Oral delayed-release mesalazine: a review of its use in ulcerative colitis and Crohn's disease

Oral delayed-release mesalazine is an enteric-coated formulation which releases mesalazine in the terminal ileum and colon. Up to 74% of patients with mild to moderately active ulcerative colitis experience endoscopic or symptomatic improvement (including remission) or both when treated with oral delayed-release mesalazine 2.4 to 4.8 g/day. There is a trend towards a better response in patients receiving higher daily dosages of oral delayed-release mesalazine, especially in patients with active distal disease. In patients with left-sided ulcerative colitis, oral balsalazide 6.75 g/day appears to be more effective than oral delayed-release mesalazine 2.4 g/day, but a higher dosage of oral delayed-release mesalazine 4.8 g/day may provide additional benefit in these patients. Oral delayed-release mesalazine 0.8 to 4.4 g/day appears to be as effective as sulfasalazine 2 to 4 g/day, prolonged-release mesalazine 1.5 g/day or balsalazide 3 g/day in maintaining remission in patients with ulcerative colitis. The optimal dosage of oral delayed-release mesalazine for the maintenance of remission is unclear. However, oral delayed-release mesalazine 1.6 g/day with rectal mesalazine 4g, administered twice weekly, was more effective than oral drug alone in maintaining remission in patients at high risk of relapse. In patients with left-sided or distal disease oral olsalazine 1 g/day appeared to be superior to oral delayed-release mesalazine 1.2 g/day for maintenance of symptomatic remission. Limited data in patients with Crohn's disease have shown oral delayed-release mesalazine 0.4 to 4.8 g/day to be an effective therapy for active disease (remission in up to 45% of patients) and for quiescent disease (relapse in 34% of recipients over a duration of up to 12 months). Preliminary data indicate that oral delayed-release mesalazine 2.4 g/day is effective in preventing postoperative recurrence of Crohn's disease. Oral delayed-release mesalazine is effective and well tolerated in sulfasalazine-intolerant patients with ulcerative colitis or Crohn's disease. CONCLUSIONS: Oral delayed-release mesalazine is effective in patients with mild to moderately active or quiescent ulcerative colitis. Available data suggest that patients with left-sided or distal ulcerative colitis are likely to require higher daily dosages of oral delayed-release mesalazine or supplementation with rectal mesalazine. Oral delayed-release mesalazine also appears to be effective in active and quiescent Crohn's disease. The drug is well tolerated and it appears to be effective in sulfasalazine-intolerant patients.     

Balsalazide: a review of its therapeutic use in mild-to-moderate ulcerative colitis

The aminosalicylate balsalazide is a prodrug which is metabolised by bacterial azo reductases in the colon to release its therapeutically active moiety mesalazine [mesalamine (US) or 5-aminosalicylic acid] and an inert carrier molecule. The systemic absorption of balsalazide and its metabolites is not required for the therapeutic efficacy of the drug, and has been demonstrated to be limited. Data from well designed trials with a duration of 8 to 12 weeks show that oral balsalazide 6.75 g/day is as effective as (two trials) or more effective than (one trial) oral delayed-release (pH-dependent) mesalazine 2.4 g/day and appears to be as effective as oral sulfasalazine 3 g/day in the treatment of active mild-to-moderate ulcerative colitis. In addition, balsalazide appears to have a faster onset of action than mesalazine. Furthermore, balsalazide was as effective as delayed-release mesalazine (dosages used were 1.2 and 1.5 g/day, where 1.6 g/day is recommended) and oral sulfasalazine 2 g/day (recommended dosage) in the prevention of relapse in ulcerative colitis in remission after 6 to 12 months of treatment; the balsalazide dosage was 3 g/day versus mesalazine and 2 g/day versus sulfasalazine. Although not well established, additional benefits may be achieved with balsalazide dosages up to 6 g/day. Data from well designed, 2- to 12-month trials show that balsalazide is well tolerated by patients with ulcerative colitis in both acute and maintenance indications, and is better tolerated than standard formulations of sulfasalazine at therapeutically relevant dosages. CONCLUSION: Balsalazide is a well tolerated and effective first-line therapeutic option for patients with ulcerative colitis, both for the treatment of active mild-to-moderate disease and as maintenance therapy to prevent disease relapse.     

Oral beclomethasone dipropionate: a critical review of its use in the management of ulcerative colitis and Crohn's disease

Crohn's disease and ulcerative colitis are inflammatory bowel diseases characterised by a chronic relapsing course. Corticosteroids represent the mainstay of medical treatment of inflammatory bowel disease for the induction of remission. Despite the high efficacy of systemic steroids, their use is limited by the high incidence of potentially serious adverse effects. The topically acting steroids are synthetic compounds characterised by high anti-inflammatory activity and low systemic effects by virtue of efficient first-pass hepatic inactivation. Budesonide and Beclomethasone Dipropionate are the two most studied topically acting steroids in inflammatory bowel disease. Oral Budesonide has been extensively studied in the treatment of mild to moderate ileo-caecal Crohn's disease but few data are available concerning oral Beclomethasone Dipropionate. This review focuses on the available evidence of efficacy and safety of oral Beclomethasone Dipropionate in the management of ulcerative colitis and Crohn's disease and a possible role of this steroid in clinical practice is suggested.     

Systematic review: the potential influence of mesalazine formulation on maintenance of remission in Crohn's disease

AIM: To evaluate the effectiveness of pH 6-/pH 7-dependent and controlled-release mesalazines in maintaining medically and surgically induced Crohn's disease remission. METHODS: A systematic search identified 13 randomized controlled trials (RCTs). The rate of symptomatic relapse (Crohn's disease activity index >150, or an increase in baseline by at least 60-100 points) was extracted from each randomized controlled trial. Pooled odds ratios (OR), the number needed to treat (NNT), and percentage therapeutic benefit (absolute risk reduction) were calculated. RESULTS: Treatment with pH 7-dependent mesalazine significantly reduced the risk of relapse in patients with either surgically [OR 0.28; 95% confidence interval (CI) 0.12-0.65; P = 0.0032] or medically induced remission (OR 0.38; 95% CI 0.17-0.85; P = 0.0113). However, treatment with controlled-release mesalazine and pH 6-dependent mesalazine failed to show any significant advantage over placebo. The NNT to maintain surgically or medically induced remission was lowest for pH 7-dependent mesalazine (NNT = 4 and 5, respectively; NNT = 15 and 16 for controlled-release mesalazine and NNT = 11 and 23 for pH 6-dependent mesalazine). Therapeutic benefit was highest for pH 7-dependent mesalazine (surgical = 30.6%, medical = 22.8%). This compared with 6.9% (surgical) and 6.4% (medical) for controlled-release mesalazine, and 9.8% and 4.4%, respectively, for pH 6-dependent mesalazine. CONCLUSION: Further trials of pH 7-dependent mesalazine formulations are warranted in the maintenance of remission in Crohn's disease.     

Systematic review: the pharmacokinetic profiles of oral mesalazine formulations and mesalazine pro-drugs used in the management of ulcerative colitis

AIM: : To quantify through systematic review the pharmacokinetic profiles of the oral delayed release and sustained release mesalazine (5-aminosalicylate, 5ASA) formulations (Asacol, Salofalk, Mesasal, Claversal, Pentasa) and pro-drugs (sulfasalazine, olsalazine, balsalazide) used in the management of ulcerative colitis. METHODS: : Selected articles had: (1) adult healthy volunteers or patients with ulcerative colitis and (2) quantification of pharmacokinetic data to include, at a minimum, urinary excretion of total 5ASA [5ASA plus N-Acetyl-5ASA (N-Ac-5ASA)]. DATA COLLECTION AND ANALYSIS: : Pharmacokinetic data (Tmax, Cmax, AUC, urinary excretion, faecal excretion) of 5ASA, its major metabolite N-Acetyl-5ASA, total 5ASA, and the parent pro-drug compounds was extracted. MAIN RESULTS: : The summary results for urinary excretion of total 5ASA over 24-96 h in all subjects (either mean or median) were: sulfasalazine mean 11-33% or median 22%; olsalazine mean 14-31% or median 16-27%; balsalazide mean 12-35% or median 20%; Asacol mean 10-35% or median 18-40%; Pentasa mean 15-53% or median 23-34%; Salofalk, Mesasal and Claversal mean 27-56% or median 31-44%. The summary results for faecal excretion of total 5ASA over 24-96 h in all subjects (either mean or median) were: sulfasalazine mean 23-75% or median 38%; olsalazine mean 47-50% or median 17-36%; balsalazide mean 46% or median 22%; Asacol mean 40-64% or median 20-56%; Pentasa mean 12-51% or median 39-59%; Salofalk, Mesasal and Claversal mean 37-44% or median 23-35%. CONCLUSIONS: : The systemic exposure to 5ASA, as measured by urinary excretion of total 5ASA, and the faecal excretion of total 5ASA is comparable for all oral mesalazine formulations and pro-drugs. Thus, selection of a mesalazine therapy for the treatment of ulcerative colitis should be based on other factors such as efficacy, dose-response, toxicity of the parent compound and its metabolites, compliance issues related to dose forms and dosing schedules, and costs.     

Absorption of delayed-release prednisolone in ulcerative colitis and Crohn's disease

The absorption and urinary excretion of [3H]prednisolone after oral ingestion was examined using hard gelatin capsules with and without a coating of Eudragit-S which delayed release of the contents. In 6 patients with ulcerative colitis absorption was delayed until the preparation reached the colon but the total absorption was unchanged. In 6 patients with Crohn's disease and ileal strictures the preparation broke proximal to the stricture and absorption was delayed until this occurred (within 4-12 h). In 5 patients with Crohn's disease and intestinal resections the capsules broke unreliably.     

Nicotine: therapeutic potential for the treatment of ulcerative colitis

Ulcerative colitis (UC) is predominantly a disease of non-smokers, and nicotine may be the agent responsible for this association. Transdermal nicotine has been shown to improve disease activity and sigmoidoscopic appearance in the active disease but in one study had no effect on maintenance of remission. Since side-effects with nicotine patches occur in up to two thirds of patients, attempts to reduce systemic levels and improve drug tolerance have been developed with colonic delivery systems of nicotine. Preliminary observations with nicotine enemas in UC have shown clinical benefit, but controlled trials are needed. Mechanisms responsible for the association of smoking with colitis and for the therapeutic effect of nicotine remain an enigma; possibilities include: modulation of the immune response, alterations of colonic mucus and eicosanoid production, changes in rectal blood flow, decreased intestinal permeability and the release of endogenous glucocorticoids. With current treatment for UC limited to corticosteroids and formulations of 5-aminosalicylic acid, alternative treatments are required and nicotine may fulfil this role.     

Targeting leukocyte migration and adhesion in Crohn's disease and ulcerative colitis

Crohn's disease and ulcerative colitis are two chronic inflammatory bowel diseases. Current biologic therapies are limited to blocking tumor necrosis factor alpha. However, some patients are primary non-responders, experience a loss of response, intolerance or side effects defining the urgent unmet need for novel treatments. The rapid recruitment and inappropriate retention of leukocytes is a hallmark of chronic inflammation and a potentially promising therapeutic target. We discuss the immunological mechanisms of leukocyte homing and adhesion in the gut mucosa. The interaction of lymphocytes (CD4+ T-cells, CD8+ T-cells, T(REG), T(H)1, T(H)17, B-cells), monocytes, macrophages, dendritic cells and granulocytes with endothelial and epithelial cells through integrins [α4β7 (LPAM-1), α(E)β? (HML1 Human Mucosal Lymphocyte Antigen 1), α?β? (VLA-4), α(L)β?, (LFA-1)] and their ligands immunoglobulin superfamily cellular adhesion molecules (CAM) (MAdCAM-1 Mucosal Addressin Cellular Adhesion Molecule 1, ICAM-1 Intercellular Cell Adhesion Molecule, VCAM-1 Vascular Cell Adhesion Molecule), fibronectin as well as chemokine receptors (CCR2, CCR4, CCR5, CCR7, CCR9, CCR10, CXCR3, CX3CR1) and chemokines [CCL5, CCL25 (TECK Thymus Expressed Chemokine), CCL28, CX3CL1, CXCL10, CXCL12] in the process of gut homing is critically reviewed and summarized in scientific cartoons. Moreover, we discuss the clinical trial results of approved and investigational antibodies and small molecules including natalizumab (anti-α? Tysabri?, Antegren?), AJM300 (anti-α4), etrolizumab (anti-β7, rhuMAb-Beta7), vedolizumab (anti-α4β7, LDP-02, MLN-02, MLN0002), PF-00547659 (anti-MAdCAM), Alicaforsen (anti-ICAM-1), and CCX282-B (anti-CCR9, GSK-1605786, Traficet-EN?) and their risks such as PML reported for natalizumab. Hopefully, the newer gut specific drug designs discussed in this article will have an impact on both efficacy and safety.     

美沙拉嗪治疗溃疡性结肠炎的疗效

目的 探讨美沙拉嗪治疗溃疡性结肠炎的临床疗效与安全性.方法 溃疡性结肠炎患者84例随机均分为两组,分别在支持治疗的基础上,观察组加用美沙拉嗪治疗,每日口服3次,1.0 g/次;对照组加用柳氮磺胺吡啶常规治疗;疗程为8周.比较两组临床疗效和治疗前后外周血C反应蛋白(CRP)、IL-6和TNF-α变化,记录治疗期的不良反应.结果 观察组的总有效率为97.6％,明显高于对照组的81.0％ (P＜0.05).治疗后两组外周血CRP和炎性细胞因子IL6和TNF-α水平均明显下降,且观察组的改变更为明显(P＜0.05).两组的不良反应发生率相仿(4.8％vs.9.5％)(P＞0.05).结论 美沙拉嗪治疗溃疡性结肠炎的临床疗效优于柳氮磺胺吡啶,能够明显改善患者体内的炎性状态.     

美沙拉嗪对溃疡性结肠炎相关结直肠癌变的化学预防作用

溃疡性结肠炎发生癌变为其最为严重的并发症。虽然肠镜监测作为二级预防能够发现异型增生和早期癌,然而当前数据尚未显示该策略可减少相应的死亡率。因此化学预防药物更为人们所青睐,其中较为明确和相关研究较多的为美沙拉嗪。     

Aspirin in the aetiology of Crohn's disease and ulcerative colitis: a European prospective cohort study

Aliment Pharmacol Ther 2011; 34: 649–655

Summary

Background Aspirin has detrimental effects on the gastrointestinal tract mucosa and may play a role in the aetiology of inflammatory bowel disease. Aim To investigate if the regular use of aspirin is associated with the development of Crohn’s disease (CD) and ulcerative colitis (UC) using, for the first time, a prospective cohort study design. Methods A total of 135 780 men and women in Europe, aged 30–74 years, were recruited into the European Prospective Investigation into Cancer and Nutrition study. Participants completed questionnaires at baseline detailing their regular aspirin use and were then followed up to identify those who developed either incident CD or UC. Each case was matched with four controls and odds ratios (OR) were calculated, adjusting for cigarette smoking. Potential interactions between aspirin and smoking were assessed. Results A total of 35 participants developed CD and a further 84 were diagnosed with UC. Regular aspirin intake was positively associated with the risk of developing CD (OR = 6.14, 95% CI = 1.76–21.35). In those who took aspirin and smoked there was no detectable increased risk of CD (OR = 0.30, 95% CI = 0.03–3.08). No association was found between regular aspirin use and UC (OR = 1.29, 95% CI = 0.67–2.46). Conclusions A strong positive association between regular aspirin use and CD, but not UC, was observed. The data suggest that regular aspirin use should be measured in epidemiological work on CD. If such findings are consistent in other work then aspirin may affect the development of CD in a middle‐aged to elderly population.     

中药组方联合美沙拉嗪/柳氮磺吡啶治疗溃疡性结肠炎有效性及安全性的系统评价

目的： 系统评价中药组方联合美沙拉嗪或柳氮磺吡啶治疗溃疡性结肠炎患者的疗效及安全性。方法： 在PubMed、Web of Science、中国知网、万方、维普数据库以"中药"、"溃疡性结肠炎"等为检索词,检索并筛选相关文献,以临床有效率及不良反应为结局指标,采用Revman 5.4进行Meta分析。结果： 本次研究共检索文献2 124篇,最终纳入117篇;Meta分析发现,美沙拉嗪联合中药组方口服（OR=3.49,95% CI[2.75,4.43]）或灌肠（OR=4.42,95% CI[3.56,5.48]）治疗均能提高临床有效率,且并未增加不良反应的发生风险（OR=0.55,95% CI[0.28,1.06];OR=0.39,95% CI[0.26,0.58]）;柳氮磺吡啶联合中药组方口服（OR=5.95,95% CI[3.76,9.40]）或灌肠（OR=3.75,95% CI[2.80,5.01]）治疗同样可提高临床有效率,不良反应的风险并未因中药组方的使用而增加（OR=0.33,95% CI[0.05,2.07];OR=0.27,95% CI[0.01,5.66]）。结论： 在美沙拉嗪/柳氮磺吡啶的基础上联合中药组方口服或灌肠治疗能有效提高溃疡性结肠炎的治愈率,且并未增加不良反应的发生风险,但中药组方联合治疗溃疡性结肠炎仍需高质量的研究。     

克罗恩病与溃疡性结肠炎的时间结构式治疗方案

本文主要对所谓的时间结构式治疗方案(或称限时性方案),即不同疾病严重度的克罗恩病(CD)和溃疡性结肠炎(UC)患者的病情评估与推荐治疗方案进行了介绍,以达到促进临床上规范治疗IBD的目的。     

Distribution of mesalazine enemas in active and quiescent ulcerative colitis.

BACKGROUND: The efficacy of mesalazine enemas depends on intraluminal concentration of the drug and is therefore limited by the enema distribution in the colon. Active ulcerative colitis changes colon motility and this leads to uncertainty about enema spread. AIM: To assess the influence of disease activity on enema distribution, we conducted a physician-blinded, longitudinal study of the retrograde spread of three mesalazine enemas. METHODS: Thirty-one patients with mild to moderate ulcerative colitis were subdivided into three groups, and treated with 2 g mesalazine in 30 mL (group I, n = 10), 4 g mesalazine in 60 mL (group II, n = 12) or 1 g mesalazine in 100 mL (group III, n = 9). All patients received oral mesalazine 500 mg t.d.s. Enemas were labelled by adding 10 MBq (99mTc)technetium-sulphur colloid. Anterior scintigraphic images were taken at the start of the study and after 12 weeks of therapy; retrograde spread was assessed by calculating the percentage of the enema in each colonic segment. RESULTS: The activity score of ulcerative colitis diminished significantly after 12 weeks of treatment, but five patients dropped out of the study. At the start of treatment enema activity in group I was mainly concentrated in the sigmoid (99%); in group II activity was found in the rectum (9%), the sigmoid (61%) and the descending colon (15%); in group III activity was distributed between the sigmoid (66%) and descending colon (25%). The colonic distribution of mesalazine enemas was not influenced by disease activity. CONCLUSION: Volume, but not disease activity, is the important determinant of retrograde colonic spread of mesalazine enemas in ulcerative colitis.