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Gastroenterology Research and Practice
Volume 2013 (2013), Article ID 761060, 7 pages
http://dx.doi.org/10.1155/2013/761060
Review Article

Recent Advances in NSAIDs-Induced Enteropathy Therapeutics: New Options, New Challenges

1Department of Internal Medicine, Dongguk University Ilsan Hospital, Dongguk University College of Medicine, 814 Siksadong, Ilsandonggu, Goyang 410-773, Republic of Korea
2Department of Internal Medicine, Korea University Anam Hospital, Korea University College of Medicine, 126-1 Anam-dong 5 ga, Seongbuk-gu, Seoul 136-705, Republic of Korea

Received 4 June 2013; Revised 2 August 2013; Accepted 13 August 2013

Academic Editor: Gerassimos Mantzaris

Copyright © 2013 Yun Jeong Lim and Hoon Jai Chun. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

The injurious effects of NSAIDs on the small intestine were not fully appreciated until the widespread use of capsule endoscopy. It is estimated that over two-thirds of regular NSAID users develop injury in the small intestinal injuries and that these injuries are more common than gastroduodenal mucosal injuries. Recently, chronic low-dose aspirin consumption was found to be associated with injury to the lower gut and to be a significant contributing factor in small bowel ulceration, hemorrhage, and strictures. The ability of aspirin and NSAIDs to inhibit the activities of cyclooxygenase (COX) contributes to the cytotoxicity of these drugs in the gastrointestinal tract. However, many studies found that, in the small intestine, COX-independent mechanisms are the main contributors to NSAID cytotoxicity. Bile and Gram-negative bacteria are important factors in the pathogenesis of NSAID enteropathy. Here, we focus on a promising strategy to prevent NSAID-induced small intestine injury. Selective COX-2 inhibitors, prostaglandin derivatives, mucoprotective drugs, phosphatidylcholine-NSAIDs, and probiotics have potential protective effects on NSAID enteropathy.

1. Introduction

Nonsteroidal anti-inflammatory drug- (NSAID-) induced lower gastrointestinal (GI) injury is more common than NSAID-associated gastropathy [18]. Historically, this has been given little clinical attention since NSAID-induced enteropathy is usually asymptomatic and is not easily detected using most common diagnostic testing modalities [9, 10]. Recently, through the introduction of capsule endoscopy and device-assisted endoscopy, NSAID enteropathy has become a popular topic of study [11] particularly since NSAID enteropathy is one of the most common causes of obscure GI bleeding [11, 12].

Until recently, no new promising drugs have been developed for NSAID-induced enteropathy. Many efforts to determine the mechanism of NSAID-induced intestinal injury and preventive modalities have been made through experiments and clinical capsule studies (Tables 1 and 2). In this paper, we intend to review potential candidates for the prevention of NSAID-induced small intestinal injuries.

tab1
Table 1: Proposed pathophysiologic mechanism and protection of NSAID-induced small intestinal injuries.
tab2
Table 2: Clinical trials using capsule endoscopy about protective effect on NSAID-induced small intestinal injuries.

2. Proton Pump Inhibitors

It is not completely clear how NSAIDs damage the lower GI tract. In contrast to the stomach, there is no evidence that gastric acid plays a role in the pathogenesis of NSAID-induced lower GI injuries [1315]. Several pharmaceutical companies are in the process of developing drugs that corelease an NSAID (naproxen, aspirin, or ibuprofen) and a proton pump inhibitor (PPI) (omeprazole, esomeprazole, or lansoprazole), and many of these compounds have already been filed with the Food and Drug Administration (FDA) or are in the late stages of development [16] (Table 3). Other companies are combining NSAIDs with high-dose H2-receptor antagonists. In both cases, these new compounds have been shown to reduce the incidence of NSAID-induced gastropathy, but not enteropathy. Moreover, there are increasing concerns about the use of PPIs in combination with aspirin or NSAIDs. Long-term use of PPIs may increase the risk of intra-abdominal infections, including spontaneous bacterial peritonitis and pseudomembranous colitis [17, 18]. Long-term use of PPIs has also been shown to cause small bowel malabsorption of certain vitamins and nutrients, resulting in osteopenia and subsequent bone fractures [19]. Many studies compared PPI use for over 5 years or longest use with last use of less than 1 year or nonuser of PPI. Long-term PPI administration worsened atrophic corpus gastritis and promoted adenocarcinoma development in Mongolian gerbils infected with Helicobacter pylori [20]. Additionally, PPIs may aggravate NSAID-induced intestinal injuries. Laboratory studies have shown that chronic acid suppression markedly alters the small intestinal flora, resulting in worsening of NSAID-induced enteropathy [21]. In these cases, further exploration of the potential of prebiotics and probiotics such as Lactobacillus to lessen these effects is warranted [21]. Unlike PPIs, the proton pump antagonist, revaprazan, did not aggravate indomethacin-induced small intestinal injuries in an animal study. However, the underlying pathophysiologic effects of this drug remain unexplained [22]. Lansoprazole was reported to have an anti-inflammatory effect through upregulation of hemeoxygenase-1, resulting in prevention of NSAID enteropathy in a rat model [23]. These results were mutually incompatible.

tab3
Table 3: New hybrid compounds.

3. Cyclooxygenase-2 Inhibitor

One of the proposed mechanisms of NSAID-induced enteropathy is impairment of mucosal defense through the inhibition of cyclooxygenase (COX), resulting in prostaglandin deficiency. Similar to the stomach, selective COX-2 inhibitors are believed to be less injurious to the small bowel than nonselective NSAIDs [24, 25]. Goldstein et al. [26] reported that a 2-week treatment course with celecoxib, a selective COX-2 inhibitor, caused fewer small intestine injuries than treatment with naproxen. Conversely, Maiden et al. [27] recently found no differences in the incidence of small intestinal injury between chronic users of nonselective NSAIDs and selective COX-2 inhibitors. While coxibs may produce less GI ulceration and bleeding than nonselective NSAIDs, they are still capable of triggering significant adverse events in the GI tract. Additionally, when given concomitantly with low-dose aspirin, the GI benefit of selective COX-2 inhibitors over nonselective NSAIDs is lost [28]. Notably, cardiovascular toxicity issues associated with highly selective COX-2 inhibitors have been a major concern, leading to the withdrawal of the highly selective COX-2 inhibitor rofecoxib (Vioxx) from the marketplace [29]. A recent large study, the Celecoxib versus Omeprazole aNd Diclofenac in Patients with Osteoarthritis and Rheumatoid Arthritis trial (CONDOR), compared the risk of injury along the entire GI tract [30]. Clinically significant decreases in hemoglobin (≥2 g/dL) and/or hematocrit (≥10% from baseline) in conjunction with a defined origin of GI bleeding were more commonly seen in patients taking diclofenac plus omeprazole rather than celecoxib (five doses or more). This clinical trial showed that celecoxib use resulted in fewer small intestinal injuries compared with a PPI plus nonselective NSAID although it is unclear whether selective COX-2 inhibitors truly prevent NSAID-associated enteropathy. Further large-scale studies are needed to determine whether the use of selective COX-2 inhibitors can abolish toxicity along the entire GI tract.

4. Prostaglandins

It is important to note that even when intestinal prostaglandin synthesis is markedly suppressed, ulceration and bleeding do not necessarily occur. However, exogenous prostaglandins have been shown to attenuate NSAID-induced intestinal damage. Bjarnason et al. [38] demonstrated a significant reduction in NSAID-induced intestinal permeability with use of misoprostol, but whether or not a reduction in permeability translates into a reduction in clinically significant injury is unclear. Fujimori et al. [31] demonstrated the benefits of misoprostol treatment in a pilot study in which small intestinal damage was assessed by capsule endoscopy. In that study, misoprostol cotherapy reduced the incidence of lesions in the small intestine induced by a 2-week course of diclofenac sodium in healthy subjects. Watanabe et al. [32] studied the therapeutic effects of misoprostol on aspirin-induced intestinal injury. Their subjects included patients with gastric ulcers who were taking low-dose enteric-coated aspirin by mouth. These patients were treated with a PPI for 8 weeks, at the end of which all patients exhibited redness and erosions in the small intestine by capsule endoscopy. Misoprostol was subsequently administered instead of a PPI for an additional 8 weeks, after which the small intestinal lesions had improved on follow-up capsule endoscopy. Thus, misoprostol showed the ability to induce healing of aspirin-induced small bowel injury. Use of misoprostol has unavoidable limitations, as it causes well-known GI side effects such as diarrhea, abdominal pain, dyspepsia, and nausea.

5. Cytoprotective Drugs

Rebamipide is a cytoprotective drug that induces the production of intracellular prostaglandins, improves blood flow, blocks increases in permeability, scavenges free radicals, and ultimately exhibits anti-inflammatory properties [39]. Two prospective, double-blind studies with capsule endoscopy using rebamipide in healthy subjects had been taken [33, 34]. When the subjects received a placebo, there were significantly more NSAID-induced mucosal injuries in the small intestine compared with when they received rebamipide. A similar randomized, placebo-controlled, double-blind, crossover study focused on the effects of 4 weeks of low-dose aspirin ingestion on small bowel damage using capsule endoscopy in healthy subjects [35]. In this study, long-term, low-dose aspirin use induced small bowel damage, while rebamipide prevented this damage. Thus, rebamipide may be a candidate drug for preventing aspirin-induced small bowel injury. However, these studies were limited by their small sample sizes. Another cytoprotective drug, geranylgeranylacetone (also known as teprenone), was reported to protect against diclofenac-induced injuries in the small intestine in a small-scale clinical trial using capsule endoscopy [36].

6. Antimicrobials

Gram-negative bacteria are important in the pathogenesis of NSAID enteropathy [40, 41]. Administration of NSAIDs to rodents has been shown to cause profound changes in the composition of enteric bacteria, resulting in the development of ulcers in the small intestine [4042]. It has also been reported that treatment with broad-spectrum antibiotics can reduce the severity of NSAID enteropathy; one study showed that germ-free rats and mice do not develop NSAID enteropathy [43]. In that study, germ-free mice were susceptible to NSAID enteropathy when colonized with Escherichia coli or Eubacterium limosum, but not when colonized with probiotics such as Bifidobacterium adolescentis or Lactobacillus acidophilus. NSAIDs invade the intestinal mucosa and activate Toll-like receptor, which is also activated by the lipopolysaccharides found on Gram-negative bacteria [44]. Toll-like receptor has been known to play a key role in a variety of intestinal injuries via stimulation of inflammatory responses.

It is suggested that metronidazole is potentially beneficial in preventing NSAID-induced intestinal injuries by reducing intestinal permeability and inflammation [45].

7. New Compounds (Table 3)

Bile is an important factor in the pathogenesis of NSAID enteropathy [40]. Ligation of the bile duct to prevent enterohepatic recirculation of NSAIDs prevents intestinal damage [46]. While NSAIDs themselves can cause damage to intestinal epithelial cells, disruption of the lipid bilayer of epithelial cells and other damaging effects are enhanced when NSAIDs are combined with bile [47]. This cytotoxic action of NSAIDs in combination with natural bile and/or synthetic bile acids can be prevented with the addition of phosphatidylcholine (PC) [48]. PC-NSAIDs have been developed by PLxPharma (Houston, TX, USA) [48, 49], and one animal study showed that PC indomethacin does not induce small intestinal injuries [22]. Mucosal surfactant phospholipids form a nonwettable, hydrophobic lining that limits the entrance of acid, bile, and other irritants [49]. Preassociating NSAIDs with exogenous PC prevented an increase in surface wettability and protected GI mucosa against the injurious side effects of NSAIDs [50, 51]. Extensive animal studies have demonstrated that PC-NSAIDs offer a lower risk of GI erosion and ulceration while maintaining the pharmacological activity and bioavailability of parent NSAIDs. In one clinical trial, ibuprofen PC was shown to be an effective osteoarthritic agent with an improved GI safety profile compared with ibuprofen alone in older (>55 years) patients, who are more susceptible to NSAID-induced gastroduodenal injury [52].

Other attempts have been made to develop new compounds such as nitric oxide (NO) NSAIDs and hydrogen sulfide (H2S) NSAIDs with the intention of improving GI tolerability [53]. NO may exert its protective effects on the GI mucosa by maintaining the defense mechanisms that are disrupted by COX inhibitors such as mucosal blood flow and mucus and bicarbonate secretion [53, 54]. In addition, NO decreases neutrophil-endothelial adherence, which plays an important role in NSAID-induced GI mucosal injury. Awareness of the protective effects of NO has led to the development of a novel class of drugs called cyclooxygenase-inhibiting NO donors (CINODs). In animal studies, CINODs produced an increase in plasma nitrite/nitrate levels and marked reductions in gastroduodenal and small bowel injuries [54]. While NO can exert both proinflammatory and anti-inflammatory effects, CINODs are generally known to exhibit enhanced anti-inflammatory activity. However, it is still unclear whether CINODs can improve total GI tolerability.

H2S is an endogenous gaseous mediator that suppresses leukocyte adherence to the vascular endothelium and inhibits proinflammatory cytokine synthesis [55, 56]. It has been reported that H2S donors can increase the resistance of the gastric mucosa to injury and accelerate the healing of preexisting ulcers [55]. These observations suggest that NSAIDs that have been modified to release H2S will exhibit reduced toxicity [56]. H2S-releasing NSAIDs, including derivatives of naproxen, diclofenac, aspirin, and indomethacin, have been synthesized and shown to have markedly improved efficacy and reduced toxicity compared with the corresponding parent anti-inflammatory drugs [57]. It is not clear whether H2S-releasing NSAIDs can also improve lower GI tolerability.

8. Probiotics

Several researchers have evaluated the role of probiotics against indomethacin or aspirin enteropathy in vitro and in animal models [37, 5861]. Their results were mutually incompatible. Double-blind, crossover, placebo-controlled studies have been done to evaluate the protective effects of probiotics [37, 60, 61]. In one study, Lactobacillus casei treatment was shown to reduce small bowel injury based on capsule endoscopic findings in chronic low-dose aspirin users [37]. However, evidence regarding the protective roles of probiotics is still weak. Larger, well-designed studies using different probiotic strains, optimal doses, and durations are necessary to clarify their roles.

9. Conclusions

NSAID-induced enteropathy is common and reported the incidence of intestinal damage up to two-thirds [16]. However, NSAID-induced small intestinal lesions did not cause the clinical outcomes including perforation, obstruction, and bleeding on every hedge. It is not clearly beneficial to prevent NSAID-induced small intestinal lesions, for example, erosions, red spots, or denuded area. However, NSAID-induced lower GI complications (perforation, bleeding, or obstruction) are increasing while upper GI complications are decreasing [9, 62]. Lower GI events accounted for 40% of all serious GI events in patients on NSAIDs [25]. Although it is generally not recommended in naïve NSAID users, we should prevent NSAID-induced lower GI injuries in persons with a prior history of NSAID-induced clinically significant lower GI events. Selective COX–2 inhibitors, prostaglandin derivatives, cytoprotective drugs, PC-NSAIDs, and probiotics have all been shown to have potential protective effects on NSAID-induced small intestinal injuries. Future directions include the development of an NSAID compound with total (upper and lower) GI tract tolerability and inappreciable cardiovascular toxicity.

Conflict of Interests

The authors have not received any financial support for this study and have no conflict of interests to declare.

References

  1. D. Y. Graham, A. R. Opekun, F. F. Willingham, and W. A. Qureshi, “Visible small-intestinal mucosal injury in chronic NSAID users,” Clinical Gastroenterology and Hepatology, vol. 3, no. 1, pp. 55–59, 2005. View at Publisher · View at Google Scholar · View at Scopus
  2. L. Maiden, B. Thjodleifsson, A. Theodors, J. Gonzalez, and I. Bjarnason, “A quantitative analysis of NSAID-induced small bowel pathology by capsule enteroscopy,” Gastroenterology, vol. 128, no. 5, pp. 1172–1178, 2005. View at Publisher · View at Google Scholar · View at Scopus
  3. J. A. Tibble, G. Sigthorsson, R. Foster et al., “High prevalence of NSAID enteropathy as shown by a simple faecal test,” Gut, vol. 45, no. 3, pp. 362–366, 1999. View at Scopus
  4. S. Fujimori, K. Gudis, Y. Takahashi et al., “Distribution of small intestinal mucosal injuries as a result of NSAID administration,” European Journal of Clinical Investigation, vol. 40, no. 6, pp. 504–510, 2010. View at Publisher · View at Google Scholar · View at Scopus
  5. T. Matsumoto, T. Kudo, M. Esaki et al., “Prevalence of non-steroidal anti-inflammatory drug-induced enteropathy determined by double-balloon endoscopy: a Japanese multicenter study,” Scandinavian Journal of Gastroenterology, vol. 43, no. 4, pp. 490–496, 2008. View at Publisher · View at Google Scholar · View at Scopus
  6. L. Maiden, “Capsule endoscopic diagnosis of nonsteroidal antiinflammatory drug-induced enteropathy,” Journal of Gastroenterology, vol. 44, no. 19, pp. 64–71, 2009. View at Publisher · View at Google Scholar · View at Scopus
  7. S. Smale, J. Tibble, G. Sigthorsson, and I. Bjarnason, “Epidemiology and differential diagnosis of NSAID-induced injury to the mucosa of the small intestine,” Best Practice and Research: Clinical Gastroenterology, vol. 15, no. 5, pp. 723–738, 2001. View at Publisher · View at Google Scholar · View at Scopus
  8. G. Zuccaro, “Epidemiology of lower gastrointestinal bleeding,” Best Practice and Research: Clinical Gastroenterology, vol. 22, no. 2, pp. 225–232, 2008. View at Publisher · View at Google Scholar · View at Scopus
  9. A. Lanas and F. Sopeña, “Nonsteroidal anti-inflammatory drugs and lower gastrointestinal complications,” Gastroenterology Clinics of North America, vol. 38, no. 2, pp. 333–352, 2009. View at Publisher · View at Google Scholar · View at Scopus
  10. C. Scarpignato and R. H. Hunt, “Nonsteroidal antiinflammatory drug-related injury to the gastrointestinal tract: clinical picture, pathogenesis, and prevention,” Gastroenterology Clinics of North America, vol. 39, no. 3, pp. 433–464, 2010. View at Publisher · View at Google Scholar · View at Scopus
  11. B. Keum and H. J. Chun, “Capsule endoscopy and double balloon enteroscopy for obscure gastrointestinal bleeding: which is better?” Journal of Gastroenterology and Hepatology, vol. 26, no. 5, pp. 794–795, 2011. View at Publisher · View at Google Scholar · View at Scopus
  12. B. J. Lee, H. J. Chun, J. S. Koo et al., “Analysis of the factors that affect the diagnostic yield of capsule endoscopy in patients with obscure gastrointestinal bleeding,” The Korean Journal of Gastroenterology, vol. 49, no. 2, pp. 79–84, 2007. View at Scopus
  13. S. C. Park, H. J. Chun, C. D. Kang, and D. Sul, “Prevention and management of non-steroidal anti-inflammatory drugs-induced small intestinal injury,” World Journal of Gastroenterology, vol. 17, no. 42, pp. 4647–4653, 2011. View at Publisher · View at Google Scholar · View at Scopus
  14. Y. J. Lim and C. H. Yang, “Non-steroidal anti-inflammatory drug-induced enteropathy,” Clinical Endoscopy, vol. 45, no. 2, pp. 138–144, 2012. View at Publisher · View at Google Scholar
  15. T. Arakawa, T. Watanabe, T. Tanigawa et al., “Small intestinal injury caused by NSAIDs/aspirin: finding new from old,” Current Medicinal Chemistry, vol. 19, no. 1, pp. 77–81, 2012. View at Scopus
  16. J. L. Wallace and J. G. P. Ferraz, “New pharmacologic therapies in gastrointestinal disease,” Gastroenterology Clinics of North America, vol. 39, no. 3, pp. 709–720, 2010. View at Publisher · View at Google Scholar · View at Scopus
  17. G. A. Goel, A. Deshpande, R. Lopez, G. S. Hall, D. van Duin, and W. D. Carey, “Increased rate of spontaneous bacterial peritonitis among cirrhotic patients receiving pharmacologic acid suppression,” Clinical Gastroenterology and Hepatology, vol. 10, no. 4, pp. 422–427, 2012. View at Publisher · View at Google Scholar · View at Scopus
  18. J. W. Kim, K. L. Lee, J. B. Jeong et al., “Proton pump inhibitors as a risk factor for recurrence of Clostridium-difficile-associated diarrhea,” World Journal of Gastroenterology, vol. 16, no. 28, pp. 3573–3577, 2010. View at Publisher · View at Google Scholar · View at Scopus
  19. L. E. Targownik, W. D. Leslie, K. S. Davison et al., “The relationship between proton pump inhibitor use and longitudinal change in bone mineral density: a population-based study [corrected] from the Canadian multicentre osteoporosis study (CaMos),” The American Journal of Gastroenterology, vol. 107, no. 9, pp. 1361–1369, 2012. View at Publisher · View at Google Scholar
  20. T. Hagiwara, K. Mukaisho, T. Nakayama, H. Sugihara, and T. Hattori, “Long-term proton pump inhibitor administration worsens atrophic corpus gastritis and promotes adenocarcinoma development in Mongolian gerbils infected with Helicobacter pylori,” Gut, vol. 60, no. 5, pp. 624–630, 2011. View at Publisher · View at Google Scholar · View at Scopus
  21. J. L. Wallace, S. Syer, E. Denou et al., “Proton pump inhibitors exacerbate NSAID-induced small intestinal injury by inducing dysbiosis,” Gastroenterology, vol. 141, no. 4, pp. 1314.e5–1322.e5, 2011. View at Publisher · View at Google Scholar · View at Scopus
  22. Y. J. Lim, T. M. Phan, E. J. Dial, D. Y. Graham, and L. M. Lichtenberger, “In vitro and in vivo protection against indomethacin-induced small intestinal injury by proton pump inhibitors, acid pump antagonists, or indomethacin-phosphatidylcholine,” Digestion, vol. 86, no. 2, pp. 171–177, 2012. View at Publisher · View at Google Scholar
  23. Y. Yoda, K. Amagase, S. Kato et al., “Prevention by lansoprazole, a proton pump inhibitor, of indomethacin-induced small intestinal ulceration in rats through induction of heme oxygenase-1,” Journal of Physiology and Pharmacology, vol. 61, no. 3, pp. 287–294, 2010. View at Scopus
  24. K. Takeuchi, A. Tanaka, S. Kato, K. Amagase, and H. Satoh, “Roles of COX inhibition in pathogenesis of NSAID-induced small intestinal damage,” Clinica Chimica Acta, vol. 411, no. 7-8, pp. 459–466, 2010. View at Publisher · View at Google Scholar · View at Scopus
  25. L. Laine, S. P. Curtis, M. Langman et al., “Lower gastrointestinal events in a double-blind trial of the cyclo-oxygenase-2 selective inhibitor etoricoxib and the traditional nonsteroidal anti-inflammatory drug diclofenac,” Gastroenterology, vol. 135, no. 5, pp. 1517–1525, 2008. View at Publisher · View at Google Scholar · View at Scopus
  26. J. L. Goldstein, G. M. Eisen, B. Lewis, I. M. Gralnek, S. Zlotnick, and J. G. Fort, “Video capsule endoscopy to prospectively assess small bowel injury with celecoxib, naproxen plus omeprazole, and placebo,” Clinical Gastroenterology and Hepatology, vol. 3, no. 2, pp. 133–141, 2005. View at Publisher · View at Google Scholar · View at Scopus
  27. L. Maiden, B. Thjodleifsson, A. Seigal et al., “Long-term effects of nonsteroidal anti-inflammatory drugs and cyclooxygenase-2 selective agents on the small bowel: a cross-sectional capsule enteroscopy study,” Clinical Gastroenterology and Hepatology, vol. 5, no. 9, pp. 1040–1045, 2007. View at Publisher · View at Google Scholar · View at Scopus
  28. L. Laine, E. S. Maller, C. Yu, H. Quan, and T. Simon, “Ulcer formation with low-dose enteric-coated aspirin and the effect of COX-2 selective inhibition: a double-blind trial,” Gastroenterology, vol. 127, no. 2, pp. 395–402, 2004. View at Publisher · View at Google Scholar · View at Scopus
  29. D. J. Watson, S. E. Harper, P. L. Zhao, H. Quan, J. A. Bolognese, and T. J. Simon, “Gastrointestinal tolerability of the selective cyclooxygenase-2 (COX-2) inhibitor rofecoxib compared with nonselective COX-1 and COX-2 inhibitors in osteoarthritis,” Archives of Internal Medicine, vol. 160, no. 19, pp. 2998–3003, 2000. View at Scopus
  30. F. K. L. Chan, A. Lanas, J. Scheiman, M. F. Berger, H. Nguyen, and J. L. Goldstein, “Celecoxib versus omeprazole and diclofenac in patients with osteoarthritis and rheumatoid arthritis (CONDOR): a randomised trial,” The Lancet, vol. 376, no. 9736, pp. 173–179, 2010. View at Publisher · View at Google Scholar · View at Scopus
  31. S. Fujimori, T. Seo, K. Gudis et al., “Prevention of nonsteroidal anti-inflammatory drug-induced small-intestinal injury by prostaglandin: a pilot randomized controlled trial evaluated by capsule endoscopy,” Gastrointestinal Endoscopy, vol. 69, no. 7, pp. 1339–1346, 2009. View at Publisher · View at Google Scholar · View at Scopus
  32. T. Watanabe, S. Sugimori, N. Kameda et al., “Small bowel injury by low-dose enteric-coated aspirin and treatment with misoprostol: a pilot study,” Clinical Gastroenterology and Hepatology, vol. 6, no. 11, pp. 1279–1282, 2008. View at Publisher · View at Google Scholar · View at Scopus
  33. Y. Niwa, M. Nakamura, N. Ohmiya et al., “Efficacy of rebamipide for diclofenac-induced small-intestinal mucosal injuries in healthy subjects: a prospective, randomized, double-blinded, placebo-controlled, cross-over study,” Journal of Gastroenterology, vol. 43, no. 4, pp. 270–276, 2008. View at Publisher · View at Google Scholar · View at Scopus
  34. S. Fujimori, Y. Takahashi, K. Gudis et al., “Rebamipide has the potential to reduce the intensity of NSAID-induced small intestinal injury: a double-blind, randomized, controlled trial evaluated by capsule endoscopy,” Journal of Gastroenterology, vol. 46, no. 1, pp. 57–64, 2011. View at Publisher · View at Google Scholar · View at Scopus
  35. K. Mizukami, K. Murakami, T. Abe et al., “Aspirin-induced small bowel injuries and the preventive effect of rebamipide,” World Journal of Gastroenterology, vol. 17, no. 46, pp. 5117–5122, 2011. View at Publisher · View at Google Scholar · View at Scopus
  36. Y. Niwa, M. Nakamura, R. Miyahara et al., “Geranylgeranylacetone protects against diclofenac-induced gastric and small intestinal mucosal injuries in healthy subjects: a prospective randomized placebo-controlled double-blind cross-over study,” Digestion, vol. 80, no. 4, pp. 260–266, 2009. View at Publisher · View at Google Scholar · View at Scopus
  37. H. Endo, T. Higurashi, K. Hosono et al., “Efficacy of Lactobacillus casei treatment on small bowel injury in chronic low-dose aspirin users: a pilot randomized controlled study,” Journal of Gastroenterology, vol. 46, no. 7, pp. 894–905, 2011. View at Publisher · View at Google Scholar · View at Scopus
  38. I. Bjarnason, J. Hayllar, A. J. MacPherson, and A. S. Russell, “Side effects of nonsteroidal anti-inflammatory drugs on the small and large intestine in humans,” Gastroenterology, vol. 104, no. 6, pp. 1832–1847, 1993. View at Scopus
  39. K. Higuchi, E. Umegaki, T. Watanabe et al., “Present status and strategy of NSAIDs-induced small bowel injury,” Journal of Gastroenterology, vol. 44, no. 9, pp. 879–888, 2009. View at Publisher · View at Google Scholar · View at Scopus
  40. J. L. Wallace, “NSAID gastropathy and enteropathy: distinct pathogenesis likely necessitates distinct prevention strategies,” The British Journal of Pharmacology, vol. 165, no. 1, pp. 67–74, 2012. View at Publisher · View at Google Scholar · View at Scopus
  41. A. Konaka, S. Kato, A. Tanaka, T. Kunikata, R. Korolkiewicz, and K. Takeuchi, “Roles of enterobacteria, nitric oxide and neutrophil in pathogenesis of indomethacin-induced small intestinal lesions in rats,” Pharmacological Research, vol. 40, no. 6, pp. 517–524, 1999. View at Publisher · View at Google Scholar · View at Scopus
  42. T. H. Kent, R. M. Cardelli, and F. W. Stamler, “Small intestinal ulcers and intestinal flora in rats given indomethacin,” The American Journal of Pathology, vol. 54, no. 2, pp. 237–249, 1969. View at Scopus
  43. M. Uejima, T. Kinouchi, K. Kataoka, I. Hiraoka, and Y. Ohnishi, “Role of intestinal bacteria in ileal ulcer formation in rats treated with a nonsteroidal antiinflammatory drug,” Microbiology and Immunology, vol. 40, no. 8, pp. 553–560, 1996. View at Scopus
  44. T. Watanabe, K. Higuchi, A. Kobata et al., “Non-steroidal anti-inflammatory drug-induced small intestinal damage is toll-like receptor 4 dependent,” Gut, vol. 57, no. 2, pp. 181–187, 2008. View at Publisher · View at Google Scholar · View at Scopus
  45. I. Bjarnason, J. Hayllar, P. Smethurst, A. Price, and M. J. Gumpel, “Metronidazole reduces intestinal inflammation and blood loss in non-steroidal anti-inflammatory drug induced enteropathy,” Gut, vol. 33, no. 9, pp. 1204–1208, 1992. View at Scopus
  46. B. K. Reuter, N. M. Davies, and J. L. Wallace, “Nonsteroidal anti-inflammatory drug enteropathy in rats: role of permeability, bacteria, and enterohepatic circulation,” Gastroenterology, vol. 112, no. 1, pp. 109–117, 1997. View at Scopus
  47. Y. Zhou, E. J. Dial, R. Doyen, and L. M. Lichtenberger, “Effect of indomethacin on bile acid-phospholipid interactions: implication for small intestinal injury induced by nonsteroidal anti-inflammatory drugs,” The American Journal of Physiology—Gastrointestinal and Liver Physiology, vol. 298, no. 5, pp. G722–G731, 2010. View at Publisher · View at Google Scholar · View at Scopus
  48. J. M. Barrios and L. M. Lichtenberger, “Role of biliary phosphatidylcholine in bile acid protection and nsaid injury of the lleal mucosa in rats,” Gastroenterology, vol. 118, no. 6, pp. 1179–1186, 2000. View at Scopus
  49. L. M. Lichtenberger, M. Barron, and U. Marathi, “Association of phosphatidylcholine and nsaids as a novel strategy to reduce gastrointestinal toxicity,” Drugs of Today, vol. 45, no. 12, pp. 877–890, 2009. View at Publisher · View at Google Scholar · View at Scopus
  50. L. M. Lichtenberger, Z. M. Wang, J. J. Romero et al., “Non-steroidal anti-inflammatory drugs (NSAIDs) associate with zwitterionic phospholipids: insight into the mechanism and reversal of NSAID-induced gastrointestinal injury,” Nature Medicine, vol. 1, no. 2, pp. 154–158, 1995. View at Scopus
  51. L. M. Lichtenberger, Y. Zhou, V. Jayaraman et al., “Insight into NSAID-induced membrane alterations, pathogenesis and therapeutics: characterization of interaction of NSAIDs with phosphatidylcholine,” Biochimica et Biophysica Acta, vol. 1821, no. 7, pp. 994–1002, 2012. View at Publisher · View at Google Scholar
  52. F. L. Lanza, U. K. Marathi, B. S. Anand, and L. M. Lichtenberger, “Clinical trial: comparison of ibuprofen-phosphatidylcholine and ibuprofen on the gastrointestinal safety and analgesic efficacy in osteoarthritic patients,” Alimentary Pharmacology and Therapeutics, vol. 28, no. 4, pp. 431–442, 2008. View at Publisher · View at Google Scholar · View at Scopus
  53. Y. J. Lim, J. S. Lee, Y. S. Ku, and K. B. Hahm, “Rescue strategies against non-steroidal anti-inflammatory drug-induced gastroduodenal damage,” Journal of Gastroenterology and Hepatology, vol. 24, no. 7, pp. 1169–1178, 2009. View at Publisher · View at Google Scholar · View at Scopus
  54. J. L. Wallace and P. Del Soldato, “The therapeutic potential of NO-NSAIDs,” Fundamental and Clinical Pharmacology, vol. 17, no. 1, pp. 11–20, 2003. View at Publisher · View at Google Scholar · View at Scopus
  55. R. Blackler, S. Syer, M. Bolla, E. Ongini, and J. L. Wallace, “Gastrointestinal-sparing effects of novel nsaids in rats with compromised mucosal defence,” PLoS ONE, vol. 7, no. 4, Article ID e35196, 2012. View at Publisher · View at Google Scholar · View at Scopus
  56. S. Fiorucci, E. Antonelli, E. Distrutti et al., “Inhibition of hydrogen sulfide generation contributes to gastric injury caused by anti-inflammatory nonsteroidal drugs,” Gastroenterology, vol. 129, no. 4, pp. 1210–1224, 2005. View at Publisher · View at Google Scholar · View at Scopus
  57. J. L. Wallace, “Hydrogen sulfide-releasing anti-inflammatory drugs,” Trends in Pharmacological Sciences, vol. 28, no. 10, pp. 501–505, 2007. View at Publisher · View at Google Scholar · View at Scopus
  58. M. Montalto, N. Maggiano, R. Ricci et al., “Lactobacillus acidophilus protects tight junctions from aspirin damage in HT-29 cells,” Digestion, vol. 69, no. 4, pp. 225–228, 2004. View at Publisher · View at Google Scholar · View at Scopus
  59. R. Kamil, M. S. Geier, R. N. Butler, and G. S. Howarth, “Lactobacillus rhamnosus GG exacerbates intestinal ulceration in a model of indomethacin-induced enteropathy,” Digestive Diseases and Sciences, vol. 52, no. 5, pp. 1247–1252, 2007. View at Publisher · View at Google Scholar · View at Scopus
  60. M. Gotteland, S. Cruchet, and S. Verbeke, “Effect of Lactobacillus ingestion on the gastrointestinal mucosal barrier alterations induced by indometacin in humans,” Alimentary Pharmacology and Therapeutics, vol. 15, no. 1, pp. 11–17, 2001. View at Publisher · View at Google Scholar · View at Scopus
  61. M. Montalto, A. Gallo, V. Curigliano et al., “Clinical trial: the effects of a probiotic mixture on non-steroidal anti-inflammatory drug enteropathy—a randomized, double-blind, cross-over, placebo-controlled study,” Alimentary Pharmacology and Therapeutics, vol. 32, no. 2, pp. 209–214, 2010. View at Publisher · View at Google Scholar · View at Scopus
  62. A. Lanas, L. A. García-Rodríguez, M. Polo-Tomás et al., “Time trends and impact of upper and lower gastrointestinal bleeding and perforation in clinical practice,” The American Journal of Gastroenterology, vol. 104, no. 2, pp. 1633–1644, 2009. View at Publisher · View at Google Scholar