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Crohn's disease and ulcerative colitis (UC) are common, chronic inflammatory bowel diseases (IBDs) characterized by episodes of life-altering symptoms such as diarrhea, bleeding, fecal urgency and incontinence, abdominal pain and cramps, and fever lasting weeks to months at a time. Existing treatments are 5-aminosalicyclates or immunosuppressants, but long-term control of IBD is a major problem for a large number of patients. Phosphodiesterase 4 (PDE4) is a key enzyme in cell homeostasis and inflammation and its inhibition has been useful in diseases such as asthma and chronic obstructive pulmonary disease, rheumatoid arthritis and multiple sclerosis. This review focuses on the role of oxidative stress in IBD and the PDE4 inhibitor OPC-6535 (tetomilast), an investigational agent for the treatment of UC. The authors detail the clinical development of the compound and report and provide insight into some of the unpublished data from the recently completed multicenter Phase III trials in UC.  相似文献   

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BACKGROUND: Conflicting data exist about proteinuria in inflammatory bowel diseases. It is still unclear whether the occurrence of proteinuria in inflammatory bowel disease patients is an extra-intestinal manifestation of disease or the result of adverse effects to medication, especially to aminosalicylates (ASA). METHODS: A total of 95 patients (51 with Crohn's disease and 44 with ulcerative colitis) were enrolled in the study. Disease activity was assessed by Crohn's Disease Activity Index (CDAI) or the Truelove index, respectively. Urine was collected over 24 h and protein excretion of specific marker proteins for tubular (alpha 1-microglobulin-alpha 1-MG) and glomerular (albumin-Alb, Immunoglobulin G-IgG) dysfunction was measured using a highly sensitive immunoluminometric assay. RESULTS: Out of 51 Crohn's disease patients, 20 showed elevated urinary alpha 1-MG. The amount of alpha 1-MGuria was strongly correlated to the CDAI (r=0.6, P < 0.001). Only four Crohn's disease patients showed slightly elevated values for glomerular proteins in urine. Similar results were obtained for ulcerative colitis: whereas only two ulcerative colitis patients showed albuminuria, tubular proteinuria was detected in 28 out of 44 ulcerative colitis patients. Proteinuria was strongly dependent on disease activity (P < 0.01) but was not related to ASA treatment. CONCLUSIONS: Proteinuria of tubular marker proteins occurs in the majority of inflammatory bowel disease patients and is related to disease activity rather than to ASA treatment. Tubular proteinuria seems to reflect a renal extra-intestinal manifestation of inflammatory bowel disease and may serve as a new relevant marker of disease activity.  相似文献   

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osteoporosis, corticosteroids and inflammatory bowel disease   总被引:4,自引:4,他引:4  
Osteoporosis is a serious complication of inflammatory bowel disease which has not received adequate recognition despite its high prevalence and potentially devastating clinical effects. Its pathogenesis remains poorly defined although corticosteroid therapy and sex hormone deficiency are likely to play a major role. Recent advances in the diagnosis and management of osteoporosis have facilitated early detection of bone loss and identified means by which this may be prevented. Bone density measurements to predict fracture risk and define thresholds for prevention and treatment should be performed routinely in patients with inflammatory disease. Hormone replacement therapy is effective in prevention of bone loss in peri- and post-menopausal patients, but the treatment of younger women and men of all ages requires further study.  相似文献   

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Inflammatory bowel disease (IBD) is associated with an increased incidence of osteoporosis. Osteoporosis with osteoporotic pain syndromes, fragility fractures and osteonecrosis accounts for significant morbidity and impacts negatively on the quality of life. It is generally agreed that there is a need to increase awareness for inflammatory bowel disease-associated osteoporosis. However, the best ways in which to identify at-risk patients, the epidemiology of fractures and an evidence-based rational prevention strategy remain to be established. The overall prevalence of IBD-associated osteoporosis is 15%, with higher rates seen in older and underweight subjects. The incidence of fractures is about 1 per 100 patient years, with fracture rates dramatically increasing with age. While old age is a significant risk factor, disease type (Crohn's disease or ulcerative colitis) is not related to osteoporosis risk. Corticosteroid use is a major variable influencing IBD-associated bone loss; however, it is difficult to separate the effects of corticosteroids from those of disease activity. The recommendations in inflammatory bowel disease are similar to those for postmenopausal osteoporosis, with emphasis on lifestyle modification, vitamin D (400-800 IE daily) and calcium (1000-1500 mg daily) supplementation and hormone replacement therapy (oestrogens/selective oestrogen receptor modulators in women, testosterone in hypogonadal men). Bisphosphonates have been approved for patients with osteoporosis (T-score < 2.5), osteoporotic fragility fractures and patients receiving continuous steroid medication. Data on the recently Food and Drug Administration-approved osteoanabolic substance parathyroid hormone and on osteoprotegerin are promising in terms of both steroid-induced and inflammation-mediated osteoporosis, the key elements of inflammatory bowel disease-associated bone disease.  相似文献   

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BACKGROUND: Enhanced MAdCAM-1 (mucosal addressin cell adhesion molecule-1) expression is associated with the aetiology of inflammatory bowel disease, but little is known about MAdCAM-1: regulation, or how inflammatory bowel disease therapies modulate MAdCAM-1. AIM: To examine how agents currently used to treat inflammatory bowel disease affect MAdCAM-1: induced by tnf-alpha in an in vitro model of inflammatory bowel disease. METHODS: Endothelial monolayers were pretreated with dexamethasone (DEX): 5-aminosalicylic acid (5-ASA), 6-mercaptopurine (6-MP), sulfasalazine or interleukin-10: (IL-10: prior to TNF-alpha (20 ng/mL), and MAdCAM-1: measured by Western blotting, RT-PCR, EMSA and lymphocyte adhesion assays. RESULTS: MAdCAM-1: was induced dose- and time-dependently by TNF-alpha on endothelial cells. Either dexamethasone or IL-10: reduced TNF-alpha-induced MAdCAM-1: protein, mRNA and lymphocyte adhesion. However, neither 5-ASA, sulfasalazine nor 6-MP blocked MAdCAM-1 induction. CONCLUSIONS: Our data indicate that dexamethasone or IL-10 can exert therapeutic activity in inflammatory bowel disease through MAdCAM-1 inhibition. 5-ASA, sulfasalazine and 6-MP, while beneficial in inflammatory bowel disease, do not directly control MAdCAM-1, and are beneficial through inhibition of other inflammatory processes.  相似文献   

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Achieving a substantial reduction in the bacterial flora of the gut is a theoretically attractive means of treating inflammatory bowel disease, particularly colonic disease. There are practical difficulties in obtaining a sustained reduction of the colonic bacterial count, and the potential role of such a treatment regimen is therefore the initiation of remission. The data in the literature supporting such a suggestion are anecdotal, and a controlled study is indicated.  相似文献   

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Aminosalicylate therapy for ulcerative colitis remains a foundational strategy for the induction and maintenance of remission for mild to moderate disease. Although it seems clear that topical mesalazine (mesalamine) is the most efficacious approach to distal ulcerative colitis, recent trials with orally delivered azo conjugates suggest that there may be an advantage over pH-released mesalazine as a first-line approach to active disease. No such comparisons are available for azo products and the prolonged-release formulation, Pentasa. However, recent meta-analyses have demonstrated that, although there is little difference in systemic exposure between marketed products, luminal concentrations may vary. In maintenance therapy, aminosalicylates remain the standard approach after aminosalicylate-induced remission. A number of gaps remain in the evidence base with regard to the optimal dosing of oral mesalazine as a maintenance agent, whether oral mesalazine can maintain remissions after rectal mesalazine induction, and the dose-response and efficacy of aminosalicylates after steroid- or ciclosporin-induced remissions. Although aminosalicylates have been advocated for several decades in Crohn's disease, a number of controversies have evolved since the original trials with sulfasalazine in active Crohn's disease. The original trials demonstrated benefits for sulfasalazine in colonic involvement, but controlled trial evidence for the role of sulfasalazine as maintenance therapy has not been as firmly established. In addition, although oral mesalazine has been demonstrated in controlled trials to be superior to placebo in mild to moderate disease, it is less efficacious than corticosteroids at inducing remissions. The maintenance benefits of mesalazine appear to be limited to patients 'induced into remission' with mesalazine and in some post-operative settings.  相似文献   

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Review article: thiopurines in inflammatory bowel disease   总被引:6,自引:0,他引:6  
BACKGROUND: In the past 10-20 years, knowledge of both thiopurine pharmacology and -pharmacogenetics has been extended dramatically and used to develop new strategies to improve efficacy and reduce toxicity. AIM: To review thiopurine efficacy, toxicity, pharmacology, pharmacogenetics, interactions in patients with inflammatory bowel disease. Special attention was paid to new strategies for optimization of pharmacotherapy. METHODS: To collect relevant scientific articles, a Pubmed search was performed from 1966 through January 2006 with the following key words (MeSH terms preferentially) in multiple combinations: 'azathioprine', '6-mercaptopurine', '6-MP', '6-thioguanine', '6-TG', 'thiopurine(s)', 'metabolites', 'level(s)', 'TDM', 'TMPT', 'ITPA', 'genotype(s)', 'phenotype(s)', 'inflammatory bowel disease', 'Crohn('s) disease', 'ulcerative colitis'. RESULTS: Strategies for optimization of pharmacotherapy include therapeutic drug monitoring of thiopurine metabolites, geno- or phenotyping crucial enzymes in thiopurine metabolism like thiopurine S-methyltransferase and inosine triphosphate pyrophosphatase, and the use of thioguanine as such. CONCLUSIONS: Thiopurine S-methyltransferase genotyping and therapeutic drug monitoring are useful instruments for individualizing thiopurine pharmacotherapy of inflammatory bowel disease. Inosine triphosphate pyrophosphatase genotyping may be helpful in case of unexplainable myelotoxicity. In case of azathioprine- or mercaptopurine-intolerance, thioguanine seems a promising alternative. However, more knowledge needs to be gathered about its potential hepatotoxicity.  相似文献   

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