Lack of cross-reactivity between 5-aminosalicylic acid-based drugs: a case report and review of the literature.

BACKGROUND: 5-Aminosalicylic acid (5-ASA)-containing drugs are the mainstay of therapy in inflammatory bowel disease, but adverse reactions to these medications are relatively common. Because there may be a lack of cross-reactivity among the various 5-ASA formulations, treatment with alternative preparations is sometimes possible even after an apparent allergic reaction to a 5-ASA product. OBJECTIVE: To describe a patient with a possible allergy to 2 different 5-ASA drugs who tolerated a third. METHODS: A 27-year-old man with Crohn disease developed a rash while taking mesalamine (Pentasa and Asacol). Treatment with 5-ASA products was discontinued, and 6-mercaptopurine and prednisone were prescribed. He then experienced multiorgan failure secondary to herpes simplex infection, which required discontinuation of the immunosuppressive therapy. After recovery from the acute infection, he underwent successful graded challenge with balsalazide. RESULTS: The patient continued treatment with balsalazide for 9 months, with good control of his inflammatory bowel disease and no adverse effects. CONCLUSIONS: Adverse reactions to 1 or more 5-ASA medications do not necessarily preclude the use of others in the same class. A treatment algorithm for patients with adverse reactions to 5-ASA is outlined based on the case report and review of the literature.     

5-Aminosalicylic acid containing drugs. Delivery, fate, and possible clinical implications in man

Since the beginning of the 1940s salazosulfapyridine (SASP) has been used in the treatment of chronic inflammatory bowel disease (CIBD). Almost 40 years later 5-aminosalicylic acid (5-ASA), which is split off by azo-reducing enzymes in the colon, was identified as the therapeutically active moiety of SASP. Thus different 5-ASA containing drugs were produced from which 5-ASA is released in the small and large intestine in a pH-dependent manner. Since there is a firm clinical indication that the 5-ASA concentration in the gut lumen is decisive for the therapeutic effect, a method was developed to evaluate the 5-ASA concentration at different levels in the intestine. The method was subsequently used to clarify factors of importance for the release of 5-ASA from the preparations. Ileostomy patients and healthy volunteers were investigated during continuous treatment with the three 5-ASA containing drugs with pH-dependent 5-ASA release: Asacol, Mesasal (Salofalk, Claversal), and Pentasa. The study confirmed release of 5-ASA in the small intestine from all preparations, but at different levels and speeds. Despite similar peroral dosage, very different 5-ASA concentration profiles were found in the ileostomy effluents, reflecting not only the difference in the release pattern of the preparations, but also the influence of the gastric residence time for larger sized tablets. The 5-ASA concentrations increased in the faeces of healthy volunteers. Furthermore the systemically absorbed fraction of 5-ASA was larger than previously found after SASP. The 5-ASA release from the preparation with the most proximal release, Pentasa, was less influenced by acceleration of the intestinal transit time than previously demonstrated after SASP in a similar study design. A comparative study of children given SASP and Pentasa showed similar results as in adults: a tendency for smaller 5-ASA concentration at rectal level after Pentasa than after SASP, and also larger systemic absorption. Despite higher 5-ASA dose per kg body weight, lower 5-ASA concentrations were seen in the faeces after both preparations, compared with adults. A peroral dose increase of Pentasa in healthy adults resulted in higher intraluminal 5-ASA concentration in the gut lumen, but also in saturation of the local and probably also systemic acetylation capacity, demonstrated by higher plasma concentrations and larger urinary excretion of 5-ASA. Similar faecal water concentrations were found after Pentasa 4 g and the azo-bond preparation with colonic 5-ASA release, Dipentum (olsalazine) 2 g, confirming the substantial 5-ASA release from Pentasa in the small intestine. Investigation of pregnant patients treated with different 5-ASA containing drugs showed a similar pattern to SASP treatment: small amounts of 5-ASA cross the placenta, whereas the concentration of the metabolite Ac-5-ASA is similar in the maternal and fetal circulations. Only minute amounts of 5-ASA were found in milk from nursing mothers, while the concentrations of Ac-5-ASA were considerably higher. The decrease in the semen quality during SASP treatment was improved by changing to a controlled-release 5-ASA drug. The concentrations of 5-ASA in seminal plasma were similar during the two treatment periods, but higher of its metabolite Ac-5-ASA during treatment with the controlled-release preparation. That indicates that the toxic effect after SASP is not caused by the 5-ASA or Ac-5-ASA moiety. All the preparations have proved effective in the treatment of ulcerative colitis, but data concerning the 5-ASA treatment of Crohn's disease are conflicting. Knowledge of the demonstrated differences in the release profiles of the 5-ASA containing drugs is therefore important when designing future clinical trials.     

The antiinflammatory moiety of sulfasalazine, 5-aminosalicylic acid,is a radical scavenger

Using a novel spectrophotometric assay to detect free radical scavengers, the effects of sulfasalazine, a compound frequently administered in the treatment of chronic inflammatory bowel disease, and its main metabolites, 5-aminosalicylic acid (5-ASA), sulfapyridine, and N-acetyl-5-ASA, were compared with biological antioxidants (nordihydroguaiaretic, acid (NDGA), -tocopherol, and ascorbic acid) and antiinflammatory salicylates (acetylsalicylic acid and sodium salicylate). The results show that 5-ASA, but neither sulfasalazine and its other metabolites, nor the salicylates, shares with the biological antioxidants the property of being a potent scavenger of free radicals. Since 5-ASA is formed in millimolar concentrations in the colon of sulfasalazine-treated patients this mode of action may explain the beneficial effect of sulfasalazine in inflammatory bowel disease. Locally formed 5-ASA may break the free radical chain reaction initiated and maintained by activated phagocytes, thus arresting the perpetuating tissue destruction. This mechanism may indicate a general potential for radical scavengers in chronic inflammation.     

Budesonide in the treatment of inflammatory bowel disease

Inflammatory bowel disease, including Crohn’s disease and ulcerative colitis, features recurrent episodes of inflammation of the GI tract. The treatment of inflammatory bowel disease is aimed at breaking the cycle of relapsing and remitting inflammation by inducing and maintaining remission. Systemically active conventional corticosteroids have long played a role in the induction of remission in both Crohn’s disease and ulcerative colitis, however, their long-term use can lead to adverse systemic effects. Budesonide, a synthetic steroid, has potent local anti-inflammatory effects and limited systemic bioavailability making it an appealing therapeutic option. Ulcerative colitis with predominantly distal disease may be treated with topical budesonide, however, novel oral controlled-release formulations have also been developed to allow for treatment of the entire colon. This article summarizes the use of budesonide in the management of inflammatory bowel disease.     

Potential use of iloprost for asthma treatment

Inflammatory bowel disease in children can be marked by aggressive disease both at presentation and over time. Risk stratification of individual patients may help identify when early biologic therapy is justified. Currently, combination biologic and immunomodulator therapy for moderate-to-severe Crohn’s disease is the most effective treatment regimen. The clinician’s conundrum arises from the recent understanding that rare but serious adverse events do occur with use of these strong immune suppressive drugs and may be more prevalent with combination therapy. An understanding of the natural history of Crohn’s disease and ulcerative colitis and the benefits and risks of the current medical armamentarium is essential to provide optimal care for each child with inflammatory bowel disease.     

Intestinal Behçet’s Disease: Epidemiology, Pathophysiology and Potential of Mesalazine

Behçet’s disease (BD) is a systemic inflammatory disease of unknown origin that affects various parts of the body. In some patients, the prognosis of the disease appears to be altered by the involvement of the intestine (intestinal BD). In intestinal BD, deep ulcers develop in the gastrointestinal tract, typically in the ileocaecum. Intestinal lesions in patients with BD are much more common in countries in the Far East, especially Japan. The tissue damage occurring in patients with BD is believed to be caused by oxygen radicals, which are promoted by proinflammatory cytokines and arachidonic acid metabolites. New formulations of mesalazine (5-aminosalicylic acid; 5-ASA) are now available for the treatment of intestinal BD. Mesalazine breaks the chain reaction of free radical production. Mesalazine may provide an effective treatment for the promotion of long term healing of mucosal ulceration of the intestine in patients with BD.     

Current status of monoclonal antibody therapy for the treatment of inflammatory bowel disease

Crohn’s disease and ulcerative colitis are complex diseases that have required the use of multiple modalities to aid in treatment. With an increasing understanding of the underlying pathogenetic mechanisms and identification of specific therapeutic targets, monoclonal antibody treatment has been an ideal strategy for inducing and maintaining remission in these patients. This article addresses approved agents and the supporting data justifying their use in Crohn’s disease and ulcerative colitis, the safety of and immunologic reactions to these agents, as well as newer agents for treatment.     

Interaction of mesalasine (5-ASA) with translational initiation factors eIF4 partially explains 5-ASA anti-inflammatory and anti-neoplastic activities

5-Aminosalicylic acid (5-ASA or mesalazine) is widely used for treatment of inflammatory bowel disease and considered to be cancer preventive. Still, the molecular mechanisms explaining its properties remain largely unknown, partially due to the lack of instrumentarium needed to identify its array of molecular targets. Modern OMICs-based technologies utilized in this study may serve as a powerful and unbiased tool to search for such targets. Here we demonstrate that 5-ASA alters β-catenin immunocomplex formation by changing complex binding of seven proteins including translation initiation factors eIF4b. OMICs-based cross-testing by reverse in-gel chemogenomics (utilizing 5-ASA's fluorescent properties), in-silico docking and surface plasmon resonance experiments identified binding of 5-ASA to eIF4e's cap-binding pocket, a key regulatory site for protein synthesis. In-vitro translation experiments with rabbit reticulocytes confirmed a dose-dependent inhibition of protein syntheses by 5-ASA. By using two unbiased and independent OMICs-based experimental approaches two members of the cellular translation machinery, eIF4b and IF4e, were identified as targets of 5-ASA. Inhibition of protein syntheses is a previously unrecognized property of 5-ASA that may add to its anti-inflammatory and anti-neoplastic activities.     

5-氨基水杨酸对炎症性肠病瘤变预防作用的meta分析报告

 目的:对5-氨基水杨酸（5-ASA）干预炎症性肠病（IBD）相关性结肠癌（CRC）或上皮内瘤变（Dys）（IBD-CRC/Dys）的作用进行临床资料的评价和meta分析。方法:检索PubMed、Web of Science、the Cochrane Library等主要数据库,将符合标准的资料纳入研究,统计优势比（OR）及其95%置信区间（CI）,并根据IBD 类型和疗程进行亚组分析。结果:共纳入15 篇文献中的5 038名IBD患者。使用5-ASA的IBD患者发生CRC/Dys的OR= 0.53（95% CI：0.37~0.76）。根据疾病类型分层分析显示,使用5-ASA的溃疡性结肠炎患者发生CRC/Dys的OR=0.45（95%CI:0.27~0.77）,克罗恩病患者发生CRC/Dys的OR= 0.39（95%CI: 0.16~0.97）;此外,疗程小于1年的患者发生CRC/Dys的OR= 0.59（95% CI: 0.26~1.34）,而疗程在1年以上（最长者达20年）发生CRC/Dys的OR= 0.43（95% CI: 0.25~0.74）。结论: 5-ASA对IBD-CRC/Dys 有预防作用,且该作用呈疗程依赖性,疗程长者效果明显,尚不能证明2~6个月的使用疗程有预防作用。     

Effect of olsalazine and mesalazine on human ileal and colonic (Na+ + K+)-ATPase

Summary Olsalazine (azodisalicylate) and mesalazine (5-aminosalicylic acid) have recently been developed as new treatment modalities for inflammatory bowel disease to avoid sulfasalazine-related side effects. However, there are reports regarding new and hitherto unexpected side effects in some patients receiving olsalazine or mesalazine, such as watery diarrhea. Since sodium pump activities play an important role in the pathogenesis of water and electrolyte disturbances, we investigated the influence of olsalazine and mesalazine on human ileal and colonic (Na⁺ + K⁺)-ATPase and its specific [³H]-ouabain binding. We found a concentration-dependent inhibition of ileal and colonic (Na⁺ + K⁺)-ATPase by olsalazine with an IC₅₀ of 4.1 mM and 4.8 mM, respectively. Mesalazine inhibited this enzyme in the ileum with an IC₅₀ of 4.5 mM and in the sigmoid colon with an IC₅₀ 3.5 mM. In addition, [³H]-ouabain binding was inhibited by mesalazine with an IC₅₀ of 3.6 mM. The maximal inhibition, however, did not exceed 80% under any conditions (up to 10 mM drug concentration). Olsalazine and mesalazine induce inhibition of the ileal and colonic sodium pump activities that may (in addition to other possible mechanisms) mediate impaired water and electrolyte absorption. This is possibly of clinical relevance in patients with severely damaged mucosa. In patients with milder forms of mucosal inflammation, this inhibition most likely is of minor importance because of the great capacitiy of the (Na⁺ + K⁺)-ATPase and the incomplete inhibition leaving at least 20% of the enzyme activity intact.Abbreviations 5-ASA 5-aminosalicylic acid - EDTA ethylenediaminetetracetic acid - IBD inflammatory bowel disease     

Leukocyte traffic control: a novel therapeutic strategy for inflammatory bowel disease – an update

Adhesion molecules play a key role in the pathogenetic mechanisms of inflammatory bowel disease (IBD), both in Crohn’s disease (CD) and ulcerative colitis (UC). In the last decade, some progress has been made in understanding their key role in leukocyte trafficking control in terms of basic research, but evidence of clinical efficacy is lacking. In the last 2 years, new molecules directed against integrins and integrin receptors have been developed and investigated in clinical trials, showing that anti-α4β7 integrin agents can be effective and safe for the induction and maintenance of remission in active CD and UC. Preliminary data show that anti-MAdCAM, anti-β7 and anti-integrin receptor agents are not all effective in IBD. Such results open new perspectives on clinical management of IBD, and new directions in understanding the role of adhesion molecules and leukocyte recruitment both in CD and UC.     

Th17 cells: interactions with predisposing factors in the immunopathogenesis of inflammatory bowel disease

Inflammatory bowel disease (IBD) is a chronic inflammatory state of the GI tract of unknown etiology. Classically, tissue injury in IBD is thought to be primarily mediated by Th1 cells in Crohn’s disease or Th2 cells in ulcerative colitis. The discoveries of new subsets of T-helper cells, especially Th17 cells, have revolutionized our understanding of the disease immunopathology. Th17 cells seem to affect both innate and adaptive immune responses by the release of regulatory cytokines. Understanding the role of Th17 cells in IBD pathogenesis and targeting their regulatory cytokines may provide potential therapeutic approaches for the treatment of IBD in the future.     

Distinct elevation of levels of anti-Caenorhabditis elegans antibody in sera of patients with inflammatory bowel disease

Dysregulation of immune responses to intestinal exogenous antigens contributes to the pathogenesis of inflammatory bowel disease, but the specific antigen responsible for the pathogenesis of inflammatory bowel disease is unknown. We measured serum antibody titers against Caenorhabditis elegans antigens. Immunoglobulin G (IgG) and IgG subclass anti-C. elegans antibodies in serum samples from 29 patients with ulcerative colitis, 30 patients with Crohn's disease, 7 patients with intestinal Beh?et's disease, and 11 healthy controls were measured by enzyme-linked immunosorbent assay. Serum IgG and IgG2 antibody titers against C. elegans were significantly higher in patients with inflammatory bowel disease than in controls. Antibody levels were not affected by age, gender, disease activity, extent of disease, or small bowel involvement. The anti-C. elegans antibody titer was significantly lower in patients with Crohn's disease taking mesalazine or sulfasalazine than in patients not taking these drugs. The increased immune responses to C. elegans found in patients with inflammatory bowel disease reflect dysregulated immune responses to enteric antigens, which might play a role in the pathogenesis of inflammatory bowel disease.     

Anti-Adhesion Molecule Strategies for Crohn Disease

The last few years have been highlighted by further knowledge and optimism regarding the use of biologic therapy in Crohn disease. The introduction of anti-tumor necrosis factor (TNF) therapy into clinical practice in the form of the murine chimeric monoclonal antibody infliximab, and more recently the fully human monoclonal antibody adalimumab, has significantly advanced treatment for Crohn disease. Despite the introduction of the anti-TNF agents, 20-40% of patients will fail to respond to initial induction therapy, and of the initial responders only 60-70% will have a sustained response at 1 year. Therefore, there remains a significant unmet need in the treatment of patients with Crohn disease. A novel approach in suppressing inflammation is to intervene in the mechanisms responsible for the migration of leukocytes into inflamed tissue. One such method is by selective adhesion molecule inhibition. Several agents based on this strategy have been evaluated in the treatment of inflammatory bowel disease. It is expected that these agents will offer an alternative to the anti-TNF agent class in patients with moderate to severe Crohn disease.     

The clinical implications of thalidomide in inflammatory bowel diseases

Thalidomide has anti-inflammatory and anti-angiogenetic activity that makes it suitable for treating inflammatory bowel diseases (IBD). The recent guidelines from the European Crohn’s and Colitis Organization/European Society for Pediatric Gastroenterology Hepatology and Nutrition conclude that thalidomide cannot be recommended in refractory pediatric Crohn’s disease but that it may be considered in selected cohorts of patients who are not anti-TNFα agent responders. The main adverse effect is the potential teratogenicity that renders the long-term use of thalidomide problematic in young adults due to the strict need for contraceptive use. In short-term use it is relatively safe; the most likely adverse effect is the neuropathy, which is highly reversible in children. So far the use of thalidomide is reported in 223 adult and pediatric IBD patients (206 with Crohn’s disease). In the following sections, the authors will discuss efficacy and safety of thalidomide, in the short-term treatment of IBD.     

Induction and maintenance treatment of inflammatory bowel disease: A comprehensive review

Ulcerative colitis (UC) and Crohn's disease (CD) are the two major types of inflammatory bowel disease (IBD). We conducted a comprehensive review of meta-analyses to summarize the reported effectiveness of different drugs for IBD. We performed a literature search and a total of 110 meta-analyses from 66 articles were summarized and re-analyzed (62 in UC and 48 in CD). In summary, 5-ASA was more effective than placebo in both induction and maintenance treatment of UC, but there were conflicting results on the effect of 5-ASA on the induction treatment or relapse of CD. The use of immunomodulatory agents in the induction or maintenance phase of UC and CD using immunomodulators appeared to be more effective than placebo, but the results were impacted by small number of patients, discordant results with the largest study and risk of biases. Anti-TNF-α and anti-integrin therapeutic antibodies in both, induction and maintenance, showed a better efficacy than placebo in a large proportion of patients analyzed. Other agents, such as probiotics, antibiotics, omega-3, were shown to be more effective than placebo, but the same issues arose as stated above with the use of immunomodulatory agents. In conclusion, we performed a comprehensive review of meta-analysis on comparative efficacy of pharmacotherapy used in the management of IBD. Our review will augment our understanding of the treatment of UC and CD by providing a guideline for interpreting the statistically significant findings and discusses the optimal choice for IBD treatment.     

The combination of fecal calprotectin with ESR,CRP and albumin discriminates more accurately children with Crohn’s disease

PurposeIncreased fecal calprotectin is a sensitive marker of various types of intestinal inflammation. We investigated correlations between high fecal calprotectin concentration and serum inflammatory markers in children with different intestinal diseases with diarrhea with/without blood and/or abdominal pain, to test whether the combination of these markers can differentiate potential patients with inflammatory bowel disease.Materials/methodsThe study included 128 children with high fecal calprotectin concentration (>150ug/g) and symptoms suggesting bowel disorders, hospitalized in the years 2013– 2015. Twenty-six (20%) patients were diagnosed with Crohn’s disease, 55 (43%) with ulcerative colitis, 32 (25%) with intestinal infection and 15 (12%) with food protein induced proctocolitis.ResultsSignificantly increased inflammatory markers were detected in children with inflammatory bowel disease, with a correlation between calprotectin and erythrocyte sedimentation rate – ESR (R = 0.53), mean corpuscular volume – MCV (R=-0.64), red blood cell distribution width (R = 0.56), albumin (R = −0.52), hemoglobin (R = −0.53) only in Crohn’s disease patients. To discriminate Crohn’s disease patients from patients with intestinal infection and patients with food protein induced proctocolitis, AUC analysis was performed. It revealed that considering ESR, CRP and albumin as additional markers to fecal calprotectin significantly improved diagnostic performance (AUC 0.917, p = 0.038).ConclusionsIn children with abdominal pain and/or diarrhea, increased ESR, CRP and decreased albumin combined with a high fecal calprotectin level yields additional diagnostic value in screening potential patients with Crohn’s disease. As far as differentiation of ulcerative colitis is concerned, low additional diagnostic value was found when high fecal calprotectin was combined with albumin.     

Use of immunomodulators and biologic therapies in children with inflammatory bowel disease

The immunomodulators (6-mercaptopurine, azathioprine and methotrexate) and biologics (infliximab, adalimumab, certolizumab and natalizumab) are medications essential in the management of pediatric inflammatory bowel disease. If properly utilized, these medications can control active disease, reduce corticosteroid exposure, induce remission, and promote normal growth and development. However, these medications also have significant toxicity and increase the risk of infections and lymphoma. This article provides information about the safety and efficacy of these medications in the treatment of children with Crohn’s disease and ulcerative colitis.     

Properties of Ligninase from Phanerochaete Chrysosporium and Their Possible Applications

Mycobacterium avium subsp. paratuberculosis (MAP) causes the disease of cattle, Johne’s. The economic impact of this disease includes early culling of infected cattle, reduced milk yield, and weight loss of cattle sold for slaughter. There is a possible link between MAP and Crohn’s disease, a human inflammatory bowel disease. MAP is also a potential human food borne pathogen because it survives current pasteurization treatments. We review the current knowledge of MAP, Johne’s disease and Crohn’s disease and note directions for future work with this organism including rapid and economical detection, effective management plans and preventative measures.     

Spectrum and prognosis of renal histopathological lesions in patients with inflammatory bowel disease: a cross-sectional study from a single center in China

Clinical and Experimental Medicine - To explore the spectrum, clinicopathological features and prognosis of patients with inflammatory bowel disease (IBD) including Crohn’s disease (CD) and...