The influence of <i><scp>CYP</scp>2C19</i> polymorphisms on exacerbating effect of rabeprazole in celecoxib‐induced small bowel injury

Nuki, Yoichiro; Umeno, Junji; Washio, Ema; Maehata, Yuji; Hirano, Atsushi; Miyazaki, Masaru; Kobayashi, Hiroyuki; Kitazono, Takanari; Matsumoto, Takayuki; Esaki, Motohiro

doi:10.1111/apt.14134

Cited by 10 publications

(9 citation statements)

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“…Interestingly, the poor metabolizer genotype of CYP2C19 was a risk factor to the development of intestinal injury in a subject that was administered celecoxib plus rabeprazole. However, this was not observed in patients who were administered celecoxib alone [51]. Since this genotype causes poor metabolism of PPIs, strong inhibition of gastric acid secretion by PPIs in subjects carrying this genotype may lead to greater alteration of small intestinal flora, resulting in high sensitivity to the damage.…”

Section: Risk Factors For Nsaids-induced Enteropathymentioning

confidence: 98%

Current knowledge on non-steroidal anti-inflammatory drug-induced small-bowel damage: a comprehensive review

2019

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Recent advances in small-bowel endoscopy such as capsule endoscopy have shown that non-steroidal antiinflammatory drugs (NSAIDs) frequently damage the small intestine, with the prevalence rate of mucosal breaks of around 50% in chronic users. A significant proportion of patients with NSAIDs-induced enteropathy are asymptomatic, but some patients develop symptomatic or complicated ulcers that need therapeutic intervention. Both inhibition of prostaglandins due to the inhibition of cyclooxygenases and mitochondrial dysfunction secondary to the topical effect of NSAIDs play a crucial role in the early process of injury. As a result, the intestinal barrier function is impaired, which allows enterobacteria to invade the mucosa. Gram-negative bacteria and endogenous molecules coordinate to trigger inflammatory cascades via Toll-like receptor 4 to induce excessive expression of cytokines such as tumor necrosis factor-a and to activate NLRP3 inflammasome, a multiprotein complex that processes pro-interleukin-1b into its mature form. Finally, neutrophils accumulate in the mucosa, resulting in intestinal ulceration. Currently, misoprostol is the only drug that has a proven beneficial effect on bleeding small intestinal ulcers induced by NSAIDs or low-dose aspirin, but its protection is insufficient. Therefore, the efficacy of the combination of misoprostol with other drugs, especially those targeting the innate immune system, should be assessed in the next step. Keywords Non-steroidal anti-inflammatory drug Á Lowdose aspirin Á Enteropathy Á Innate immunity Á Misoprostol Abbreviations NSAID Non-steroidal anti-inflammatory drug RA Rheumatoid arthritis

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Section: Risk Factors For Nsaids-induced Enteropathymentioning

confidence: 98%

Current knowledge on non-steroidal anti-inflammatory drug-induced small-bowel damage: a comprehensive review

2019

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“…proximal duodenum, they offer no benefit in the remainder of the GI tract, where significant NSAID-induced ulceration and bleeding can occur (25a). Indeed, suppressors of acid secretion can significantly exacerbate ulceration and bleeding in the intestine (17,30,35,36).…”

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confidence: 99%

Enhanced Analgesic Effects and Gastrointestinal Safety of a Novel, Hydrogen Sulfide-Releasing Anti-Inflammatory Drug (ATB-352): A Role for Endogenous Cannabinoids

Costa

Muscará

Allain

et al. 2020

Antioxidants & Redox Signaling

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Aims:The covalent linking of nonsteroidal anti-inflammatory drugs to a hydrogen sulfide (H 2 S)-releasing moiety has been shown to dramatically reduce gastrointestinal (GI) damage and bleeding, as well as increase anti-inflammatory and analgesic potency. We have tested the hypothesis that an H 2 S-releasing derivative of ketoprofen (ATB-352) would exhibit enhanced efficacy without significant GI damage in a mouse model of allodynia/hyperalgesia. Results: ATB-352 was significantly more potent and effective as an analgesic than ketoprofen and did not elicit GI damage. Pretreatment with an antagonist of the CB1 cannabinoid receptor (AM251) significantly reduced the analgesic effects of ATB-352. The CB1 antagonist exacerbated GI damage when coadministered with ketoprofen, but GI damage was not induced by the combination of ATB-352 and the CB1 antagonist. In vitro, ATB-352 was substantially more potent than ketoprofen as an inhibitor of fatty acid amide hydrolase, consistent with a contribution of endogenous cannabinoids to the analgesic effects of this drug. Blood anandamide levels were significantly depressed by ketoprofen, but remained unchanged after treatment with ATB-352. Innovation: Ketoprofen is a potent analgesic, but its clinical use, even in the short term, is significantly limited by its propensity to cause significant ulceration and bleeding in the GI tract. Covalently linking an H 2 S-releasing moiety to ketoprofen profoundly reduces the GI toxicity of the drug, while boosting analgesic effectiveness. Conclusion: This study demonstrates a marked enhancement of the potency and effectiveness of ATB-352, an H 2 S-releasing derivative of ketoprofen, in part, through the involvement of the endogenous cannabinoid system. This may have significant advantages for the control and management of pain, such as in a postoperative setting.

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“…Наличие данной аллели ассоциируется с меньшей эффективностью ИПП и более высокой частотой развития НПВП-гастропатии [20,21]. И, напротив, есть данные, что носительство аллелей CYP2C19, определяющих замедленный метаболизм ИПП, повышает риск возникновения НПВП-энтеропатии [22]. Значение выявленного нами генетического феномена в развитии НПВП-колопатии требует дальнейшего углубленного изучения.…”

Section: ф а к т о р ы в л и я ю щ и е н а р а з в и т и е с о ч е unclassified

The frequency and clinical and endoscopic features of mixed NSAIDs-induced gastrointestinal injuries

Балабанцева

Каратеев²

2018

Sovremennaâ revmatologiâ

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Non-steroidal anti-inflammatory drugs (NSAIDs) can cause undesirable reactions in all parts of the gastrointestinal tract (GIT). However, the frequency of mixed injuries of various GIT parts due to the use of these drugs has not been investigated.Objective: to estimate the frequency of mixed NSAID-induced injuries of the upper GIT, small and large intestine.Patients and methods. A total of 112 patients (62.5% were women) (mean age, 56.2±14.6 years) with rheumatic diseases who had regularly taken NSAIDs were examined. All the patients underwent esophagogastroduodenoscopy and video colonoscopy. Video capsule endoscopy was performed in 35 patients with signs of NSAID-induced gastropathy.Results and discussion. The signs of NSAID-induced gastropathy (gastric and duodenal erosions and/or ulcers) were found in 43.8% of patients; those of NSAID-induced enteropathy (small bowel hemorrhages, erosions, and ulcers) were present in 68.6%; and those of NSAIDinduced colopathy (colonic hemorrhages, erosions, and ulcers) were in 14.3%. The concurrence of NSAID-induced gastro- and colonopathy was present in 28.6% of the patients (odds ratio 12.2; 95% confidence interval, 2.619–56.84); that of NSAID-induced gastro-, entero-, and colopathy was in 10 (20.4% of all the patients with NSAID-induced gastropathy). There was a significant association of the risk of mixed pathology in all GIT parts with the diagnosis of spondylarthritis, the presence of abdominal pain, the signs of dysbiosis and bacterial overgrowth syndrome, as well as with the carriage of CYP2C19 gene polymorphism (the CYP2C19*17*1/*17 allele).Conclusion. Mixed injury of various GIT parts due to the use of NSAIDs is a frequent and serious pathology that requires comprehensive diagnostic tests and combined use of preventive therapies with different mechanisms of action.

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The influence of CYP2C19 polymorphisms on exacerbating effect of rabeprazole in celecoxib‐induced small bowel injury

Abstract: The CYP2C19 genotype might be associated with the risk of small bowel injury when celecoxib is combined with rabeprazole.

Cited by 10 publications

References 29 publications

Current knowledge on non-steroidal anti-inflammatory drug-induced small-bowel damage: a comprehensive review

Current knowledge on non-steroidal anti-inflammatory drug-induced small-bowel damage: a comprehensive review

Enhanced Analgesic Effects and Gastrointestinal Safety of a Novel, Hydrogen Sulfide-Releasing Anti-Inflammatory Drug (ATB-352): A Role for Endogenous Cannabinoids

The frequency and clinical and endoscopic features of mixed NSAIDs-induced gastrointestinal injuries

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