar, New Delhi 110 076, India. Correspondence to: Dr DK Bhargava, Senior Consultant,Department of Gastroenterology and Hepatology, Indraprastha Apollo Hospitals, Sarita Vihar, New Delhi 110 076, India. Non-steroidal anti inflammatory drugs (NSAIDs) because of their high efficacy as both anti-inflammatory and analgesic agents, are one of the most commonly prescribed drugs world-wide. They are used in treatment of many commonly occurring disorders such as chronic arthropathies, headache and low back pain. Their widespread and uncontrolled use is promoted by their over the counter availability. This acts as a double edge sword. One of the most common adverse effects that add largely to its morbidity and mortality is the gastrointestinal tract damage. Key words: NSAIDS, Gastrointestinal disorders, Hodgkin’s disease. EPIDEMIOLOGY Because of the broad and nonspecific definitions of gastrointestinal disorders caused by the use of NSAIDs, as well as differences in patient populations, drugs, dosages, and periods of use, estimates of the prevalence of adverse effect vary greatly. In general, at least 10-20% of patients have dyspepsia while taking an NSAID, although the prevalence may range from 5-50% [1,2]. According to prospective data from the Arthritis, Rheumatism, and Aging Medical Information System (ARAMIS), 13 of every 1000 patients with rheumatoid arthritis (RA) who take NSAIDs for one year have a serious gastrointestinal complication. The risk in patients with osteoarthritis is somewhat lower (7.3 per 1000 patients per year) [3]. The mortality rate among patients who are hospitalized for NSAID-induced upper gastrointestinal bleeding is about 5-10% [4]. An analysis of data from ARAMIS has shown that the mortality rate attributed to NSAID-related gastrointestinal toxic effects is 0.22% per year, with an annual relative risk of 4.21 as compared with the risk for persons not using NSAIDs [3]. An estimated cost of $15,000 to $20,000 per hospitalization, the annual direct costs of gastrointestinal complications may exceed $2 billion [5]. It has been estimated conservatively that 16,500 NSAID-related deaths occur among patients with RA or OA every year in United States. This figure is similar to the number of deaths from the acquired immunodeficiency syndrome and considerably greater than the number of deaths from multiple myeloma, asthma, cervical cancer, or Hodgkin’s disease (Fig. 1) [3]. 251 To the worse these mortality statistics did not include deaths ascribed to the use of over-the-counter NSAIDs. Yet these toxic effects remain largely a silent epidemic with many physicians and most patients unaware of the magnitude of the problem. In UK, based on a widely quoted population study by Rockall TA, et al [6], it was estimated that there are 8528 hospitalisations for gastric and duodenal ulcer bleeding per annum in the UK. Three large cohort studies have found that the total risk of hospitalisation for gastrointestinal complications associated with NSAID use as between 1.3 – 2.2 events per 1000 patient years [7,8]. Risk factors for GI complications [3,9-21] Predisposing factors for NSAID induced GI ulceration Previous history or active peptic ulceration • • • • • • • • • • Advanced age (>65) - (linear increase in risk) Female gender Smoking, alcoholism Heavy coffee consumption Concomitant ingestion of GI toxic drugs (e.g., steroids) Prolonged use of heavy doses of NSAIDs Use of multiple NSAIDs; concomitant administration of anticoagulant Hepatic-renal dysfunction Serious systemic illness Concomitant infection with Helicobacter pylori Apollo Medicine, Vol. 7, No. 4, December 2010
    • Review Article after the end of combination therapy, the cumulative rate of recurrent ulcers was 31% among the patients in whom H. Pylori had been eradicated and 46% among those who were still infected. Chan, et al. [30] found that the use of a regimen that included bismuth subcitrate to eradicate H. Pylori significantly decreased the rate of ulcer development associated with the use of naproxen. In this study, gastroduodenal ulcers developed in 26% of H. Pylori – infected persons, but in only 7% of those in whom H. pylori was eradicated. Fig.1. US Mortality data for seven selected disorders. A total of 16,500 patients with rheumatoid arthritis or osteoarthritis died from the gastrointestinal toxic effects of NSAIDS. Data are from the National Center for Health Statistics and the Arthritis, Rheumatism, and Aging Medical Information System. Advanced age (>65 yrs) has been consistently found to be a primary risk factor for adverse gastrointestinal events. The risk increases linearly with age [9-13]. Elderly patients are particularly prone to develop GI toxicity and unfortunately they are the most frequent users of this group of drugs [22]. These patients are deficient in cytoprotective PGs (PGE2 and PGI2) that increase mucous production and improve ulcer healing. Moreover, the vascular integrity of the ulcer base is poor; therefore, ulcers bleed easily [23, 24]. In one study by Hawkey, et al. [31] randomly assigned 285 patients with current ulcers or a history of ulcers who were using NSAIDs to combined treatment with omeprazole, clarithromycin, and amoxicillin or to treatment with omeprazole alone. They found that the eradication of H. Pylori did not affect the rate of recurrent ulcer; in addition, ulcer healing was impaired even in the patients who were successfully treated with antibiotics for H. Pylori infection hence concluding that infection with H. Pylori increases the risk of gastroduodenal mucosal injury associated with NSAID use only minimally, if at all. Identification of Helicobacter pylori infection as an important factor in the development of peptic ulcer has raised the question of a possible synergistic relation between the presence of H. Pylori infection and NSAID use. Although several studies have found these two factors to be independent; two prospective studies have suggested a synergistic relation [25-28]. In another study by Hawkey CJ, et al. [32] did a multivariate regression analyses of three large trials {OPPULENT (Omeprazole versus Placebo as Prophylaxis against Ulcers or Erosions from NSAID Treatment) study, maintenance phases of the OMNIUM (Omeprazole versus Misoprostol for NSAID Induced Ulcer Management) and ASTRONAUT (Acid Suppression Trial: Ranitidine or Omeprazole for NSAID Associated Ulcer Treatment) study} to find whether the increased risk of developing ulcer in a person with a past history of peptic ulceration during NSAID use is due to H. pylori infection or to reactivation of the original lesion by comparing the efficacy of omeprazole 20 mg daily, misoprostol 200 μg twice daily, and ranitidine 150 mg twice daily in preventing ulcers and erosions at different sites and in patients who were H pylori positive and negative. They found that there was a highly significant tendency for the relapse lesion to replicate the site and type of the original lesion (mean odds ratios ranging from 3 to 14) and was not adversely affected by H. Pylori status. Treatment failure was significantly less likely with omeprazole than with placebo, misoprostol, or ranitidine. This advantage was especially evident in H. pylori positive patients receiving acid suppression (5.7% v 16.6% for gastric ulcer with omeprazole). Bianchi Porro, et al. [29] used the combination of amoxicillin and omeprazole to treat NSAID users infected with H. pylori. They found that the eradication of H. Pylori did not affect the rate of ulcer healing. However, six months In a prospective placebo-controlled, double blind randomized trial by Feldman M, et al., 61 healthy men and women were recruited. Out of these, 46 received low dose aspirin therapy. Among them, 22 were H.pylori positive and Many studies have shown that use of multiple NSAIDs; non-use of anti-ulcer medication, and NSAID use in patients with previous history of peptic ulcers raises the possibility of developing GI ulcers by 14-17 folds [23]. Other risk factors that have been identified are higher doses of NSAIDs (including use of two or more NSAIDs), a history of gastroduodenal ulcer or gastrointestinal bleeding, concomitant use of corticosteroids, serious coexisting conditions, and concomitant use of anticoagulants. Apollo Medicine, Vol. 7, No. 4, December 2010 252
    • Review Article 24 were H.pylori negative. They were assessed after a period of 45 days treatment with aspirin and it was found that erosive disease from low dose aspirin occurred in 50% of H.pylori infected volunteers and in 16% of their non-infected counter parts (p=0.02). Therefore, in light of the increasing use of low dose aspirin for cardiovascular prophylaxis, screening and treating H.pylori might be a useful preventive strategy for patients who are at risk of ulcer bleeding [33]. In a meta-analysis by Huang JQ, et al. to study the role of H.pylori infection and NSAIDs in 1625 NSAIDs takers, uncomplicated peptic ulcer disease was significantly more common in patients positive than in those negative for H.pylori [341/817 (41.7%) vs 209/808 (25.9%)]; OR 2.12 (95% CI 1.68-2.67). H.pylori infection increases the risk of PUD in NSAID users by 3.53 fold in addition to the risk associated with NSAID use. Similarly NSAID increases risk of PUD in H.pylori infection by 3.55 fold [34]. But how much cost-effective this approach is, it is yet to be found. The general practice today which is followed is that when NSAIDs are to be used for short term then there is no need to screen for H. pylori, but if they are to be used chronically (>3 months) then we may screen for and treat H. pylori . damage by diminishing the hydrophobicity of gastric mucus, thereby allowing endogenous gastric acid and pepsin to injure the surface epithelium [37]. In addition, topical mucosal injury may occur as a result of indirect mechanisms, mediated through the biliary excretion and subsequent duodenogastric reflux of active NSAID metabolites [38,39]. The role of prostaglandins Topical injury caused by NSAIDs contributes to the development of gastroduodenal mucosal injury. However, the systemic effects of these agents appear to have the predominant role, [33,40,41] largely through the decreased synthesis of mucosal prostaglandins [42]. The use of enteric-coated aspirin preparations [42], parenteral [43] or rectal [44] administration of NSAIDs in order to prevent topical mucosal injury has also failed to prevent the development of ulcers. Moreover, doses of aspirin as low as 30 mg are sufficient to suppress prostaglandin synthesis in the gastric mucosa [45]. Prostaglandins are derived from arachidonic acid, which originates from cell-membrane phospholipids through the action of phospholipase A2 (Fig. 2). Mechanism of GI toxicity Gastroduodenal mucosal injury develops when the deleterious effect of gastric acid overwhelms the normal defensive properties of the mucosa. There are multiple mechanisms with both local and systemic effects in causing this injury The systemic effects are largely the result of the inhibition of endogenous prostaglandin (PG) synthesis [35]. PG inhibition, in turn, leads to decreases in epithelial mucus, secretion of bicarbonate, mucosal blood flow, epithelial proliferation, and mucosal resistance to injury [36,37]. The impairment in mucosal resistance permits injury by endogenous factors, including acid, pepsin, and bile salts, as well as by exogenous factors such as NSAIDs and possibly ethanol and other noxious agents. Topical injury Mucosal injury is initiated topically by the acidic properties of aspirin and many other NSAIDs. Most NSAIDs are weak organic acids and have low pKa, which varies according to the particular agent; these weak acids remain in their non-ionized lipophilic form in the highly acidic gastric lumen. Such conditions favour migration through the gastric mucus across plasma membranes and into surface epithelial cells; they encounter a basic pH (e.g., 7.1). This causes so called “trapping” of the drugs inside the cell, where NSAIDs are dissociated into the ionized form, resulting in trapping of hydrogen ions [35]. NSAIDs can also cause topical mucosal Fig.2. Biosynthesis of prostaglandins through the cyclooxygenase Pathways. The immediate precursor of prostaglandins, arachidonic acid, is derived from membrane phospholipids and is catalyzed by the two cyclooxygenase isoenzymes (also designated as prostaglandin H synthase), cyclooxygenase-1 and cyclooxygenase-2. The gene for cyclooxygenase-1, the housekeeping enzyme, is expressed constitutively and maintains the homeostasis of organs, including gastric mucosal integrity. In contrast, the gene for cyclooxygenase-2, the inflammatory enzyme, is inducible. Although both pathways can be variably inhibited by different NSAIDS, only the gene for cycloozygenase-2 contains a corticosteroidresponsive repressor element in its promoter region. The broken arrows indicate the inhibitory effects of pharmacologic agents. 253 Apollo Medicine, Vol. 7, No. 4, December 2010
    • Review Article PGs protect GI mucosa by forming a cytoprotective layer and increasing the secretion of bicarbonate ions that neutralise the gastric acidity. All therapeutically useful NSAIDs act by inhibiting the synthesis of PGs [46]. The metabolism of arachidonic acid to prostaglandins and leukotrienes is catalyzed by the cyclooxygenase pathway and the 5-lipoxygenase pathway, respectively [1,35] (Fig. 3). There are two isoforms of cyclooxygenases: COX-1 (COX-1) and COX- 2 (COX-2) [47,48]. Despite their structural similarities, they are encoded by distinct genes and differ with regard to their distribution and expression in tissues [49,50]. The COX-1 gene contains a promoter region without a TATA sequence and is primarily expressed constitutively. In contrast, the COX-2 gene is thought to be the inducible form that is nearly undetectable in most (but not all) tissues under normal physiologic conditions. COX-1 appears to function as a “housekeeping” enzyme in most tissues, including the gastric mucosa, the kidneys, and the platelets, whereas the expression of COX-2 can be induced by inflammatory stimuli and mitogens in many different types of tissue, including macrophages and synovial cells [41]. It has thus been suggested that the antiinflammatory properties of NSAIDs are mediated through the inhibition of COX-2, whereas adverse effects, such as gastroduodenal ulceration, occur as a result of effects on the constitutively expressed COX-1 [41,48]. NSAID use is four times more than non-users [1,2]. Overthe-counter availability of PPIs and H2– receptor antagonists for short-term treatment of dyspepsia may lead a patient to delay optimal care for more severe gastrointestinal disease; if the drug is taken on a long- term basis, its use could delay a diagnosis of gastric cancer also [7]. Even aspirin use for prophylactic reasons in low dosages is not free of gastrointestinal complications. All formulations of aspirin like buffered, enteric coated and plain aspirin carry same amount of risk [24]. Besides this, there is evidence that other mechanisms are also involved. For example, ulcers do not develop spontaneously in mice with a disrupted COX-1 gene, [51] and Wallace, et al. [52,53] reported that NSAID-induced injury occurred in association with enhanced adherence of neutrophils to the gastric vascular endothelium, as the result of an increase in the expression of intercellular adhesion molecule 1 (ICAM 1) in the basal endothelium [54-57]. Neutrophil adherence, in turn, causes mucosal injury through the release of oxygen-derived free radicals and proteases [1]. The relative COX-1 inhibition of various NSAIDs is shown in Fig. 4. Arthritis, rheumatism, and ageing medical information system (ARAMIS) data suggested that risk of death from Many modifications of NSAIDs have been formulated to reduce their toxicity. Surveillance and various endoscopic studies have confirmed that the incidence of gastroduodenal mucosal injury is reduced with the use of nabumetone, etodolac, and meloxicam [58-60]. The improved safety of meloxicam appears to be due to its preferential inhibition of COX-2, with a minimal effect on COX-1. In contrast, nabumetone and etodolac appear to inhibit COX-2 preferentially at low doses, but the preferential inhibition of COX-2 is diminished at higher doses. These agents also have other properties that contribute to their safety. Etodolac has a low level of enterohepatic recirculation and a short half- life; nabumetone is a nonacidic prodrug formulation and has no enterohepatic recirculation [61]. Fig.3. Mechanism of action of NSAIDs Fig.4. Comparison between different NSAIDs including COX1 Vs COX-2. Conventional NSAIDs cause non-selective inhibition of COX, which leads to reduction in bicarbonate secretion and reduced mucous production. Coupled with it is vasoconstriction that occurs due to NSAIDs, which causes hypoxia and consequent formation of ulcer. Even short-term (<1 week) use of aspirin and other nonsteroidal antiinflammatory drugs (NSAIDs) can precipitate ulcer-related bleeding. Apollo Medicine, Vol. 7, No. 4, December 2010 254
    • Review Article Highly selective cyclooxygenase-2 inhibitors Many new highly selective COX-2 inhibitors have recently been developed that, in studies to date, have had a markedly reduced capacity to cause injury to the gastroduodenal mucosa. Celecoxib and rofecoxib, are now not new to us and they have been studied extensively for their selective COX-2 inhibitory action. But there are still few important questions to be answered regarding these selective COX-2 inhibitor. For example, COX-2 might generate endogenous prostanoids that are biologically important. Mice in which the gene for COX-2 has been disrupted have defects in renal function and regulation of bone resorption, and female mice have impaired reproductive physiology [61]. Mizuno, et al. [62] have suggested that an increase in mucosal COX-2 expression may be necessary for the normal healing of gastroduodenal ulcers. However, nonselective NSAIDs also inhibit cyclooxygenase-2 to varying degrees, and the critical factor may be the ratio of isoenzyme inhibition. McAdam, et al. [63] recently reported that celecoxib, but not ibuprofen, suppressed the urinary excretion of prostacyclin in healthy subjects, whereas thromboxane activity related to COX-1 was suppressed only by ibuprofen. It is speculated that long-term therapy with these agents might increase the rate of thrombotic events in patients who were at increased risk for cardiovascular disease [63]. However, it is seen that the expression of cyclooxygenase-2 messenger RNA is enhanced in human colorectal adenomas and adenocarcinomas, and selective COX-2 inhibition may thereby reduce the risk of colorectal cancer [64]. NSAIDs containing nitric oxide Nitric oxide and PGs act synergistically to mediate mucosal protective effects [1] and Salvemini, et al. [65] demonstrated that nitric oxide stimulates COX enzymes. A formulation which releases nitric oxide was thought that it may compensate for the suppression of mucosal PGs. Under these conditions, the desired effects of NSAIDs are maintained, including the inhibition of both COX isoenzymes, while toxicity is minimized (Fig. 5) [66-68]. Nitric oxide–containing compounds have anti-inflammatory and antipyretic activities that are similar to those of the parent compound and may have analgesic effects that are greater than those of the parent compound [67]. Effect on upper GIT On esophagus Because of the above explained mechanism, NSAIDs Fig.5. Postulated mechanism by which nitric oxide-releasing NSAIDs maintain the ability to protect the gastroduodenal mucosa while suppressing the level of endogenous mucosal prostaglandins. Nitric oxide appears to stimulate some of the defensive properties of the mucosa that are affected by inhibition of the cyclooxygenase-1 isoenzyme. In addition, nitric oxide inhibits intercellular adhesion molecule 1, thereby decreasing neutrophil adherence, resulting in the prevention of NSAID-induced gastroduodenal mucosal injury. causes various injuries to the GIT. It may lead to the formation of esophageal ulcers; the common mechanism is prolonged mucosal contact with a medicine having caustic physical activity. The diagnosis of NSAID induced esophageal ulcer is made by excluding other probable causes (Like GERD, cancer, infection). Simple measures like avoiding taking NSAID’s empty stomach or taking with atleast 6 oz water or before recumbency can prevent them. Also strictures which are less widely appreciated (more commonly due to GERD) may be formed. Important differentiating feature between the two is that unlike in NSAID induced stricture, in GERD induced strictures mucosa between GE junction and stricture will be inflammed. NSAIDs are also found to exacerbate esophagitis caused by GERD. On stomach and duodenum Stomach is most common organ affected by NSAIDs. In an endoscipic study by Graham DY, et al, he has shown incidence of gastric ulcer as 10-40% and that of duodenal ulcer as 4-15% during the first 3 months of NSAID use [69]. Features of NSAID induced problem ulcers More than 3 mm in size Deep lesions Prone to complications like bleeding, perforation, and obstruction Gastric duodenal in location Multiple erosions (more than 10) Antral in location 255 Apollo Medicine, Vol. 7, No. 4, December 2010
    • Review Article NSAID ingestion and GI injury Injury type Gastro-duodenal lesion Frequency Acute (1-2 weeks) mucosal erythema, superficial erosions, submucosal haemorrhage, increased faecal blood loss 60-100% Chronic (>4 weeks) gastric antral erosions and ulcers, duodenal ulcers and erosions 5-30% Management of UGI toxicity Management of upper GI complications is based on two strategies – either prevention or treatment. Prevention can be done by two ways – either by using some protective agent or by using a safer NSAID. Concurrent use of protective agent- it is seen that majority of NSAID uses do not develop PUD clinically. So protective agents should be better used in high risk groups like short comings of these studies endoscopic rather than clinical assessment was used as the criteria and it did not compare with high dose of H2R blockers. Safe NSAIDs COX-2 specific inhibitors: found 3-5% incidence of endoscopically seen gastroduodenal ulcers with COX-2 inhibitors as compared with 10-40% by traditional NSAID’s. Various COX2 selective inhibitors available are: • First generation • Age > 65 years • H/o PUD or presently having PUD • Using other anticoagulants - Rofecoxib - drugs like Celecoxib • Second generation - Valdicoxib corticosteroids, - A. H2 receptor antagonists B. Prostaglandin analogues C. PPI’s The MUCOSA (Misoprostol Ulcer Complications Outcome Safety Assessment) trial was a 6 months randomized, double-blind, placebo controlled multi-centric trial in 8843 subjects receiving continuous therapy with NSAID for RA were studied. Patients were randomly assigned to receive 200μg of misoprostol or placebo QID. Serious upper GI complications were found to be reduced by 40% among patients receiving misoprostol compared with those receiving placebo. Also the rate of withdrawal from study was more in misoprostol group (because of diarrhea and related problems) (20% vs. 15%). [70]. In another study done by Andreas Maetzel, et al. showed that for averting 1 serious GI complication by prescribing misoprostol would cost around $ 94, 766 [71]. Two endoscopic studies demonstrated omeprazole (20mg OD) to be more effective than ranitidine (150mg BD) or misoprostol (200μg BD) in prevention of NSAID induced gastric and duodenal ulcer [72,73]. However, there were 2 Apollo Medicine, Vol. 7, No. 4, December 2010 Etoricoxib - Various options which are available are: Paracoxib Lumicoxib In the CLASS study (Celecoxib Long-term Arthritis Safety Study) [8] – a double blind randomized controlled trial conducted from Sept 1998 to March 2000 in which 7968 patients with osteoarthritis (72%) or rheumatoid arthritis (28%) were enrolled. In this about half received celecoxib and others received non-specific NSAID’s. 21% of these were also taking low dose aspirin (≤325 mg OD). It was seen that in patients not taking aspirin, the annualized incidence rates of UGI ulcer complications alone and combined with symptomatic ulcers for celecoxib vs NSAID were 0.44% vs 1.27% (p=0.04) and 1.40% vs 2.91% (p=0.002). But in those who were also receiving aspirin, this difference was not statistically significant. In the VIGOR study (Vioxx Gastrointestinal Outcomes Research) [7] – a multi-centric, double blind, randomized controlled trial involving 8076 patients of rheumatoid arthritis and none was receiving aspirin, comparison of rofecoxib (50mg OD) with naproxen (500mg BD) was done with a follow up of 9 months. 2.1 confirmed gastrointestinal events per 100 patients years with rofecoxib as compared with 4.5 per 100 patientsyears with naproxen (p<0.001). Rates of complicated confirmed events were 0.6 per 100 patients-years and 1.4 256
    • Review Article per 100 patient years respectively (p=0.005). Incidence of MI was lower among patients in naproxen group than among those in rofecoxib group. blood stained stools, blood in vamitus, and malena, etc. Two importa2nt studies have shown the superior efficacy of PPI’s over H2R blockers and PG analogues. Adverse events in the lower GI tract due to NSAIDs have been increasingly reported and include increased mucosal permeability and inflammation, anemia, malabsorption, protein loss, diarrhea, mucosal ulceration, bleeding, perforation, symptomatic diverticular disease, and strictures due to fibrous diaphragms [76]. The frequency of these events has not been well studied, but estimates from randomized clinical trials suggest that GI complications beyond the duodenum may represent no less than 40% of all gastrointestinal complications associated with NSAIDs. However, one recent study from Canada by Rahme E, et al. evaluating the rates of hospitalization due to ulceration, perforation, or bleeding in the upper or lower gastrointestinal tract among elderly patients (65 years of age or older) taking NSAIDs and/or acetaminophen with and without a proton-pump inhibitor (PPI) reported lower figures for GI events in the distal tract than in the upper tract [77]. They conducted a population-based retrospective cohort study that included 644183 elderly patients who received 1778541 prescriptions for NSAIDs (315222, 17.7% with a PPI). Among users of NSAIDs without PPIs, the crude rates of hospitalization were 0.7 cases/1000 patient-years for complications in the lower GI tract compared with 4.4/1000 patient-years for complications in the upper GI tract. Among users of NSAIDs and PPIs, the rates were of 1.4/1000 patientyears for the lower GI tract compared with 2.0/1000 patient-years for the upper GI, suggesting that PPIs reduced hospitalizations for upper but not lower GI complications associated with NSAIDs. Of interest, they confirmed that NSAIDs increased the risk of hospitalization from lesions of either the upper or the lower GI tract when compared with acetaminophen at less than 3 g/day. Also they found that among elderly patients requiring analgesic/ antiinflammatory treatment, use of the combination of a NSAID and acetaminophen may increase the risk of gastrointestinal bleeding compared with either of the agents alone. In ASTRONAUT study, a randomized double blind trial in which 541 patients who were on NSAID and has peptic ulcers were randomly assigned to Omeprazole 20mg OD and Ranitidine 150mg BD. At eight weeks, treatment was successful in 80% of patients in group receiving 20mg of omeprazole and 63% in ramitidine group (p<0.001). During maintenance therapy, the proportion of patients in remission at end of six months was 72% in omeprazole group and 59% in ranitidine group [72]. In OMNIUM study, a randomized double blind trial in which 935 patients of RA were taken - at eight weeks, treatment was successful in 76% of patients receiving omeprazole and 71% of those given misoprostol. During maintenance phase, the proportion of patients in remission was 61% in omeprazole group and 48% in misoprostol group (p=0.001). The percentage of adverse events was more with misoprostol as compared to omeprazole. Thus omeprazole is more effective and better tolerated [74]. In a double blind randomized trial by Singh G, et al. [75], efficacy of pantoprazole was compared to omeprazole and misoprostol in NSAID associated gastric ulcer. 120 patients were randomly divided into three groups (pantoprazole 40 mg qd, omeprazole 20 mg qd and misoprostol 200μg BD). They found that rate of ulcer healing in first 4 weeks was 87% vs 75% vs 72%, but all ulcers healed within 8 weeks. The rate of maintaining remission was 66% vs 55% vs 44% on duration of follow up for 3 months. Prevention of NSAIDs induced ulcers Use single NSAIDs Use the lowest possible doses Use for short durations Use less gastrotoxic drugs like paracetamol, ibuprofen, and diclofenac Use selective COX-2 inhibitors wherever possible and especially in high risk cases Review drug use in elderly Avoid concomitant gastrotoxic drugs like steroids Consider prophylaxis with omepraxole in high risk cases Have a high index of suspicion on GI symptoms in NSAID users Educate patients against non-prescription use; counsel them about the warning symptoms of GI damage such as Adverse effects on the GI tract Several studies have shown that coxibs perform better than NSAIDs and PPIs in the small bowel in healthy volunteers. Hawkey, et al. have recently showed that lumiracoxib 100 mg once daily induces less damage to the lower gastrointestinal tract (small bowel) than naproxen 500 mg twice daily and omeprazole 20 mg once daily. This study provides evidence from a multifactorial perspective, including videocapsule endoscopy and biochemical test of inflammation and permeability that the COX-2 selective inhibitor, lumiracoixb, induces less damage to the small bowel than a traditional NSAID and a PPI [78]. 257 Apollo Medicine, Vol. 7, No. 4, December 2010
    • Review Article However, Maiden L, et al. found no differences in the proportion and type of small bowel lesions in patients taking NSAIDs in comparison with coxibs [79]. Therefore, to test this hypothesis, we will need new studies, ideally focused on clinically relevant events. To avoid direct contact of NSAIDs with the upper GI tract, several enteric-coated formulations have been introduced in the market. In most cases, these formulations have reduced the incidence of acute mucosal damage to the stomach, but have not decreased the risk of major upper gastrointestinal bleeding. A new formulation releasing naproxen in the distal small bowel and the upper colon was recently proposed and preliminary work suggests that it induces little or no direct damage to the distal GI tract mucosa [80]. However, this new formulation may well have the same problems associated with the enteric-coated compounds. Inflammatory bowel diseases and NSAIDs There is clear evidence that prostaglandin (PG) production is increased in active inflammatory bowel disease (IBD). PG levels correlate with disease activity and decrease with successful medical intervention. Disease activity has also been correlated with COX expression, especially COX-2. Prostaglandins derived from COX-1 and COX-2 seems to play a protective role. Evidence from inhibition of prostaglandin synthesis with NSAIDs or COX-2 selective inhibitors has also shown conflicting data in both clinical studies and animal models. On theoretical grounds, both NSAIDs and COX-2 inhibitors appear to be capable of triggering a flare-up of IBD by inhibiting the intestinal production of prostaglandins involved in the tissue reparative processes. One experimental study by Dudhgaonkar SP, et al. found that the selective inhibition of inducible nitric oxide synthase (iNOS) and COX-2, as occurs with the potent anti-inflammatory glucocorticoids, afforded maximal protection from colonic injury induced by a trinitrobenzenesulphonic acid (TNBS) enema. This study supports the idea that simultaneous inhibition of iNOS and COX-2 has a promising potential in the treatment of colitis [81]. In a different experimental model of colitis, induced by treatment with 2.5% dextran sulfate sodium (DSS) in drinking water for 6 days, indomethacin (a nonselective COX inhibitor), SC-560 (a selective COX-1 inhibitor), and celecoxib (a selective COX-2 inhibitor) given for 6 days significantly worsened the severity of DSS-induced colonic damage. However, each agent had a different effect on the time of colonic damage. The aggravation was observed in the first 3 days of SC-560 administration and in the last 3 days of celecoxib administration. The expression of COXApollo Medicine, Vol. 7, No. 4, December 2010 2 mRNA in the colon was upregulated on day 3 during DSS treatment, with a significant increase in prostaglandin E2 (PGE2) production, suggesting that endogenous prostaglandins derived from the COX activity afford protection against colonic ulceration; COX-1 in the early stage and COX-2 in the late stage [82]. Elevated levels of the proinflammatory leukotriene B4 (LTB4) have been found in preclinical models of IBD, as well as in colonic tissue from individuals with IBD. The role of 5lipoxigenase (5-LO) derivates like LTB4 has been investigated in another model of colitis in IL-10 (-/-) mice. In these animals, 5-LO-derived leukotrienes were not required for the development or maintenance of spontaneous or NSAID-induced colonic inflammation [83]. The relevance of these animal models to humans is unclear; although all of the tested agents induced ulceration and inflammation in the animals, different and complex mechanisms were involved in these reactions, and these mechanisms may differ significantly from those in humans. Good clinical studies are required before we can reach appropriate conclusions. In a study by Sidhu R, et al. [84] on 76 patients (52 female; mean age 50 years) undergoing routine capsule endoscopy (CE) for some small bowel pathology like anaemia, bleeding or symptoms suggestive of Crohn’s disease he found that urinalysis (a salicylate spot test and gas chromatography mass spectrometry for NSAID metabolites urine samples) was positive in 13.6% of patients (n=10/76), although only one of these patients declared the relevant drug (aspirin) in their drug history. The presence of salicylates was detected in 3.9% of patients (n=3) while NSAID metabolites were detected in 9.2% (n=7: 6 patients ibuprofen alone and both ibuprofen and diclofenac in 1 patient). While CE was normal in 2 patients, positive findings were seen in 80% of patients (n=8) which included the presence of erosions ± red patches in 5 patients, small bowel ulceration in 2 patients and ulceration with early stricturing in one patient. Follow-up in these patients revealed that the patient with small bowel stricturing was subsequently diagnosed as Crohn’s disease while a patient with small bowel ulceration underwent small bowel resection at a further presentation which confirmed NSAID enteropathy histologically. CONCLUSION Inhibition of COX-1 and COX-2 by NSAIDs in the gastrointestinal tract has been associated with both adverse and beneficial effects. NSAIDs increase the risk of hospitalizations due to complications from both the upper and the lower in the lower gastrointestinal tract, including the colon. The effects of NSAIDs and COX-2 inhibitors in patients with inflammatory bowel disease are still unclear. 258
    • Review Article Experimental studies suggest that COX activity affords protection against colonic ulceration and that 5-LO-derived leukotrienes are not required for the development or maintenance of spontaneous or NSAID-induced colonic inflammation. By inhibiting COX-2 or other tumorigenic linked targets, long-term treatment with NSAIDs, especially ASA, or the new nitric oxide-NSAIDs derivates, may prevent colon cancer in selected populations. REFERENCES 1. Larkai EN, Smith JL, Lidsky MD, Graham DY. Gastroduodenal mucosa and dyspeptic symptoms in arthritic patients during chronic steroidal antiinflammatory drug use. Am J Gastroenterol 1987;82:1153-1158. 2. Singh G, Ramey DR, Morfeld D, Shi H, Hatoum HT, Fries JF. Gastrointestinal tract complications of nonsteroidal anti-inflammatory drug treatment in rheumatoid arthritis: a prospective observational cohort study. Arch Intern Med 1996;156:1530-1536. 3. Singh G, Triadafilopoulus G. Epidemiology of NSAIDinduced GI complications. J Rheumatol 1999; 26 (Suppl):18-24. 4. Armstrong CP, Blower AL. Non-steroidal antiinflammatory drugs and life threatening complications of peptic ulceration. Gut 1987; 28: 527-532. 5. Singh G, Ramey DR, Terry R, Khraishi M, Triadafilopoulos G. NSAID-related effects on the GI tract: an ever widening spectrum. Arthritis Rheum 1997; 40: (Suppl):S93. [abstract]. 6. Rockall TA, Logan RF, Devlin HB, et al. Incidence of and mortality from acute upper gastrointestinal haemorrhage in the United Kingdom. Steering Committee and members of the National Audit of Acute Upper Gastrointestinal Haemorrhage. BMJ 1995; 311: 222226. 7. Bombardier C, Laine L, Reicin A, et al. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR Study Group. N Engl J Med 2000; 343:1520-1528. 8. Silverstein FE, Faich G, Goldstein JL, et al. Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: A randomized controlled trial. Celecoxib Long-term Arthritis Safety Study. JAMA 2000; 284:1247-1255. 9. Bjorkman DJ. Nonsteroidal anti-inflammatory druginduced gastrointestinal injury. Am J Med 1996; 101: (Suppl 1A) :25S-32S. 10. Longstreth GF. Epidemiology of hospitalization for acute upper gastrointestinal hemorrhage: a population-based study. Am J Gastroenterol 1995; 90: 206-210. 11. Greene JM, Winickoff RN. Cost-conscious prescribing of nonsteroidal anti-inflammatory drugs for adults with arthritis: a review and suggestions. Arch Intern Med 1992; 152:1995-2002. 12. Gabriel SE, Jaakkimainen L, Bombardier C. Risk for serious gastrointestinal complications related to use of nonsteroidal anti-inflammatory drugs: a meta-analysis. Ann Intern Med 1991; 115: 787-796. 13. Griffin MR, Piper JM, Daugherty JR, Snowden M, Ray WA. Nonsteroidal anti-inflammatory drug use and increased risk for peptic ulcer disease in elderly persons. Ann Intern Med 1991; 114: 257-263. 14. Langman MJ, Weil J, Wainwright P, et al. Risks of bleeding peptic ulcer associated with individual nonsteroidal anti-inflammatory drugs. Lancet 1994; 343: 1075-1078. 15. Garcia Rodriguez LA, Jick H. Risk of upper gastrointestinal bleeding and perforation associated with individual non-steroidal anti-inflammatory drugs. Lancet 1994; 343: 769-772. 16. Hallas J, Lauritsen J, Villadsen HD, Gram LF. Nonsteroidal anti-inflammatory drugs and upper gastrointestinal bleeding, identifying high risk groups by excess risk estimates. Scand J Gastroenterol 1995; 30: 438-444. 17. Silverstein FE, Graham DY, Senior JR, et al. Misoprostol reduces serious gastrointestinal complications in patients with rheumatoid arthritis receiving nonsteroidal anti-inflammatory drugs: a randomized, doubleblind, placebo-controlled trial. Ann Intern Med 1995;123: 241249. 18. Hochain P, Berkelmans I, Czernichow P, et al. Which patients taking non-aspirin non-steroidal antiinflammatory drugs bleed? A case-control study. Eur J Gastroenterol Hepatol 1995;7:419-426. 19. Piper JM, Ray WA, Daugherty JR, Griffin MR. Corticosteroid use and peptic ulcer disease: role of nonsteroidal anti-inflammatory drugs. Ann Intern Med 1991;114: 735-740. 20. Shorr RI, Ray WA, Daugherty JR, Griffin MR. Concurrent use of nonsteroidal anti-inflammatory drugs and oral anticoagulants places elderly persons at high risk for hemorrhagic peptic ulcer disease. Arch Intern Med 1993;153:1665-1670. 21. Barkin J. The relation between Helicobacter pylori and nonsteroidal anti-inflammatory drugs. Am J Med 1998;105: 22S-27S. 22. Yeoman ND. Approaches to healing and protection of NSAID induced ulcers. Am J Med 2001; 110 (1A): 24S28S. 23. Dhikav V, Sindhu S, Anand KS. Newer non-steroidal antiinflammatory drugs: A review of their therapeutic potential and adverse drug reactions. JIACM 2002; 3 (4): 332-338. 24. Dhikav V. Aspirin misconceptions. Drugs News and Views 2001; 6 (1): 64-65. 25. Goggin PM, Collins DA Jazrawi RP, et al. Prevalence of 259 Apollo Medicine, Vol. 7, No. 4, December 2010
    • Review Article Helicobacter pylori infection and its effect on symptoms and non-steroidal anti-inflammatory drug induced gastrointestinal damage in patients with rheumatoid arthritis. Gut 1993;34:1677-1680. 26. Kim JG, Graham DY. Helicobacter pylori infection and development of gastric or duodenal ulcer in arthritic patients receiving chronic NSAID therapy. Am J Gastroenterol 1994; 89: 203-207. 27. Thillainayagam AV, Tabaqchali S, Warrington SJ, Farthing MJ. Interrelationships between Helicobacter pylori infection, nonsteroidal anti-inflammatory drugs, and gastroduodenal disease: a prospective study in healthy volunteers. Dig Dis Sci 1994; 39:1085-1089. 28. Laine L, Cominelli F, Sloane R, Casini-Raggi V, MarinSorensen M, Weinstein WM. Interaction of NSAIDs and Helicobacter pylori on gastrointestinal injury and prostaglandin production: a controlled double-blind study. Aliment Pharmacol Ther 1995; 9: 127-135. 29. Bianchi Porro G, Parente F, Imbesi V, Montrone F, Caruso I. Role of Helicobacter pylori in ulcer healing and recurrence of gastric and duodenal ulcers in longterm NSAID users: response to omeprazole dual therapy. Gut 1996; 39: 22-26. 30. Chan FK, Sung JJ, Chung SC, et al. Randomised trial of eradication of Helicobacter pylori before non-steroidal anti-inflammatory drug therapy to prevent peptic ulcers. Lancet 1997;350: 975-979. 31. Hawkey CJ, Tulassay Z, Szczepañski L, et al. Randomised controlled trial of Helicobacter pylori eradication in patients on non-steroidal antiinflammatory drugs: HELP NSAIDs study. Lancet 1998; 352:1016-1021. 32. C J Hawkey, J Næsdal, I Wilson, G Långström, A J Swannell, R A Peacock, N D Yeomans. Relative contribution of mucosal injury and Helicobacter pylori in the development of gastroduodenal lesions in patients taking non-steroidal anti-inflammatory drugs. Gut 2002; 51: 336–343. 33. Feldman M, Cryer B, Mallat D, Go MF. Role of H.pylori infection in Gastroduodenal injury during long-term low dose aspirin therapy. Am J Gastroenterol 2001; 96(6):1751-1757. 34. Huang JQ, Sridhar S, Hunt RH. Role of H.pylori infection and non-steroidal anti-inflammatory drugs in peptic ulcer disease - Meta analysis. Lancet 2002; 359: 14-22. 35. Schoen RT, Vender RJ. Mechanisms of nonsteroidal antiinflammatory drug-induced gastric damage. Am J Med 1989;86:449-458. 36. Whittle BJR. Mechanisms underlying gastric mucosal damage induced by indomethacin and bile salts, and the actions of prostaglandins. Br J Pharmacol 1977;60:455460. Nonsteroidal anti-inflammatory effect of sulindac sulfoxide and sulfide on gastric mucosa. Clin Pharmacol Ther 1985; 38: 65-70. 39. Carson JL, Strom BL, Morse L, et al. The relative gastrointestinal toxicity of the nonsteroidal antiinflammatory drugs. Arch Intern Med 1987;147: 10541059. 40. Soll AH, Weinstein WM, Kurata J, McCarthy D. Nonsteroidal anti-inflammatory drugs and peptic ulcer disease. Ann Intern Med 1991; 114: 307-319. 41. Needleman P, Isakson PC. The discovery and function of COX-2. J Rheumatol 1997; 24: (Suppl 49): 6-8. 42. Lanza FL, Royer GL Jr, Nelson RS. Endoscopic evaluation of the effects of aspirin, buffered aspirin, and enteric-coated aspirin on gastric and duodenal mucosa. N Engl J Med 1980; 303:136-138. 43. Maliekal J, Elboim CM. Gastrointestinal complications associated with intramuscular ketorolac tromethamine therapy in the elderly. Ann Pharmacother 1995;29:698701. 44. Henry D, Dobson A, Turner C. Variability in the risk of major gastrointestinal complications from nonaspirin nonsteroidal anti-inflammatory drugs. Gastroenterology 1993;105:1078-1088. 45. Lee M, Cryer B, Feldman M. Dose effects of aspirin on gastric prostaglandins and stomach mucosal injury. Ann Intern Med 1994;120:184-189. 46. Tamblyn, Robyn, et al. Unnecessary prescribing of NSAIDs and the management of NSAID-related gastropathy in medical practice. Ann Intern Med 1997; 127: 429-438. 47. Masferrer JL, Seibert K, Zweifel B, Needleman P. Endogenous glucocorticoids regulate an inducible cyclooxygenase enzyme. Proc Natl Acad Sci U S A 1992; 89: 3917-3921. 48. Crofford LJ. COX-1 and COX-2 tissue expression: implications and predictions. J Rheumatol 1997; 24 (Suppl 49):15-19. 49. DeWitt DL, Smith WL. Primary structure of prostaglandin G/H synthase from sheep vesicular gland determined from the complementary DNA sequence. Proc Natl Acad Sci USA 1988; 85:1412-1416. 50. Hla T, Neilson K. Human cyclooxygenase-2 cDNA. Proc Natl Acad Sci USA 1992; 89:7384-7388. 51. Langenbach R, Morham SG, Tiano HF, et al. Prostaglandin synthase 1 gene disruption in mice reduces arachidonic acid-induced inflammation and indomethacin-induced gastric ulceration. Cell 1995; 83: 483-492. 37. Wolfe MM, Soll AH. The physiology of gastric acid secretion. N Engl J Med 1988;319:1707-1715. 52. Wallace JL, Keenan CM, Granger DN. Gastric ulceration induced by nonsteroidal anti- inflammatory drugs is a neutrophil-dependent process. Am J Physiol 1990; 259: G462-G467. 38. Graham DY, Smith JL, Holmes GI, Davies RO. 53. Wallace JL, McKnight W, Miyasaka M, et al. Role of Apollo Medicine, Vol. 7, No. 4, December 2010 260
    • Review Article endothelial adhesion molecules in NSAID-induced gastric mucosal injury. Am J Physiol 1993; 265: G993G998. 54. McCafferty DM, Granger DN, Wallace JL. Indomethacininduced gastric injury and leukocyte adherence in arthritic versus healthy rats. Gastroenterology 1995;109:1173-1180. 55. Santucci L, Fiorucci S, Giansanti M, Brunori PM, Di Matteo FM, Morelli A. Pentoxifylline prevents indomethacin induced acute gastric mucosal damage in rats: role of tumour necrosis factor alpha. Gut 1994; 35: 909-915. 56. Vaananen PM, Keenan CM, Grisham MB, Wallace JL. Pharmacological investigation of the role of leukotrienes in the pathogenesis of experimental NSAID gastropathy. Inflammation 1992;16: 227-240. 57. Hudson N, Balsitis M, Everitt S, Hawkey CJ. Enhanced gastric mucosal leukotriene B4 synthesis in patients taking non-steroidal anti-inflammatory drugs. Gut 1993; 34: 742-747. 58. Roth SH, Tindall EA, Jain AK, et al. A controlled study comparing the effects of nabumetone, ibuprofen, and ibuprofen plus misoprostol on the upper gastrointestinal tract mucosa. Arch Intern Med 1993;153: 2565-2571. 59. Schattenkirchner M. An updated safety profile of etodolac in several thousand patients. Eur J Rheumatol Inflamm 1990;10: 56-65. 60. Distel M, Mueller C, Bluhmki E, Fries J. Safety of meloxicam: a global analysis of clinical trials. Br J Rheumatol 1996;35: [Suppl 1]: 68-77. 61. Wolfe MM. Future trends in the development of safer nonsteroidal anti-inflammatory drugs. Am J Med 1998;105 (Suppl 5A): 44S-52S. 67. Davies NM, Røseth AG, Appleyard CB, et al. NO-naproxen vs. naproxen: ulcerogenic, analgesic and antiinflammatory effects. Aliment Pharmacol Ther 1997;11: 69-79. 68. Saha JK, Schroeder JD, Chen L, et al. Nitrosothiolbased SNONSAIDs as novel anti-inflammatory, analgesic drugs with reduced gastrointestinal toxicity. Gastro-enterology 1998; 114: A274. [abstract]. 69. Graham DY, Agrawal NM, Roth SH. Prevention of NSAIDinduced gastric ulcer with misoprostol: multicentre, double-blind, placebo-controlled trial. Lancet 1988; 2: 1277-1280. 70. Fred ES, Graham DY, John RS, et al. Misoprostol Reduces Serious Gastrointestinal Complications in Patients with Rheumatoid Arthritis Receiving Nonsteroidal Anti-Inflammatory Drugs: A Randomized, Double-Blind, Placebo-Controlled Trial. Ann Intern Med 1995; 123 (4): 241-249. 71. Andreas Maetzel, Marcos BF, Claire Bombardier. The cost-effectiveness of misoprostol in preventing serious gastrointestinal events associated with the use of nonsteroidal antiinflammatory drugs. Arthritis and Rheumatism 1998; 41: 16-25. 72. Neville DY, Zsolt Tulassay, Laszlo Juhasz, et al. A Comparison of Omeprazole with Ranitidine for Ulcers Associated with Nonsteroidal Antiinflammatory Drugs (ASTRONAUT) Study Group. N Engl J Med 1998; 338: 719-726. 73. MacDonald TM, Morant SV, Robinson GC, Shield MJ, McGilchrist MM, Murray FE, McDevitt DG. Association of upper gastrointestinal toxicity of non-steroidal antiinflammatory drugs with continued exposure: cohort study. BMJ. 1997 Nov 22;315(7119):1333–1337. 62. Mizuno H, Sakamoto C, Matsuda K, et al. Induction of cyclooxygenases 2 in gastric mucosal lesions and its inhibition by the specific antagonist delays healing in mice. Gastroenterology 1997;112: 387-397. 74. Hawkey CJ, Karrasch JA, Szczepanski L, et al. Omeprazole Compared with Misoprostol for Ulcers Associated with Nonsteroidal Antiinflammatory Drugs: Omeprazole versus Misoprostol for NSAID-Induced Ulcer Management (OMNIUM) Study Group. N Engl J Med 1998; 338:727-734. 63. McAdam BF, Catella-Lawson F, Mardini IA, Kapoor S, Lawson JA, FitzGerald GA. Systemic biosynthesis of prostacyclin by cyclooxygenases (COX)-2: the human pharmacology of a selective inhibitor of COX-2. Proc Natl Acad Sci USA 1999; 96: 272-277. 75. Singh G, Triadafilopoulos G. Appropriate choice of proton pump inhibitor therapy in the prevention and management of NSAID-related gastrointestinal damage. International Journal of Clinical Practice 2005; 59 (10): 1210-1217. 64. Eberhart CE, Coffey RJ, Radhika A, Giardiello FM, Ferrenbach S, DuBois RN. Up-regulation of cyclooxygenase 2 gene expression in human colorectal adenomas and adenocarcinomas. Gastroenterology 1994;107: 1183-1188. 76. Angel Lanas; Angel Ferrandez. Effect of NSAIDs on colon. Curr Opin Gastroenterol.2009; 25(1):44-49. 65. Salvemini D, Misko TP, Masferrer JL, Seibert K, Currie MG, Needleman P. Nitric oxide activates cyclooxygenase enzymes. Proc Natl Acad Sci USA 1993;90:7240-7244. 66. Wallace JL, Reuter B, Cicala C, McKnight W, Grisham MB, Cirino G. Novel nonsteroidal anti-inflammatory drug derivatives with markedly reduced ulcerogenic properties in the rat. Gastroenterology 1994;107:173-179. 77. Rahme E, Barkun A, Nedjar H, et al. Hospitalizations for upper and lower GI events associated with traditional NSAIDs and acetaminophen among the elderly in Quebec, Canada. Am J Gastroenterol 2008; 103:872882. 78. Hawkey CJ, Ell C, Simon B, et al. Less small-bowel injury with lumiracoxib compared with naproxen plus omeprazole. Clin Gastroenterol Hepatol 2008; 6:536544. 79. Maiden L, Thjodleifsson B, Seigal A, et al. Long-term 261 Apollo Medicine, Vol. 7, No. 4, December 2010
    • Review Article effects of nonsteroidal anti-inflammatory drugs and cyclooxygenase-2 selective agents on the small bowel: a cross-sectional capsule enteroscopy study. Clin Gastroenterol Hepatol 2007; 5:1040-1045. 82. Okayama M, Hayashi S, Aoi Y, et al. Aggravation by selective COX-1 and COX-2 inhibitors of dextran sulfate sodium (DSS)-induced colon lesions in rats. Dig Dis Sci 2007; 52:2095-2103. 80. Piao ZZ, Lee MK, Lee BJ. Colonic release and reduced intestinal tissue damage of coated tablets containing naproxen inclusion complex. Int J Pharm 2008; 350:205-211. 83. Narushima S, DiMeo D, Tian J, et al. 5-Lipoxygenasederived lipid mediators are not required for the development of NSAID-induced inflammatory bowel disease in IL-10-/- mice. Am J Physiol Gastrointest Liver Physiol 2008; 294:G477-G488. 81. Dudhgaonkar SP, Tandan SK, Kumar D, et al. Influence of simultaneous inhibition of cyclooxygenase-2 and inducible nitric oxide synthase in experimental colitis in rats. Inflammopharmacology 2007; 15: 188-195. 84. Sidhu R, Morley S, Brunt L, et al. Surreptitious use of non-steroidal anti-inflammatory drugs and aspirin may be responsible for small bowel injury seen by capsule endoscopy. Gut 2010;59:A162. Apollo Medicine, Vol. 7, No. 4, December 2010 262
    • A o oh s i l ht:w wa o o o p a . m/ p l o p a : t / w .p l h s i lc l ts p / l ts o T ie: t s / ie. m/o p a A o o wt rht :t t r o H s i l p l t p /w t c ts l Y uu e ht:w wy uu ec m/p l h s i ln i o tb : t / w . tb . a o o o p a i a p/ o o l ts d F c b o : t :w wfc b o . m/h A o o o p a a e o k ht / w . e o k o T e p l H s i l p/ a c l ts Si s ae ht:w wsd s aen t p l _ o p a l e h r: t / w .i h r.e/ o o H s i l d p/ le A l ts L k d : t :w wl k d . m/ mp n /p l -o p a i e i ht / w . e i c c a y o oh s i l n n p/ i n no o a l ts Bo : t :w wl s l e l . / l ht / w . t a h a hi g p/ e tk t n