Exacerbation of Nonsteroidal Anti-Inflammatory Drug-Induced Small Intestinal Lesions by Antisecretory Drugs in Rats: The Role of Intestinal Motility

Satoh, Hiroshi; Amagase, Kikuko; Takeuchi, Koji

doi:10.1124/jpet.112.197475

Cited by 54 publications

(41 citation statements)

References 29 publications

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“…Of note, both these conflicting observations are corroborated by literature data. Indeed, Kuroda et al (2006) observed that lansoprazole counteracted small bowel injury in a rat model of indomethacin-induced enteropathy, whereas Wallace et al (2011) and Satoh et al (2012) found that some PPIs exacerbated the detrimental effects of naproxen or indomethacin on rat small bowel. In clinical settings, both Goldstein et al (2005) and Hawkey et al (2008) observed an increase in small intestinal lesions in healthy volunteers taking a combination of omeprazole and naproxen.…”

Section: Discussionmentioning

confidence: 99%

NSAID-Induced Enteropathy: Are the Currently Available Selective COX-2 Inhibitors All the Same?

Fornai

Antonioli

Colucci

et al. 2013

J Pharmacol Exp Ther

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Nonsteroidal anti-inflammatory drugs (NSAIDs) can induce intestinal mucosal damage, but the underlying mechanisms remain poorly understood. The present study investigated the effects of celecoxib, etoricoxib, indomethacin, and diclofenac on small bowel integrity in rats. Male rats were treated orally with test drugs for 14 days. Animals were processed for assessment of blood hemoglobin levels and hepatic mitochondrial functions, microscopic evaluation of small intestinal damage, Western blot analysis of cyclooxygenase-1 and -2 (COX-1, COX-2) expression, and assay of malondialdehyde (MDA), myeloperoxidase (MPO), and prostaglandin E 2 (PGE 2 ) levels in small intestine. Indomethacin and diclofenac decreased blood hemoglobin levels, whereas etoricoxib and celecoxib were without effects. Celecoxib caused a lower degree of intestinal damage in comparison with the other test drugs. Indomethacin and diclofenac, but not etoricoxib or celecoxib, reduced intestinal PGE 2 levels. Test drugs did not modify intestinal COX-1 expression, although they enhanced COX-2, with the exception of celecoxib, which downregulated COX-2. Indomethacin, diclofenac, and etoricoxib altered mitochondrial respiratory parameters, although celecoxib was without effects. Indomethacin or diclofenac increased MDA and MPO levels in both jejunum and ileum. In the jejunum, etoricoxib or celecoxib did not modify such parameters, whereas in the ileum, etoricoxib, but not celecoxib, increased both MDA and MPO levels. These findings suggest that nonselective NSAIDs and etoricoxib can induce enteropathy through a topic action, whereas celecoxib lacks relevant detrimental actions. The selectivity profile of COX-1/COX-2 inhibition by test drugs and the related effects on prostaglandin production do not appear to play a major role in the pathogenesis of enteropathy.

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Section: Discussionmentioning

confidence: 99%

NSAID-Induced Enteropathy: Are the Currently Available Selective COX-2 Inhibitors All the Same?

Fornai

Antonioli

Colucci

et al. 2013

J Pharmacol Exp Ther

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“…Intestinal hypermotility is also considered to play a role in the pathogenesis of NSAID-induced small intestinal damage (Takeuchi et al, , 2010aKunikata et al, 2002b;Satoh et al, 2012). The abnormal hypermotility caused by NSAIDs may disrupt the unstirred mucus layer over the epithelium, leading to the expedition of enterobacterial invasion.…”

Section: Discussionmentioning

confidence: 99%

“…This situation has been markedly intensified by recent findings in which drugs inhibiting acid secretion, such as proton pump inhibitors and histamine H 2 receptor antagonists, were ineffective against NSAID-induced small intestinal damage (Kato et al, 2000;Goldstein et al, 2005) and even worsened the severity of these lesions (Wallace et al, 2011;Satoh et al, 2012). However, they were shown to prevent the gastric ulcerogenic response to NSAIDs (Takeuchi et al, 1986;Satoh et al, 2012). Thus, the development of effective therapies to treat NSAID-induced small intestinal lesions remains an urgent priority.…”

Section: Introductionmentioning

confidence: 93%

Lubiprostone Prevents Nonsteroidal Anti-Inflammatory Drug–Induced Small Intestinal Damage by Suppressing the Expression of Inflammatory Mediators via EP4 Receptors

Hayashi

Kurata²,

Yamaguchi

et al. 2014

J Pharmacol Exp Ther

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Lubiprostone, a bicyclic fatty acid derived from prostaglandin E 1 , has been used to treat chronic constipation and irritable bowel syndrome, and its mechanism of action has been attributed to the stimulation of intestinal fluid secretion via the activation of the chloride channel protein 2/cystic fibrosis transmembrane regulator (ClC-2/CFTR) chloride channels. We examined the effects of lubiprostone on indomethacin-induced enteropathy and investigated the functional mechanisms involved, including its relationship with the EP4 receptor subtype. Male Sprague-Dawley rats were administered indomethacin (10 mg/kg p.o.) and killed 24 hours later to examine the hemorrhagic lesions that developed in the small intestine. Lubiprostone (0.01-1 mg/kg) was administered orally twice 30 minutes before and 9 h after the indomethacin treatment. Indomethacin markedly damaged the small intestine, accompanied by intestinal hypermotility, a decrease in mucus and fluid secretion, and an increase in enterobacterial invasion as well as the up-regulation of inducible nitric-oxide synthase (iNOS) and tumor necrosis factor a (TNFa) mRNAs. Lubiprostone significantly reduced the severity of these lesions, with the concomitant suppression of the functional changes. The effects of lubiprostone on the intestinal lesions and functional alterations were significantly abrogated by the coadministration of AE3-208 [4-(4-cyano-2-(2-(4-fluoronaphthalen-1-yl)propionylamino)phenyl)butyric acid], a selective EP4 antagonist, but not by CFTR(inh)-172, a CFTR inhibitor. These results suggest that lubiprostone may prevent indomethacin-induced enteropathy via an EP4 receptor-dependent mechanism. This effect may be functionally associated with the inhibition of intestinal hypermotility and increase in mucus/fluid secretion, resulting in the suppression of bacterial invasion and iNOS/ TNFa expression, which are major pathogenic events in enteropathy. The direct activation of CFTR/ClC-2 chloride channels is not likely to have contributed to the protective effects of lubiprostone.

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“…In 2011, we reported that in rodents, suppression of acid secretion with PPIs, although effective at preventing gastroduodenal damage, resulted in a dramatic worsening of distal intestinal damage [13]. This was confirmed by others, and was shown to occur also with histamine H 2 receptor antagonists [14][15][16]. Moreover, there is clinical evidence linking use of PPIs and H 2 receptor antagonists to severe intestinal damage observed in rheumatoid arthritis patients taking NSAIDs [8].…”

mentioning

confidence: 56%

NSAID enteropathy and bacteria: a complicated relationship

et al. 2015

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The clinical significance of small intestinal damage caused by nonsteroidal anti-inflammatory drugs (NSAIDs) remains under-appreciated. It occurs with greater frequency than the damage caused by these drugs in the upper gastrointestinal tract, but is much more difficult to diagnose and treat. Although the pathogenesis of NSAID enteropathy remains incompletely understood, it is clear that bacteria, bile, and the enterohepatic circulation of NSAIDs are all important factors. However, they are also interrelated with one another. Bacterial enzymes can affect the cytotoxicity of bile and are essential for enterohepatic circulation of NSAIDs. Gram-negative bacteria appear to be particularly important in the pathogenesis of NSAID enteropathy, possibly through release of endotoxin. Inhibitors of gastric acid secretion significantly aggravate NSAID enteropathy, and this effect is due to significant changes in the intestinal microbiome. Treatment with antibiotics can, in some circumstances, reduce the severity of NSAID enteropathy, but published results are inconsistent. Specific antibiotic-induced changes in the microbiota have not been causally linked to prevention of intestinal damage. Treatment with probiotics, particularly Bifidobacterium, Lactobacillus, and Faecalibacteriaum prausnitzii, has shown promising effects in animal models. Our studies suggest that these beneficial effects are due to colonization by the bacteria, rather than to products released by the bacteria.

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Exacerbation of Nonsteroidal Anti-Inflammatory Drug-Induced Small Intestinal Lesions by Antisecretory Drugs in Rats: The Role of Intestinal Motility

Cited by 54 publications

References 29 publications

NSAID-Induced Enteropathy: Are the Currently Available Selective COX-2 Inhibitors All the Same?

NSAID-Induced Enteropathy: Are the Currently Available Selective COX-2 Inhibitors All the Same?

Lubiprostone Prevents Nonsteroidal Anti-Inflammatory Drug–Induced Small Intestinal Damage by Suppressing the Expression of Inflammatory Mediators via EP4 Receptors

NSAID enteropathy and bacteria: a complicated relationship

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