Mucosal Protective Agents Prevent Exacerbation of NSAID-Induced Small Intestinal Lesions Caused by Antisecretory Drugs in Rats

Satoh, Hiroshi; Amagase, Kikuko; Takeuchi, Koji

doi:10.1124/jpet.113.208991

Cited by 42 publications

(26 citation statements)

References 41 publications

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“…Pronase alone did not exhibit an inhibitory effect on H. pylori in vitro, even at concentrations of 3.3 ϫ 10 3 mg/liter, in previous studies (data not shown), which was consistent with previous reports demonstrating that pronase did not inhibit the growth of H. pylori (11). Misoprostol is a mucosal protective agent (26). The eradication rate of the PMG was 0% (0/15), and there was a significant difference between the eradication rates of the PMG and the HPG (P ϭ 0.022).…”

Section: Discussionsupporting

confidence: 92%

Efficacy and Pharmacological Mechanism of Pronase-Enhanced Low-Dose Antibiotics for Helicobacter pylori Eradication

Liu

et al. 2014

Antimicrob Agents Chemother

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bThis study examined the efficacy and pharmacological mechanism of pronase-assisted low-dose antibiotics for eradication of Helicobacter pylori. Mongolian gerbils infected with H. pylori received 7-day treatment (omeprazole, different concentrations of pronase, amoxicillin, and clarithromycin), and the efficacy was assessed using the eradication rate and the colonization of H. pylori. In Mongolian gerbils orally administered pronase, the thickness of the gastric mucous layer (GML) was examined using immunohistochemical and alcian blue staining, and the concentrations of amoxicillin in gastric tissue and serum were detected using high-performance liquid chromatography (HPLC). The eradication rates were 80.0% (12/15) in the high-pronase quadruple group (HPQG) and 86.7% (13/15) in the high-antibiotic group (HAG) (P ‫؍‬ 1.000). The antibiotic dose in the HPQG was only 1/20 that in the HAG. Thirty minutes after oral treatment with pronase, the sticky protein of the GML was hydrolyzed, and the GML became thinner. Higher amoxicillin concentrations in both the gastric tissue and serum were observed in the pronase group than in the Am10 group. The concentration of amoxicillin in the Am10-plus-Pr108 group in gastric tissue was 3.8 times higher than in the Am10 group in 5 min. Together, these data suggest that pronase significantly reduced the dose of antibiotics used in H. pylori eradication. The pharmacological mechanism is likely pronase removal of the mucus layer, promoting chemical factor (i.e., gastric acid and pepsinogen) distribution and increasing the antibiotic concentrations in the deep GML, which acted on H. pylori collectively. Thus, pronase may enhance the level of antibiotics for eradication of H. pylori in the clinic.

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Section: Discussionsupporting

confidence: 92%

Efficacy and Pharmacological Mechanism of Pronase-Enhanced Low-Dose Antibiotics for Helicobacter pylori Eradication

Liu

et al. 2014

Antimicrob Agents Chemother

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“…Previous studies reported the beneficial effects of prostanoids, especially the E type of PG, against NSAID-induced small intestinal damage in experimental animals Hatazawa et al, 2006;Takeuchi et al, 2010b;Satoh et al, 2014). Furthermore, because intestinal fluid secretion is thought to hamper enterobacterial invasion, the major pathogenic event in NSAID-induced enteropathy (Takeuchi et al, 2010a), the activation of ClC-2 chloride channels may alleviate the occurrence of intestinal damage by stimulating fluid secretion.…”

Section: Discussionmentioning

confidence: 99%

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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“…Since the protective effect of lansoprazole was attenuated by the prior administration of tin-protoporphyrin IX (SnPP), an inhibitor of hemoxygenase (HO)-1, this action was assumed to be caused by the induction of HO-1 and carbon monoxide. Recent studies reported that antisecretory drugs such as PPIs and H 2 -RAs exacerbated the intestinal ulcerogenic response to NSAIDs such as indomethacin and naproxen, and this was attributed, at least partly, to dysbiosis of microbiota or intestinal hypermotility [41,42,43]. These findings suggest the possible risk of the co-administration of NSAIDs and antisecretory drugs; however, this treatment is known to be effective for preventing NSAID-induced gastric and duodenal damage.…”

Section: Effects Of Various Drugs On Nsaid-induced Small Intestinal Dmentioning

confidence: 99%

NSAID-Induced Small Intestinal Damage - Roles of Various Pathogenic Factors

Takeuchi

Satoh²

2015

Digestion

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Background/Aims: NSAID-induced enteropathy has been the focus of recent basic and clinical research subsequent to the development of the capsule endoscope and double-balloon endoscope. We review the possible pathogenic mechanisms underlying NSAID-induced enteropathy and discuss the role of the inhibition of COX-1/COX-2 and the influences of food as well as various prophylactic treatments on these lesions. Methods: Studies were performed in experimental animals. Results: Multiple factors, such as intestinal hypermotility, decreased mucus secretion, enterobacteria, and upregulation of iNOS/NO expression, are involved in the pathogenesis of NSAID-induced enteropathy, in addition to the decreased production of PGs due to the inhibition of COX. Enterobacterial invasion is the most important pathogenic event, and intestinal hypermotility, which was associated with this event, is essential for the development of these lesions. NSAIDs also upregulate the expression of COX-2, and the inhibition of both COX-1 and COX-2 is required for the intestinal ulcerogenic properties of NSAIDs to manifest. NSAID-induced enteropathy is prevented by PGE₂, atropine, ampicillin, and aminoguanidine as well as soluble dietary fiber, and exacerbated by antisecretory drugs such as proton pump inhibitors. Conclusion: These findings on the pathogenesis of NSAID-induced enteropathy will be useful for the future development of intestinal-sparing alternatives to standard NSAIDs.

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Mucosal Protective Agents Prevent Exacerbation of NSAID-Induced Small Intestinal Lesions Caused by Antisecretory Drugs in Rats

Cited by 42 publications

References 41 publications

Efficacy and Pharmacological Mechanism of Pronase-Enhanced Low-Dose Antibiotics for Helicobacter pylori Eradication

Efficacy and Pharmacological Mechanism of Pronase-Enhanced Low-Dose Antibiotics for Helicobacter pylori Eradication

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

NSAID-Induced Small Intestinal Damage - Roles of Various Pathogenic Factors

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