salicylates and Colitis

Collagenous colitis is a disorder that is recognized as a cause of chronic diarrhea. Treatment has been based mainly on anecdotal evidence. This review was performed to identify therapies for collagenous colitis that have been proven in randomized trials.. To determine effective treatments for patients with clinically active collagenous colitis.. Relevant papers published between 1970 and June 2005 were identified via the MEDLINE and PUBMED databases. Manual searches from the references of identified papers, as well as review papers on collagenous or microscopic colitis were performed to identify additional studies. Abstracts from major gastroenterological meetings were searched to identify research submitted in abstract form only. Finally, the Cochrane Controlled Trials Register and the Cochrane Inflammatory Bowel Disease and Functional Bowel Disorders Group Specialized Trials Register were searched for other studies.. Six randomized trials were identified. One trial studied bismuth subsalicylate (published in abstract form only), one trial studied Boswellia serrata extract (published in abstract form only), one trial studied prednisolone, and 3 trials studied budesonide in the therapy of collagenous colitis.. Data were extracted independently by each author onto 2x2 tables (treatment versus placebo and response versus no response). For therapies assessed in one trial only, p-values were derived using the chi-square test. For therapies assessed in more than one trial, summary test statistics were derived using the Peto odds ratio and 95% confidence intervals. Data were combined for analysis only if the outcomes were sufficiently similar in definition.. There were 9 patients with collagenous colitis in the trial studying bismuth subsalicylate (nine 262 mg tablets daily for 8 weeks). Those randomized to active drug were more likely to have clinical (p = 0.003) and histological (p = 0.003) improvement than those assigned to placebo. Eleven patients were enrolled in the trial studying prednisolone (50 mg daily for 2 weeks). There was a trend towards clinical response in patients on active medication compared to placebo (p = 0.064). The effect of prednisolone on histologic improvement was not studied. Thirty-one patients were enrolled in the Boswellia serrata extract trial. Clinical improvement was noted in 44% of patients who received active treatment compared to 27% of patients who received placebo (p = 0.32). A total of 94 patients were enrolled in 3 trials studying budesonide (9 mg daily or in a tapering schedule for 6 to 8 weeks). The pooled odds ratio for clinical response to treatment with budesonide was 12.32 (95% CI 5.53 - 27.46), with a number needed to treat of 2 patients. There was significant histological improvement with treatment in all 3 trials studying budesonide therapy. Budesonide also appears to improve patients' quality of life.. Budesonide is effective for the treatment of collagenous colitis. The evidence for benefit with bismuth subsalicylate is weaker. The effectiveness of prednisolone and Boswellia serrata extract and other therapies for induction or maintenance of remission of collagenous colitis is unknown and requires further study.

Topics: Anti-Inflammatory Agents; Bismuth; Budesonide; Chronic Disease; Colitis; Collagen; Diarrhea; Humans; Organometallic Compounds; Randomized Controlled Trials as Topic; Salicylates

Collagenous colitis is a disorder that is recognized as a cause of chronic diarrhea. Treatment has been based mainly on anecdotal evidence. This review was performed to identify therapies for collagenous colitis that have been proven in randomized trials.. To determine effective treatments for patients with clinically active collagenous colitis.. Relevant papers published between 1970 and August 2003 were identified via the MEDLINE and PUBMED databases. Manual searches from the references of identified papers, as well as review papers on collagenous or microscopic colitis were performed to identify additional studies. Abstracts from major gastroenterological meetings were searched to identify research submitted in abstract form only. Finally, the Cochrane Controlled Trials Register and the Cochrane Inflammatory Bowel Disease Group Specialized Trials Register were searched for other studies.. Five randomized trials were identified. One trial studied bismuth subsalicylate (published in abstract form only), one trial studied prednisolone, and 3 trials studied budesonide in the therapy of collagenous colitis.. Data were extracted independently by each author onto 2x2 tables (treatment versus placebo and response versus no response). For therapies assessed in one trial only, p-values were derived using the chi-square test. For therapies assessed in more than one trial, summary test statistics were derived using the Peto odds ratio and 95% confidence intervals. Data were combined for analysis only if the outcomes were sufficiently similar in definition.. There were 9 patients with collagenous colitis in the trial studying bismuth subsalicylate (nine 262 mg tablets daily for 8 weeks). Those randomized to active drug were more likely to have clinical (p=0.003) and histological (p=0.003) improvement than those assigned to placebo. Eleven patients were enrolled in the trial studying prednisolone (50 mg daily for 2 weeks). There was a trend towards clinical response in patients on active medication compared to placebo (p=0.064). The effect of prednisolone on histologic improvement was not studied. A total of 94 patients were enrolled in 3 trials studying budesonide (9 mg daily or in a tapering schedule for 6 to 8 weeks). The pooled odds ratio for clinical response to treatment with budesonide was 12.32 (95% CI 5.53-27.46), with a number needed to treat of 2 patients. There was significant histological improvement with treatment in all 3 trials studying budesonide therapy.. Budesonide is effective for the treatment of collagenous colitis. The evidence for benefit with bismuth subsalicylate is weaker. Prednisolone may be effective for treatment of collagenous colitis, but only a single very small study has been reported. The effectiveness of these and other therapies for induction or maintenance of remission (as opposed to producing clinical or histological improvement) of collagenous colitis is unknown.

Topics: Anti-Inflammatory Agents; Bismuth; Budesonide; Chronic Disease; Colitis; Collagen; Diarrhea; Humans; Organometallic Compounds; Randomized Controlled Trials as Topic; Salicylates

Collagenous colitis is a disorder that is recognized as a cause of chronic diarrhea. Treatment has been based mainly on anecdotal evidence. This review was performed to identify therapies for collagenous colitis that have been proven in randomized trials.. To determine effective treatments for patients with clinically active collagenous colitis.. Relevant papers published between 1970 and October 2002 were identified via the MEDLINE, PUBMED, and EMBASE databases. Manual searches from the references of identified papers, as well as review papers on collagenous or microscopic colitis were performed to identify additional studies. Abstracts from major gastroenterological meetings were searched to identify research submitted in abstract form only. Finally, the Cochrane Controlled Trials Register and the Cochrane Inflammatory Bowel Disease Group Specialized Trials Register were searched for other studies.. Four randomized trials were identified. One trial studied bismuth subsalicylate (published in abstract form only), and 3 trials (1 published in abstract form only) studied budesonide in the therapy of collagenous colitis.. Data were extracted independently by each author onto 2x2 tables (treatment versus placebo and response versus no response). For therapies assessed in one trial only, p-values were derived using the chi-square test. For therapies assessed in more than one trial, summary test statistics were derived using the Peto odds ratio and 95% confidence intervals. Data were combined for analysis only if the outcomes were sufficiently similar in definition.. There were 9 patients with collagenous colitis in the trial studying bismuth subsalicylate (nine 262 mg tablets daily for 8 weeks). Those randomized to active drug were more likely to have clinical (p=0.003) and histological (p=0.003) improvement than those assigned to placebo. A total of 94 patients were enrolled in 3 trials studying budesonide (9 mg daily for 6 to 8 weeks). The pooled odds ratio for clinical response to treatment with budesonide was 12.32 (95% CI 5.53-27.46), with a number needed to treat of 2 patients. There was significant histological improvement with treatment in all 3 trials studying budesonide therapy.. Budesonide is effective in the treatment of collagenous colitis. The evidence for bismuth subsalicylate is weaker, but still important. The roles of these and other therapies in inducing or maintaining remission (as opposed to clinical or histological improvement) of collagenous colitis are unknown.

Topics: Anti-Inflammatory Agents; Bismuth; Budesonide; Chronic Disease; Colitis; Diarrhea; Humans; Organometallic Compounds; Salicylates

Microscopic colitis (MC) encompasses the two morphologically distinct entities of collagenous colitis (CC) and lymphocytic colitis (LC). MC was first described less than 30 years ago but is presently recognized as a relatively common cause of chronic diarrhea in the adult population. Remarkably, up to 10% of adults who have a colonoscopy for the investigation of chronic diarrhea, and have endoscopically normal appearing mucosa, may have MC. Patients with MC generally present with chronic diarrhea, which can be associated with cramping and bloating. Endoscopic and radiological examinations are usually normal. Histological assessment reveals inflammation consisting predominantly of lymphocytic infiltration, and a thickened subepithelial collagen band is diagnostic of CC. Both LC and CC can be associated with autoimmune diseases such as celiac disease, diabetes, arthritis and thyroiditis, yet the mechanisms involved in the pathogenesis remain unclear. Emerging studies suggest that a stepwise approach be taken in the medical management of MC. This approach includes antidiarrheal agents and stopping of any offending agents; budesonide or bismuth subsalicylate; and cholestyramine or 5-acetylsalicylic acid agents. In resistant cases, oral corticosteroids and other immune modulatory therapy have been used.

Topics: Algorithms; Antidiarrheals; Bismuth; Budesonide; Colitis; Humans; Organometallic Compounds; Salicylates; T-Lymphocytes

Collagenous colitis is a disorder that is recognized as a cause of chronic diarrhea. Treatment has been based mainly on anecdotal evidence. This review was performed to identify therapies for collagenous colitis that have been proven in randomized trials.. To determine effective treatments for patients with clinically active collagenous colitis.. Relevant papers published between 1970 and April 2003 were identified via the MEDLINE and PUBMED databases. Manual searches from the references of identified papers, as well as review papers on collagenous or microscopic colitis were performed to identify additional studies. Abstracts from major gastroenterological meetings were searched to identify research submitted in abstract form only. Finally, the Cochrane Controlled Trials Register and the Cochrane Inflammatory Bowel Disease Group Specialized Trials Register were searched for other studies.. Four randomized trials were identified. One trial studied bismuth subsalicylate (published in abstract form only), and 3 trials studied budesonide in the therapy of collagenous colitis.. Data were extracted independently by each author onto 2x2 tables (treatment versus placebo and response versus no response). For therapies assessed in one trial only, p-values were derived using the chi-square test. For therapies assessed in more than one trial, summary test statistics were derived using the Peto odds ratio and 95% confidence intervals. Data were combined for analysis only if the outcomes were sufficiently similar in definition.. There were 9 patients with collagenous colitis in the trial studying bismuth subsalicylate (nine 262 mg tablets daily for 8 weeks). Those randomized to active drug were more likely to have clinical (p=0.003) and histological (p=0.003) improvement than those assigned to placebo. A total of 94 patients were enrolled in 3 trials studying budesonide (9 mg daily or in a tapering schedule for 6 to 8 weeks). The pooled odds ratio for clinical response to treatment with budesonide was 12.32 (95% CI 5.53-27.46), with a number needed to treat of 2 patients. There was significant histological improvement with treatment in all 3 trials studying budesonide therapy.. Budesonide is effective in the treatment of collagenous colitis. The evidence for bismuth subsalicylate is weaker, but still important. The roles of these and other therapies in inducing or maintaining remission (as opposed to clinical or histological improvement) of collagenous colitis are unknown.

Topics: Anti-Inflammatory Agents; Bismuth; Budesonide; Chronic Disease; Colitis; Collagen; Diarrhea; Humans; Organometallic Compounds; Randomized Controlled Trials as Topic; Salicylates

Collagenous colitis is a disorder that is recognized as a cause of chronic diarrhea. Treatment has been based mainly on anecdotal evidence. This review was performed to identify therapies for collagenous colitis that have been proven in randomized trials.. To determine effective treatments for patients with clinically active collagenous colitis.. Relevant papers published between 1970 and January 2002 were identified via the MEDLINE, PUBMED, and EMBASE databases. Manual searches from the references of identified papers, as well as review papers on collagenous or microscopic colitis were performed to identify additional studies. Abstracts from major gastroenterological meetings were searched to identify research submitted in abstract form only. Finally, the Cochrane Controlled Trials Register and the Cochrane Inflammatory Bowel Disease Group Specialized Trials Register were searched for other studies.. Four randomized trials were identified. One trial studied bismuth subsalicylate (published in abstract form only), and 3 trials (2 published in abstract form only) studied budesonide in the therapy of collagenous colitis.. Data were extracted independently by each author onto 2x2 tables (treatment versus placebo and response versus no response). For therapies assessed in one trial only, p-values were derived using the chi-square test. For therapies assessed in more than one trial, summary test statistics were derived using the Peto odds ratio and 95% confidence intervals. Data were combined for analysis only if the outcomes were sufficiently similar in definition.. There were 9 patients with collagenous colitis in the trial studying bismuth subsalicylate (nine 262 mg tablets daily for 8 weeks). Those randomized to active drug were more likely to have clinical (p=0.003) and histological (p=0.003) improvement than those assigned to placebo. A total of 86 patients were enrolled in 3 trials studying budesonide (9 mg daily for 6 to 8 weeks). The pooled odds ratio for clinical response to treatment with budesonide was 16.79 (95% CI 7.28-38.74), with a number needed to treat of 2 patients. There was significant histological improvement with treatment in all 3 trials studying budesonide therapy.. Budesonide is effective in the treatment of collagenous colitis. The evidence for bismuth subsalicylate is weaker, but still important. The roles of these and other therapies in inducing or maintaining remission (as opposed to clinical or histological improvement) of collagenous colitis are unknown.

Topics: Anti-Inflammatory Agents; Bismuth; Budesonide; Colitis; Collagen; Humans; Organometallic Compounds; Randomized Controlled Trials as Topic; Salicylates

Peptic gastroduodenal lesions due to nonsteroidal antiinflammatory drugs (NSAID) are well known, but not the adverse effects of these preparations in the lower GI tract. The cases of 5 patients with NSAID-induced colitis are described and the pertinent literature is reviewed, which reveals a wide spectrum of alterations ranging from mild non-specific colitis to acute bleeding or perforation. The most important key to correct diagnosis is a careful drug history, and treatment is to discontinue the NSAID.

Topics: Adult; Anti-Inflammatory Agents, Non-Steroidal; Colitis; Diclofenac; Female; Humans; Male; Mefenamic Acid; Middle Aged; Proctitis; Salicylates

Topics: Bismuth; Colitis; Humans; Organometallic Compounds; Salicylates

The pathogenesis of the microscopic colitis syndrome is unknown but may involve bacteria, an intestinal luminal antigen, and/or autoimmunity. It was hypothesized that bismuth subsalicylate would resolve both diarrhea and colonic inflammation in microscopic colitis because it possesses antidiarrheal, antibacterial, and anti-inflammatory properties.. Thirteen patients with microscopic colitis (7 with subepithelial collagen deposition and 6 without) were treated with eight chewable 262-mg bismuth subsalicylate tablets per day for 8 weeks. Patients recorded the frequency of bowel movements daily. Forty-eight-hour stool collections and flexible sigmoidoscopy with 24 biopsies were performed before and after treatment in each patient.. Twelve patients completed the trial. Eleven patients had a resolution of diarrhea and a reduction in fecal weight. The average time to respond was 2 weeks. In 9 patients, colitis resolved. When present before treatment, subepithelial collagen thickening disappeared. Those completing the trial experienced no side effects. Posttreatment follow-up for 7-28 months shows that 9 patients remain well having undergone no further treatment, 2 are well but required retreatment, and 1 has continued diarrhea.. Bismuth subsalicylate treatment for 8 weeks is safe and well tolerated. This regimen appears to be efficacious for the treatment of microscopic colitis and is worthy of further study in a controlled trial.

Topics: Administration, Oral; Adult; Aged; Bismuth; Colitis; Female; Follow-Up Studies; Humans; Male; Middle Aged; Organometallic Compounds; Salicylates; Treatment Outcome

Ulcerative colitis (UC) is a chronic recurrent idiopathic disease characterized by damage to the colonic epithelial barrier and disruption of inflammatory homeostasis. At present, there is no curative therapy for UC, and the development of effective and low-cost therapies is strongly advocated.. Multiple lines of evidence support that tannic acid (TA) and berberine (BBR), two active ingredients derived from Chinese herb pair (Rhei Radix et Rhizoma and Coptidis Rhizoma), have promising therapeutic effects on colonic inflammation. This study aims to develop a targeted delivery system based on BBR/TA-based self-assemblies for the treatment of UC.. TA and BBR self-assemblies were optimized, and hyaluronic acid (HA) was coated to achieve targeted colon delivery via HA-cluster of differentiation 44 (CD44) interactions. The system was systematically characterized and dextran sodium sulfate (DSS)-induced mouse colitis model was further used to investigate the biodistribution behavior, effect and mechanism of the natural system.. TA and BBR could self-assemble into stable particles (TB) and HA-coated TB (HTB) further increased cellular uptake and accumulation in inflamed colon lesions. Treatment of HTB inhibited pro-inflammatory cytokine levels, restored expression of tight junction-associated proteins and recovered gut microbiome alteration, thereby exerting anti-inflammatory effects against DSS-induced acute colitis.. Our targeted strategy may provide a convenient and powerful platform for UC and reveal new modes of application of herbal combinations.

Topics: Animals; Antineoplastic Agents; Benzopyrans; Berberine; China; Colitis; Colitis, Ulcerative; Dextran Sulfate; Disease Models, Animal; Mice; Salicylates; Tannins; Tight Junction Proteins; Tissue Distribution

Inflammatory bowel diseases are the most common chronic intestinal inflammatory conditions, and their incidence has shown a dramatic increase in recent decades. Limited efficacy and questionable safety profiles with existing therapies suggest the need for better targeting of therapeutic strategies. Adenosine monophosphate-activated protein kinase (AMPK) is a key regulator of cellular metabolism and has been implicated in intestinal inflammation. Macrophages execute an important role in the generation of intestinal inflammation. Impaired AMPK in macrophages has been shown to be associated with higher production of proinflammatory cytokines; however, the role of macrophage AMPK in intestinal inflammation and the mechanism by which it regulates inflammation remain to be determined. In this study, we investigated the role of AMPK with a specific focus on macrophages in the pathogenesis of intestinal inflammation.. A dextran sodium sulfate-induced colitis model was used to assess the disease activity index, histological scores, macroscopic scores, and myeloperoxidase level. Proinflammatory cytokines such as tumor necrosis factor-α, interleukin-6, and interleukin-1β were measured by enzyme-linked immunosorbent assay. Transient transfection of AMPKβ1 and LC3-II siRNA in RAW 264.7 cells was performed to elucidate the regulation of autophagy by AMPK. The expression of p-AMPK, AMPK, and autophagy markers (eg, LC3-II, p62, Beclin-1, and Atg-12) was analyzed by Western blot.. Genetic deletion of AMPKβ1 in macrophages upregulated the production of proinflammatory cytokines, aggravated the severity of dextran sodium sulfate-induced colitis in mice, which was associated with an increased nuclear translocation of nuclear factor-κB, and impaired autophagy both in vitro and in vivo. Notably, the commonly used anti-inflammatory 5-aminosalicylic acid (ie, mesalazine) and sodium salicylate ameliorated dextran sodium sulfate-induced colitis through the activation of macrophage AMPK targeting the β1 subunit.. Together, these data suggest that the development of therapeutic agents targeting AMPKβ1 may be effective in the treatment of intestinal inflammatory conditions including inflammatory bowel disease.

Topics: AMP-Activated Protein Kinases; Animals; Colitis; Cytokines; Dextran Sulfate; Inflammation; Macrophages; Mice; Mice, Inbred C57BL; RAW 264.7 Cells; Salicylates

High-fat diets (HFDs) and adiposity increase colorectal cancer risk, in part by elevating pro-inflammatory cytokines that activate pro-cancerous signaling pathways. Curcumin (CUR), a dietary polyphenol and salsalate (SAL), an non-steroidal anti-inflammatory drug (NSAID) lacking the gastrotoxicity of aspirin, each suppress inflammatory signaling, but via different cellular pathways.. A/J mice (n = 110) are fed a low-fat diet (LFD, 10% kcal), a HFD (60% kcal), a HFD containing 0.4% CUR, a HFD containing 0.3% SAL, or a HFD containing both agents (CUR/SAL). All mice receive six injections of azoxymethane. Compared to LFD-fed mice, HFD-fed mice display elevated colonic cytokines, crypt cell proliferation, and increased tumorigenesis (p < 0.05). CUR/SAL significantly reduces colonic cytokines (p < 0.01), suppresses activation of the PI3K/Akt/mTOR/NF-κB/Wnt pathways (p < 0.01), activates AMPK (p < 0.01), attenuates abnormal proliferation of the colonic mucosa (p < 0.05), and reduces tumor multiplicity and burden (p < 0.05), in comparison to the HFD control. In contrast, CUR or SAL alone does not suppress abnormal crypt cell proliferation or tumor multiplicity, and is largely ineffective in modifying activation of these signaling pathways.. These observations demonstrate the superiority of the CUR/SAL over the individual agents and provide a scientific basis for future translational studies in obese subjects and/or those habitually consuming HFDs.

Topics: Adiposity; Animals; Anti-Inflammatory Agents, Non-Steroidal; Anticarcinogenic Agents; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cell Proliferation; Colitis; Colorectal Neoplasms; Curcumin; Diet, High-Fat; Intestinal Mucosa; Male; Mice, Inbred Strains; Obesity; Precancerous Conditions; Salicylates; Signal Transduction

Ras proteins are crucial for cell differentiation and proliferation. Targeting Ras with farnesylthiosalicylic acid (FTS), a Ras antagonist, has been suggested as a therapeutic strategy in proliferative and inflammatory diseases.. To examine the role of Ras and the therapeutic potential of FTS in experimental colitis.. Colitis was induced in 26 mice by adding 2.5% dextran sodium sulfate to their drinking water for 7 days during which 12 study mice were treated with FTS and 14 control mice were given normal saline. Two additional controls included 10 naïve mice treated with FTS and 7 naïve non-treated mice. The animals were followed clinically and sacrificed after 7 days. Their colons were isolated for histological assessment and for measurement of myeloperoxidase activity (MPO), tumor necrosis factor-α(TNF-α), and interleukin-1β(Il-1β) levels. Ras and activated Ras expression was determined by immunoblotting assays. T cell populations in the colon and spleen were analyzed by flow-cytometry.. FTS induced a 2.1-fold reduction in activated Ras levels (P < 0.004). FTS-treated mice had lower disease activity scores (3.9 ± 1.7 vs. 7.5 ± 2.3, P < 0.001), and lower levels of MPO activity (1.65 ± 0.6 vs. 2.6 ± 0.8 units/g, P < 0.007), Il-1β (2.4 ± 3.6 vs. 24.3 ± 17.5 pg/mg, P < 0.01) and TNF-α (0.63 ± 0.5 vs. 1.9 ± 1 pg/mg, P < 0.04). FTS increased regulatory T cell population in the spleen (1.9 ± 0.4-fold, P < 0.04), and decreased effector T cell populations in the colon and spleen by 24 ± 3% (P < 0.03) and 27 ± 1% (P < 0.02), respectively. FTS had no remarkable side effects.. Ras is involved in the inflammatory processes of induced colitis in mice and its inhibition by FTS ameliorates the severity of the inflammation.

Topics: Animals; Blotting, Western; Colitis; Colon; Enzyme Inhibitors; Farnesol; Female; Flow Cytometry; Interleukin-1beta; Mice; Mice, Inbred BALB C; Organ Culture Techniques; ras Proteins; Salicylates; Tumor Necrosis Factor-alpha

To develop a more potent NFκB inhibitor from salicylic acid which is known to inhibit activity of NFκB, a transcription factor regulating genes involved in immunity, inflammation and tumorigenesis, derivatives of salicylic acid (SA) where the 5 position, carboxyl or hydroxyl group was modified were treated in HCT116 cells transfected with an NFκB dependent luciferase gene and LPS-stimulated RAW264.7 cells. Amidation of the carboxylic group or substitution of chlorine at the 5 position increased the ability of SA to suppress the expression of NFκB dependent luciferase and inducible nitric oxide synthase, a product of an NFκB target gene. Moreover, simultaneous amidation and chlorination of SA (5-chlorosalicylamide; 5-CSAM) conferred an additive NFκB inhibitory activity on SA. To further enhance the inhibitory activity, N-modification was imposed on 5-CSAM. N-(5-chlorosalicyloyl)phenethylamine (5-CSPA), N-(5-chlorosalicyloyl)3-phenylpropylamine (5-CSPPA) and N-(5-chlorosalicyloyl)4-hydroxyphenylethylamine (5-CSHPA) showed greater potencies for inhibiting NFκB activity than other derivatives. Their IC(50)s' in the luciferase assay measured 15μM (5-CSPA), 17μM (5-CSPPA) and 91μM (5-CSHPA). Rectal administration of 5-CSPA ameliorated TNBS-induced rat colitis, which was more effective than a conventional drug, 5-aminosalicylic acid. These data may provide useful information for development of a therapeutic agent for treatment of diseases where NFκB plays a critical role in the pathogenic progresses.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Cell Survival; Chemokine CXCL2; Colitis; HCT116 Cells; Humans; Inhibitory Concentration 50; Magnetic Resonance Spectroscopy; Mass Spectrometry; Mice; Molecular Structure; NF-kappa B; Rats; Salicylates; Spectrophotometry, Infrared; Structure-Activity Relationship; Tumor Necrosis Factor-alpha

Topics: Antidiarrheals; Bismuth; Colitis; Colitis, Collagenous; Crohn Disease; Drug Therapy, Combination; Female; Humans; Loperamide; Middle Aged; Organometallic Compounds; Psychoses, Substance-Induced; Rectal Fistula; Salicylates; Steroids

The aim of the present study was to evaluate the inmunomodulatory effects of UR-1505, a new salicylate derivative, on the T helper (Th)2/humoral response produced during dextran sodium sulfate (DSS)-induced rat colitis. In the in vitro studies, UR-1505 (300 microM) inhibited both the production of interleukin (IL)-10 and IL-5 in concanavalin A (Con A)-activated splenocytes and the production of immunoglobulin (Ig) G and IgA by B-lymphocytes. However, in contrast to the in vitro results, the administration of UR-1505 (10 and 30 mg/kg per day) to rats with established DSS-colitis enhanced both IL-10 and IgA production, whereas it inhibited IgG production, thus ameliorating the intestinal inflammation.

Topics: Animals; Anti-Inflammatory Agents; Colitis; Colitis, Ulcerative; Colon; Cytokines; Dextran Sulfate; Disease Models, Animal; Immunoglobulin A; Immunoglobulin G; Rats; Salicylates; Th2 Cells

UR-1505 is a novel salicylate derivative compound that has been demonstrated to selectively down-regulate T-cell activation. The aim of the present study was to elucidate the mechanisms involved in the intestinal anti-inflammatory effects of UR-1505 in 2 protocols of a dextran sodium sulfate (DSS) model of rat colitis: acute and established colitis.. The first protocol consisted of incorporating DSS into the drinking water at a concentration of 5% (w/v) for 5 days (acute initial colitis). In the second protocol, once the acute colitis had been induced, the concentration of DSS was reduced to 2% (w/v) and maintained for 10 days (established colitis).. The results obtained demonstrated that although UR-1505 did not exert a significant intestinal anti-inflammatory effect in ameliorating the initial steps of the intestinal inflammation induced by DSS, it had a beneficial effect on ongoing inflammation, most probably through inhibiting activation of T lymphocytes, thus avoiding perpetuation of the inflammatory process.. These results suggest that this compound is a good candidate for inducing remission or maintaining therapies in human inflammatory bowel disease (IBD). Moreover, the different results obtained by UR-1505 in these 2 protocols of colitis induction (acute initial colitis versus established colitis) confirm the importance of selection and optimization of the experimental model to evaluate the drugs to be used in IBD therapy.

Topics: Acute Disease; Animals; Anti-Inflammatory Agents, Non-Steroidal; Cells, Cultured; Chronic Disease; Colitis; Dextran Sulfate; Male; Mice; Mice, Inbred BALB C; Rats; Rats, Wistar; Salicylates; T-Lymphocytes

UR-1505 is a novel pentafluoropropoxy derivative of salicylic acid, selected from a series of salicylate derivatives, according to their activity as inhibitors of T-lymphocyte activation. This study describes the anti-inflammatory activity of UR-1505 on trinitrobenzenesulphonic acid-induced colitis in rat, an experimental model that resembles to Crohn's disease (CD), as well as its in vitro effects on T-cells and bone marrow-derived macrophages (BMDM) activation. UR-1505 showed intestinal anti-inflammatory effect, associated with reduced colonic levels of TNFalpha and LTB(4), inhibition of the expression of IFNgamma and iNOS, and lower colonic leukocyte infiltration. The in vitro assays revealed that UR-1505 also inhibited T-lymphocyte proliferation and IL-12/IFNgamma production, two of the main pro-inflammatory cytokines involved in the pathogenesis of CD. However, UR-1505 did not modify LPS- nor IFNgamma-induced activation in BMDM. Thus, UR-1505 specifically affects T-cells without modifying the activation of BMDM. In conclusion, the intestinal anti-inflammatory activity of UR-1505 seems to be mediated by a reduction in the recruitment of immune cells to the inflammatory foci, together with the inhibition of T-cell activation. These results suggest that UR-1505 may be an interesting candidate to be explored for the treatment of CD.

Topics: Animals; Anti-Inflammatory Agents; Cells, Cultured; Colitis; Colon; Crohn Disease; Disease Models, Animal; Female; Glutathione; Interferon-gamma; Leukotriene B4; Macrophages; Mice; Mice, Inbred BALB C; Nitric Oxide Synthase Type II; Rats; Rats, Wistar; Salicylates; Spleen; T-Lymphocytes; Trinitrobenzenesulfonic Acid; Tumor Necrosis Factor-alpha

Collagenous colitis is a disorder that is recognized as a cause of chronic diarrhea. Treatment has been based mainly on anecdotal evidence. This review was performed to identify therapies for collagenous colitis that have been proven in randomized trials.. To determine effective treatments for patients with clinically active collagenous colitis.. Relevant papers published between 1970 and October 2002 were identified via the MEDLINE, PUBMED, and EMBASE databases. Manual searches from the references of identified papers, as well as review papers on collagenous or microscopic colitis were performed to identify additional studies. Abstracts from major gastroenterological meetings were searched to identify research submitted in abstract form only. Finally, the Cochrane Controlled Trials Register and the Cochrane Inflammatory Bowel Disease Group Specialized Trials Register were searched for other studies.. Four randomized trials were identified. One trial studied bismuth subsalicylate (published in abstract form only), and 3 trials (1 published in abstract form only) studied budesonide in the therapy of collagenous colitis.. Data were extracted independently by each author onto 2 x 2 tables (treatment versus placebo and response versus no response). For therapies assessed in one trial only, p-values were derived using the chi-square test. For therapies assessed in more than one trial, summary test statistics were derived using the Peto odds ratio and 95% confidence intervals. Data were combined for analysis only if the outcomes were sufficiently similar in definition.. There were 9 patients with collagenous colitis in the trial studying bismuth subsalicylate (nine 262 mg tablets daily for 8 weeks). Those randomized to active drug were more likely to have clinical (p = 0.003) and histological (p = 0.003) improvement than those assigned to placebo. A total of 94 patients were enrolled in 3 trials studying budesonide (9 mg daily for 6 to 8 weeks). The pooled odds ratio for clinical response to treatment with budesonide was 12.32 (95% CI 5.53-27.46), with a number needed to treat of 2 patients. There was significant histological improvement with treatment in all 3 trials studying budesonide therapy.. Budesonide is effective in the treatment of collagenous colitis. The evidence for bismuth subsalicylate is weaker, but still important. The roles of these and other therapies in inducing or maintaining remission (as opposed to clinical or histological improvement) of collagenous colitis are unknown.

Topics: Anti-Inflammatory Agents; Bismuth; Budesonide; Colitis; Evidence-Based Medicine; Humans; Meta-Analysis as Topic; Organometallic Compounds; Randomized Controlled Trials as Topic; Salicylates

The 2,4,6-trinitrobenzene sulfonic acid (TNBS) -induced model of chronic inflammation of the rat colon was used to determine the efficacy of bismuth subsalicylate (BSS), bismuth subcitrate (CBS), and 5-aminosalicylic acid (5-ASA) administered in enema form. A novel bismuth compound 1, 2-bis[2-(1,3-dithiobismolane)thio]ethane [Bi2(EDT)3] was also tested. On day 1 colitis was induced with 50 mg TNBS/50% ethanol in female Sprague-Dawley rats, while controls received a saline enema. On day 3, twice-daily treatment with enemas of either saline, BSS, CBS, Bi2(EDT)3, or 5-ASA were initiated in the colitis and control rats. All rats were killed on day 14, and the colons excised, weighed, rated macroscopically, and then fixed for hematoxylin and eosin staining. Blinded microscopic scoring was used to determine injury and healing in all groups. Colon mass and macroscopic scores were increased (P < 0.05) in the group of rats treated with TNBS (N = 16) compared to saline controls (N = 12). Colon mass and macroscopic scores in controls treated with BSS (N = 4), CBS (N = 4), Bi2(EDT)3 (N = 4), and 5-ASA (N = 4) alone did not differ from saline control animals. Macroscopic scoring showed a decrease (P < 0.05) in the degree of damage in the group of rats treated with TNBS plus BSS (N = 15), TNBS plus Bi2(EDT)3 (N = 10) and TNBS plus CBS (N = 4) compared to the group of rats treated with TNBS plus saline (N = 16). A decrease (P < 0.05) in injury and an increase (P < 0.05, Kruskal-Wallis) in healing was observed in the groups of rats treated with TNBS plus BSS, TNBS plus CBS, and TNBS plus 5-ASA compared to the group of rats treated with TNBS plus saline. It appeared that Bi2(EDT)3 was not protective against injury at the microscopic level but that the novel Bi2(EDT)3 has an effective healing capacity at the macroscopic level. We conclude that BSS and CBS decrease injury and/or promote healing as effectively as 5-ASA in this model.

Topics: Animals; Anti-Ulcer Agents; Bismuth; Colitis; Female; Mesalamine; Organometallic Compounds; Rats; Rats, Sprague-Dawley; Salicylates; Trinitrobenzenesulfonic Acid

Several lines of evidence suggest that ulcerative colitis could be caused by excessive bacterial production of H2S in the colon. A rodent model of colitis involves the feeding of nonabsorbable, carbohydrate-bound sulfate in the form of dextran sulfate or carrageenan. The observation that metronidazole blocks the development of this colitis suggested that the injurious agent could be a sulfur-containing compound (such as H2S) that is released during the bacterial metabolism of the nonabsorbed sulfate. We tested this possibility by feeding rats dextran sulfate, with or without bismuth subsalicylate, a compound that avidly binds H2S. Bismuth subsalicylate reduced the fecal release of H2S in dextran sulfate-treated rats to values well below that of controls. Nevertheless, all the animals developed colitis. We conclude that excessive H2S production does not play a role in the dextran sulfate model of colitis.

Topics: Animals; Bismuth; Colitis; Colon; Dextran Sulfate; Feces; Hydrogen Sulfide; Male; Organometallic Compounds; Rats; Rats, Sprague-Dawley; Reference Values; Salicylates

Topics: Aged; Biopsy; Bismuth; Colitis; Collagen; Colon; Female; Humans; Organometallic Compounds; Salicylates

Microscopic colitis is a syndrome consisting of chronic watery diarrhea, a normal or near-normal gross appearance of the colonic lining, and a specific histological picture described as either lymphocytic colitis or collagenous colitis. Since its initial descriptions a quarter of a century ago, microscopic colitis has become a frequent diagnosis in patients with chronic diarrhea. Understanding of the cause and pathogenesis of microscopic colitis remain incomplete, but potentially important clues have been discovered that shed light on predisposing factors. In particular, specific HLA-DQ genotypes may be permissive for the development of microscopic colitis, and suggest a linkage to the pathogenesis of celiac sprue. Although the differential diagnosis of chronic watery diarrhea is broad, the diagnosis of microscopic colitis is straightforward, involving endoscopic inspection of the colonic mucosa and proper pathologic interpretation of biopsy specimens. As the limitations of drugs ordinarily used for other forms of inflammatory bowel disease are being recognized, new approaches, such as the use of bismuth subsalicylate, are being evaluated. The prognosis of patients with microscopic colitis syndrome remains good, and symptomatic improvement can be expected in most patients.

Topics: Adult; Bismuth; Chronic Disease; Colitis; Colonoscopy; Diagnosis, Differential; Diarrhea; Female; Humans; Inflammatory Bowel Diseases; Intestinal Mucosa; Organometallic Compounds; Pancreatic Neoplasms; Prognosis; Salicylates; Vipoma

Reactive oxygen and nitrogen species have been implicated as mediators of mucosal injury in inflammatory bowel disease. This study investigated hydroxyl radical (.OH) generation in the inflamed colon of dextran sulfate sodium (DSS)-induced colitis by measuring the .OH-specific product of salicylate hydroxylation, 2,3-dihydroxybenzoic acid (DHB). Colitis was induced in 6-7 week old CBA/H male mice by supplementing the drinking water with 5% DSS for 7 days. On the last day of dextran exposure, mice were injected with salicylate (SAL) (100 mg/kg i.p.) 60 min before sacrifice, and mucosal homogenates were assayed for SAL and 2,3-DHB by HPLC with fluorescence and electrochemical detection. Mucosal 2,3-DHB levels in mice exposed to 5% DSS were increased by 83% (p < .005); however, SAL levels were also elevated by 182% (p < .001). This translated to a 34% decrease in the ratio 2,3-DHB:SAL in inflamed mucosa, possibly indicating greater catabolism or decreased production of 2,3-DHB. In vitro investigation of the stability of DHBs and SAL in the presence of oxidants of inflammatory lesions revealed that 2,3-DHB and 2,5-DHB were rapidly degraded by hypochlorous acid (HOCl), with initial decomposition rates of 190 and 281 nmol/min, respectively (100microM DHB with 200microM HOCl). Methionine prevented decomposition of DHBs in vitro; however, in mice with 5% DSS-induced colitis, where mucosal myeloperoxidase activity was ten-fold control levels (p < .001), administration of methionine (up to 200 mg/kg i.p.) with SAL was ineffective at increasing the ratio 2,3-DHB:SAL. SAL was also degraded in vitro by HOCl (4.7 nmol/min) resulting in the formation of new fluorescent species which may be useful as indicators of HOCl-mediated injury. Salicylate hydroxylation was unable to provide conclusive evidence supporting a role for .OH in the tissue injury of DSS-induced colitis, as metabolic disturbances in the diseased animals other than changes in .OH generation may have altered 2,3-DHB levels. This problem is relevant to any study involving the in vivo use of trapping molecules. In particular, the susceptibility of 2,3-DHB to degradation by HOCl brings into question the usefulness of salicylate hydroxylation for measurement of .OH-generation in any neutrophilic inflammatory lesion.

Topics: Animals; Chromatography, High Pressure Liquid; Colitis; Dextran Sulfate; Hydrogen Peroxide; Hydroxybenzoates; Hydroxyl Radical; Hydroxylation; Hypochlorous Acid; Intestinal Mucosa; Kinetics; Male; Methionine; Mice; Mice, Inbred CBA; Peroxidase; Salicylates; Salicylic Acid

Topics: Adult; Anti-Inflammatory Agents, Non-Steroidal; Colitis; Female; Humans; Male; Middle Aged; Prospective Studies; Salicylates

Reactive oxygen species (ROS) such as superoxide anion, hydrogen peroxide, hydroxyl radical, and hypochlorous acid have been implicated in the pathogenesis of inflammation and tissue injury in colitis. To determine whether or not anti-ROS agents can decrease the severity of colitis, we evaluated the effects of three known anti-ROS agents: catalase, WR-2721, and Cu(II)2(3,5-DIPS)4 on acetic acid-induced colonic inflammation in rats. Histologically, all three compounds significantly decreased the severity of colonic inflammation. The anti-ROS activity of these compounds was also tested using the luminol-enhanced chemiluminescence assay. Catalase, WR-2721, or Cu(II)2(3,5-DIPS)4 significantly inhibited luminol-enhanced chemiluminescence produced by inflamed colonic mucosa. These findings suggest that ROS, and in particular superoxide, hydrogen peroxide, and/or one of its secondarily derived species, may play an important role in acetic acid-induced colitis. Further studies are needed to determine the potential effectiveness of these compounds in human colitis.

Topics: Acetates; Acetic Acid; Amifostine; Animals; Catalase; Colitis; Female; Luminescent Measurements; Rats; Rats, Inbred F344; Reactive Oxygen Species; Salicylates

Topics: Adult; Antidiarrheals; Bismuth; Colitis; Humans; Male; Organometallic Compounds; Salicylates

Topics: Arthritis; Arthritis, Rheumatoid; Colitis; Colitis, Ulcerative; Erythema Nodosum; Humans; Salicylates

Topics: Chronic Disease; Colitis; Humans; Salicylates; Salicylic Acid

Topics: Chronic Disease; Colitis; Colitis, Ulcerative; Humans; Salicylates