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Evaluate factors influencing risk of colorectal cancer development in inflammatory bowel disease patients.
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A total of 218 consecutive eligible patients (131 males, 87 females age 64.3 years, range 51-79), affected by diverticulitis were monitored. Of these, 109 patients were treated with rifaximin 400 mg bid plus mesalazine 800 mg tid for 7 days, followed by rifaximin 400 mg bid plus mesalazine 800 mg bid for 7 days/month (group A); 109 patients were treated with rifaximin 400 mg bid for 7 days, followed by rifaximin 400 mg bid for 7 days/month (group B). Colonoscopy was performed after 3, 6 and 12 months of therapy.
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In view of a high recurrence rate of Crohn's disease after surgical resection prophylaxis is desirable. The value of various medical therapies to maintain remission after surgery has thus far only partially been established in clinical trials. Therefore, no clear guidelines are presently available. In patients with complete resection and a low risk of recurrence prophylactic treatment seems not to be necessary. In patients with a high risk of recurrence prophylactic treatment is recommended. This recommendation is supported by some clinical trials, although major trials are still ongoing. 5-Aminosalicylic acid in a daily dose of ca. 2-3 g is the primary choice for prophylaxis of recurrence. It reduces the risk of recurrence presumably by about 50%. In patients with a complicated course of the disease who have undergone several previous resections immunosuppressive treatment with azathioprine (1-2 mg/kg body weight/day) is recommended to avoid further recurrences. Conventional corticosteroids are not effective for postoperative prophylaxis. Ongoing studies evaluate the non-systemic steroid budesonide as prophylactic treatment. There is no specific nutritional therapy to prevent recurrences; however, patients are advised to avoid nutrients which they do not tolerate. When patients have a clinical relapse systemic or topical corticosteroids are the treatment of choice. In moderately active disease and in patients who refuse to take corticosteroids high dose 5-aminosalicylic acid (at least 4 g/day) may be used alternatively. In patients with chronic complicated disease azathioprine is recommended.
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Two authors independently extracted data and assessed the risk of bias for each study. The primary outcome was the occurrence of clinical or endoscopic relapse as defined by the primary studies. Secondary outcomes included frequency and nature of adverse events, change of disease activity score and steroid-sparing effect. We calculated the risk ratio and corresponding 95% confidence interval for dichotomous outcomes. Data were analyzed on an intention-to-treat basis. The overall quality of the evidence supporting the outcomes was evaluated using the GRADE criteria.
Randomized controlled trials of at least 12 months duration that compared azathioprine or 6-mercaptopurine with placebo or standard maintenance therapy (mesalamine) were included.
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Ulcerative colitis is largely a disease of nonsmokers. Having found previously that treatment with transdermal nicotine patches and mesalamine (5-aminosalicylic acid) has a beneficial effect on active colitis, we examined the value of transdermal nicotine for the maintenance of remission.
One hundred and sixty patients with active inflammation limited to the rectum were treated with mesalazine 1 g suppository once daily for 8 weeks. Patients who achieved clinical remission were advised to maintain the treatment, and were followed up for further 40 weeks. FC levels were measured every 8 weeks during the study.
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This population-based inception cohort showed that reduction in surgical rates was independently associated with increased and earlier azathioprine use.
Recombinant L. casei CECT 5276, which can secrete IL-10, was constructed. The length of colon tissue, disease activity index (DAI) and histological score (HS) of the mice were determined to evaluate the modeling and the effectiveness of L. casei. Real-time polymerase chain reaction (PCR), Western blot and ELISA were used to determine the levels of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), peroxisome proliferator-activated receptor (PPAR)-γ, interferon (IFN)-γ, transforming growth factor (TGF)-β and IL-10.
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The first 2-3 years after the enrollment of patients with UC in remission was the period at higher risk of relapse. No relationship was found between the different anatomic locations of the disease and the risk of relapse, even if distal colitis showed a slightly better course.
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The current findings show that RWE ameliorates intestinal oxidative and inflammatory damages in DSS and TNBS models of rat colitis, suggesting its beneficial use for the treatment of intestinal inflammatory disorders.
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Three trials fulfilled the selection criteria (double-blind, placebo-controlled, randomized studies in adult patients treated with Pentasa 4 g/day for active Crohn's disease). The efficacy and safety was evaluated in these trials by using the Crohn's Disease Activity Index (CDAI) as the primary efficacy variable. The study duration was 16 weeks in all 3 trials. The total numbers of patients were 304 in the Pentasa 4-g/day treatment groups and 311 in the placebo groups. A meta-analysis was performed based on the study reports.
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The standard therapy of ulcerative colitis and Crohn's disease is based on the treatment with corticosteroids, sulfasalazine and 5-aminosalicylic acid (mesalazine). Depending on the localization and the extent of bowel inflammation these drugs are given topically (proctosigmoiditis, left-side colitis) or systemically (total and subtotal colitis). Azathioprin and metronidazole are considered to be reserve drugs (the latter one having proven to be effective only in Crohn's disease). During the last years, the efficacy of several new agents has been investigated. At present, their routine administration cannot be advised. The clinical usefulness of new topical corticosteroids showing both high antiinflammatory effect and no or at least minor systemic side effects is promising.
Release of platelet-activating factor (PAF) by cultured colonic mucosa of patients with ulcerative colitis and healthy controls was determined. Before stimulation with calcium ionophore or antihuman IgE, no PAF release by control mucosa and minimal PAF release by mucosa of the colitis patients were detected. After stimulation with calcium ionophore, PAF release was four to five times higher by colonic mucosa of the colitis patients than of the controls. After stimulation with antihuman IgE, PAF release was twice as high by colonic mucosa of colitis patients as by control mucosa. Prednisolone, sulphasalazine, and mesalazine inhibited PAF activity stimulated by calcium ionophore in a dose-dependent manner. The results suggest that the use of PAF antagonists in the treatment of ulcerative colitis should be investigated.
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Current evidence supports the use of MMX mesalamine for treatment of mild-to-moderate UC by demonstrating that MMX mesalamine 2.4-4.8 g daily induces remission. It has the advantage of once-daily dosing regimens with lower pill burden than comparable products and, as an oral agent, may have better patient acceptability compared with topical mesalamine formulations. Therefore, MMX mesalamine is an option in patients with UC. The cost of MMX mesalamine is comparable to that of oral and rectal formulations of mesalamine. Further pharmacoeconomic studies are warranted to examine the cost impact of MMX mesalamine.
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To estimate inflammatory bowel disease (IBD) prevalence in Portugal from 2003 to 2007, and to obtain disease, sex and age specific estimates.
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The radioprotective effect of 5-aminosalicylic acid (5ASA) was investigated in mouse bone marrow. The present study was aimed at investigating the radioprotective effect of pre-irradiation treatment with 5ASA against a range of whole-body lethal (8-11 Gy) and sublethal (1-4 Gy) doses of gamma-radiation (RT) in adult Swiss albino mice. Protection against lethal irradiation was evaluated from 30-day mouse survival and against sublethal doses was assessed from chromosomal aberrations in the bone marrow 24 h after irradiation. An intraperitoneal injection of 5ASA at a dose of 25mg/kg body weight (b. wt.) 30 min before lethal RT increased survival, giving a dose modification factor (DMF) of 1.08. Injection of 5ASA (25 mg/kg b. wt.) 60 or 30 min before or within 15 min after 3 Gy whole body RT resulted in a significant decrease in the radiation-induced aberrant metaphases, at 24 h post-irradiation. Maximum effect was seen when the drug was administered 30 min before irradiation. 5ASA (25 mg/kg b. wt.) significantly reduced the number of aberrant metaphases and the different types of aberrations at all the radiation doses (1-4 Gy) tested, giving a DMFs of 1.43 for number of aberrant metaphases. 5ASA pretreatment also significantly enhanced the endogenous spleen colonies in mouse exposed to 11 Gy RT. Pretreatment with 5ASA, protected plasmid DNA (pGEM-7Zf) against breakage induced by RT and Fenton reactants. Using nanosecond pulse radiolysis technique, the bimolecular rate constant of the reaction of 5ASA with hydroxyl radical was found to be 6.7x10(9)M(-1)s(-1). The p53 and p21 protein levels of bone marrow and spleen were evaluated to identify the specific molecular mechanisms. Both p53 and p21 increased 24h after 6 Gy irradiation, while treatment with 5ASA inhibited this RT-induced increase. Therefore, the present data suggest that 5ASA pretreatment decreases death caused by RT-induced gastrointestinal and hemopoeitic syndromes. The proposed mechanism of radioprotection by 5ASA is through the inhibition of damage to DNA, lipids, and proteins; and prevention of RT-induced increased expression of p53 and p21.
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An 18-year-old male patient treated for Crohn's disease for 3 years developed buccal manifestations. The oro-facial symptoms disappeared completely with systemic corticosteroid treatment. Diagnosis, pathological features, treatment and pathogenesis hypotheses are discussed.
Adriamycin (ADM) is a broad-spectrum antineoplastic antibiotic used to treat cancer patients. However, the usefulness of this drug is presently limited by the development of a dose-dependent cardiotoxicity. A current hypothesis for the ADM-induced cardiotoxicity is the production of reactive oxygen radicals by the drug. We utilized the fluorescent indicator 2',7'-dichlorodihydrofluorescein diacetate (DCFH/DA), in which fluorescence appears if reactive oxygen species (ROS) are present, to investigate the ability of ADM to generate reactive oxygen species and the potential protective effect of antioxidants in a cultured cardiomyocyte model. All three of the antioxidants (alpha-phenyl-tert-butyl nitrone (PBN), trolox, and 5-aminosalicylic acid (5-ASA)) tested in our ADM-treated myocytes provided protection against the oxidative stress induced by the drug. These findings suggest that antioxidants modulate ADM-induced oxidative stress, and they are discussed in terms of a possible therapeutic strategy in the prevention of cardiotoxicity resulting from ADM administration.
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Medical treatment was curative only in 21 of 123 patients. Overall, medical and surgical treatment either cured or improved 62 percent of the cases. Fifty percent had an intestinal resection. Abscess drainage and fistulotomy were the most common anal surgeries. Rectovaginal fistulas (n = 30) required intestinal surgery in 36 percent and anal surgery in 20 percent of the cases, 50 percent with good results. Of 166 patients who had anal surgery, 97 (58 percent) had a positive outcome. Recurrence of anal disease requiring further surgery occurred in 24.5 percent of the cases.
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A cohort of patients with ulcerative colitis was prospectively enrolled in this observational study and followed for 12 months. Adherence was assessed by tracking pharmacy refills (medication possession ratio). Individual interviews were undertaken in a subset of subjects. Transcripts from the focus groups and interviews were analyzed to identify themes and links between these themes using qualitative data software (MaxQDA).
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There is epidemiological evidence, that mesalazine can inhibit colon cancer development by affecting proliferation and apoptosis. Several studies suggest that supplementary intake of butyrate may yield to improved efficacy of mesalazine. However, the underlying molecular mechanisms of such interaction remain unknown. This study addressed the combinatory effect of both substances on the growth of Caco-2 cells. Challenging of cells with mesalazine and butyrate provoked a time-dependent decrease in both cell counts and proliferation. Co-treatment with the substances could further intensify these effects. The growth-inhibitory action of mesalazine and butyrate was accompanied by a significant increase in caspase-3 activity, cleavage of PARP and caspase-8, while decreasing the expression of Xiap and Survivin simultaneously. Co-incubation of both substances exaggerated effects on all examined apoptosis-regulatory proteins except for Xiap. Our data demonstrate that co-treatment of mesalazine and butyrate evoked additive effects on inhibition of cell growth and induction of apoptosis in Caco-2 cells.
Ulcerative colitis (UC) is a chronic inflammatory disorder of the gastrointestinal tract of unknown etiology that frequently presents in the pediatric population. The evaluation of pediatric UC involves excluding infection, and a colonoscopy that documents the clinical and histologic features of chronic colitis. Initial management of mild UC is typically with mesalamine therapy for induction and maintenance. Moderate UC is often initially treated with oral prednisone. Depending on disease severity and response to prednisone, maintenance options include mesalamine, mercaptopurine, azathioprine, infliximab, or adalimumab. Severe UC is typically treated with intravenous corticosteroids. Corticosteroid nonresponders should either undergo a colectomy or be treated with second-line medical rescue therapy (infliximab or calcineurin inhibitors). The severe UC patients who respond to medical rescue therapy can be maintained on infliximab or thiopurine, but 1-year remission rates for such patients are under 50 %. These medications are discussed in detail along with the initial work-up and a treatment algorithm.
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The activation of a self-amplifying cascade of caspases, of which caspase-8 is the apical protease, mediates Fas-, tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)-, and TNF-alpha-induced apoptosis in colon cell lines. Nitric oxide (NO) protects from apoptosis induced by Fas and TNF-alpha. We examined whether NCX-456, an NO-releasing derivative of mesalamine, protects colon epithelial cells from cytokine-induced apoptosis. Caco-2 and HT-29 cell lines express death factor receptors and are driven to apoptosis in response to incubation with Fas-agonistic antibody, TNF-alpha/interferon-gamma, and TRAIL. The two novel observations reported here are that 1) cotreatment of cells with NCX-456, but not mesalamine, resulted in concentration-dependent protection against death factor-induced apoptosis and inhibition of caspase activity, and 2) exposure to dithiothreitol, an agent that effectively removes NO from thiol groups, resulted in a 70% recovery of caspase activity, which is consistent with S-nitrosation as a major mechanism for caspase inactivation. These data suggest that caspase S-nitrosation represents a mechanism for protection of colonic mucosal epithelial cells from death factor-induced death.
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Our meta-analysis yielded inconsistent results that were dependent on the inclusion of either non-referral or clinic-based populations. Based on non-referral studies, there does not seem to be a protective effect of 5-ASA on CRC in IBD. However, heterogeneity among these studies limits their interpretation.
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In eight healthy volunteers accelerated intestinal transit time was induced with bisacodyl, and urinary and faecal excretion of sulphasalazine, olsalazine, 5-aminosalicylic acid (5-ASA), and acetyl-5-ASA was studied after a single oral dose of 3.3 mmol sulphasalazine, olsalazine, Pentasa, and Salofalk and 2.6 mmol of Asacol. The faecal and urinary excretion of acetyl-5-ASA was lowest after intake of sulphasalazine and olsalazine and highest after intake of Pentasa and Salofalk. The figures for Asacol were intermediate. This indicates insufficient release of 5-ASA from sulphasalazine and olsalazine. When the results of this study are compared with those of a previous study without accelerated transit time, the disposition of 5-ASA from all the 5-ASA-delivering drugs is influenced unfavourably by an accelerated gut transit but most pronounced in the case of sulphasalazine, olsalazine, and Asacol. The impaired release from the azo compounds sulphasalazine and olsalazine is a result of far less complete splitting of the diazo bond.
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The aim of this study was to evaluate the effect of active ulcerative colitis (UC) treatment on transforming growth factor beta(1) (TGF-beta(1)) concentration in plasma and rectal mucosa measured in 28 patients. The highest plasma values were observed in patients with the severe course of the disease (74.2+/-14.0 ng/ml), and they were significantly higher than in the group with mild one (43.7+/-5.6 ng/ml). Mean TGF-beta(1) measured in mucosal samples from patients with severe UC (563+/-146 pg/mg protein) doubled values from patients with mild UC (286+/-65 pg/mg protein). Plasma and mucosal TGF-beta(1) correlated significantly with disease activity index (DAI) and clinical activity index (CAI). Plasma TGF-beta(1) correlated additionally with scored endoscopic degree of mucosal injury. Treatment caused significant decrease of plasma and mucosal TGF-beta(1) concentrations. Patients who responded completely had higher baseline plasma and mucosal TGF-beta(1) that decreased significantly after the treatment. These results show that plasma and mucosal concentrations of transforming growth factor beta(1) are strongly associated with ulcerative colitis activity, and successful treatment of the disease results with decrease of their levels. More effective response to the treatment can be achieved in patients with higher baseline concentrations of TGF-beta(1).
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5-aminosalicylates (5-ASA) are widely used to treat patients with ulcerative colitis. Experimental data suggest that these agents can potentially be used in a chemopreventive fashion to inhibit the development of colitis-associated colorectal cancer (CRC); however, observational studies investigating a possible risk reduction of CRC by 5-ASA therapy have revealed conflicting results. Currently, it appears that 5-ASA have no or only a very limited effect as a deterrence against CRC. Thus, a general recommendation for long-term use of 5-ASA solely for chemopreventive measures is not warranted.
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Recombinant L. casei combined with 5-ASA is effective in the treatment of DSS-induced colitis. The possible mechanism might be the blocking of the excessive activation of NF-κB pathway, thus suppressing the release of inflammation-related factors.