Multiple Indomethacin-Induced Jejunal Ulcerations with Perforation: A Case Report with Histology

Risty, Gina M.; Najarian, Melissa M.; Shapiro, Stephen B.

doi:10.1177/000313480707300406

Cited by 7 publications

(7 citation statements)

References 19 publications

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“…Despite the growing repository of newly synthesized NSAIDs, the development of new compounds is strictly required due to the side effects of the currently approved NSAIDs. For instance, even in short-term applications, a high dose of ibuprofen resulted in jejunal perforations [ 23 ]; naproxen affects bowel and jejunal integrity [ 24 ]. Within days of intake, diclofenac has been proven to raise the risk of heart attacks and strokes by 50% [ 25 ].…”

Section: Discussionmentioning

confidence: 99%

Drug Discovery of New Anti-Inflammatory Compounds by Targeting Cyclooxygenases

2022

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The goal of achieving anti-inflammatory efficacy with the fewest possible adverse effects through selective COX-2 inhibition is still being investigated in order to develop drugs with safe profiles. This work shows the efficacy and safety profile of two novel benzimidazole piperidine and phenoxy pyridine derivatives in reaching this goal, which would be considered a major achievement in inflammatory therapy. The compounds were evaluated by virtual screening campaign, in vitro cyclooxygenase 1 and 2 (COX-1 and COX-2) inhibition, in vivo carrageenan-induced rat paw edema assay, cytotoxicity against Raw264.7 cells, and histopathological examination of rat paw and stomach. Two new compounds, compound 1 ([(2-{[3-(4-methyl-1H-benzimidazol-2-yl)piperidin-1-yl]carbonyl}phenyl)amino]acetic acid) and compound 2 (ethyl 1-(5-cyano-2-hydroxyphenyl)-4-oxo-5-phenoxy-1,4-dihydropyridine-3-carboxylate) showed high selectivity against COX-2, favourable drug-likeness and ADME descriptors, a lack of cytotoxicity, relived paw edema, and inflammation without noticeable side effects on the stomach. These two compounds are promising new NSAIDs.

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Section: Discussionmentioning

confidence: 99%

Drug Discovery of New Anti-Inflammatory Compounds by Targeting Cyclooxygenases

2022

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“… 18 Another anti-inflammatory drug, naproxen, causes gastric antral ulcerations, and an increase of lipid peroxide levels, but the effect was reversed with curcumin. 19 Similarly perforated jejunal ulcers 20 and small bowel ulcerations 21 have been reported with the usage of NSAIDs. The simultaneous use of proton pump inhibitors and non-selective short-course NSAIDs increases the risk of bowel injury.…”

Section: Current Targets and Their Limitationsmentioning

confidence: 96%

Overview on the Discovery and Development of Anti-Inflammatory Drugs: Should the Focus Be on Synthesis or Degradation of PGE2?

Mahesh¹,

Kumar²,

Reddanna³

2021

JIR

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Inflammation is a protective response that develops against tissue injury and infection. Chronic inflammation, on the other hand, is the key player in the pathogenesis of many inflammatory disorders including cancer. The cytokine storm, an inflammatory response flaring out of control, is mostly responsible for the mortality in COVID-19 patients. Anti-inflammatory drugs inhibit cyclooxygenases (COX), which are involved in the biosynthesis of prostaglandins that promote inflammation. The conventional non-steroidal anti-inflammatory drugs (NSAIDs) are associated with gastric and renal side-effects, as they inhibit both the constitutive COX-1 and the inducible COX-2. The majority of selective COX-2 inhibitors (COXIBs) are without gastric side-effects but are associated with cardiac side-effects on long-term use. The search for anti-inflammatory drugs without side-effects, therefore, has become a dream and ongoing effort of the Pharma companies. As PGE 2 is the key mediator of inflammatory disorders, coming up with a strategy to reduce the levels of PGE 2 alone without affecting other metabolites may form a better choice for the development of next generation anti-inflammatory drugs. In this direction the options being explored are on synthesis of PGE 2 -mPGES-1; PGE 2 degradation through a specific PG dehydrogenase, 15-PGDH, and by blocking its activity mediated through a specific PGE receptor, EP4. As leukotrienes formed via the 5-lipoxygenase (5-LOX) pathway also play an important role in the mediation of inflammation, efforts are also being made to target both COX and LOX pathways. This review focuses on addressing the following three points: 1) How NSAIDs and COXIBs are associated with gastric, renal and cardiac side-effects; 2) Should the focus be on the targets upstream or downstream of PGE 2 ; and 3) the status of alternative targets being explored for the discovery and development of anti-inflammatory drugs without side-effects.

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“…For example, even with short-term use, a high ibuprofen dosage causes jejunal perforations, 13 and naproxen affects bowel and jejunal integrity. 14 In addition, diclofenac has been shown to increase the risk of heart attacks and strokes by 50% within days after administration. 15 Thus, improving the selectivity of the currently used NSAIDs will lead to the rapid delivery of effective and safer compounds.…”

Section: Introductionmentioning

confidence: 99%

Functional Role of Novel Anthranilic Acid Derivatives as Anti-inflammatory Agents

Morsy¹,

Patel²,

Parmar³

et al. 2022

Ind. J. Pharm. Edu. Res

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Background:The discovery of new cyclooxygenase (COX) inhibitors with high efficacy and safety would greatly aid in developing anti-inflammatory drugs. This study evaluated the anti-inflammatory activity and the expected side effect of two synthesized anthranilic acid derivatives (JS-3 and JS-4). Materials and Methods: The COX selectivity of compounds was assessed in a whole blood assay. The results were confirmed by molecular docking studies. In vivo anti-inflammatory activity was tested in complete Freund's adjuvant (CFA)-induced rheumatoid arthritis (RA) in rats. The safety profile was determined by administering a dose three times the therapeutic dose. Results: In vitro COX-2 selectivity of JS-4 was higher than JS-3 (13.70 vs. 5.56). Docking studies supported the higher selectivity of both derivatives against COX-2 than mefenamic acid. Treatment of CFA-arthritic rats with both compounds showed significant (P < 0.01) decreases in paw volume, paw thickness, arthritic index, and inflammatory parameters such as rheumatoid factor, interleukin (IL)-1β, IL-6, prostaglandin (PG) E 2 , PGI 2 , and TXB 2 compared to untreated RA animals. JS-3 and JS-4 improved knee joint histopathology and protected against RA-induced pathological changes: splenomegaly, thymomegaly, and cardiomyopathy. Both derivatives produced minimal effects on liver and renal functions, without any ulcerogenic effects. Conclusion: These results suggest that JS-4 is a potential and safe candidate for managing RA without renal, liver, gastrointestinal, or cardiovascular toxicity.

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Multiple Indomethacin-Induced Jejunal Ulcerations with Perforation: A Case Report with Histology

Cited by 7 publications

References 19 publications

Drug Discovery of New Anti-Inflammatory Compounds by Targeting Cyclooxygenases

Drug Discovery of New Anti-Inflammatory Compounds by Targeting Cyclooxygenases

Overview on the Discovery and Development of Anti-Inflammatory Drugs: Should the Focus Be on Synthesis or Degradation of PGE2?

Functional Role of Novel Anthranilic Acid Derivatives as Anti-inflammatory Agents

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