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Alnaqbi KA, Riaz A, Alaswad M. Paradoxical Inflammatory Bowel Disease Induced by Golimumab in a Patient With Ankylosing Spondylitis: A Case Report and Systematic Review. Cureus 2025; 17:e77363. [PMID: 39807347 PMCID: PMC11726622 DOI: 10.7759/cureus.77363] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/12/2025] [Indexed: 01/16/2025] Open
Abstract
Paradoxical reactions (PRs) to biologic medications, such as psoriasis, arthritis, and inflammatory bowel disease (IBD), have been increasingly recognized. The aim of reporting this case is to establish an association between golimumab and exacerbation or new (de novo) IBD in patients with axial spondyloarthritis (SpA). Our case involves a young patient with juvenile-onset ankylosing spondylitis (AS) who developed de novo IBD following golimumab therapy for active spinal disease. The patient had no prior gastrointestinal (GI) symptoms, and AS symptoms significantly improved with golimumab. However, before the third dose, he experienced non-bloody diarrhea, mild abdominal cramping, and constitutional symptoms (fever, chills, and weight loss). Colonoscopy and biopsy confirmed unclassified IBD. The discontinuation of golimumab resulted in marked improvement in GI symptoms, but the recurrence of AS symptoms necessitated the initiation of infliximab, which resolved both AS and IBD symptoms. A comprehensive systematic literature review was conducted (from 2008 to October 2024) on Medical Literature Analysis and Retrieval System Online (MEDLINE) Complete/PubMed and Scopus databases using both Medical Subject Heading (MeSH) terms and keywords related to golimumab, SpA, and paradoxical IBD. Data from included cases were extracted by two researchers, and the quality assessment of case reports was performed using a standardized tool. Four cases of paradoxical IBD development following golimumab treatment in patients with pre-existing IBD were identified. This is the first reported case of de novo IBD development in a biologic-naïve patient with AS treated with golimumab. This case highlights the importance of prompt evaluation of gastrointestinal symptoms and early gastroenterology referral during biologic therapy.
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Affiliation(s)
- Khalid A Alnaqbi
- Department of Research, Emirates Medical Association, Dubai, ARE
- Department of Internal Medicine, College of Medicine and Health Sciences, United Arab Emirates (UAE) University, Al Ain, ARE
- Division of Rheumatology, Sheikh Tahnoon Medical City, Al Ain, ARE
- Division of Rheumatology, Tawam Hospital, Al Ain, ARE
| | - Amna Riaz
- Department of Internal Medicine, Sheikh Tahnoon Medical City, Al Ain, ARE
- Department of Internal Medicine, Tawam Hospital, Al Ain, ARE
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Motavallian A, Bouzari S, Zamani E, Karimian P, Dabirian S, Molavi M, Torshkooh FA. An investigation of the anti-inflammatory effects of gabapentin on acetic acid-induced colitis in rats. Mol Biol Rep 2021; 48:3423-3430. [PMID: 33928442 DOI: 10.1007/s11033-021-06357-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Accepted: 04/16/2021] [Indexed: 12/31/2022]
Abstract
Inflammatory bowel disease (IBD) is considered a chronic inflammatory gastrointestinal disease with treatment options which exhibit low efficacies and lead to considerable side effects. Hence, the challenge to alleviate IBD complications is remained to be resolved. The purpose of this study is evaluating anti-inflammatory impacts of gabapentin on acetic acid-induced colitis in rats. Colitis was induced by the instillation of 2 mL of 3% acetic acid solution into rat's colons. Rats were randomly allocated into six groups including normal group, colitis control group, gabapentin-treated groups (25, 50, and 100 mg/kg; i.p.), and dexamethasone-treated group (1 mg/kg; i.p.). Based on the macroscopic assessment besides histological and biochemical findings [myeloperoxidase (MPO), pro-inflammatory cytokines], the efficacy of gabapentin was investigated. Gabapentin (50 and 100 mg/kg), and dexamethasone considerably reduced macroscopic and microscopic colonic lesions induced by acetic acid in rats in comparison with colitis control group. These results were confirmed by reduced levels of MPO activity and colonic concentrations of interleukin-6, interleukin-1 beta, and tumor necrosis factor-alpha, in inflamed colon tissue. Our data demonstrated that gabapentin exerts profitable impacts in experimental colitis that might be ascribed to its anti-inflammatory features and thus can be a potential therapeutic agent for IBD treatment.
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Affiliation(s)
- Azadeh Motavallian
- Department of Pharmacology and Toxicology, School of Pharmacy, Guilan University of Medical Sciences, Rasht, Iran. .,Rhino-Sinus, Ear, and Skull Base Diseases Research Center, Department of Otolaryngology and Head and Neck Surgery, Amiralmomenin Hospital, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran.
| | - Saba Bouzari
- Student Research Committee, School of Pharmacy, Guilan University of Medical Sciences, Rasht, Iran
| | - Ehsan Zamani
- Department of Pharmacology and Toxicology, School of Pharmacy, Guilan University of Medical Sciences, Rasht, Iran
| | - Paridokht Karimian
- Department of Pathology and Histology, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran
| | - Sara Dabirian
- Department of Pharmaceutical Biotechnology, School of Pharmacy, Guilan University of Medical Sciences, Rasht, Iran
| | - Mehdi Molavi
- Department of Internal Medicine, School of Medicine, Sabzevar University of Medical Sciences, Sabzevar, Iran
| | - Forough Aghajani Torshkooh
- Department of Pharmacology and Toxicology, School of Pharmacy, Guilan University of Medical Sciences, Rasht, Iran
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Kamalian A, Sohrabi Asl M, Dolatshahi M, Afshari K, Shamshiri S, Momeni Roudsari N, Momtaz S, Rahimi R, Abdollahi M, Abdolghaffari AH. Interventions of natural and synthetic agents in inflammatory bowel disease, modulation of nitric oxide pathways. World J Gastroenterol 2020; 26:3365-3400. [PMID: 32655263 PMCID: PMC7327787 DOI: 10.3748/wjg.v26.i24.3365] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Revised: 05/09/2020] [Accepted: 06/03/2020] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel disease (IBD) refers to a group of disorders characterized by chronic inflammation of the gastrointestinal (GI) tract. The elevated levels of nitric oxide (NO) in serum and affected tissues; mainly synthesized by the inducible nitric oxide synthase (iNOS) enzyme; can exacerbate GI inflammation and is one of the major biomarkers of GI inflammation. Various natural and synthetic agents are able to ameliorate GI inflammation and decrease iNOS expression to the extent comparable with some IBD drugs. Thereby, the purpose of this study was to gather a list of natural or synthetic mediators capable of modulating IBD through the NO pathway. Electronic databases including Google Scholar and PubMed were searched from 1980 to May 2018. We found that polyphenols and particularly flavonoids are able to markedly attenuate NO production and iNOS expression through the nuclear factor κB (NF-κB) and JAK/STAT signaling pathways. Prebiotics and probiotics can also alter the GI microbiota and reduce NO expression in IBD models through a broad array of mechanisms. A number of synthetic molecules have been found to suppress NO expression either dependent on the NF-κB signaling pathway (i.e., dexamethasone, pioglitazone, tropisetron) or independent from this pathway (i.e., nicotine, prednisolone, celecoxib, β-adrenoceptor antagonists). Co-administration of natural and synthetic agents can affect the tissue level of NO and may improve IBD symptoms mainly by modulating the Toll like receptor-4 and NF-κB signaling pathways.
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Affiliation(s)
- Aida Kamalian
- Department of Medicine, Tehran University of Medical Sciences, Tehran 1417614411, Iran
| | - Masoud Sohrabi Asl
- Department of Medicine, Tehran University of Medical Sciences, Tehran 1417614411, Iran
| | - Mahsa Dolatshahi
- Department of Medicine, Tehran University of Medical Sciences, Tehran 1417614411, Iran
- Students' Scientific Research Center, Tehran University of Medical Sciences, Tehran 1417614411, Iran
| | - Khashayar Afshari
- Department of Medicine, Tehran University of Medical Sciences, Tehran 1417614411, Iran
| | - Shiva Shamshiri
- Department of Traditional Pharmacy, School of Persian Medicine, Tehran University of Medical Sciences, Tehran 1417614411, Iran
| | - Nazanin Momeni Roudsari
- Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran Medical Sciences, Islamic Azad University, Tehran 1941933111, Iran
| | - Saeideh Momtaz
- Medicinal Plants Research Center, Institute of Medicinal Plants, ACECR, Tehran 1417614411, Iran
- Toxicology and Diseases Group (TDG), Pharmaceutical Sciences Research Center (PSRC), The Institute of Pharmaceutical Sciences (TIPS), and Department of Toxicology and Pharmacology, School of Pharmacy, Tehran University of Medical Sciences, Tehran 1417614411, Iran
- Gastrointestinal Pharmacology Interest Group, Universal Scientific Education and Research Network, Tehran 1417614411, Iran
| | - Roja Rahimi
- Department of Traditional Pharmacy, School of Persian Medicine, Tehran University of Medical Sciences, Tehran 1417614411, Iran
| | - Mohammad Abdollahi
- Toxicology and Diseases Group (TDG), Pharmaceutical Sciences Research Center (PSRC), The Institute of Pharmaceutical Sciences (TIPS), and Department of Toxicology and Pharmacology, School of Pharmacy, Tehran University of Medical Sciences, Tehran 1417614411, Iran
| | - Amir Hossein Abdolghaffari
- Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran Medical Sciences, Islamic Azad University, Tehran 1941933111, Iran
- Medicinal Plants Research Center, Institute of Medicinal Plants, ACECR, Tehran 1417614411, Iran
- Toxicology and Diseases Group (TDG), Pharmaceutical Sciences Research Center (PSRC), The Institute of Pharmaceutical Sciences (TIPS), and Department of Toxicology and Pharmacology, School of Pharmacy, Tehran University of Medical Sciences, Tehran 1417614411, Iran
- Gastrointestinal Pharmacology Interest Group, Universal Scientific Education and Research Network, Tehran 1417614411, Iran
- Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran 1417614411, Iran
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The Proteolytic Fraction From Vasconcellea cundinamarcensis Latex Displays Anti-Inflammatory Effect in A Mouse Model of Acute TNBS-Induced Colitis. Sci Rep 2020; 10:3074. [PMID: 32080277 PMCID: PMC7033115 DOI: 10.1038/s41598-020-59895-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2019] [Accepted: 02/03/2020] [Indexed: 11/08/2022] Open
Abstract
The proteolytic fraction (P1G10) from Vasconcellea cundinamarcensis, displays gastric protective and healing activities in different skin lesions in mice and human. In an excisional model, this fraction accelerates resolution of lesions and modulates inflammatory mediators. Based on these data, we assessed its anti-inflammatory activity in murine colitis model, induced by 2,4,6-trinitrobenzenesulfonic acid (TNBS) adopted by its physiopathological similarity with human colitis. Twenty four hours after colitis induction followed by three days of treatment, P1G10 at 0.3 and 3.0 mg/Kg induced 30% increase in body weight (p < 0.0001) and ~80% reduction in colon macroscopic damage score (p < 0.05) compared to the untreated TNBS-induced colitis group. Histological analyses showed that 0.3 mg/Kg P1G10 reduced the inflammatory profile and tissue damage (47%, p < 0.05) when it was proteolytically active. Compared to TNBS group, 0.3 mg/Kg P1G10 reduced MPO activity (80%, p < 0.01), MCP-1 (47%, p < 0.05) and TNF-α (50%, no significant) and increased IL-10 (330%, p < 0.001) levels in the supernatant of colonic tissue homogenate. P1G10 treatment also reduced COX-2 expression (60%, p < 0.05) and metalloprotease-2 activity (39%, p < 0.05) while increased globet cell density (140%, p < 0.01), that contributes to mucus layer protection in colonic tissue. Taken together, these findings suggest that low doses of active P1G10 promotes lesion resolution, at least in part by its anti-inflammatory activity, in TNBS-colitis model.
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Alabi QK, Akomolafe RO, Omole JG, Adefisayo MA, Ogundipe OL, Aturamu A, Sanya JO. Polyphenol-rich extract of Ocimum gratissimum leaves ameliorates colitis via attenuating colonic mucosa injury and regulating pro-inflammatory cytokines production and oxidative stress. Biomed Pharmacother 2018; 103:812-822. [PMID: 29684860 DOI: 10.1016/j.biopha.2018.04.071] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2018] [Revised: 04/09/2018] [Accepted: 04/09/2018] [Indexed: 12/13/2022] Open
Abstract
Colitis is a chronic inflammation and ulcer on the inner lining of the large intestine. For many centuries Ocimum gratissimum (OG) leaves have been used in folk medicine in Nigeria to treat inflammatory bowel diseases, however, to date, the anti-colitis effects of OG have not been scientifically proven. In this study we investigated the effects of polyphenol rich extract of Ocimum gratissimum (PREOG) leaf on colonic mucosa injury in colitis, its mechanisms, initial administration time and dosage. Dextran sodium sulfate (DSS)-induced rat colitis models was used. PREOG administration was initiated at 3 and 7 d after the model was established at doses of 200, 400 and 800 mg/kg for 7 d. 5-aminosalicylic acid (5-ASA) was used as a reference drug. The disease activity index (DAI), vascular permeability, markers of oxidative stress, granulocyte infiltration, inflammation and histopathological alteration were evaluated. Obvious colonic inflammation and mucosa injuries were observed in DSS-induced colitis groups. PREOG administration promoted repair of colonic mucosa injuries, attenuated inflammation, and decreased DAI scores in rats with colitis. PREOG also decreased the plasma concentrations of Interleukin-(IL)-6 and tumor necrosis factor (TNF)-α, and concentrations of myeloperoxidase, nitric oxide, cyclooxygenase-2 and malondialdehyde in the colon, and increased the plasma concentrations of IL-4 and IL-10 as well as the concentration of superoxide dismutase, catalase and reduced glutathione in the colon. The efficacy of PREOG was dosage dependent. In conclusion, OG repairs colonic mucosa injury in experimental colitis through its ant-inflammatory and ant-oxidant. Its efficacy related to initial administration time and dose.
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Affiliation(s)
- Quadri K Alabi
- Department of Physiological Sciences, Faculty of Basic Medical Sciences, Obafemi Awolowo University, Ile-Ife, Osun State, Nigeria; Department of Physiology, Faculty of Basic Medical Sciences, College of Medicine, Afe Babalola University, Ado Ekiti, Ekiti State, Nigeria.
| | - Rufus O Akomolafe
- Department of Physiological Sciences, Faculty of Basic Medical Sciences, Obafemi Awolowo University, Ile-Ife, Osun State, Nigeria
| | - Joseph G Omole
- Department of Physiological Sciences, Faculty of Basic Medical Sciences, Obafemi Awolowo University, Ile-Ife, Osun State, Nigeria
| | - Modinat A Adefisayo
- Department of Physiology, Faculty of Basic Medical Sciences, University of Medical Sciences,Ondo State, Nigeria
| | - Olaofe L Ogundipe
- Department of Public Health and Community Medicine, Afe Babalola University, Ado Ekiti, Ekiti State, Nigeria
| | - Ayodeji Aturamu
- Health Center College of Education, Ikere Ekiti, Ekiti State, Nigeria
| | - Joseph O Sanya
- Department of Physiology, Faculty of Basic Medical Sciences, College of Medicine, Afe Babalola University, Ado Ekiti, Ekiti State, Nigeria
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Effect of bevacizumab on acetic acid–induced ulcerative colitis in rats. J Surg Res 2017; 216:191-200. [DOI: 10.1016/j.jss.2017.05.011] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2017] [Revised: 04/05/2017] [Accepted: 05/02/2017] [Indexed: 02/01/2023]
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The effect of sodium valproate on acetic acid-induced colitis in rats. Inflammopharmacology 2016; 25:137-145. [DOI: 10.1007/s10787-016-0304-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2016] [Accepted: 12/10/2016] [Indexed: 01/22/2023]
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Parra RS, Lopes AH, Carreira EU, Feitosa MR, Cunha FQ, Garcia SB, Cunha TM, da Rocha JJR, Féres O. Hyperbaric oxygen therapy ameliorates TNBS-induced acute distal colitis in rats. Med Gas Res 2015; 5:6. [PMID: 25926972 PMCID: PMC4414439 DOI: 10.1186/s13618-015-0026-2] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2015] [Accepted: 04/06/2015] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND This study investigated the therapeutic effects of hyperbaric oxygen in experimental acute distal colitis focusing on its effect on the production of pro-inflammatory cytokines, nitric oxide and hypoxia-inducible factor 1alpha. METHODS Colitis was induced with a rectal infusion of 150 mg/kg of TNBS under anesthesia with Ketamine (50 mg/kg) and Xylazine (10 mg/kg). Control animals received only rectal saline. After colitis induction, animals were subjected to two sessions of hyperbaric oxygen and were then euthanized. The distal intestine was resected for macroscopic analysis, determination of myeloperoxidase activity, western-blotting analyses of inducible nitric oxide synthase and cyclooxygenase-2 expression and immunohistochemical analysis of hypoxia-inducible factor 1alpha and cyclooxygenase-2. Cytokines levels in the distal intestine were measured using an enzyme-linked immunosorbent assay. RESULTS Hyperbaric oxygen therapy attenuated the severity of acute distal colitis, with reduced macroscopic damage score. This effect was associated with prevention in the increase of pro-inflammatory cytokine production; myeloperoxidase activity, in the expression of inducible nitric oxide synthase and cyclooxygenase-2. Finally, hyperbaric oxygen inhibited the acute distal colitis-induced up-regulation of hypoxia-inducible factor 1alpha. CONCLUSIONS The results indicate that hyperbaric oxygen attenuates the severity of acute distal colitis through the down-regulation of pro-inflammatory events.
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Affiliation(s)
- Rogério S Parra
- />Division of Coloproctology, Department of Surgery and Anatomy. Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP Brazil
| | - Alexandre H Lopes
- />Department of Pharmacology, Ribeirão Preto Medical School, University of Sao Paulo, Ribeirão Preto, SP Brazil
| | - Eleonora U Carreira
- />Department of Pharmacology, Ribeirão Preto Medical School, University of Sao Paulo, Ribeirão Preto, SP Brazil
| | - Marley R Feitosa
- />Division of Coloproctology, Department of Surgery and Anatomy. Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP Brazil
| | - Fernando Q Cunha
- />Department of Pharmacology, Ribeirão Preto Medical School, University of Sao Paulo, Ribeirão Preto, SP Brazil
| | - Sérgio B Garcia
- />Department of Pathology, Ribeirão Preto Medical School, University of Sao Paulo, Ribeirão Preto, SP Brazil
| | - Thiago M Cunha
- />Department of Pharmacology, Ribeirão Preto Medical School, University of Sao Paulo, Ribeirão Preto, SP Brazil
| | - José J R da Rocha
- />Division of Coloproctology, Department of Surgery and Anatomy. Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP Brazil
| | - Omar Féres
- />Division of Coloproctology, Department of Surgery and Anatomy. Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP Brazil
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Andersen V, Nimmo E, Krarup HB, Drummond H, Christensen J, Ho GT, Ostergaard M, Ernst A, Lees C, Jacobsen BA, Satsangi J, Vogel U. Cyclooxygenase-2 (COX-2) polymorphisms and risk of inflammatory bowel disease in a Scottish and Danish case-control study. Inflamm Bowel Dis 2011; 17:937-46. [PMID: 20803508 DOI: 10.1002/ibd.21440] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2010] [Accepted: 06/29/2010] [Indexed: 12/19/2022]
Abstract
BACKGROUND Inflammatory bowel diseases (IBDs) are a result of interactions between luminal pathogens and the intestinal immune response. Cyclooxygenase-2 (COX-2) plays a key role in the regulation of the inflammatory response upon stimulation by luminal pathogens via Toll-like receptors. METHODS Genotypes of the COX-2/PTGS2/PGHS2 A-1195G (rs689466), G-765C (rs20417), and T8473C (rs5275) polymorphisms were assessed in a Scottish and Danish case-control study including 732 Crohn's disease (CD) cases, 973 ulcerative colitis (UC) cases, and 1157 healthy controls using logistic regression. RESULTS Carriers of the COX-2 A-1195G variant allele had increased risk of UC (odds ratio [OR], 95% confidence interval [CI] = 1.25 [1.02-1.54], P = 0.03) and of both UC and IBD among never smokers (OR [95% CI] = 1.47 [1.11-1.96], P = 0.01 and OR [95% CI] = 1.37 [1.06-1.77], P = 0.02, respectively). Furthermore, this variant genotype was associated with increased risk of diagnosis of UC before age 40 years and with extensive UC (OR [95% CI] = 1.34 [1.11-1.62], P = 0.002 and OR [95% CI] = 1.32 [1.03-1.69], P = 0.03, respectively). CONCLUSIONS COX-2 A-1195G polymorphism was associated with the risk of UC, especially among never-smokers, suggesting that low activity of COX-2 may predispose to UC. Our results suggest that inclusion of smoking status may be essential for the evaluation of the role of genetic predisposition to IBD.
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Affiliation(s)
- Vibeke Andersen
- Medical Department, Viborg Regional Hospital, Viborg, Denmark.
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Fornai M, Antonioli L, Colucci R, Bernardini N, Ghisu N, Tuccori M, De Giorgio R, Del Tacca M, Blandizzi C. Emerging role of cyclooxygenase isoforms in the control of gastrointestinal neuromuscular functions. Pharmacol Ther 2010; 125:62-78. [DOI: 10.1016/j.pharmthera.2009.09.007] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2009] [Accepted: 09/16/2009] [Indexed: 02/06/2023]
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Liu ESL, Ye YN, Shin VY, Wu WKK, Wong BCY, Cho CH. Interaction of cigarette smoking with cyclooxygenase-2 on ulcerative colitis-associated neoplasia in mice. Cancer Invest 2007; 25:750-7. [PMID: 18058473 DOI: 10.1080/07357900701563897] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
The interactions of cigarette smoking with COX-2 on colitis and colitis-associated adenoma formation were studied. Mice were induced with colitis and exposed to cigarette smoke (CS) and/or SC236 (a COX-2 inhibitor). Results indicated that CS did not alter acute colonic inflammation. Addition of SC236 abolished the induction of proliferation and oxidative damage by colitis. Chronic SC236 treatment abolished the promoting effect of CS on colonic adenoma formation, via suppression of COX-2- and VEGF-mediated proliferation and angiogenesis, and reversed bcl-2-mediated inhibition of apoptosis by CS. To conclude, COX-2 inhibitor could be an implication on cancer prevention in smokers with chronic colitis.
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Affiliation(s)
- Edgar Shiu-Lam Liu
- Department of Pharmacology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
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Kawada M, Arihiro A, Mizoguchi E. Insights from advances in research of chemically induced experimental models of human inflammatory bowel disease. World J Gastroenterol 2007; 13:5581-93. [PMID: 17948932 PMCID: PMC4172737 DOI: 10.3748/wjg.v13.i42.5581] [Citation(s) in RCA: 140] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel disease (IBD), the most important being Crohn's disease and ulcerative colitis, results from chronic dysregulation of the mucosal immune system in the gastrointestinal tract. Although the pathogenesis of IBD remains unclear, it is widely accepted that genetic, environmental, and immunological factors are involved. Recent studies suggest that intestinal epithelial defenses are important to prevent inflammation by protecting against microbial pathogens and oxidative stresses. To investigate the etiology of IBD, animal models of experimental colitis have been developed and are frequently used to evaluate new anti-inflammatory treatments for IBD. Several models of experimental colitis that demonstrate various pathophysiological aspects of the human disease have been described. In this manuscript, we review the characteristic features of IBD through a discussion of the various chemically induced experimental models of colitis (e.g., dextran sodium sulfate-, 2,4,6-trinitrobenzene sulfonic acid-, oxazolone-, acetic acid-, and indomethacin-induced models). We also summarize some regulatory and pathogenic factors demonstrated by these models that can, hopefully, be exploited to develop future therapeutic strategies against IBD.
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13
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Menozzi A, Pozzoli C, Giovannini E, Solenghi E, Grandi D, Bonardi S, Bertini S, Vasina V, Coruzzi G. Intestinal effects of nonselective and selective cyclooxygenase inhibitors in the rat. Eur J Pharmacol 2006; 552:143-50. [PMID: 17069793 DOI: 10.1016/j.ejphar.2006.08.089] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2006] [Revised: 08/29/2006] [Accepted: 08/31/2006] [Indexed: 01/15/2023]
Abstract
It is now widely recognized that nonsteroidal anti-inflammatory drugs (NSAIDs) may cause extensive damage to the intestine. The pathogenesis of NSAID-induced intestinal injury, however, is still controversial and both local irritant actions and cyclooxygenase (COX) inhibition have been proposed as underlying mechanisms. In this study we investigated further on NSAID-induced intestinal damage by using nonselective (indomethacin and ibuprofen), COX-1 selective (SC-560) or COX-2 selective (celecoxib) inhibitors. NSAIDs were administered orally to conscious rats and small intestinal injury was evaluated 24 h afterwards in terms of macroscopic and microscopic alterations, myeloperoxidase activity, lipid peroxidation, number of enterobacteria in the mucosa and epithelial mucin content. Oral administration of indomethacin (20 mg/kg) induced macroscopic and microscopic damage to the small intestine, increased translocation of enterobacteria from lumen into the mucosa, myeloperoxidase activity and lipid peroxidation. Ibuprofen (120 mg/kg), SC-560 (20 mg/kg), celecoxib (60 mg/kg) or the combination of SC-560 plus celecoxib did not cause any intestinal injury nor modified the number of bacteria in mucosal homogenates. SC-560 significantly increased both myeloperoxidase activity and lipid peroxidation, whereas celecoxib significantly reduced myeloperoxidase levels, while leaving unaltered lipid peroxidation. Finally, all NSAIDs, mostly indomethacin, increased neutral mucins and decreased acidic mucins in the intestinal goblet cells. These results indicate that inhibition of cyclooxygenase, although variably influencing mucosal integrity homeostasis, is not sufficient to initiate acute intestinal damage in rats. Moreover, topical mucosal injury induced by the NSAID molecule seems to be a critical factor in the development of intestinal injury.
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Affiliation(s)
- Alessandro Menozzi
- Department of Human Anatomy, Pharmacology and Forensic Medicine, University of Parma, Italy
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14
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Radi ZA, Khan NK. Effects of cyclooxygenase inhibition on the gastrointestinal tract. ACTA ACUST UNITED AC 2006; 58:163-73. [PMID: 16859903 DOI: 10.1016/j.etp.2006.06.004] [Citation(s) in RCA: 49] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2006] [Accepted: 06/07/2006] [Indexed: 10/24/2022]
Abstract
Cyclooxygenase (COX) is a rate-limiting enzyme that catalyzes the conversion of arachidonic acid, an essential fatty acid present in cell membrane phospholipids and liberated by phospholipase, into prostaglandins (PGs) and prostanoids. COX has two distinct membrane-anchored isoenzymes; COX-1 and COX-2. COX-1 is a constitutively expressed and found in most normal body tissues; COX-2 is expressed in normal tissues at low levels and is highly induced by pro-inflammatory mediators in the setting of inflammation, injury, and pain. Inhibitors of COX activity include: (1) conventional non-selective non-steroidal anti-inflammatory drugs (ns-NSAIDs); (2) selective COX-2 inhibitors (COXIBs); and (3) COX-1 inhibitors. Non-selective NSAIDs, at therapeutic doses, inhibit both COX-1 and COX-2. The anti-inflammatory benefits of these drugs are primarily derived from COX-2 inhibition, while inhibition of COX-1 often elicits gastrointestinal (GI) toxicity. Therefore, COXIBs were developed to provide a selective COX-2 agent, i.e., one, that at fully therapeutic doses demonstrated comparable therapeutic benefit to non-selective NSAIDs, without the attendant COX-1-mediated GI toxicities. In this review, we evaluate available literature describing the pathophysiologic role of cyclooxygenases and the effects of their inhibition in GI system in experimental and domestic animal species.
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Affiliation(s)
- Zaher A Radi
- Worldwide Safety Sciences, Michigan Laboratories, Pfizer Global Research and Development, Building 35-1A/5, 2800 Plymouth Road, Ann Arbor, MI 48105, USA.
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Jiang H, Deng CS, Zhang M, Xia J. Curcumin-attenuated trinitrobenzene sulphonic acid induces chronic colitis by inhibiting expression of cyclooxygenase-2. World J Gastroenterol 2006; 12:3848-53. [PMID: 16804969 PMCID: PMC4087932 DOI: 10.3748/wjg.v12.i24.3848] [Citation(s) in RCA: 52] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To explore the possible mechanisms of curcumin in rat colitis induced by trinitrobenzene sulfonic (TNBS) acid.
METHODS: Rats with TNBS acid-induced colitis were treated with curcumin (30 mg/kg or 60 mg/kg per day ip). Changes of body weight and histological scores as well as survival rate were evaluated. Leukocyte infiltration was detected by myeloperoxidase (MPO) activity assay. The expression of cyclooxygenase-2 (COX-2) was detected by RT-PCR and Western blot. Inflammation cytokines were determined by RT-PCR. Local concentration of prostaglandin E2 (PGE2) in colon mucosa was determined by ELISA.
RESULTS: Curcumin improved survival rate and histological image, decreased the macroscopic scores and MPO activity. Also curcumin reduced the expression of COX-2 and inflammation cytokines. In addition, treatment with curcumin increased the PGE2 level.
CONCLUSION: Curcumin has therapeutic effects on TNBS acid-induced colitis, the mechanisms seem to be related to COX-2 inhibition and PGE2 improvement.
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Affiliation(s)
- Hua Jiang
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Hubei Province, China.
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Zhang M, Deng C, Zheng J, Xia J, Sheng D. Curcumin inhibits trinitrobenzene sulphonic acid-induced colitis in rats by activation of peroxisome proliferator-activated receptor gamma. Int Immunopharmacol 2006; 6:1233-42. [PMID: 16782535 DOI: 10.1016/j.intimp.2006.02.013] [Citation(s) in RCA: 51] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2006] [Accepted: 02/24/2006] [Indexed: 12/19/2022]
Abstract
Curcumin is a widely used spice with anti-inflammatory and anti-cancer properties. It has been reported that curcumin held therapeutic effects on experimental colitis by inhibition of nuclear factor kappa B (NF-kappaB). The peroxisome proliferator-activated receptor gamma (PPARgamma) is a nuclear receptor with anti-tumor and anti-inflammatory effects and its activation may inhibit the nuclear translocation of NF-kappaB. Several studies have shown that PPARgamma ligands had an important therapeutic effect in colitis. However there is no report about the alteration of PPARgamma in trinitrobenzene sulphonic acid (TNBS)-induced colitis treated with curcumin. In this study, we administered curcumin (30 mg/kg/day) by intraperitoneal injection immediately after colitis was induced and the injection lasted for two weeks. have evaluated the effects of curcumin on the colitis induced by trinitrobenzene sulphonic acid (TNBS). Curcumin (30 mg/kg d) was administered by intraperitoneal just after colitis was induced and lasted for two weeks. Therapeutic effects of dexamethasone (Dex, 2 mg/kg d) alone and the combined effects of curcumin+Dex were also examined. We found that curcumin improved long-term survival rate of disease-bearing rats, promoted rat body weight recovery, and decreased macroscopic scores of the colitis. The expression levels of PPARgamma, 15-deoxy-D12,14-prostaglandin J(2) (15d-PGJ(2)) and prostaglandin E(2) (PGE(2)) were all increased, but the expression level of cyclooxygenase-2 (COX-2) was decreased in rats after administration of curcumin. Treatment with Dex improved PPARgamma expression and inhibited the expression of COX-2, 15d-PGJ(2) and PGE(2). Combined effects of curcumin+Dex were similar to that of Dex. In summary, curcumin showed therapeutic effects on TNBS-induced colitis and the mechanisms by which curcumin exerts its effects may involve activation of PPARgamma and its ligands.
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Affiliation(s)
- Ming Zhang
- Gastroenterology Department of Zhongnan Hospital, Wuhan University, East Lake Road, Hubei Province, PR China
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Kruschewski M, Anderson T, Buhr HJ, Loddenkemper C. Selective COX-2 inhibition reduces leukocyte sticking and improves the microcirculation in TNBS colitis. Dig Dis Sci 2006; 51:662-70. [PMID: 16614986 DOI: 10.1007/s10620-006-3189-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2005] [Accepted: 07/12/2005] [Indexed: 12/18/2022]
Abstract
The role of cyclooxygenase-2 inhibitors in the course of experimental colitis is controversially discussed. The aim of this study was to evaluate leukocyte-endothelium interaction and colitis activity after applying the selective cyclooxygenase-2 inhibitor NS-398 in a rat trinitrobenzene sulfonic acid (TNBS) colitis model. The acute phase of TNBS colitis is characterized by a significant reduction of capillary blood flow, capillary density, diuresis, and weight and a significant increase in capillary permeability, leukocyte sticking, and hematocrit. Applying the selective cyclooxygenase-2 inhibitor NS-398 leads to a significant improvement of all microcirculatory parameters and clinical findings compared to the (untreated) colitis group. There are no histopathological differences between the individual colitis groups. Acute colitis is characterized by an extensive disturbance of microcirculation together with signs of systemic inflammatory response syndrome. These alterations are significantly improved by inhibiting cyclooxygenase-2. The results support the described correlation between cyclooxygenase activation and leukocyte-endothelium interaction. Moreover, they underscore the postulated relation between leukocyte-endothelium interaction and capillary blood flow.
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Affiliation(s)
- Martin Kruschewski
- Department of Surgery, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, 12200 Berlin, Germany.
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El Miedany Y, Youssef S, Ahmed I, El Gaafary M. The gastrointestinal safety and effect on disease activity of etoricoxib, a selective cox-2 inhibitor in inflammatory bowel diseases. Am J Gastroenterol 2006; 101:311-7. [PMID: 16454836 DOI: 10.1111/j.1572-0241.2006.00384.x] [Citation(s) in RCA: 115] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND While traditional nonsteroidal antiinflammatory drugs (t-NSAIDs) are relatively contraindicated in patients with inflammatory bowel disease (IBD) for fear of disease aggravation, controlled clinical trials showed that cyclo-oxygenase-2 inhibitors have fewer gastrointestinal side effects than the t-NSAIDs. Etoricoxib is a new antiinflammatory inhibitor that has high Cox-2 selectivity. OBJECTIVES To assess the safety of etoricoxib and effect on disease activity in patients with IBD in a multicenter, double-blind, placebo-control study. METHODS Study group included 76 patients suffering from IBD (ulcerative colitis (UC) (38), and Crohn's disease (CD) (38)). The control group included 70 patients known to have UC (35) and Crohn's disease (CD) (35). Patients of both groups were referred to the rheumatology clinic for rheumatic manifestations that require antiinflammatory therapy and were intolerable to the t-NSAIDs. The level of the IBD activity at the baseline visit, when drug/placebo therapy was initiated, was scored for all subjects included in the study. In the study group the dose of etoricoxib ranged from 60 to 120 mg tablet once a day according to their rheumatic condition. The control group received a placebo tablet once a day. Adverse events related to the use of the study medication in 1 and 3 months time were documented. Etoricoxib/placebo therapy was stopped once the patient experience flare up of their IBD. RESULTS There was no significant difference between the patients and the control groups. After 3 months of etoricoxib therapy, 8 of 76 (10.53%) of the study group had aggravation of their underlying IBD and stopped the drug therapy, while 68 of 76 (89.5%) completed the study. The mean disease activity index before etoricoxib therapy was 1.15 + 0.794, whereas it was 1.19 + 0.683 after therapy. In the control group 8 of 70 (11.43%) experienced exacerbation of their symptoms while 62 of 70 (88.6%) completed the study. In the control group the mean disease activity before treatment was 1.16 + 0.253, whereas after placebo therapy was 1.20 + 0.481. 67 of 76 (88.2%) of the study group and 62 of 70 (88.6%) of the control group gave history of using t-NSAID therapy in addition to PPI that caused flare up of their IBD. For the patients who had to stop their drug therapy, all the adverse events occurred in the first month of drug/placebo challenge and all symptoms were reversible. CONCLUSION Etoricoxib therapy is safe and beneficial in most patients with IBD treatment with etoricoxib was not associated with exacerbation of the underlying IBD- and GI-related complications.
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Meyer AM, Ramzan NN, Heigh RI, Leighton JA. Relapse of inflammatory bowel disease associated with use of nonsteroidal anti-inflammatory drugs. Dig Dis Sci 2006; 51:168-72. [PMID: 16416231 DOI: 10.1007/s10620-006-3103-5] [Citation(s) in RCA: 36] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2005] [Accepted: 04/18/2005] [Indexed: 12/14/2022]
Abstract
To determine whether an association exists between relapse in inflammatory bowel disease and use of nonsteroidal anti-inflammatory drugs (NSAIDs), a retrospective records review was conducted of patients with Crohn's disease, ulcerative colitis, or indeterminate colitis examined at an outpatient tertiary care center between July 17, 2000, and November 1, 2001. Extracted data collected during the patient's last visit included medication use, maintenance therapy, disease activity, and smoking status. Use of NSAIDs was defined as a daily dose or more of any type the month before relapse. Of 60 patients (22, relapse; 38, remission), 9 (41%) in relapse and 10 (26%) in remission used NSAIDs. Maintenance therapy varied from 68% (relapse) to 92% (remission). The adjusted odds ratio between medication use and relapse was 6.31 (95% confidence interval, 1.16-34.38; P = .03). Use of NSAIDs was associated with relapse. A prospective cohort study that corrects for maintenance therapy is needed to evaluate this relationship.
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Affiliation(s)
- Angela M Meyer
- Division of Gastroenterology and Hepatology, Mayo Clinic, Scottsdale, Arizona 85259, USA
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20
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Abstract
Ulcerative colitis is associated with altered contractile activity and transit time of colon. On the other hand, cholecystokinin (CCK) has been shown to play an important role in regulation of gastrointestinal motor function including colonic contraction and transit. In the present study, an attempt was made to study the effect of proglumide, a CCK receptor antagonist on experimental colitis in rats. Experimental colitis was induced in male Sprague-Dawley rats by instilling 1 ml of 4% acetic acid followed by flushing with 0.5 ml air. The rats were kept in a head-down position for 30s. Finally, each rat received 1.5 ml colonic wash with 1.5 ml saline. Four groups of rats received proglumide orally (0, 250, 500 and 1000mg/kg). The first dose of proglumide was given 1 h before acetic acid challenge, whereas the second dose of proglumide was given 25 h after the first dose. Sham control rats received an equal volume of saline instead of acetic acid. Forty-eight hours after the acetic acid challenge, the colon was removed, weighed and split longitudinally and scored for injury. Part of the colon was used for histopathological study as well as analysis of myeloperoxidase (MPO) activity (as a marker of neutrophil activity). Acetic acid produced severe diarrhea and exfoliation of the colonic epithelium accompanied by extensive destruction of the mucosal interstitium. Proglumide dose dependently protected rats against acetic acid-induced increase in colon weight, diarrhea, MPO activity and colonic injury. Inhibition of CCK exerts a beneficial effect in experimental colitis. Further studies are warranted to determine the mechanism of protection and the therapeutic potential of CCK inhibitors.
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Affiliation(s)
- Ahmed Al Moutaery
- Department of Pathology, Armed Forces Hospital, Riyadh 11159, Saudi Arabia.
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Abir F, Alva S, Kaminski DL, Longo WE. The role of arachidonic acid regulatory enzymes in colorectal disease. Dis Colon Rectum 2005; 48:1471-83. [PMID: 15868226 DOI: 10.1007/s10350-005-0015-y] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
PURPOSE Nonsteroidal anti-inflammatory drugs have a wide ranging effect on diseases of the colon and rectum. Interestingly, nonsteroidal anti-inflammatory drugs seem to play a beneficial role in colorectal cancer chemoprevention and adenoma regression, but may have a deleterious effect in inflammatory bowel disease. Prostaglandin inhibition is central to both the beneficial and toxic effects of this class of drugs. Arachidonic acid metabolism is essential to prostaglandin synthesis. METHODS A Medline search using "nonsteroidal anti-inflammatory drugs," "colon cancer," "inflammatory bowel disease," "colitis," "COX inhibitors," "arachidonic acid," and "chemoprevention" as key words was performed for English-language articles. Further references were obtained through cross-referencing the bibliography cited in each work. RESULTS Based on numerous studies, nonsteroidal anti-inflammatory drugs have a beneficial role in colon cancer and colonic adenomas. However, they have been reported to have a deleterious effect on the colon in inflammatory bowel disease and have been shown to cause colitis. Nonsteroidal anti-inflammatory drugs work via multiple pathways, some well defined, and others unknown. CONCLUSIONS In the new millennium, nonsteroidal anti-inflammatory drugs may be used for chemoprevention of colorectal and other cancers. In addition, they may be used in combination with surgery and chemotherapy to primarily treat colorectal carcinoma. Undoubtedly, the use of novel cyclooxygenase inhibitors with less of a toxicity profile will allow more widespread use of nonsteroidal anti-inflammatory drugs for a variety of diseases. The future of this class of drugs is promising.
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Affiliation(s)
- Farshad Abir
- Department of Surgery, Yale University School of Medicine, New Haven, Connecticut 06520-8062, USA
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22
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Abstract
Nonsteroidal anti-inflammatory drugs (NSAIDs) are generally prescribed to ameliorate symptoms associated with acute pain and chronic inflammatory diseases such as arthritis. Recent epidemiologic studies and clinical trials indicate that use of NSAIDs and cyclooxygenase (COX)-2 selective inhibitors are associated with a reduced risk of certain malignancies, especially gastrointestinal cancer. The cyclooxygenase enzymes are the best known targets of NSAIDs; this diverse class of compounds blocks conversion of arachidonic acid to prostanoids. Prostaglandins and other eicosanoids derived from COX-1 and COX-2 are involved in a variety of physiologic and pathologic processes in the gastrointestinal tract. Recent efforts to identify the molecular mechanisms by which COX-2-derived prostanoids exert their proneoplastic effects have provided a rationale for the possible use of NSAIDs alone or in a combination with conventional or experimental anticancer agents for the treatment or prevention of gastrointestinal cancers.
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Affiliation(s)
- Dingzhi Wang
- Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
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Wang GH, Dong HY, Dong WG, Wang XP, Luo HS, Yu JP. Protective effect of Radix Acanthopanacis Senticosi capsule on colon of rat depression model. World J Gastroenterol 2005; 11:1373-7. [PMID: 15761979 PMCID: PMC4250688 DOI: 10.3748/wjg.v11.i9.1373] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the abnormity of rat colon caused by depression and the ameliorative effects of Radix Acanthopanacis Senticosi (RAS) capsule on colon and their mechanisms in rat depression model.
METHODS: Chronic stress-induced model of depression of Wistar rats was produced. The experimental animals were randomly divided into model control, 5-aminosalicylic acid (5-ASA) therapy group and three RAS capsule therapy groups. These five groups were intracolonically treated daily (8:00 a.m.) for 2 wk with normal saline, 5-ASA (100 mg/kg) and RAS capsule at the doses of 300, 600 and 900 mg/kg, respectively. A normal control group of rats was also included in the study. Colonic activities of nitric oxide (NO) and superoxide dismutase (SOD), levels of malondialdehyde (MDA) and inducible nitric oxide synthase (iNOS) were determined by ultraviolet spectrophotometry. The expression of cyclooxygenase-2 (COX-2) in colonic tissue was detected by immunohistochemistry.
RESULTS: Enhanced colon inflammatory response and oxidative stress were observed in the chronic stress-induced rat depression model, which manifested as the significant increase of MDA, iNOS and NO levels, as well as the expressions of COX-2 in the colon tissue, but the colonic SOD activity was significantly decreased compared with the normal control (MDA: 10.34±2.77 vs 2.55±0.70; iNOS: 1.11±0.44 vs 0.25±0.16; COX-2: 53.26±8.16 vs 4.87±1.65; NO: 11.28±5.66 vs 4.76±1.55; SOD: 53.39±11.15 vs 84.45±22.31; P<0.01). However, these parameters were significantly ameliorated in rats treated locally with RAS capsule at the doses of 300, 600 and 900 mg/kg (iNOS: 0.65±0.31, 0.58±0.22 and 0.64±0.33; NO: 5.99±2.73, 6.87±1.96 and 6.50±1.58; MDA: 2.92±0.75, 3.19±1.08 and 3.26±1.24; SOD: 70.81±12.36, 73.30±15.30 and 69.09±11.03, respectively). The expressions of COX-2 in the colon were significantly ameliorated (28.83±9.48 and 27.04±9.56, respectively) when RAS capsule was administered at the doses of 600 and 900 mg/kg.
CONCLUSION: Administration of RAS capsule intracolonically may have significant therapeutic effects on the colon of rat depression model, which are probably due to its antioxidative action and inhibition of arachidonic acid metabolism.
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Affiliation(s)
- Gao-Hua Wang
- Department of Mental Health Center, Renmin Hospital of Wuhan University, 238 Jiefang Road, Wuhan 430060, Hubei Province, China
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El-Medany A, Mahgoub A, Mustafa A, Arafa M, Morsi M. The effects of selective cyclooxygenase-2 inhibitors, celecoxib and rofecoxib, on experimental colitis induced by acetic acid in rats. Eur J Pharmacol 2004; 507:291-9. [PMID: 15659320 DOI: 10.1016/j.ejphar.2004.11.036] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2004] [Revised: 11/11/2004] [Accepted: 11/16/2004] [Indexed: 12/18/2022]
Abstract
Several mediators may be involved in the pathogenesis of inflammatory bowel disease, as well as in experimental colitis. The present work was conducted to investigate the effects of the two selective cyclooxygenase-2 inhibitors, celecoxib and rofecoxib, on experimentally induced colitis in rats. Rectal instillation of acetic acid was used to induce the colitis. Acetic acid treatment caused haemorrhagic diarrhoea and weight loss in rats. Celecoxib (5 mg/kg) or rofecoxib (2.5 mg/kg), when given twice daily by the oral route, reduced the degree of haemorrhagic diarrhoea and the weight loss produced. In addition, they produced a significant reduction in the degree of colonic injury, the rise in myeloperoxidase (MPO) levels, total nitric oxide synthetase (NOS) activity, platelet-activating factor (PAF), histamine levels and prostaglandin E2 levels. In contrast, there was a significant increase in the levels of reduced glutathione (GSH). Thus, the findings of the present study provide evidence that selective cyclooxygenase-2 inhibitors may be beneficial in patients with inflammatory bowel disease.
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Affiliation(s)
- Azza El-Medany
- Department of Pharmacology, College of Medicine, King Saud University, Riyadh 11461, P.O. Box 22452, Saudi Arabia
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Thiéfin G, Beaugerie L. Toxic effects of nonsteroidal antiinflammatory drugs on the small bowel, colon, and rectum. Joint Bone Spine 2004; 72:286-94. [PMID: 16038840 DOI: 10.1016/j.jbspin.2004.10.004] [Citation(s) in RCA: 82] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2004] [Accepted: 10/04/2004] [Indexed: 02/07/2023]
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.
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Affiliation(s)
- Gérard Thiéfin
- Hepatogastroenterology Department, Robert Debré Teaching Hospital, Reims, France.
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Singh VP, Patil CS, Jain NK, Singh A, Kulkarni SK. Effect of nimesulide on acetic acid- and leukotriene-induced inflammatory bowel disease in rats. Prostaglandins Other Lipid Mediat 2004; 71:163-75. [PMID: 14518559 DOI: 10.1016/s1098-8823(03)00038-8] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Inflammatory bowel disease (IBD) is a relapsing inflammation of intestine, which is mediated by release of inflammatory mediators. Both cyclo-oxygenase product prostaglandin (PGE2) and lipo-oxygenase product leukotriene (LTB4), may contribute to the pathogenesis of the inflammatory response. Nimesulide, a preferential COX-2 inhibitor was evaluated for its efficacy against experimental colitis in two different models (acetic acid- and LTB4-induced IBD) in rats. Inflammatory response was induced by intrarectal single administration of acetic acid or LTB4. Nimesulide (9 and 18 mg/kg, p.o.) significantly prevented development of inflammatory changes, decreased myeloperoxidase (MPO) activity, and also restored the altered contractility response of the isolated colon segment to KCl. The results suggested the involvement of both cyclo-oxygenase (COX) and lipo-oxygenase-mediated proinflammatory agents in colonic inflammatory process associated with IBD. Further, this study suggests that such therapeutic interventions may be of value in the treatment of IBD.
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Affiliation(s)
- Vijay Pal Singh
- Research and Development Division, Panacea Biotec Ltd., P.O. Lalru 140 501, Punjab, India
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Abstract
Chronic use of non-salicylate NSAIDs causes in most individuals an asymptomatic enteropathy involving the small bowel, particularly its distal part. This enteropathy is characterised by an increase in intestinal permeability and a mild mucosal inflammation. Hypoalbuminemia and iron deficiency may occur. In addition, non-salicylate NSAIDs may cause focal lesions of the small intestine. Ulcerations and ulcers, that can be accidentally discovered during an ileoscopy, may cause acute or chronic bleeding. Deep ulcers may provoke sudden peritonitis. Small bowel diaphragms are rare fibrotic lesions, specifically associated with the use of non-salicylate NSAIDs or salicylates (duodenal diaphragms only). NSAID use is not associated with a constant toxicity on colonic mucosa. NSAID-induced colonic ulcers and diaphragms are rare. In patients with colonic diverticulosis, NSAID intake is a risk factor for severe attacks of diverticulitis. Acute or chronic use of non-salicylate NSAIDs increases the risk for ischemic colitis and flare-ups of inflammatory bowel disease. De novo colitis caused by non-salicylate NSAIDs are rare. The definite diagnosis of this entity relies on the absence of recurrence of colitis in the 2-3 following years. Such a recurrence would lead to the post-hoc diagnosis of first attack of inflammatory bowel disease triggered by NSAID use. Experimental data suggest that selective COX-2 inhibitors do not alter constantly mucosa of the small intestine. Pilot epidemiological works suggest that severe intestinal lesions are less frequent in association with COX-2 inhibitor use than in association with conventional NSAIDs. However, COX-2 appears as playing a beneficial role in mucosal healing, and it seems that COX-2 inhibitors, like conventional NSAIDs, may trigger flare-ups of inflammatory bowel disease.
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Affiliation(s)
- Laurent Beaugerie
- Federation d'Hépato-Gastroentérologie, Hôpital Saint-Antoine, Paris.
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Liu SP, Dong WG, Luo HS, Yu BP, Yu JP. Protective effects of sodium ferulate on injury in acetic acid-induced rat colitis. Shijie Huaren Xiaohua Zazhi 2004; 12:108-111. [DOI: 10.11569/wcjd.v12.i1.108] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To study the effects of sodium ferulate on acetic acid-induced rat colitis and its mechanism.
METHODS: The colitis model of rats was produced by intracolon enema with acetic acid. The experiment animals were divided into 5 groups: normal group, model group, SF groups (200 mg/kg, 400 mg/kg, 800 mg/kg), and treated intracolonically with saline and SF respectively once per day for 7 d. At the end of the experiment, the colon mucosa damage index (CMDI) and the occult blood test (OBT) were evaluated.The contents of MDA, NO, PGE2, and TXB2 , the activities of myelopexoxidase (MPO) and SOD, the expression of COX-2 and NF-Bp65 in the rat colon were detected. Platelet agglutinability was also measured.
RESULTS: The extents of CMDI and OBT, the contents of MDA, NO, PGE2 and TXB2, the activity of MPO, the expression of COX-2 and NF-Bp65 in the colon and the platelet agglutinability in the model group were higher than those in normal group, while the activity of SOD was lower than that in normal group. SF could alleviate the CMDI and OBT, and ameliorate the abnormity of these detected indexes in a dose-depended manner.
CONCLUSION: Treatment with SF intracolon can relieve the inflammation reaction, attenuate the colon mucosal damage in the rat colitis through resisting oxidative stress, restraining arachidonic acid metabolism, platelet activation and the expression of NF-B.
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Dong WG, Liu SP, Yu BP, Wu DF, Luo HS, Yu JP. Ameliorative effects of sodium ferulate on experimental colitis and their mechanisms in rats. World J Gastroenterol 2003; 9:2533-8. [PMID: 14606091 PMCID: PMC4656535 DOI: 10.3748/wjg.v9.i11.2533] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the ameliorative effects of sodium ferulate (SF) on acetic acid-induced colitis and their mechanisms in rats.
METHODS: The colitis model of Sprague-Dawley rats was induced by intracolon enema with 8% (V/V) of acetic acid. The experimental animals were randomly divided into model control, 5-aminosalicylic acid therapy group and three dose of SF therapy groups. The 5 groups were treated intracolonically with normal saline, 5-aminosalicylic acid (100 mg•kg-1), and SF at the doses of 200, 400 and 800 mg·kg-1 respectively and daily (8: 00 am) for 7 d 24 h following the induction of colitis. A normal control group of rats clystered with normal saline instead of acetic acid was also included in the study. Pathological changes of the colonic mucosa were evaluated by the colon mucosa damage index (CMDI) and the histopathological score (HS). The insulted colonic mucosa was sampled for a variety of determinations at the end of experiment when the animals were sacrificed by decapitation. Colonic activities of myeloperoxidase (MPO) and superoxide dismutase (SOD), and levels of malondialdehyde (MDA) and nitric oxide (NO) were assayed with ultraviolet spectrophotometry. Colonic contents of prostaglandin E2 (PGE2) and thromboxane B2 (TXB2) were determined by radioimmunoassay. The expressions of inducible nitric oxide synthase (iNOS), cyclo-oxygenase-2 (COX-2) and nuclear factor kappa B (NF-κB) p65 proteins in the colonic tissue were detected with immunohistochemistry.
RESULTS: Enhanced colonic mucosal injury, inflammatory response and oxidative stress were observed in the animals clystered with acetic acid, which manifested as the significant increase of CMDI, HS, MPO activities, MDA and NO levels, PGE2 and TXB2 contents, as well as the expressions of iNOS, COX-2 and NF-κB p65 proteins in the colonic mucosa, although the colonic SOD activity was significantly decreased compared with the normal control (CMDI: 2.9 ± 0.6 vs 0.0 ± 0.0; HS: 4.3 ± 0.9 vs 0.7 ± 1.1; MPO: 98.1 ± 26.9 vs 24.8 ± 11.5; MDA: 57.53 ± 12.36 vs 9.21 ± 3.85; NO: 0.331 ± 0.092 vs 0.176 ± 0.045; PGE2: 186.2 ± 96.2 vs 42.8 ± 32.8; TXB2: 34.26 ± 13.51 vs 8.83 ± 3.75; iNOS: 0.365 ± 0.026 vs 0.053 ± 0.015; COX-2: 0.296 ± 0.028 vs 0.034 ± 0.013; NF-κB p65: 0.314 ± 0.026 vs 0.039 ± 0.012; SOD: 28.33 ± 1.17 vs 36.14 ± 1.91; P < 0.01). However, these parameters were found to be significantly ameliorated in rats treated locally with SF at the given dose protocols, especially at 400 mg·kg-1 and 800 mg·kg-1 doses (CMDI: 1.8 ± 0.8, 1.6 ± 0.9; HS: 3.3 ± 0.9, 3.1 ± 1.0; MPO: 63.8 ± 30.5, 36.2 ± 14.2; MDA: 41.84 ± 10.62, 37.34 ± 8.58; NO: 0.247 ± 0.042; 0.216 ± 0.033; PGE2: 77.2 ± 26.9, 58.4 ± 23.9; TXB2: 18.07 ± 14.83; 15.52 ± 8.62; iNOS:0.175 ± 0.018, 0.106 ± 0.019; COX-2: 0.064 ± 0.018, 0.056 ± 0.014; NF-κBp65: 0.215 ± 0.019, 0.189 ± 0.016; SOD: 32.15 ± 4.26, 33.24 ± 3.69; P < 0.05-0.01). Moreover, a therapeutic dose protocol of 800 mg·kg-1 SF was observed as effective as 100 mg·kg-1 of 5-ASA in the amelioration of colonic mucosal injury as evaluated by CMDI and HS.
CONCLUSION: Administration of SF intracolonically may have significant therapeutic effects on the rat model of colitis induced by acetic acid enema, which was probably due to the mechanism of antioxidation, inhibition of arachidonic acid metabolism and NF-κB expression.
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Affiliation(s)
- Wei-Guo Dong
- Department of Gastroenterology, Renmin Hospital of Wuhan University, 238 Jiefang Road, Wuhan 430060, Hubei Province, China.
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Zhang YH, Lu J, Elmquist JK, Saper CB. Specific roles of cyclooxygenase-1 and cyclooxygenase-2 in lipopolysaccharide-induced fever and Fos expression in rat brain. J Comp Neurol 2003; 463:3-12. [PMID: 12811798 DOI: 10.1002/cne.10743] [Citation(s) in RCA: 72] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Fever is a coordinated autonomic, endocrine, and behavioral response mediated by the brain in reaction to inflammatory stimuli. An essential step in transmitting the immune signal to the brain is the formation of prostaglandin E2. Cyclooxygenase (COX) is the critical enzyme in the synthesis of prostaglandins and COX-2, the inducible form of the enzyme, is markedly induced in cells associated with the cerebral blood vessels and the leptomeninges by immune stimuli such as intravenous administration of lipopolysaccharide (LPS). However, the specific roles of COX-1, the constitutive form of cyclooxygenase, and COX-2 in LPS-induced fever are not well understood. We injected LPS i.v. in combination with either a highly selective COX-1 (SC-560) or COX-2 (SC-236) inhibitor to determine the effects of each drug on the subsequent fever response and on the pattern of expression of Fos protein in the brain. The COX-2 inhibitor blocked LPS-induced fever and Fos expression in sites such as the ventromedial preoptic nucleus (VMPO) and the hypothalamic paraventricular nucleus (PVH), although Fos-immunoreactivity in the nucleus of the solitary tract (NTS), ventrolateral medulla (VLM), and parabrachial nucleus (PB) remained. In contrast, the COX-1 inhibitor resulted in a profound hypothermic response to LPS and blocked LPS-induced Fos-immunoreactivity in the PVH, PB, NTS, and VLM, although it had no effect on the VMPO. Although COX-2 plays a dominant role in mediating fever responses to i.v. LPS, at least some components of the response, including avoiding hypothermia and the induction of Fos in the NTS, VLM, PB, and PVH, appear to depend on COX-1. J.
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Affiliation(s)
- Yi-Hong Zhang
- Department of Neurology and Program in Neuroscience, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA
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Hegazi RAF, Mady HH, Melhem MF, Sepulveda AR, Mohi M, Kandil HM. Celecoxib and rofecoxib potentiate chronic colitis and premalignant changes in interleukin 10 knockout mice. Inflamm Bowel Dis 2003; 9:230-6. [PMID: 12902846 DOI: 10.1097/00054725-200307000-00003] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Nonsteroidal anti-inflammatory drugs decrease sporadic colorectal carcinoma and adenomas in patients with familial adenomatous polyposis and in rodent models of sporadic colon cancer and familial adenomatous polyposis. Similarly, selective cyclooxygenase 2 inhibitors decrease adenomas in humans and rodents. However, their effects on chronic colitis and colitis-associated neoplasia are unknown. Interleukin 10-/- mice (C57/B6) were fed regular chow (n = 20) or chow with celecoxib (1,500 ppm, n = 18) or rofecoxib (75 ppm, n = 20) for 12 weeks. Twenty-eight percent of the celecoxib group died versus 5% of the control and rofecoxib groups (p < 0.05 compared with control). Celecoxib and rofecoxib increased the incidence of colitis (26% vs. 92% and 68%, p < 0.01), colitis score (0.4 +/- 0.2 vs. 2.5 +/- 0.3 and 2 +/- 0.4, p < 0.01), aberrant crypt foci (0.5 +/- 0.3 vs. 3.7 +/- 2.6 and 2.8 +/- 0.7, p < 0.01), aberrant crypts per mouse (4.11 +/- 2.1 vs. 41.2 +/- 9.7 and 27.1 +/- 7.5, p < 0.01) and dysplasia (11% vs. 54% and 42%, p < 0.01). Similarly, indomethacin (9 ppm, n = 15) increased colitis score, aberrant crypt foci, and dysplasia after 27 days of treatment. Two selective cyclooxygenase 2 inhibitors exacerbate colitis and premalignant changes in the interleukin 10-/- mouse model of chronic colitis and colitis-associated colon carcinoma.
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Affiliation(s)
- Refaat A F Hegazi
- Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh Medical Center and Pittsburgh Veterans Administration Medical Center, Pittsburgh, Pennsylvania 15213, U.S.A
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Reinisch W, Miehsler W, Dejaco C, Harrer M, Waldhoer T, Lichtenberger C, Vogelsang H. An open-label trial of the selective cyclo-oxygenase-2 inhibitor, rofecoxib, in inflammatory bowel disease-associated peripheral arthritis and arthralgia. Aliment Pharmacol Ther 2003; 17:1371-80. [PMID: 12786631 DOI: 10.1046/j.1365-2036.2003.01596.x] [Citation(s) in RCA: 58] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
BACKGROUND Conventional non-steroidal anti-inflammatory drugs have been associated with an increased risk of exacerbation of inflammatory bowel disease. AIM To evaluate, in a prospective, open-label study, the safety and efficacy of a 20-day regimen of the selective cyclo-oxygenase-2 inhibitor, rofecoxib, 12.5-25 mg/day, in inflammatory bowel disease patients with associated peripheral arthropathy and/or arthritis. METHODS Patients with clinically inactive to mild inflammatory bowel disease and a joint pain score of at least two points on a scale ranging from zero (none) to four (very poor) were eligible. Response was defined by a decrease of at least two points in the arthralgia score. RESULTS Of the 32 patients included, 26 (81%) were treated with rofecoxib, 25 mg/day, and six (19%) with rofecoxib, 12.5 mg/day. In three patients (9%), rofecoxib had to be withdrawn after a few days due to gastrointestinal complaints which ceased immediately after drug discontinuation. No flare of inflammatory bowel disease occurred. Thirteen of the 32 patients (41%) were responders and, overall, the arthralgia score decreased from two to one (P = 0.0001). CONCLUSIONS This is the first prospective study on the use of a selective cyclo-oxygenase-2 inhibitor in inflammatory bowel disease patients with peripheral arthropathy and/or arthralgia. The promising safety and efficacy profile warrants further evaluation in controlled trials.
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Affiliation(s)
- W Reinisch
- Department of Internal Medicine IV, Division of Gastroenterology and Hepatology, University of Vienna, Vienna, Austria
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Boissé L, Van Sickle MD, Sharkey KA, Pittman QJ. Compromised neuroimmune status in rats with experimental colitis. J Physiol 2003; 548:929-39. [PMID: 12640019 PMCID: PMC2342880 DOI: 10.1113/jphysiol.2002.034546] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
In colitis, chronic and recurrent inflammation is associated with a breakdown in host defence mechanisms that leads to local and systemic infection. Whether this is due to a compromised neuroimmune response has not been studied. Our aim was to determine if colitis altered the host neuroimmune response as reflected in either body temperature rhythm or the febrile responses to lipopolysaccharide (LPS). Body temperature was monitored by telemetry from conscious, unrestrained male rats treated with trinitrobenzene sulphonic acid or saline. Twenty-six days after initial induction, colitis was reactivated. Animals were given LPS (50 microg kg-1 Escherichia coli LPS) during colitis and after reactivation. At the peak of colitis, treated rats showed a disruption of circadian body temperature rhythm, manifested as day-time fever followed by night-time hypothermia. In response to LPS, controls displayed a characteristic fever, whereas treated animals had a significantly reduced fever and low plasma levels of interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNF-alpha). During reactivation of colitis, treated animals did not mount a fever or exhibit increased plasma levels of IL-6 and TNF-alpha after LPS. We conclude that experimental colitis is associated with a compromised neuroimmune status.
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Affiliation(s)
- Lysa Boissé
- Neuroscience Research Group, Department of Physiology and Biophysics, University of Calgary, Alberta, Canada
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Gleeson MH, Davis AJM. Non-steroidal anti-inflammatory drugs, aspirin and newly diagnosed colitis: a case-control study. Aliment Pharmacol Ther 2003; 17:817-25. [PMID: 12641504 DOI: 10.1046/j.1365-2036.2003.01519.x] [Citation(s) in RCA: 58] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND There have been a number of reports of colitis following exposure to non-steroidal anti-inflammatory drugs (NSAIDs) and salicylates. AIM To conduct a case-control analysis of new cases of colitis, with particular reference to the usage of NSAIDs and salicylates prior to the development of the disease. METHODS One hundred and five consecutive new cases of colitis presenting to a single gastroenterologist were questioned about their recent usage of NSAIDs and salicylates. For comparison, the frequency of usage of these compounds was studied in two groups of 105 age- and sex-matched controls taken from hospital in-patients and community cases attending the Accident and Emergency Department. RESULTS Of the 105 cases of colitis studied, 78 patients (74%) had been taking NSAIDs or salicylates prior to or during the development of their disease. By comparison, 20% of community controls were using NSAIDs or salicylates (P < 0.001) and 30% of hospital in-patients were taking these compounds (P < 0.001). Comparison of these frequencies with those of the colitis group gave odds ratios of 9.1 (4.5, 21.9) with the community controls and 6.2 (3.2, 13.5) with the hospital controls. CONCLUSIONS In new patients presenting with colitis, there is a significantly high frequency of antecedent exposure to NSAIDs or salicylates, supporting the concept that these agents may be important in the pathogenesis of colitis.
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Affiliation(s)
- M H Gleeson
- Department of Gastroenterology, The General Hospital, St Helier, Jersey, Channel Islands, UK.
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Kojima K, Naruse Y, Iijima N, Wakabayashi N, Mitsufuji S, Ibata Y, Tanaka M. HPA-axis responses during experimental colitis in the rat. Am J Physiol Regul Integr Comp Physiol 2002; 282:R1348-55. [PMID: 11959675 DOI: 10.1152/ajpregu.00260.2001] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
We investigated the responses of the hypothalamic-pituitary-adrenal (HPA) axis during experimental colitis induced by intracolonic administration of 2,4,6-trinitrobenzenesulfonic acid in the rat. On days 3 and 7 after induction of colitis, the corticotropin-releasing hormone (CRH) mRNA level in the parvocellular paraventricular nucleus (pPVN) of the hypothalamus was reduced, the plasma ACTH level remained at the basal level, and the plasma corticosterone (Cort) level was high. Induction of colitis on day 3 after adrenalectomy with Cort pellet replacement (ADX + Cort) resulted in a marked increase in CRH mRNA on day 7 after induction of colitis compared with noncolitic ADX + Cort animals. Pair feeding to match the food intake of the colitic animals resulted in no significant change in CRH mRNA in the pPVN, plasma ACTH, and Cort compared with healthy control animals. These findings indicated that CRH mRNA expression in the pPVN was inhibited by glucocorticoid feedback during this experimental colitis, and the decrease in food intake during colitis was not simply responsible for the expression of CRH mRNA. It is inferred that the HPA axis including the CRH level in the pPVN is altered in patients with inflammatory bowel disease.
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Affiliation(s)
- Kensaku Kojima
- Third Department of Internal Medicine, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-0841, Japan
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Abstract
Cyclooxygenase (COX), also known as prostaglandin endoperoxide synthase, is the key enzyme required for the conversion of arachidonic acid to prostaglandins. Two COX isoforms have been identified, COX-1 and COX-2. In many situations, the COX-1 enzyme is produced constitutively (e.g., in gastric mucosa), whereas COX-2 is highly inducible (e.g., at sites of inflammation and cancer). Traditional nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit both enzymes, and a new class of COX-2 selective inhibitors (COXIBs) preferentially inhibit the COX-2 enzyme. This review summarizes our current understanding of the role of COX-1 and COX-2 in normal physiology and disease.
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Affiliation(s)
- Marco E Turini
- Department of Nutrition, Nestlé Research Center, CH-1000 Lausanne 26, Switzerland
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Rachmilewitz D, Karmeli F, Takabayashi K, Hayashi T, Leider-Trejo L, Lee J, Leoni LM, Raz E. Immunostimulatory DNA ameliorates experimental and spontaneous murine colitis. Gastroenterology 2002; 122:1428-41. [PMID: 11984528 DOI: 10.1053/gast.2002.32994] [Citation(s) in RCA: 257] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
BACKGROUND & AIMS Impaired mucosal barrier, cytokine imbalance, and dysregulated CD4(+) T cells play important roles in the pathogenesis of experimental colitis and human inflammatory bowel disease. Immunostimulatory DNA sequences (ISS-DNA) and their synthetic oligonucleotide analogs (ISS-ODNs) are derived from bacterial DNA, are potent activators of innate immunity at systemic and mucosal sites, and can rescue cells from death inflicted by different agents. We hypothesized that these combined effects of ISS-DNA could inhibit the damage to the colonic mucosa in chemically induced colitis and thereby limit subsequent intestinal inflammation. METHODS The protective and the anti-inflammatory effect of ISS-ODN administration were assessed in dextran sodium sulfate-induced colitis and in 2 models of hapten-induced colitis in Balb/c mice. Similarly, these effects of ISS-ODN were assessed in spontaneous colitis occurring in IL-10 knockout mice. RESULTS In all models of experimental and spontaneous colitis examined, ISS-ODN administration ameliorated clinical, biochemical, and histologic scores of colonic inflammation. ISS-ODN administration inhibited the induction of colonic proinflammatory cytokines and chemokines and suppressed the induction of colonic matrix metalloproteinases in both dextran sodium sulfate- and hapten-induced colitis. CONCLUSIONS As the colon is continuously exposed to bacterial DNA, these findings suggest a physiologic, anti-inflammatory role for immunostimulatory DNA in the GI tract. Immunostimulatory DNA deserves further evaluation for the treatment of human inflammatory bowel disease.
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Mahadevan U, Loftus EV, Tremaine WJ, Sandborn WJ. Safety of selective cyclooxygenase-2 inhibitors in inflammatory bowel disease. Am J Gastroenterol 2002; 97:910-4. [PMID: 12008668 DOI: 10.1111/j.1572-0241.2002.05608.x] [Citation(s) in RCA: 104] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
OBJECTIVES Nonsteroidal anti-inflammatory drugs (NSAIDs) are relatively contraindicated in patients with inflammatory bowel disease (IBD) for fear of disease aggravation. Cyclooxygenase-2 inhibitors have fewer GI side effects than traditional NSAIDs in unselected patients. We report the safety of these agents in patients with IBD. METHODS Patients with Crohn's disease, ulcerative colitis, or pouchitis who used celecoxib or rofecoxib were identified from computerized prescription records. A retrospective chart review was conducted. Concomitant medications, past NSAID use, indication for cyclooxygenase-2 inhibitor, dose, and duration were obtained. IBD disease activity before cyclooxygenase-2 inhibitor use was graded using a modified disease activity index. Change in disease activity was graded as improved, no change, or worsened. Patients were contacted to provide data not found in the charts. The proportion of patients receiving cyclooxygenase-2 inhibitors who experienced exacerbation of IBD was determined. RESULTS Eleven patients were treated with celecoxib (median dose = 200 mg/day), and 16 patients were treated with rofecoxib (median dose = 25 mg/day). Median duration of therapy was 9 months (range = 1 wk-22 months). The drug was beneficial in 14 patients, of partial benefit in eight, and of no benefit in five. Two patients (7.4%) (95% CI = 2-23%) had aggravations of IBD. Three patients (11%) had other adverse events (renal insufficiency, rash, and asymptomatic colonic ulceration). All adverse events were reversible. CONCLUSIONS Our preliminary results suggest that cyclooxygenase-2 inhibitors may be safe and beneficial in most patients with IBD. A placebo-controlled trial to confirm these preliminary observations is needed.
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Affiliation(s)
- Uma Mahadevan
- Division of Gastroenterology and Hepatology, University of California, San Francisco, 55905, USA
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Smale S, Natt RS, Orchard TR, Russell AS, Bjarnason I. Inflammatory bowel disease and spondylarthropathy. ARTHRITIS AND RHEUMATISM 2001; 44:2728-36. [PMID: 11762932 DOI: 10.1002/1529-0131(200112)44:12<2728::aid-art459>3.0.co;2-8] [Citation(s) in RCA: 81] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Affiliation(s)
- S Smale
- Guy's, King's, St Thomas' School of Medicine, London, UK
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Cuzzocrea S, Mazzon E, Serraino I, Dugo L, Centorrino T, Ciccolo A, Sautebin L, Caputi AP. Celecoxib, a selective cyclo-oxygenase-2 inhibitor reduces the severity of experimental colitis induced by dinitrobenzene sulfonic acid in rats. Eur J Pharmacol 2001; 431:91-102. [PMID: 11716847 DOI: 10.1016/s0014-2999(01)01403-0] [Citation(s) in RCA: 46] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Inflammatory bowel disease is characterised by oxidative and nitrosative stress, leukocyte infiltration, upregulation of the expression of intercellular adhesion molecule 1 (ICAM-1) and upregulation of P-selectin in the colon. Here, we investigate the effects of the selective cyclo-oxygenase-2 inhibitor, celecoxib, in rats subjected to experimental colitis. Colitis was induced in rats by intracolonic instillation of dinitrobenzene sulfonic acid (DNBS). Rats experienced hemorrhagic diarrhoea and weight loss. At 4 days after administration of DNBS, the mucosa of the colon exhibited large areas of necrosis. Neutrophil infiltration (determined by histology, as well as an increase in myeloperoxidase activity in the mucosa) was associated with upregulation of ICAM-1 and P-selectin, as well as high tissue levels of malondialdehyde. Immunohistochemistry for nitrotyrosine and poly(ADP-ribose) polymerase showed intense staining in the inflamed colon. Celecoxib (5 mg/kg twice a day orally) significantly reduced the degree of hemorrhagic diarrhoea and the weight loss caused by administration of DNBS. Celecoxib also caused a substantial reduction of (i) the degree of colonic injury, (ii) the rise in myeloperoxidase activity (mucosa), (iii) the increase in the tissue levels of malondialdehyde, (iv) the increase in staining (immunohistochemistry) for nitrotyrosine, as well as (v) the upregulation of ICAM-1 and P-selectin caused by DNBS in the colon. Thus, we provide the first evidence that a selective cyclo-oxygenase-2 inhibitor celecoxib reduces the degree of colitis caused by DNBS.
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Affiliation(s)
- S Cuzzocrea
- Institute of Pharmacology, School of Medicine, University of Messina, Torre Biologica, Policlinico Universitario Via C. Valera, Gazzi, 98100, Messina, Italy.
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Holma R, Salmenperä P, Riutta A, Virtanen I, Korpela R, Vapaatalo H. Acute effects of the cys-leukotriene-1 receptor antagonist, montelukast, on experimental colitis in rats. Eur J Pharmacol 2001; 429:309-18. [PMID: 11698051 DOI: 10.1016/s0014-2999(01)01330-9] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Cysteinyl leukotrienes play a part in inflammatory reactions such as inflammatory bowel diseases. The aim of the present study was to evaluate the acute effects of a cys-leukotriene-1 receptor antagonist, montelukast, on trinitrobenzene sulphonic acid (TNBS)-induced colitis in rats. Montelukast (5, 10 or 20 mg kg(-1) day(-1)), a 5-lipoxygenase inhibitor, zileuton (50 or 100 mg kg(-1) day(-1), a positive control), or the vehicle was administered intracolonically to the rats twice daily throughout the study, starting 12 h before the induction of colitis with TNBS. The severity of colitis (macroscopic and histological assessment, as well as myeloperoxidase activity), the protein expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2, and eicosanoid production in colonic tissue incubation were assessed 24 and 72 h after colitis induction. Montelukast increased prostaglandin E(2) production at 24 h and tended to reduce the cyclooxygenase-2 protein expression at 72 h, but did not influence the severity of colitis. Zileuton failed to decrease the inflammatory reaction in spite of reduced leukotriene B(4) production at 72 h. The results suggest that drugs that block cysteinyl leukotriene receptors have limited potential to ameliorate acute TNBS-induced colitis, but that they exert some beneficial effects which make them capable of modulating the course of colitis.
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Affiliation(s)
- R Holma
- Institute of Biomedicine, Pharmacology, Biomedicum Helsinki, P.O. Box 63, FIN-00014 University of Helsinki, Helsinki, Finland
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Bjarnason I, Rainsford KD. Are cyclooxygenase 2 inhibitors free of gastrointestinal side effects? West J Med 2001; 175:267-8. [PMID: 11577061 PMCID: PMC1071578 DOI: 10.1136/ewjm.175.4.267] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Affiliation(s)
- I Bjarnason
- Department of Medicine, Guy's, King's, St Thomas' Medical School, Bessemer Rd, London SE5 9PJ, UK.
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Affiliation(s)
- I Bjarnason
- Department of Medicine, Guy's, King's, St Thomas' Medical School, London, UK.
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Davies NM, Gudde TW, de Leeuw MA. Celecoxib: a new option in the treatment of arthropathies and familial adenomatous polyposis. Expert Opin Pharmacother 2001; 2:139-52. [PMID: 11336575 DOI: 10.1517/14656566.2.1.139] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
The discovery of the two isoenzymes of cyclooxygenase (COX) has recently lead to the development and clinical introduction of specific inhibitors of cyclooxygenase-2 (COX-2), such as celecoxib, onto the market. Celecoxib is an effective anti-inflammatory, analgesic and antipyretic agent therapeutically utilised in the management of osteoarthritis and rheumatoid arthritis. In addition, celecoxib has some novel therapeutic and pharmacological activities. Celecoxib inhibits anti-apoptotic kinase activation and is the first specific COX-2 inhibitor to be marketed for familial adenomatous polyposis, an inheritable predisposition for colorectal cancer. Celecoxib is not without gastrointestinal (GI) side effects but demonstrates markedly reduced GI ulceration in clinical trials when compared to traditional non-specific non-steroidal anti-inflammatory drugs (NSAIDs). The specific COX-2 inhibitors each have distinctive pharmacokinetic properties. Celecoxib can be given either once or twice daily. Racial differences in drug disposition, and pharmacokinetic changes in elderly patients, patients with chronic renal insufficiency and patients with mild to moderate hepatic impairment, are evident with celecoxib. Despite the specific action of these drugs, there remains the potential for significant drug interactions. Celecoxib has demonstrated interactions with fluconazole, lithium and warfarin. Increased clinical vigilance should be maintained when co-prescribing medications with celecoxib until further clinical experience is gained. Celecoxib represents a major therapeutic advance in terms of GI safety. However, long-term safety in other organ systems, safety with concomitant drug administration, and pharmacoeconomic benefits still remain to be proven.
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Affiliation(s)
- N M Davies
- Faculty of Pharmacy, University of Sydney, Sydney, New South Wales 2006, Australia.
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