Toxic effects of nonsteroidal antiinflammatory drugs on the small bowel, colon, and rectum

doi:10.1016/j.jbspin.2004.10.004

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Volume 72, Issue 4, July 2005, Pages 286-294

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Abstract

The gastrointestinal toxicity of conventional nonsteroidal antiinflammatory drugs (NSAIDs) is not confined to the stomach and proximal duodenum but extends also to the rest of the small bowel, colon, and rectum. Long-term NSAID therapy usually induces clinically silent enteropathy characterized by increased intestinal permeability and inflammation. Chronic occult bleeding and protein loss may result in iron-deficiency anemia and hypoalbuminemia. NSAIDs can also induce small bowel ulcers that infrequently lead to acute bleeding, perforation, or chronic scarring responsible for diaphragm-like strictures. At the colon and rectum, NSAID use can result in de novo lesions such as nonspecific colitis and rectitis, ulcers, and diaphragm-like strictures. NSAIDs have been implicated in the development of segmental ischemic colitis. In patients with diverticular disease, NSAID use increases the risk of severe diverticular infection and perforation. NSAIDs can trigger exacerbations of ulcerative colitis or Crohn’s disease. With selective COX-2 inhibitors, the risk of gastrointestinal toxicity is reduced as compared to conventional NSAIDs but is not completely eliminated. Experimental studies suggest that long-term COX-2 inhibitor therapy may cause damage to the previously healthy small bowel. Similar to conventional NSAIDs, COX-2 inhibitors may be capable of triggering exacerbations of inflammatory bowel disease.

Introduction

The gastroduodenal toxicity of conventional nonsteroidal antiinflammatory drugs (NSAIDs) is widely recognized. Side effects involving the more distal portions of the intestinal tract are not only less common, but also frequently underestimated. It is now well established that NSAID-induced toxicity extends to the entire gastrointestinal tract including the small bowel, colon, and rectum [1], [2]. NSAID-induced lesions may develop either in the healthy gut or at sites of pre-existing bowel disease. In some cases NSAID therapy may reveal previously undiagnosed bowel disease. Many adverse events involving the lower intestine have been reported, some of them being potentially life-threatening (Table 1). Physicians must be thoroughly familiar with all the gastrointestinal side effects of NSAIDs. The development of selective COX-2 inhibitors has not provided a definitive solution, and the toxicity of these new agents for the lower intestine remains incompletely understood.

The objective of this review is to describe NSAID-induced adverse effects involving the lower intestinal tract, to discuss their management, and to examine current knowledge on the intestinal toxicity of COX-2 inhibitors.

Section snippets

Pathogenesis

Fig. 1 summarizes the main pathogenic steps in the development of NSAID-induced lesions of the small bowel. Increased permeability of the gut mucosa is the earliest event. Bjarnason and coworkers [3] have suggested that the main underlying mechanism may be inhibition of oxidative phosphorylation within enterocytes exposed to high intraluminal NSAID levels after oral dosing and repeated enterohepatic cycling. Support for this hypothesis comes from ultrastructural studies showing vacuolization

Epidemiology

Few epidemiological data are available on the rate of NSAID-induced intestinal events (Table 2). The North American ARAMIS database contains clinical and therapeutic data collected over 30 years in a cohort of patients with musculoskeletal diseases [17]. From these data, the annual incidence of admissions for NSAID-induced adverse events involving the lower intestinal tract can be estimated at 0.19/100 patient-years in patients with rheumatoid arthritis (RA) and 0.23/100 patient-years in

Adverse effects of NSAIDs on the small bowel

An important distinction is that between clinically silent abnormalities and clinically patent events. Clinically silent abnormalities consist of increased intestinal permeability and mucosal inflammation, which are found in most patients on long-term NSAID therapy. Clinically patent events, such as bleeding and perforation, are infrequent but potentially life-threatening.

Toxic effects of NSAIDs on the colon and rectum

NSAIDs can not only induce de novo colorectal lesions in patients with no history of bowel disease, but also worsen the manifestations of pre-existing disorders such as diverticular disease or chronic inflammatory bowel disease (IBD) (Table 1). Colonic toxicity is more common with sustained-release formulations, which result in higher NSAID levels in contact with the proximal colonic mucosa. NSAID rectal suppositories can induce local lesions.

Intestinal toxicity of COX-2 inhibitors

The simple model in which COX-1 ensures physiological prostaglandin production and COX-2 the production of prostaglandins in response to abnormal events does not match biological reality. There is now sound evidence that inhibition of each isoenzyme can have either beneficial or deleterious effects according to the setting.

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Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most frequently used pharmaceuticals for human therapy, pet therapeutics, and veterinary feeds, enabling them to enter into water sources such as wastewater, soil and sediment, and seawater. The control of NSAIDs has led to the advent of the novel materials for treatment techniques. Herein, we review the occurrence, impact and toxicity of NSAIDs against aquatic microorganisms, plants and humans. Typical NSAIDs, e.g., ibuprofen, ketoprofen, diclofenac, naproxen and aspirin were detected at high concentrations in wastewater up to 2,747,000 ng L⁻¹. NSAIDs in water could cause genotoxicity, endocrine disruption, locomotive disorders, body deformations, organs damage, and photosynthetic corruption. Considering treatment methods, among adsorbents for removal of NSAIDs from water, metal-organic frameworks (10.7–638 mg g⁻¹) and advanced porous carbons (7.4–400 mg g⁻¹) were the most robust. Therefore, these carbon-based adsorbents showed promise in efficiency for the treatment of NSAIDs.
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In particular, non-steroidal anti-inflammatory drugs (NSAIDs) were originally formulated to reduce pain and inflammation, largely reflecting the non-selective inhibition of COX-1 and COX-2 (Dubois et al., 1998; Simmons et al., 2004). Although clinically useful for their intended purpose, these drugs cause gastric and enteric complications in animals and a subset of individuals (Bjarnason et al., 1993; Halter et al., 2001; Sigthorsson et al., 2002; Thiefin and Beaugerie, 2005; Wallace and Devchand, 2005; Whittle, 2004), calling for the development of next-generation NSAIDs selectively targeting COX-2 (Everts et al., 2000). Second-generation NSAIDs were associated with reduced gastrointestinal events, but their use was rapidly linked with adverse cardiovascular effects (Bombardier et al., 2000; Silverstein et al., 2000).
As compared to their normal counterparts, neoplastic cells exhibit a variety of metabolic changes that reflect not only genetic and epigenetic defects underlying malignant transformation, but also the nutritional and immunobiological conditions of the tumor microenvironment. Such alterations, including the so-called Warburg effect (an increase in glucose uptake largely feeding anabolic and antioxidant metabolism), have attracted considerable attention as potential targets for the development of novel anticancer therapeutics. However, very few drugs specifically conceived to target bioenergetic cancer metabolism are currently approved by regulatory agencies for use in humans. This reflects the elevated degree of heterogeneity and redundancy in the metabolic circuitries exploited by neoplastic cells from different tumors (even of the same type), as well as the resemblance of such metabolic pathways to those employed by highly proliferating normal cells. Here, we summarize the major metabolic alterations that accompany oncogenesis, the potential of targeting bioenergetic metabolism for cancer therapy, and the obstacles that still prevent the clinical translation of such a promising therapeutic paradigm.
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The early events by which inflammation promotes cancer are still not fully defined. The MCC gene is silenced by promoter methylation in colitis-associated and sporadic colon tumors, but its functional significance in precancerous lesions or polyps is not known. Here, we aimed to determine the impact of Mcc deletion on the cellular pathways and carcinogenesis associated with inflammation in the mouse proximal colon.
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Transcriptome profiling of the lesions showed a strong response to colon barrier destruction, such as up-regulation of key inflammation and cancer-associated genes as well as 28 interferon γ–induced guanosine triphosphatase genes, including the homologs of Crohn’s disease susceptibility gene IRGM. These features were shared by both Mcc-expressing and Mcc-deficient mice and many of the altered gene expression pathways were similar to the mesenchymal colorectal cancer subtype known as consensus molecular subtype 4 (CMS4). However, Mcc deletion was required for increased carcinogenesis in the lesions, with adenocarcinoma in 59% of Mcc^ΔIEC compared with 19% of Mcc-expressing mice (P = .002). This was not accompanied by hyperactivation of β-catenin, but Mcc deletion caused down-regulation of DNA repair genes and a disruption of DNA damage signaling.
Loss of Mcc may promote cancer through a failure to repair inflammation-induced DNA damage. We provide a comprehensive transcriptome data set of early colorectal lesions and evidence for the in vivo significance of MCC silencing in colorectal cancer.
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Les anti-inflammatoires non stéroïdiens (AINS) sont susceptibles d’endommager n’importe quel segment du tractus digestif. Ce sont toutefois les dyspepsies fonctionnelles qui en sont l’effet indésirable le plus fréquent et, du reste, la principale cause de leur abandon par les patients. Bien plus rares, les ulcères chroniques symptomatiques et les saignements ou perforation gastro-intestinaux connaissent des facteurs favorisants bien établis (ulcère évolutif et hémorragie gastro-intestinale, ou antécédent ; âge ; administration concomitante d’un anticoagulant, d’un anti-agrégant, d’un corticoïde systémique) – dont la présence contre-indique le recours aux AINS ou justifie la coprescription d’un inhibiteur de la pompe à protons. La nature de l’AINS, sa posologie et sa durée d’utilisation influencent également le risque de développer un ulcère peptique. Le rôle d’Helicobacter pylori (Hp) est plus complexe ; il apparaît néanmoins qu’il est inutile de dépister et, le cas échéant, d’éradiquer l’Hp quand les malades prennent déjà des AINS au long cours. Les relations entre AINS et maladies inflammatoires chroniques de l’intestin (MICI) restent débattues quand bien même les AINS ont été incriminés dans l’exacerbation de MICI, la réactivation de formes en rémission, voire dans des MICI de novo. Quant aux corticoïdes, leur potentiel ulcérogène demeure controversé, surtout aux faibles posologies. On leur impute, en revanche, des perforations de diverticules coliques et, à cet égard, ils sont plus dangereux que les AINS.
Nonsteroidal anti-inflammatory drugs (NSAIDs) may damage any segment of the digestive tract. However, functional dyspepsia is the most common NSAID-related untoward effect as well as the major reason for discontinuing NSAID therapy. Chronic gastroduodenal ulcer, gastrointestinal bleeding or perforation are by far less frequent. There are well-established predisposing factors to these side effects, including past or active peptic ulcer, gastrointestinal bleeding, aging, and concomitant use of anticoagulants, platelet antiaggregants or systemic corticosteroids. These factors either require to combine an NSAID with a proton pump inhibitor or contraindicate NSAID use. The NSAID type, its dosage and the duration of treatment also influence the risk for developing a peptic ulcer. The relationships between NSAIDs and Helicobacter pylori (Hp) are complex. There is, however, evidence that testing Hp and, if positive, eradicating Hp do not provide any clear benefit in those patients who are already long-term NSAIDs users. Furthermore, it has been reported that NSAIDs may exacerbate chronic inflammatory bowel diseases (CIBD), precipitate their flares, and even induce them. Conversely, some studies suggest that these detrimental effects would not occur with conventional NSAIDs at low doses and short-term use of coxibs. Regarding corticosteroids, their ulcerogenic potential is uncertain, especially when given at low dosages. On the other hand, systemic corticosteroids may cause sigmoid diverticular abscess perforation. In this respect, they are more toxic than NSAIDs.
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ReviewToxic effects of nonsteroidal antiinflammatory drugs on the small bowel, colon, and rectum

Abstract

Introduction

Section snippets

Pathogenesis

Epidemiology

Adverse effects of NSAIDs on the small bowel

Toxic effects of NSAIDs on the colon and rectum

Intestinal toxicity of COX-2 inhibitors

Gastroenterology

Gastroenterology

Gastroenterology

Gastroenterology

Gastroenterology

Gastroenterology

Gastroenterology

Prostaglandins

Eur. J. Pharmacol.

Am. J. Med.

Gastroenterology

Lancet

Gastroenterology

Lancet

Gastroenterology

Gastroenterology

J Paediat Surg

Gastrointest. Endosc.

Am. J. Med.

Am. J. Gastroenterol.

Prostaglandins

Am. J. Gastroenterol.

Gen. Pharmacol.

Cell

Gastroenterology

Am. J. Med.

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Am. J. Gastroenterol.

Am. J. Gastroenterol.

Am. J. Gastroenterol.

Adverse effects of nonsteroidal anti-inflammatory drugs on the small and large bowel

Endoscopy

Mitochondrial damage: a possible mechanism of the “topical” phase of NSAID induced injury to rat intestine

Gut

Uncoupling of intestinal mitochondrial oxidative phosphorylation and inhibition of cyclooxygenase are required for the development of NSAID-enteropathy in the rat

Aliment. Pharmacol. Ther.

Nabumetone evidence for the lack of enterohepatic circulation of the active metabolite 6-MNA in humans

Drugs

Effects of cholestyramine and synthetic hydrotalcite on acute gastric or intestinal lesion formation in rats and dogs

Dig. Dis. Sci.

Leucocyte-endothelial cell adhesion in a model of intestinal inflammation

Gut

Neutrophil migration into indomethacin induced rat small intestinal injury is CD11a/CD18 and CD11b/CD18 co-dependent

Gut

Effect of non-steroidal anti-inflammatory drugs and prostaglandins on the permeability of the human small intestine

Gut

High prevalence of NSAID enteropathy as shown by a simple faecal test

Gut

Gastrointestinal damage associated with the use of nonsteroidal antiinflammatory drugs

N. Engl. J. Med.

Review
Toxic effects of nonsteroidal antiinflammatory drugs on the small bowel, colon, and rectum