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.     

Prolonged-release mesalazine: a review of its therapeutic potential in ulcerative colitis and Crohn's disease

Prolonged-release mesalazine (Pentasa) consists of ethylcellulose-coated microgranules from which mesalazine (known in the US as mesalamine) is released in the small and large intestine in a diffusion-dependent manner. Dose-dependent improvements in clinical and endoscopic parameters have been reported with prolonged-release mesalazine 2 and 4 g/day in clinical trials in patients with mild to moderately active ulcerative colitis. Induction of clinical and endoscopic remission was achieved in more patients receiving a daily dosage of 4 g/day than in those receiving placebo. In patients with ulcerative colitis in remission, prolonged-release mesalazine is effective in reducing the rate of relapse. Higher dosages tend to be more effective, and a 12-month remission rate of 64% has been reported for patients treated with a 4 g daily dosage of this formulation. Comparative data indicate that prolonged-release mesalazine has similar efficacy in maintaining remission to molar equivalent doses of sulfasalazine. Data from a study in patients with mild to moderately active Crohn's disease indicates that higher dosages (4 g/day) of prolonged-release mesalazine are more effective than placebo in reducing disease activity. After 16 weeks' treatment, 64% of patients receiving a 4 g/day dosage experienced clinical improvement and 43% attained remission. In studies of patients in remission of Crohn's disease, the formulation appears to be more effective in preventing relapse in patients with isolated small bowel disease than in those with colonic involvement. The tolerability profile of oral prolonged-release mesalazine is similar to that of placebo and the incidence of adverse events does not appear to be dose-related. Nausea/vomiting, diarrhoea, abdominal pain and dyspepsia occur most frequently, although their incidence is low. Reports of nephrotoxicity during prolonged-release mesalazine treatment are rare. Conclusions: Oral prolonged-release mesalazine is effective for maintenance and induction of remission of mild to moderately active colitis, both in patients with distal disease and in those with pancolitis. The formulation has similar efficacy to that of equimolar concentrations of sulfasalazine. Prolonged-release mesalazine also appears to be effective in the treatment of Crohn's disease, and maintenance therapy is of particular value in patients with isolated small bowel involvement. Evidence suggests that higher dosages (3 to 4 g/day) of prolonged-release mesalazine have additional therapeutic benefits over lower dosages in patients with inflammatory bowel disease without increasing the incidence of adverse events.     

MMX mesalamine: a novel high-dose,once-daily 5-aminosalicylate formulation for the treatment of ulcerative colitis

Background: 5-Aminosalicylate (5-ASA) agents are the first-line therapy for ulcerative colitis (UC). A high-dose, once-daily formulation of 5-ASA known as MMX mesalamine has recently been approved for the treatment of UC. Objective: To summarize current data on MMX mesalamine and to discuss its impact on management of UC. Methods: A systematic review of published literature was performed on PubMed using the search terms ‘MMX mesalamine’ and ‘Lialda^®’. Abstracts presented at US gastroenterology conferences between 2006 and 2007, were also reviewed. Results: MMX mesalamine uses a novel multi-matrix delivery system to achieve a sustained release of 5-ASA throughout the colon. Clinical trials have demonstrated MMX mesalamine 2.4 g/day or 4.8 g/day to be superior to placebo in inducing remission in active mild to moderate UC. The drug is well tolerated with a safety profile comparable to other oral 5-ASA agents. With a high-dose formulation of 1.2 g 5-ASA per tablet, MMX mesalamine can be administered conveniently at two to four pills once a day. Conclusion: MMX mesalamine is the first and only approved once-daily 5-ASA treatment option for patients with UC. It is efficacious for the induction of remission in mild to moderate UC and has a favorable safety profile. With the advantage of low pill burden and easy dosing schedule, it may potentially improve patient compliance and treatment success.     

Once daily MMX mesalazine for the treatment of mild-to-moderate ulcerative colitis: a phase II, dose-ranging study

Background SPD476 (MMX? mesalazine), is a novel, once daily, high‐strength mesalazine formulation (1.2 g/tablet) that utilizes Multi Matrix System? (MMX) technology to delay and extend delivery of the active drug throughout the colon. Aim To assess the safety and efficacy of MMX mesalazine in patients with mild‐to‐moderately active ulcerative colitis, in a pilot, phase II, randomized, multicentre, double‐blind, parallel‐group, dose‐ranging study (SPD476‐202). Methods Thirty‐eight patients with mild‐to‐moderately active ulcerative colitis were randomized to MMX mesalazine 1.2, 2.4 or 4.8 g/day given once daily for 8 weeks. Remission ulcerative colitis‐disease activity index (UC‐DAI) ≤1, a score of 0 for rectal bleeding and stool frequency, and ≥1‐point reduction in sigmoidoscopy score from baseline was the primary end point. Results Week 8 remission rates were 0%, 31% and 18% of patients receiving MMX mesalazine 1.2, 2.4 and 4.8 g/day respectively. No statistically significant difference in remission was observed between treatment groups. MMX mesalazine 2.4 and 4.8 g/day groups demonstrated greater improvement in overall UC‐DAI and component scores from baseline, compared with the 1.2 g/day group. Conclusion MMX mesalazine given as 2.4 or 4.8 g/day once daily is well tolerated and effective for the treatment of mild‐to‐moderately active ulcerative colitis.     

MMX mesalazine for the induction of remission of mild-to-moderately active ulcerative colitis: efficacy and tolerability in specific patient subpopulations

Background  Two phase III studies have evaluated mesalazine (mesalamine) with MMX (Multi Matrix System) technology in patients with active mild-to-moderate ulcerative colitis.
Aim  To determine the efficacy of MMX mesalazine for the induction of clinical and endoscopic remission in specific subgroups of patients with active, mild-to-moderate ulcerative colitis.
Methods  Data from two double-blind, placebo-controlled trials were analysed (517 out-patients). Patients were randomized to receive MMX mesalazine [2.4 g/day (once daily or 1.2 g twice daily) or 4.8 g/day (once daily)] or placebo for 8 weeks.
Results  The percentages of patients treated with MMX mesalazine, 2.4 or 4.8 g/day, in clinical and endoscopic remission at week 8 were similar and significantly ( P  < 0.05) greater than placebo in subgroups stratified by disease extent, disease severity and gender and among patients not previously receiving low-dose 5-aminosalicylic acid. Among patients transferring directly from prior low-dose oral 5-aminosalicylic acid, MMX mesalazine 4.8 g/day was significantly ( P  = 0.018) more effective than placebo in inducing clinical and endoscopic remission. Efficacy over placebo did not reach significance in patients transferring directly to MMX mesalazine 2.4 g/day.
Conclusion  MMX mesalazine is effective in active UC regardless of disease extent, disease severity, gender and previous, low-dose, 5-ASA therapy.     

Drug Therapy of Inflammatory Bowel Disease

Although the etiology of inflammatory bowel disease is unknown and specific therapy is unavailable, enough information on existing empiric agents is availble to allow rational therapy. These agents include sulfasalazine, steroids, immunosuppressive drugs, metronidazole and cholestyramine. Sulfasalazine is a two-part molecule that depends on bacterial cleavage in the colon to deliver locally acting 5-aminosalicylate, whose mechanism of action may relate to inhibition of prostaglandin synthesis. The other half of the molecule, sulfapyridine, is responsible for most of the side effects of the drug. While the efficacy of sulfasalazine in the treatment and prevention of attacks of ulcerative colitis is well established, its use in Crohn's disease appears to be limited to patients with active colitis and ileo-colitis. Sulfasalazine is of major benefit in preventing relapses in patients with ulcerative colitis in remission. New formulations of 5-aminosalicylate may allow delivery of the apparently active moiety to the small bowel and colon without concomitant sulfapyridine toxicity. Corticosteroids are highly effective in acute attacks of ulcerative colitis and Crohn's ileitis and ileo-colitis; the mechanism of antiinflammatory action remains speculative. However, maintenance therapy with steroids is ineffective in preventing relapses or recurrent attacks of either ulcerative colitis or Crohn's disease. Steroid enemas allow topical administration to patients with distal colitis and proctitis with few systemic side effects. In children with growth failure associated with active Crohn's disease, amelioration by steroid therapy may actually restore normal growth. Immunosuppressive agents such as azathioprine and 6-mercaptopurine are of little value in active Crohn's disease when administered alone; however, in combination with other agents they may help diminish steroid dose, close fistulae and prevent relapse. Their mode of action likely depends on long-term cytostatic effects on immune effector cells. Concern for leukopenia and the development of late malignancy has limited their use to patients not responding to other therapies. Metronidazole, an antimicrobial agent that is effective against anaerobes, has recently been shown useful in Crohn's disease involving the colon and perianal area. Its mechanism of action is uncertain, but may be related to its antibacterial actions on anaerobes. Cholestyramine can be successfully used to control bile salt-induced diarrhea in Crohn's patients with terminal ileal resections. Effective drug therapy of inflammatory bowel disease is only part of a total program of management including reassurance, frequent explanations, well-timed use of surgery, and an understanding physician.     

Mesalazine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in chronic inflammatory bowel disease

Mesalazine (5-aminosalicylic acid; mesalamine), the active moiety of sulphasalazine (salazosulfapyridine), is available in specially formulated oral and rectal forms for the treatment of active ulcerative colitis of mild to moderate severity and for maintenance therapy during disease remission. Tablets or capsules coated with acrylic-based resin and tablets containing microgranules coated with ethylcellulose deliver mesalazine to the distal small intestine and colon, thus avoiding the need for the carrier, sulphapyridine, which is responsible for many of the adverse effects associated with sulphasalazine. Since mesalazine is released in the small intestine from some coated preparations in contrast to sulphasalazine, these oral formulations have therapeutic potential in Crohn's disease. A limited number of therapeutic trials suggest that orally administered mesalazine 1.5 to 2.4g daily is of similar efficacy to sulphasalazine 2 to 3g daily in patients with mild to moderate ulcerative colitis. The efficacy of mesalazine enemas has been more widely investigated, a dose of 1 to 4g once daily being consistently more effective than placebo and apparently similar to enemas of prednisone 25mg or oral sulphasalazine 3g. Initial results suggest that mesalazine 4g enemas may be more effective than those containing hydrocortisone 100mg. Mesalazine and sulphasalazine in approximately equivalent oral dosages are similarly effective in maintaining remission in ulcerative colitis. Orally administered coated mesalazine is generally well tolerated by about 85% of patients allergic to or intolerant of sulphasalazine, the remainder experiencing similar reactions to both drugs. Adverse effects of mesalazine enemas are confined to local irritation and effects resulting from enema-tip insertion. Thus, orally administered coated mesalazine is a suitable alternative to sulphasalazine in the treatment of patients with mild to moderate active distal ulcerative colitis and for maintaining remission particularly in patients allergic to or intolerant of sulphasalazine. In patients who find enema therapy acceptable, mesalazine enemas are effective and well tolerated.     

Multi-Matrix System (MMX®) mesalamine for the treatment of mild-to-moderate ulcerative colitis

Introduction: Ulcerative colitis (UC) is an inflammatory disease of the colon characterized by periods of active disease and remission. The pathogenesis of this disease is likely a complex interaction of genetic predisposition, environmental factors, and immune system dysregulation, and is not completely understood. A Multi-MatriX (MMX®) system formulation of mesalamine, MMX mesalamine (SPD476; Lialda®; Mesavancol®; Mezavant®), allows for high-dose, once-daily dosing for patients with mild-to-moderate UC. Mesalamine is a topically active agent with anti-inflammatory properties.

Areas covered: Available literature regarding MMX mesalamine is extensively reviewed in this article, covering its chemical makeup, mechanism of action, pharmaceutics and pharmacokinetics, clinical efficacy, and safety and tolerability.

Expert opinion: A dose of 2.4 and 4.8 g was used in large Phase III clinical trials and was efficacious for induction of clinical and endoscopic remission in UC. MMX mesalamine was also efficacious in large multicenter maintenance studies for the maintenance of clinical and endoscopic remission. The introduction of the first once-daily mesalamine has given practitioners and patients more flexibility in dosing administration, which will ultimately lead to higher satisfaction and improved clinical outcomes.     

Prediction of clinical effects of infliximab administered for inflammatory bowel disease based on pharmacokinetic and pharmacodynamic modeling

Infliximab (IFX) is used as a therapeutic agent for ulcerative colitis (UC) and Crohn's disease (CD). Although the dosage regimen has been established through clinical trial experience, it has yet to be assessed with a pharmacokinetic and pharmacodynamic model. The present study analysed sequential changes of clinical response in patients with ulcerative colitis and Crohn's disease following repeated administrations of infliximab using the pharmacokinetic/pharmacodynamic model. In addition, the dosage regimen presently used for patients with ulcerative colitis was evaluated, as well as the potential efficacy gained by increasing the dose and/or reducing the interval of administration for patients with Crohn's disease. Furthermore, the possibility of evaluating the difference between both diseases with regard to the efficacy of infliximab was investigated. Sequential changes in the clinical response values obtained with our model were in good agreement with the observed values following administration of infliximab in patients with ulcerative colitis and Crohn's disease. The results showed the importance of a loading dose for patients with ulcerative colitis, as well as the efficacy of increasing the dose and reducing the interval for patients with Crohn's disease. Also, the efficacy of infliximab for both diseases is suggested to be similar. In conclusion, our results show a possible modeling scenario that can accommodate the clinical response to infliximab administered for ulcerative colitis and Crohn's disease. Furthermore, it provides confirmation for the present dosage regimens given for these diseases.     

Clinical trial: once-daily mesalamine granules for maintenance of remission of ulcerative colitis - a 6-month placebo-controlled trial

Aliment Pharmacol Ther 2010; 32: 990–999

Summary

Background Ulcerative colitis (UC) is a chronic relapsing and remitting idiopathic inflammatory bowel disorder. Aim To evaluate once‐daily mesalamine (mesalazine) granules (MG) for maintenance of remission of UC. Methods Randomized, double‐blind, placebo‐controlled trial of patients (n = 209 MG, n = 96 placebo) with UC in remission [revised Sutherland Disease Activity Index (SDAI) rectal bleeding = 0, mucosal appearance <2] who took MG 1.5 g or placebo once‐daily for up to 6 months. Primary efficacy endpoint: the percentage of patients who remained relapse‐free at month 6/end of treatment. Relapse was defined as SDAI rectal bleeding score ≥1 and a mucosal appearance score ≥2, a UC flare, or initiation of medication to treat a UC flare. Results The percentage of relapse‐free patients at month 6/end of treatment was higher with MG than placebo (78.9% vs. 58.3%, P < 0.001) in the intent‐to‐treat analysis. Significant differences (P ≤ 0.025) favouring MG were observed for most secondary endpoints including improvement in rectal bleeding, physician’s disease activity rating, stool frequency, the SDAI at month 6/end of treatment, patients classified as a treatment success and relapse‐free duration. The incidence of adverse events was similar between groups. Conclusions Once‐daily mesalamine (mesalazine) was effective in maintaining remission of UC for 6 months.     

Olsalazine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in inflammatory bowel disease.

Olsalazine (sodium azodisalicylate; azodisal sodium) is an anti-inflammatory agent designed to deliver its active moiety, mesalazine (5-aminosalicylic acid; mesalamine), to the colon while avoiding the adverse effects associated with the use of a sulfapyridine carrier. As a prodrug, olsalazine is an effective oral treatment for both active ulcerative colitis and for maintenance of disease remission and may possibly be of benefit in patients with Crohn's colitis. Findings from both short and long term noncomparative and comparative studies demonstrate that olsalazine 1 to 3g daily in divided doses improves clinical signs and symptoms of colitis in approximately 60 to 80% of patients with acute ulcerative colitis of mild to moderate severity. This improvement rate was similar to that obtained with sulfasalazine. Lower doses of olsalazine, usually 1g daily in divided doses, also maintained remission in patients with chronic ulcerative colitis. While olsalazine effectively delivers mesalazine to the colon, the prodrug itself increases net luminal water secretion and accelerates gastrointestinal transit of a meal. The resulting diarrhoea (occurring in approximately 17% of patients and resulting in withdrawal from therapy in 6% of patients) is distinguishable from that associated with inflammatory bowel disease by the high water content and the absence of blood. Olsalazine-induced diarrhoea usually occurred soon after initiation of olsalazine therapy or dosage increase, was more frequent with higher doses and was usually transient. Dosage reduction, increases in frequency of dosing and concomitant administration with food reduced the severity in many patients with persistent olsalazine-induced diarrhoea. With the exception of diarrhoea, olsalazine was generally well tolerated. Fewer than 14% of patients allergic to or intolerant of sulfasalazine had similar reactions to olsalazine. Olsalazine appears to be a suitable therapy for the treatment of first attacks as well as acute exacerbation of mild to moderate acute ulcerative colitis, and for the maintenance of remission in patients with chronic ulcerative colitis.     

C反应蛋白检测对溃疡性结肠炎活动性的评价

目的探讨12反应蛋白（CRP）检测对溃疡性结肠炎活动性的评估价值。方法分析41例活动期和17例缓解期溃疡性结肠炎患者血清CRP,比较临床病情程度对CRP的影响。结果活动性UC患者的血清CRP水平为（8．58±2．43）mg／L,其中重度UC患者CRP水平为（14．38±4．46）mg／L,中度UC患者CRP水平为（6．68±2．35）mg／L,轻度UC患者CRP水平为（4．94±1．21）mg／L,而缓解期UC患者CRP水平为（3．05±0．88）mg／L。活动期溃疡性结肠炎患者血清CRP表达率明显高于缓解期患者,差异有统计学意义（x^2=18．72,P〈0．05）;重型溃疡性结肠炎患者血清CRP表达率高于中型溃疡性结肠炎患者,差异有统计学意义（P〈0．05）;中型溃疡性结肠炎患者血清CRP表达率亦高于轻型溃疡性结肠炎患者,差异有统计学意义（x^2=8．16,P〈0．05）。结论CRP水平升高能反映活动期溃疡性结肠炎患者临床病情严重程度,为临床诊治提供重要理论依据。     

Oral versus combination mesalazine therapy in active ulcerative colitis: a double-blind, double-dummy, randomized multicentre study

BACKGROUND: Oral and topical mesalazine formulations are effective in active ulcerative colitis, but little is known on the efficacy of combined treatment. AIM: To compare the efficacy of oral mesalazine vs. combined oral and topical mesalazine in mildly to moderately active ulcerative colitis. METHODS: Patients with mildly to moderately active ulcerative colitis (Clinical Activity Index, CAI 4-12) were identified at 15 participating centres. They were randomized to receive either mesalazine 4 g orally plus placebo enema, or mesalazine 2 g orally plus mesalazine 2 g rectally as a liquid enema for 6 weeks. The rate of clinical remission (CAI < 4) or clinical remission/improvement (reduction of CAI of 50% from baseline) at 6 weeks and time to clinical remission/improvement were primary end-points; the rate of endoscopic remission was a secondary end-point. RESULTS: 67 patients were assigned to oral treatment and 63 to combined treatment. One patient in the oral group and 2 in the combined group discontinued the treatment due to adverse events. Following an intention-to-treat analysis, the rate of clinical remission was 82% for oral treatment and 87% for combined treatment (P=0.56); the mean time to remission 22.2 and 20.2 days, respectively (P=0.29); the rate of clinical remission/improvement and the rate of endoscopic remission were 85% and 91% (P=0.503) and 58% and 71% (P=0.21), respectively. CONCLUSIONS: In patients with mild active ulcerative colitis, mesalazine 4 g orally and 2 g orally plus 2 g enema are equally effective in inducing disease remission.     

Randomised clinical trial: delayed-release oral mesalazine 4.8 g/day vs. 2.4 g/day in endoscopic mucosal healing--ASCEND I and II combined analysis

Aliment Pharmacol Ther 2011; 33: 672–678

Summary

Background Recent studies have focused on the importance of mucosal healing in ulcerative colitis (UC). However, it was still unclear whether higher doses of delayed‐release mesalazine (mesalamine) could provide additional benefit. Aim To examine how two doses of delayed‐release mesalazine (4.8 g/day and 2.4 g/day) from ASCEND I and II compare in their relative ability to heal colonic mucosa over time. Methods Primary data from two prospective 6‐week, double‐blind, randomised studies in patients with mildly to moderately active UC were pooled and analysed retrospectively. The mucosal healing analysis focuses on moderately active UC patients (n = 391), comprising a majority of patients (84%). Additional analyses examined the relationship between mucosal healing and dose, clinical response to therapy and patient quality of life (Inflammatory Bowel Disease Questionnaire, IBDQ). Results At week 3, mucosal healing (endoscopy subscore of 0 or 1) was achieved in 65% of moderately active UC patients on 4.8 g/day and 58% of patients on 2.4 g/day (P = 0.219). At week 6, this increased to 80% for 4.8 g/day and 68% for 2.4 g/day (P = 0.012). Healing rates with the higher dose were also greater across all extents of disease and in patients with prior steroid use. At 6 weeks, clinical response to therapy and mucosal healing were found to be well correlated (kappa = 0.694). Likewise, the change in IBDQ at week 6 showed a significant relationship with mucosal healing (P < 0.0001). Conclusion Mucosal healing rates in UC achieved at 6 weeks were statistically significantly higher with delayed‐release mesalazine at 4.8 g/day vs. 2.4 g/day (Clinicaltrials.gov: NCT00577473, NCT00073021).     

Mesalamine in the treatment and maintenance of remission of ulcerative colitis

Ulcerative colitis (UC) is a chronic disease of the GI tract that is characterized by mucosal inflammation in the colon. Mesalamine (mesalazine) is a 5-aminosalicylic acid compound that is the first-line treatment for patients with mild-to-moderate UC. There are multiple formulations of mesalamine available, primarily differentiated by their means of delivering active mesalamine to the colon. Mesalamine has been demonstrated in randomized controlled trials to induce both clinical response and remission, and maintain clinical remission, in these patients. It has few serious adverse effects and is generally well tolerated by patients. The main areas of uncertainty with use of mesalamine in patients with UC center on the optimal dose for induction of response, how to maintain patient adherence and the role of mesalamine in cancer chemoprophylaxis. Generic forms of mesalamine have yet to be approved by regulatory bodies in the USA.     

Mesalamine in the treatment and maintenance of remission of ulcerative colitis

Ulcerative colitis (UC) is a chronic disease of the GI tract that is characterized by mucosal inflammation in the colon. Mesalamine (mesalazine) is a 5-aminosalicylic acid compound that is the first-line treatment for patients with mild-to-moderate UC. There are multiple formulations of mesalamine available, primarily differentiated by their means of delivering active mesalamine to the colon. Mesalamine has been demonstrated in randomized controlled trials to induce both clinical response and remission, and maintain clinical remission, in these patients. It has few serious adverse effects and is generally well tolerated by patients. The main areas of uncertainty with use of mesalamine in patients with UC center on the optimal dose for induction of response, how to maintain patient adherence and the role of mesalamine in cancer chemoprophylaxis. Generic forms of mesalamine have yet to be approved by regulatory bodies in the USA.     

Risk-benefit assessment of drugs used in the treatment of inflammatory bowel disease.

Although the aetiology of inflammatory bowel disease remains elusive, many agents are available for the control of symptoms and inflammation. Knowledge of drug pharmacology, indications and side effects is essential to ensure the best possible clinical care while minimising toxicity and inappropriate use. Sulfasalazine consists of sulfapyridine linked to mesalazine (5-aminosalicylic acid) via an azobond. Its use is indicated in the treatment of mild to moderately active ulcerative colitis and in the prevention of relapse in patients with quiescent disease. Patients with mild to moderate colonic or ileocolonic Crohn's disease also benefit from this drug, as do a proportion of patients with isolated small bowel disease. Sulfasalazine has not been uniformly effective in preventing relapse in Crohn's disease, although many clinicians continue its use in patients who respond initially. A high incidence of side effects which limit therapy include intolerance, hypersensitivity reactions and impairment of male infertility. The newer aminosalicylates offer targeted delivery of mesalazine to the bowel, with fewer side effects. Topical mesalazine has proved extremely effective in patients with distal ulcerative colitis; oral forms are effective in the treatment of mild to moderately active ulcerative colitis and in relapse. Both types appear to be effective in the treatment of Crohn's disease, and possibly in preventing relapse. There is no current clinical advantage of one mesalazine preparation over another, nor is there an indication for their use in sulfasalazine-treated patients who have satisfactory response without adverse effects. Corticosteroids are indicated for more severe disease activity where the aminosalicylates have limited efficacy-specifically to induce remission in patients with severe or refractory ulcerative colitis or Crohn's disease. They should not be used to maintain disease remission or in the prevention of postoperative recurrence. Topical corticosteroids allow their local use in distal colitis with minimal systemic side effects. Long term use is limited by side effects, many of which are dose related, although alternate-day therapy may lessen the incidence. Immunosuppressive agents are beneficial for the treatment of refractory inflammatory bowel disease unresponsive to other medications, and may also facilitate the withdrawal of steroids in refractory patients. Mercaptopurine has an added benefit in the treatment of Crohn's disease fistulae; the role of cyclosporin in bowel disease has not been established and its use cannot currently be recommended. The potential toxicity of immunosuppressive agents warrants careful consideration of their use by both physician and patient. Metronidazole is indicated for the treatment of mild to moderate Crohn's disease, including perineal disease. Common side effects include peripheral neuropathy and nausea.(ABSTRACT TRUNCATED AT 400 WORDS)     

Efficacy and safety of thalidomide in children and young adults with intractable inflammatory bowel disease: long-term results

BACKGROUND: Anti-tumour necrosis factor-alpha antibodies are useful for the treatment of refractory Crohn's disease and ulcerative colitis. Thalidomide is another agent with tumour necrosis factor-alpha suppressive properties. AIM: To investigate the long-term efficacy and safety of thalidomide in a group of children and young adults with refractory inflammatory bowel disease. METHODS: Twenty-eight patients with refractory moderate-severe inflammatory bowel disease (19 Crohn's disease, 9 ulcerative colitis) received thalidomide 1.5-2.5 mg/kg/day. Patients were assessed at baseline, at weeks 2, 4, 8 and 12, and then every 12 weeks by patient's diary, physical examinations, laboratory analyses and scoring on activity indexes. Primary outcomes were: (i) efficacy in inducing remission; and (ii) efficacy in maintaining remission. RESULTS: Remission was achieved with thalidomide in 21 of 28 (75%) patients (17 with Crohn's disease, 4 with ulcerative colitis). Mean duration of remission was 34.5 months. Sixteen of 20 (80%) patients suspended steroids. Reversible neuropathy occurred in seven of 28 (25%) patients, but only with cumulative doses over 28 g. Other side effects requiring thalidomide suspension were vertigo/somnolence (one of 28), and agitation/hallucinations (one of 28). CONCLUSIONS: Thalidomide seems to be effective in inducing long-term remission in children and adolescents with intractable inflammatory bowel disease. Neuropathy is the main adverse effect, but appears to be cumulative dose-dependent, thus allowing long-term remission before drug suspension.     

5-aminosalicylic acid preparations in the treatment of inflammatory bowel disease

Multiple new 5-aminosalicylic acid preparations have joined sulphasalazine in our armamentarium of agents for the treatment of inflammatory bowel disease. Rowasa enemas are clearly an advance in our ability to treat distal ulcerative colitis. Oral 5-ASA analogues are equivalent to sulphasalazine in maintaining ulcerative colitis in remission but may have some increased efficacy in high doses for treating mild to moderate active ulcerative colitis. These agents are particularly useful in the sulphasalazine-intolerant individual. Some of the new 5-ASA preparations have been found to be helpful in the treatment of active Crohn’s disease. There is hope that the newer agents having distal small bowel drug release may be beneficial in maintaining Crohn’s disease in remission.     

A double-blind dose-escalating trial comparing novel mesalazine pellets with mesalazine tablets in active ulcerative colitis

BACKGROUND: Mesalazine as the treatment standard for ulcerative colitis can be applied in different galenical preparations. AIM: A novel formulation of mesalazine pellets with delayed and prolonged release characteristics was compared with conventional Eudragit L-coated tablets. Furthermore, the effect of mesalazine dose escalation on nonresponders was evaluated in both treatment groups. METHODS: A total of 233 patients with mild to moderately active ulcerative colitis were randomized to receive either mesalazine (1.5 g/day in three doses) as pellets (n = 115) or tablets (n = 118) for 8 weeks. At insufficient response, the dose was increased to 3.0 g. RESULTS: The clinical remission rate (clinical activity index < or = 4) for pellets was 67% vs. 68% for tablets which statistically proved to be not inferior (significance level alpha = 2.5%). In patients without dose increase, the remission rate was 47% (pellets) vs. 42% (tablets). Endoscopic improvement was observed in 80% (pellets) vs. 83% (tablets), and histological improvement in 48% (pellets) vs. 52% (tablets) of patients. CONCLUSIONS: Mesalazine pellets are as effective as tablets in the treatment of mild to moderately active ulcerative colitis. Dose escalation to 3.0 g/day is a valid option for nonresponders to a starting dose of 1.5 g/day.