salicylates and Inflammatory-Bowel-Diseases

Inflammatory bowel diseases (IBDs) are a group of debilitating inflammatory complications specially inflicting colonic tissue in which full long term remission with current standardized treatments is yet intangible. Therapeutic side effects and efficacy considerations necessitate the development of more effective systems which lower the required drug doses, reduce systemic adverse effects and deliver the drug specifically to the desired site of action in colon. The large surface area in large intestine is suitable for drug absorption but the primary approaches to treatment depend on the gastrointestinal (GI) condition and its movements. Hereafter, there are novel GI-independent targeted drug delivery systems or therapeutic approaches, including micro- and nanoparticles that have been developed for IBD treatment and have the potential to overcome some of the current drawbacks of conventional IBD therapy. This review provides broad but concise information over the arena of the evolving systems aimed at different targets involved in IBD which are being studied in animal or in vitro models of this complication, while comparing these to conventional treatments. It further discusses important pros and cons of therapeutic approaches against IBD while helping to better understand and evaluate the future impact of novel drug delivery systems on human IBD and assisting in focusing the future research in this topic, on strategies which could provide maximum remission in IBD patients.

Topics: Adrenal Cortex Hormones; Animals; Antibodies, Monoclonal; Drug Delivery Systems; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Probiotics; Salicylates

Diarrhea is a common clinical feature of inflammatory bowel diseases and may be accompanied by abdominal pain, urgency, and fecal incontinence. The pathophysiology of diarrhea in these diseases is complex, but defective absorption of salt and water by the inflamed bowel is the most important mechanism involved. In addition to inflammation secondary to the disease, diarrhea may arise from a variety of other conditions. It is important to differentiate the pathophysiologic mechanisms involved in the diarrhea in the individual patient to provide the appropriate therapy. This article reviews microscopic colitis, ulcerative colitis, and Crohn's disease, focusing on diarrhea.

Topics: Anti-Bacterial Agents; Anti-Inflammatory Agents, Non-Steroidal; Antidiarrheals; Bacterial Infections; Biopsy; Bismuth; Blood Cell Count; Blood Chemical Analysis; Body Water; Breath Tests; Budesonide; Cholestyramine Resin; Colitis, Microscopic; Diarrhea; Drug-Related Side Effects and Adverse Reactions; Endoscopy, Gastrointestinal; Feces; Glucocorticoids; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Intestinal Absorption; Intestinal Fistula; Intestinal Mucosa; Intestines; Ion Transport; Malabsorption Syndromes; Medical History Taking; Mesalamine; Organometallic Compounds; Physical Examination; Postoperative Complications; Prednisolone; Salicylates; Sodium; Tumor Necrosis Factor-alpha

The ideal chemopreventative agent, in addition to being efficacious in the prevention of cancer, must be easily administered, affordable, safe, and well tolerated, with minimal side effects. In the past decade, a growing body of literature has emerged on the prevention of CRC in patients with long-standing CD and UC. The data are not definitive and consist almost exclusively of retrospective case-control and cohort studies rather than the more rigorous prospective RCTs. 5-ASA compounds have been most thoroughly studied, and most of the existing data support the use of 5-ASA in the prevention of CRC. Although the precise dose and duration are unclear, studies suggest that chronic systemic administration of 5-ASA at a dose of at least 1.2 g/d is most likely to be effective. A beneficial effect of folate, albeit not statistically significant, has been consistently shown in every study performed for this purpose. Folate supplementation, which is safe and affordable, should also be recommended for all patients with IBD, especially those taking sulfasalazine. UDCA has been shown to exert a protective effect in most studies on patients with UC and concomitant PSC. Because this patient population is at particularly high risk for CRC, it is advisable to consider UDCA in all patients with colitis complicated by PSC. For patients without PSC, sufficient data do not exist to recommend it for the purpose of cancer prevention. Five of the six corticosteroid studies have found a beneficial effect of systemic steroids, although most did not reach statistical significance. Regardless, given the frequent and serious adverse effects associated with chronic steroid use, systemic corticosteroids should not be prescribed for this indication. Budesonide, an oral corticosteroid with minimal systemic absorption, is a potential alternative, although it has not yet been studied as a chemopreventative agent. Similarly, until the long-term safety of chronic NSAID use can be demonstrated in patients with IBD, the role of NSAIDs in chemoprevention remains undefined. Although the data are conflicting, immune-modulating medications, such as AZA, do not seem to confer any reduction in the risk of dysplasia or CRC. The data on calcium supplementation and statin use are still too limited to endorse their use for the prevention of colitis-related CRC. Chemoprevention is an area that holds great promise in the reduction of morbidity and mortality associated with IBD. Further studies, includin

Topics: Anti-Inflammatory Agents, Non-Steroidal; Chemoprevention; Colorectal Neoplasms; Epidemiologic Studies; Gastrointestinal Agents; Glucocorticoids; Humans; Inflammatory Bowel Diseases; Risk Reduction Behavior; Salicylates

Although new salicylates are now available for the treatment of ulcerative colitis, sulphasazaline still has an important therapeutic role. The role of salicylates in Crohn's disease is limited to the mild activity phase; further data are required to clarify its role in maintenance on remission. New steroids are a real alternative to traditional steroids in active ulcerative colitis and Crohn's disease.

Topics: Acute Disease; Aspirin; Beclomethasone; Budesonide; Colitis, Ulcerative; Crohn Disease; Drug Therapy, Combination; Glucocorticoids; Humans; Inflammatory Bowel Diseases; Prednisolone; Randomized Controlled Trials as Topic; Salicylates; Sulfasalazine

CD and UC represent a spectrum of chronic IBD that present in protean ways and are accompanied by a variety of systemic sequelae. Sulfasalazine and the newer 5-aminosalicylates are important in the management of mild-to-moderate disease, whereas corticosteroids remain the primary therapy for most patients with moderate-to-severe disease (Tables 2-5). The toxicities associated with long-term steroid therapy, combined with their ineffectiveness as maintenance medications, have led to increased use of immunomodulators, such as azathioprine and 6-MP, for the treatment of steroid-dependent and steroid-resistant IBD. Infliximab is a novel therapeutic adjunct for chronically active and fistulizing CD that will herald a new era of biologic therapy for IBD. Meanwhile, CSA remains an alternative to urgent colectomy in severe UC unresponsive to corticosteroids and also for CD patients with severe disease or refractory fistulas. Finally, continued insights into the etiopathogenic pathways in IBD will provide evolving and innovative approaches until the eventual causes and cures are elucidated. In the meantime, clinicians should remain optimistic regarding current ability to reduce the morbidity and maintain the quality of life for patients suffering with these frustrating diseases.

Topics: Acute Disease; Adrenal Cortex Hormones; Anti-Bacterial Agents; Anti-Inflammatory Agents; Colitis, Ulcerative; Crohn Disease; Cyclosporine; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Methotrexate; Recurrence; Salicylates; Severity of Illness Index; Steroids

Inflammatory bowel disease is associated with an increased risk of gastrointestinal malignancy. There has been concern that either diagnostic medical radiation and long-term drug therapy--particularly immunosuppression--might contribute to this increased cancer risk. For the major drug groups (5-aminosalicylates, steroids and immunosuppressants) data are scant but broadly reassuring. Only azathioprine (including 6-mercaptopurine) has been investigated at all carefully. Short- to medium-term therapy probably poses a very slightly increased risk of malignancy which is easily accepted given the current limitation of this agent to second-line use. Continuous therapy for more than two years is much less well documented, and caution should be maintained. A hypothetical model based on data from occupational radiation exposure has been constructed; this permits reasonable confidence that the medical use of ionising radiation contributes a negligibly increased risk of malignancy overall, and is particularly unlikely to add significantly to the incidence of gastrointestinal malignancy.

Topics: Azathioprine; Cyclosporins; Gastrointestinal Neoplasms; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Radiography; Risk Factors; Salicylates; Steroids

Targeted delivery of 5-aminosalicylic acid to the small intestine and colon by controlled-release or azo-bonded compounds potentially offers treatment for ileal Crohn's disease as well as ulcerative colitis. The pharmacokinetics of sulphasalazine and aminosalicylate derivatives have been discussed and potential modes of action reviewed. These include actions on epithelial cell-surface receptors, cellular events and barrier function. Evidence for an influence of salicylates on circulating and tissue inflammatory cells is presented, as well as actions on adhesion molecules, chemotactic peptides, eicosanoids, cytokines and reactive oxygen metabolites. The precise mechanism remains unknown, but a pluripotential mode of action is an advantage when influencing the network of events that constitutes chronic inflammation. Controlled clinical trials of salicylates in ulcerative colitis and Crohn's disease have been reviewed. Their main role remains as maintenance therapy for ulcerative colitis, but relatively high doses of controlled-release preparations benefit patients with ileal Crohn's disease, following resection, or those who have recently relapsed. Finally, issues of clinical relevance have been addressed, including the choice of salicylate and safety, indications for initiating therapy, dose and duration of treatment, role in managing refractory colitis and future developments.

Topics: Aminosalicylic Acids; Controlled Clinical Trials as Topic; Humans; Inflammatory Bowel Diseases; Mesalamine; Randomized Controlled Trials as Topic; Salicylates; Sulfasalazine

After decades of therapeutic stasis, treatment advances are occurring in inflammatory bowel disease. Recognition that mesalazine was the active moiety of sulphasalazine has led to a number of new methods of delivering mesalazine without sulphapyridine, with improved toxicity ratios. Current attempts to deliver topical steroids directly to the large bowel have yet to be established as therapeutically effective. Immunosuppressive treatment has been used for many years but recent evidence has firmly established its value and cyclosporin has recently been added to the therapeutic armamentarium. Increasing understanding of the basic processes of inflammation has yielded targets for anti-inflammatory treatments aimed both at the processes of immune activation and of attraction by chemotaxis of neutrophils from the circulation to the lamina propria. Some of these novel treatments, which will be assessed in forthcoming years, involve large molecular weight bioengineered peptides and antibodies that are likely to be expensive and difficult to administer. Other treatment, e.g. 5-lipoxygenase or thromboxane synthesis inhibitors or platelet-activating factor antagonists, are conventional lower molecular weight compounds that are easier to produce and are orally active. It is predicted that 5-lipoxygenase inhibitors will be the next therapeutic advance in inflammatory bowel disease. Such a prediction may founder if blanket suppression of multiple inflammatory mechanisms, rather than targeted actions, is required in inflammation.

Topics: Adrenal Cortex Hormones; Controlled Clinical Trials as Topic; Diet Therapy; Forecasting; Humans; Immunosuppressive Agents; Immunotherapy; Inflammatory Bowel Diseases; Randomized Controlled Trials as Topic; Salicylates

Topics: Adrenal Cortex Hormones; Adult; Colitis, Ulcerative; Colostomy; Crohn Disease; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Male; Proctocolectomy, Restorative; Salicylates

Topics: Humans; Inflammatory Bowel Diseases; Salicylates; Tumor Necrosis Factor-alpha; Vascular Stiffness

Topics: Aorta; Humans; Inflammatory Bowel Diseases; Salicylates

The study is carried out to identify the expression pattern of indoleamine 2,3-dioxygenase (IDO) in human Crohn's disease and ulcerative colitis and to investigate the effect of different therapies (salicylates, steroids, and antitumor necrosis factor antibody) on the intestinal expression of IDO.. Immunohistochemistry was used. A total of 10 high power fields were counted for each patient.. IDO was expressed in the both lamina propria and epithelium. IDO expression increased in the lesions from ulcerative colitis and Crohn's disease and was positively related to the severity of inflammation. IDO-positive mononuclear cells also expressed CD11c, CD68, and TLR4. IDO expression decreased significantly after treatment with steroids and salicylates, but remained unchanged after infliximab therapy.. IDO was over-expressed in human inflammatory bowel disease. It may be a bridge between innate immunity and adaptive immunity. Steroids and salicylates may act through the inhibition of IDO expression. IDO upregulation may be a promising therapy to achieve inflammatory bowel disease remission.

Topics: Adult; Anti-Inflammatory Agents, Non-Steroidal; Antibodies, Monoclonal; Antigens, CD; Antigens, Differentiation, Myelomonocytic; CD11c Antigen; Colitis, Ulcerative; Crohn Disease; Epithelial Cells; Female; Gastrointestinal Agents; Glucocorticoids; Humans; Immunoenzyme Techniques; Indoleamine-Pyrrole 2,3,-Dioxygenase; Inflammatory Bowel Diseases; Infliximab; Intestinal Mucosa; Male; Middle Aged; Salicylates; Toll-Like Receptor 4; Tumor Necrosis Factor-alpha

Aminosalicylates are widely used with azathioprine in the treatment of IBD. The association results in an increase in 6-TGN levels in adults with IBD with a difference in the occurrence of myelotoxic effects. Scarce data are available in pediatric population. We proposed to investigate the effect of the coadministration of aminosalicylates on thiopurine concentrations in pediatric IBD patients.. Data from 71 patients treated for at least 1 y by azathioprine and aminosalicylates were recorded. 6-TGN and 6-MeMPN concentrations, blood cell counts and liver function tests were compared between patients taking and those not taking aminosalicylates.. Aminosalicylate therapy was associated with a significant increase in mean 6-TGN but also 6-MeMPN concentrations. In patients in remission, 6-TGN level was related to aminosalicylate dosage (r = 0.561, p = 0.010). Lymphopenia rate was higher in patients receiving combined therapy compared to monotherapy whereas a slight rise in leucopenia was found.. This observation suggests that the higher frequency of lymphopenia may be associated with the elevated 6-TGN concentrations recovered in patients treated with aminosalicylates. This combination does not improve remission rate but could increase adverse effects especially lymphopenia.

Topics: Adolescent; Aminosalicylic Acids; Azathioprine; Biotransformation; Child; Child, Preschool; Drug Therapy, Combination; Erythrocytes; Female; Gastrointestinal Agents; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Lymphopenia; Male; Mesalamine; Purines; Salicylates; Sulfasalazine

Na+/H+ exchanger isoform 3 (NHE-3) is responsible for net uptake of NaCl and water from the gastrointestinal (GI) tract. However, its status in human inflammatory bowel diseases (IBDs) such as ulcerative colitis(UC) and Crohn's disease (CD) remains poorly understood. The aim of this study was to investigate the underlying mechanism of NHE-3 isoform expression and its modulation by 5'-aminosalicylate in human CD and UC.. Subjects were divided into three groups: 1) controls; 2) untreated/new IBD cases (n = 13) and 3) 5'-aminosalicylate-treated IBD patients (n = 13). Subjects presenting with abdominal pain but with endoscopically normal colons served as normal controls. Inflammation was confirmed by the level of myeloperoxidase (MPO) activity, malondialdehyde (MDA) concentrations and by histologic evaluation. Expressions of NHE-3 protein and mRNA, sodium pump activity and IL-1beta and TNF-alpha mRNA were estimated in the colonic biopsies using ECL-Western blot analysis,reverse transcription-polymerase chain reaction (RT-PCR) and enzyme assays.. The level of NHE-3 protein and sodium pump activity was reduced (p < 0.05) in both the untreated and treated CD and UC patients. NHE-3 mRNA was reduced only in CD patients but not in those with UC. The treatment reversed the symptoms, but levels of MPO activity, MDA concentration, IL-1beta, TNF-alpha and infiltration of inflammatory cells remained high with the exception of IL-1beta mRNA in the treated patients.. NHE-3 suppression is regulated differentially in CD and UC, which together with suppression of sodium pump activity will reduce NaCl and water uptake from the colonic lumen. These findings suggest a role of TNF-a in the regulation of NHE-3 expression in IBD.

Topics: Adult; Anti-Inflammatory Agents, Non-Steroidal; Biopsy; Blotting, Western; Case-Control Studies; Colitis, Ulcerative; Colon; Crohn Disease; Female; Humans; Inflammatory Bowel Diseases; Interleukin-1beta; Male; Malondialdehyde; Middle Aged; Peroxidase; Protein Isoforms; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Salicylates; Sodium Chloride; Sodium-Hydrogen Exchanger 3; Sodium-Hydrogen Exchangers; Sodium-Potassium-Exchanging ATPase; Tumor Necrosis Factor-alpha; Water

Respiratory symptoms are over-represented in inflammatory bowel disease. There are similarities between the epidemiology of inflammatory bowel disease and that of respiratory conditions for which an adverse influence of salicylate has been identified. Natural salicylates exist within our diet.. To determine whether a lower intake of dietary salicylates is associated with less active inflammatory bowel disease and fewer concurrent respiratory symptoms.. Respiratory status, inflammatory bowel disease activity, quality of life, and dietary habits were established in 73 patients with Crohn's disease and 69 with ulcerative colitis, using a self-administered questionnaire and peak expiratory flow rate readings. Harvey-Bradshaw and Simple Birmingham/Royal Free Colitis indices, an internally validated respiratory score, and estimated weekly dietary salicylate intake, were calculated for each patient.. There was at least one respiratory symptom in 63.4% of patients. The commonest underlying respiratory diagnosis was asthma. Respiratory impairment was similar in ulcerative colitis and Crohn's disease; 56.3% of Crohn's disease patients with an active respiratory diagnosis had other extra-intestinal manifestations. The dietary salicylate intake was independent of respiratory status, but inversely correlated with ulcerative colitis activity (dietary salicylate intake 37.0mg versus 21.4mg for low and higher Simple Birmingham/Royal Free Colitis index, respectively; p<0.02). A similar association was not seen in Crohn's disease.. Respiratory impairment is common in inflammatory bowel disease. Higher intake of dietary salicylates is associated with less active colitis and possibly causally so.

Topics: Adolescent; Adult; Asthma; Comorbidity; Diet; Female; Humans; Inflammatory Bowel Diseases; Male; Respiratory Tract Diseases; Salicylates

Topics: Comorbidity; Diet; Humans; Inflammatory Bowel Diseases; Respiratory Tract Diseases; Salicylates

Poor compliance with 5-aminosalicylic acid therapy has been reported amongst patients with inflammatory bowel disease. Currently, there is no easy method to monitor 5-aminosalicylic acid; however, the chemical similarity between 5-aminosalicylic acid and salicylate might provide a solution.. To determine the feasibility of using salicylate levels to monitor compliance with 5-aminosalicylic acid medication.. Thirty-six patients with inflammatory bowel disease, taking maintenance 5-aminosalicylic acid, provided either a paired serum and urine sample or an intestinal biopsy. Samples were split into two: half were sent to the hospital biochemistry department for salicylate measurement, and half were analysed for 5-aminosalicylic acid and its metabolite, N-acetyl-5-aminosalicylic acid, using high performance liquid chromatography. Correlation between the results was calculated.. Serum and urine were available for 25 patients. Serum salicylate was undetectable, but urinary salicylate ranged from 31 to 3254 microg/mL. The correlations between urinary salicylate and 5-aminosalicylic acid and N-acetyl-5-aminosalicylic acid were 0.96 (95% confidence interval, 0.91-0.98) and 0.9 (95% confidence interval, 0.77-0.96), respectively. Sixteen biopsies were available from 13 patients. The 5-aminosalicylic acid and N-acetyl-5-aminosalicylic acid concentrations were 0.2-657 ng/mg and 1.6-1598 ng/mg, respectively; there was no correlation with bowel salicylate.. The close correlation between 5-aminosalicylic acid and salicylate levels offers a simple method to assess compliance with 5-aminosalicylic acid therapy.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Biopsy; Chromatography, High Pressure Liquid; Feasibility Studies; Humans; Inflammatory Bowel Diseases; Intestines; Mesalamine; Patient Compliance; Reproducibility of Results; Salicylates; Self Administration

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

Topics: Animals; Cells, Cultured; Fatty Acids, Volatile; Gastric Mucosa; Hydrogen-Ion Concentration; Inflammatory Bowel Diseases; Intestinal Mucosa; Mice; Microscopy, Confocal; Salicylates

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Atmosphere; Chemistry, Pharmaceutical; Drug Carriers; Humans; Inflammatory Bowel Diseases; Mass Spectrometry; Polymers; Salicylates; Salicylic Acid

Colonic epithelial cells express HLA-DR in inflammatory bowel disease. The effect of drugs used in the treatment of inflammatory bowel disease and colchicine on interferon-gamma (IFN-gamma) induced DR expression has been investigated. HT-29 cells were cultured in 25 cm2 flasks. At 48 hours interferon-gamma (0, 50, or 100 U/ml) +/- drug were added. At 120 hours the cells were stained for HLA-DR and analysed by flow cytometry. 10(-2) M 5ASA reduced DR expression induced by 50 U/ml interferon-gamma from 62 (12)% of cells (mean SD) to 29 (20)% (p less than 0.005). Corresponding figures for 10(-2) M N-acetyl 5ASA were 68 (16)% to 39 (17)% (p less than 0.05); for 10(-2) M 4ASA, 61 (4)% to 57 (4)% (p = 0.6); for 10(-2) M N-acetyl 4ASA, 60 (12)% to 35 (13)% (p less than 0.05); for 10(-2) M olsalazine, 72 (9)% to 3 (1)% (p less than 0.001); for 10(-3) M olsalazine, 72 (9)% to 16 (10)% (p less than 0.001); for 10(-6) M colchicine, 62 (13)% to 5 (3)% (p less than 0.001); and for 10(-7) M colchicine, 62 (13)% to 10 (3)%. Similar results were obtained when DR was induced by 100 U/ml of interferon-gamma except with 10(-2) M 4ASA which reduced expression from 77 (4)% to 68 (3)% (p less than 0.05). Sulphapyridine, prednisolone, indomethacin and cyclosporin A had no effect. Concurrent staining with propidium iodide showed that these results were unchanged when viable cells alone were analysed. Prior incubation of cells with drug, followed by washing, had no effect on interferon-gamma induced DR expression. 5ASA, N-acetyl 5ASA, 4ASA, N-acetyl 4ASA, olsalazine and colchicine reduce interferon-gamma induced HLA-DR expression. In inflammatory bowel disease these compounds may impair antigen presentation by the colonic epithelium.

Topics: Aminosalicylic Acid; Aminosalicylic Acids; Cell Line; Colchicine; Colon; Epithelium; Flow Cytometry; HLA-DR Antigens; Humans; Inflammatory Bowel Diseases; Interferon-gamma; Male; Mesalamine; Middle Aged; Salicylates