Relapse of Inflammatory Bowel Disease Associated With Use of Nonsteroidal Anti-Inflammatory Drugs

Meyer, Alyssa J.; Ramzan, Nizar N.; Heigh, Russell I.; Leighton, Jonathan A.

doi:10.1007/s10620-006-3103-5

Cited by 59 publications

(37 citation statements)

References 38 publications

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“…These observations are also consistent with our current observations that only a combined treatment with DSS and indomethacin at a low dose (4 mg/kg/day) produced significant retardation in body weight gain and bloody diarrhea. In addition, clinically, NSAIDs have been reported to trigger or worsen IBD patients (Thiefin and Beaugerie, 2005;Meyer et al, 2006). These results indicate some protective effects of prostanoids synthesized by COX against colitis development (Morteau et al, 2000).…”

Section: Discussionmentioning

confidence: 96%

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The Prevention of Colitis by E Prostanoid Receptor 4 Agonist through Enhancement of Epithelium Survival and Regeneration

Jiang¹,

Nieves²,

Im³

et al. 2006

J Pharmacol Exp Ther

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Inflammatory bowel disease (IBD) is often triggered and/or exacerbated by nonsteroidal anti-inflammatory drugs (NSAIDs). Among various prostanoids affected by NSAIDs, prostaglandin E 2 (PGE 2 ), in particular, seems to play critical roles in IBD via the EP4 receptor, one of the four PGE 2 receptor subtypes (EP1-4). An EP4 agonist, [[3-[[(1R,2S,3R)(ONO-AE1-329), for example, when topically applied, has been reported to ameliorate typical colitis symptoms by suppressing the production of cytotoxic cytokines in the dextran sodium sulfate (DSS)-induced colitis model. EP4 agonists are also known, however, for their ability to protect epithelial cells from apoptosis in vitro, which may contribute to the protection of mucosal barrier functions. To investigate this potential application, we have tested another EP4-selective agonist in the DSS-indomethacin mouse colitis model. 7-[2-(3-Hydroxy-4-phenyl-but-1-enyl)-6-oxo-piperidin-1-yl]-heptanoic acid methyl ester, C 23 H 33 NO 4 (AGN205203), an analog from the 8-azapiperidinone series of EP4 agonists, is metabolically and chemically more stable than the ONO agonist, because of its lack of oxidizable sulfur atoms in the ␣-chain and of 11-OH group, a potential source of ␤-elimination reaction. Treatment of mice subcutaneously with AGN205203 at 3 mg/kg/day minimized colitis symptoms, such as weight loss, diarrhea, and colonic bleeding. Further histological examination of colons revealed healthy surface columnar epithelial cells free of erosion and ulceration compared with those without the drug treatment. At cellular level, the drug treatment decreased colon epithelial apoptosis, prevented goblet cell depletion, and promoted epithelial regeneration. AGN205203 may be unique among known EP4 agonists for its metabolic and chemical stability, and it is amenable to systemic applications for the prevention and recovery of IBD.Inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn's disease (CD), affect approximately 1.4 million United States patients with 15,000 to 30,000 new cases annually at a mean age between 30s and early 40s. IBD patients suffer from body weight loss, diarrhea, fecal blood, and pain. Such symptoms could last for 15 to 25 years, frequently alternating between exacerbation and remission, thus severely affecting the quality of patient life and retarding the growth of young patients (Loftus, 2004;Isaacs et al., 2005). General consensus in the field is that IBD may arise from compromised colonic mucosal barrier functions that allow colonic antigens access to submucosal monocytes, which, upon activation, initiate innate immune responses and trigger cytotoxic cytokine production. Prevention and recovery of IBD thus largely depend on the integrity and maintenance of colonic mucosal barrier functions, which are compromised by inflammations along the entire bowel wall in CD and at the mucosal surface in UC.Current therapies primarily aim at the symptomatic remission by anti-inflammatory agents such as aminosalicylates and/or immunosuppres...

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Section: Discussionmentioning

confidence: 96%

“…NSAIDs and COX-2 inhibitors often trigger and worsen IBD in humans (Thiefin and Beaugerie, 2005;Meyer et al, 2006). Among various prostanoids affected by COX inhibitors, PGE 2 has received much attention because of its important roles in gastrointestinal physiology.…”

mentioning

confidence: 99%

The Prevention of Colitis by E Prostanoid Receptor 4 Agonist through Enhancement of Epithelium Survival and Regeneration

Jiang¹,

Nieves²,

Im³

et al. 2006

J Pharmacol Exp Ther

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“…However, several reports indicate that Cox inhibitors, which block endogenous PG release, have a detrimental effect in patients with CrD or UC and in IBD animal models (43)(44)(45)(46)(47). Therefore, we sought to determine whether blockade of endogenous PG synthesis by using Cox inhibitors affects TNBS-induced colitis and whether this is associated with increased IL-23/IL-17 expression.…”

Section: Cyclooxygenase (Cox) Inhibitors Exacerbate Tnbs-induced Colimentioning

confidence: 99%

The Proinflammatory Effect of Prostaglandin E2 in Experimental Inflammatory Bowel Disease Is Mediated through the IL-23→IL-17 Axis

Sheibanie

Yen

Khayrullina

et al. 2007

The Journal of Immunology

252

196

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Although Crohn’s disease has been traditionally considered to be Th1-mediated, the newly identified Th17 cells emerged recently as crucial participants. Th1/Th17 differentiation is controlled primarily by the IL-12 family of cytokines secreted by activated dendritic cells (DCs) and macrophages. IL-23 and IL-12/IL-27 have opposite effects, supporting the Th17 and Th1 phenotypes, respectively. We found that PGE2, a major lipid mediator released in inflammatory conditions, shifts the IL-12/IL-23 balance in DCs in favor of IL-23, and propose that high levels of PGE2 exacerbate the inflammatory process in inflammatory bowel disease through the IL-23→IL-17 axis. We assessed the effects of PGE2 on IL-12, IL-27, and IL-23 and found that PGE2 promotes IL-23, inhibits IL-12 and IL-27 expression and release from stimulated DCs, and subsequently induces IL-17 production in activated T cells. The effects of PGE2 are mediated through the EP2/EP4 receptors on DCs. In vivo, we assessed the effects of PGE analogs in an experimental model for inflammatory bowel disease and found that the exacerbation of clinical symptoms and histopathology correlated with an increase in IL-23 and IL-17, a decrease in IL-12p35 expression in colon and mesenteric lymph nodes, and a substantial increase in the number of infiltrating neutrophils and of CD4+IL-17+ T cells in the colonic tissue. These studies suggest that high levels of PGE2 exacerbate the inflammatory process through the preferential expression and release of DC-derived IL-23 and the subsequent support of the autoreactive/inflammatory Th17 phenotype.

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“…NSAIDs are considered to be the first-line treatment for the abnormalities just mentioned (i.e, relieve pain and treat inflammation), although immunosuppressive and biological agents [methotrexate (MTX), thalidomide, tumor necrosis factor alpha (TNF-α) antigen] have also been used [5]. They inhibit the production of both cyclooxygenase enzymes (COX-1 and COX-2), and thereby decrease the production of prostaglandins (PG) [6] that leads to the antiinflammatory, antipyretic, and analgesic effects of NSAIDs [7,8]. They also have topical actions such as surface membrane phospholipid interaction and effect on mitochondrial energy (acidity, lipophilicity) [4].…”

Section: Introductionmentioning

confidence: 99%

Exacerbation of inflammatory bowel diseases associated with the use of nonsteroidal anti-inflammatory drugs: myth or reality?

Kefalakes

Stylianides

Amanakis

et al. 2009

Eur J Clin Pharmacol

115

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Background Nonsteroidal anti-inflammatory drugs (NSAIDs), conventional and selective cyclooxygenase-2 (COX-2) inhibitors, are among the most widely used medications for the treatment of various inflammatory conditions. There is strong evidence of a possible association between the use of these drugs and the relapse of inflammatory bowel diseases (IBD). Objective Our objective was to examine the literature regarding the exacerbation of IBD associated with the use of conventional NSAIDs and selective COX-2 inhibitors and the underlying pathogenetic mechanisms. Study design We reviewed articles, including original papers, controlled trials, case reports, reviews, and editorials published in English at the PubMed, Scopus Database, and Science Direct database, searching with the following keywords: nonsteroidal anti-inflammatory drugs (NSAIDs), COX-2 inhibitors, Coxibs, inflammatory bowel diseases (IBD), ulcerative colitis (UC), Crohn's disease (CD). Results There is substantial evidence that exacerbation of IBD happens after treatment with NSAIDs, but the available data remain conflicting, and it is not clear whether selective COX-2 inhibitors are safer than traditional NSAIDs. However, there is some evidence that selective COX-2 inhibition and COX-1 inhibition (with low-dose aspirin) appear to be well-tolerated in the short term. Regarding the mechanisms of relapse, the reduction of prostaglandins appears to be the hallmark of the NSAIDs adverse effects. Conclusions Further randomized, double-blind, controlled trials should be performed to address this issue, and more in vitro studies to identify the pathways involved are required.

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Relapse of Inflammatory Bowel Disease Associated With Use of Nonsteroidal Anti-Inflammatory Drugs

Cited by 59 publications

References 38 publications

The Prevention of Colitis by E Prostanoid Receptor 4 Agonist through Enhancement of Epithelium Survival and Regeneration

The Prevention of Colitis by E Prostanoid Receptor 4 Agonist through Enhancement of Epithelium Survival and Regeneration

The Proinflammatory Effect of Prostaglandin E2 in Experimental Inflammatory Bowel Disease Is Mediated through the IL-23→IL-17 Axis

Exacerbation of inflammatory bowel diseases associated with the use of nonsteroidal anti-inflammatory drugs: myth or reality?

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