Clinical experience of the tolerance of mesalazine and olsalazine in patients intolerant of sulphasalazine

We assessed the tolerance and safety of two new preparations designed to release 5-aminosalicylic acid in the colon in patients with ulcerative colitis who were intolerant of sulphasalazine. Twenty-eight of 37 patients (76%) given mesalazine and 18 of 21 patients (86%) given olsalazine tolerated the new preparations with no adverse effects. No haematologic or biochemical abnormalities were detected. Adverse reactions to the new preparations were usually but not always similar to those they had previously encountered with sulphasalazine, but a few patients experienced rash and diarrhoea. In some patients intolerant of one of the new preparations, their tolerance of the other was assessed. Three patients intolerant of mesalazine tolerated olsalazine. Similarly, three other patients intolerant of olsalazine tolerated mesalazine. We conclude that not all adverse effects of sulphasalazine are due to the sulphapyridine part of the molecule. Some are due to the released 5-aminosalicylic acid and some to the parent compound. Both drugs are likely to prove useful in the management of patients intolerant of sulphasalazine.     

巴柳氮、美沙拉嗪和柳氮磺吡啶治疗活动性溃疡性结肠炎的荟萃分析

目的:评价巴柳氮、美沙拉嗪和柳氮磺吡啶治疗活动性溃疡性结肠炎(UC)的疗效与安全性,并探讨三种药物不同的药物动力学.方法:检索Medline、EMBASE、OVID、Cochrane Library、Cinahl、CESJ、ASP、VIP和CNKI中国期刊全文数据库2008-07-01前已发表的关于巴柳氮、美沙拉嗪和柳氮磺吡啶相互比较治疗活动性UC的随机对照临床试验研究.再通过手工检索2008-01/2008-06已发表的关于三种药物相互比较治疗活动性溃疡性结肠炎的随机对照临床试验研究.利用Stata9.0软件进行荟萃分析.结果:按入选标准,共纳入10个随机对照临床试验,共1119例UC患者纳入荟萃分析.巴柳氮与柳氮磺吡啶相比,其疗效相似(OR=1.24,95% CI:0.80-1.93,P=0.345),副作用发生率低(OR=0.27,95% CI:0.13-0.59,P=0.001),副作用致停药率低(OR=0.12,95%CI:0.03-0.44,P=0.002).巴柳氮与美沙拉嗪相比,疗效相似(OR=1.55,95% CI:1.00-2.42,P=0.051),副作用发生率低(OR=0.59,95%CI:0.39-0.90,P=0.014),副作用致停药率相似(OR=1.34,95% CI:0.29-6.22,P=0.709).美沙拉嗪与柳氮磺吡啶相比,疗效相似(OR=0.71,95% CI:0.19-2.59,P=0.599),副作用发生率低(OR=0.44,95% CI:0.27-0.71,P=0.001),副作用致停药率相似(OR=0.69,95%CI:0.26-1.88,P=0.470).结论:巴柳氮、美沙拉嗪和柳氮磺吡啶均能有效的治疗活动性UC,而巴柳氮和美沙拉嗪副作用发生率低于柳氮磺吡啶副作用发生率;偶氮5-ASA前药可能较5-ASA控释剂更能有效地治疗UC.     

Controlled trial comparing olsalazine and sulphasalazine for the maintenance treatment of ulcerative colitis.

One hundred and sixty four patients with ulcerative colitis in remission were entered into a double blind, double dummy trial comparing olsalazine 500 mg bd and sulphasalazine 1 g bd. Clinical examination, sigmoidoscopy and rectal biopsy were performed at 0, three, and six months. Sixteen of 82 (19.5%) patients relapsed on olsalazine and 10/82 (12.2%) relapsed on sulphasalazine. The difference was not statistically significant (p = 0.1632). Adverse events were minor and were similar in both groups. No haematological or biochemical abnormalities were detected. Thus, olsalazine is as effective as sulphasalazine for preventing a relapse of ulcerative colitis.     

Role of mesalazine in acute and long-term treatment of ulcerative colitis and its complications

BACKGROUND: Sulfasalazine, consisting of 5-aminosalicylic acid bound to sulfapyridine by a diazo bond, was first used for treatment of ulcerative colitis in the early 1940s and later found effective in placebo-controlled trials for acute disease and for long-term maintenance of remission. Later studies found that the active moiety is 5-ASA (mesalazine, mesalamine) and the sulfapyridine moiety acts as a carrier molecule but causes many of the symptomatic adverse reactions. METHODS: Review of the literature. RESULTS: The finding that 5-ASA in the active motility led to the development of mesalazine prodrugs, olsalazine (Dipentum) and balsalazide (Colazide, Colazal), and targeted release mesalazine preparations, such as Asacol, Pentasa, and Salofalk, as well as enemas and suppository preparations for distal disease. Most patients with adverse effects from sulfasalazine will tolerate mesalazine. Mesalazine has been shown equivalent or superior to sulfasalazine, and superior to placebo, with a dose-response benefit, in inducing remission of acute disease. and comparable to sulfasalazine and superior to placebo for long-term maintenance of remission. Better tolerance of mesalazine and the ability to use higher doses favor its use in patients intolerant of sulfasalazine and in patients failing to respond to usual doses of sulfasalazine. Adverse effects from mesalazine are uncommon, but include idiosyncratic worsening of the colitis symptoms and renal toxicity. Mesalazine is safe to use during pregnancy and for nursing mothers. As maintenance therapy, mesalazine may reduce the risk of developing colorectal carcinoma. CONCLUSION: Mesalazine represents effective and well-tolerated first-line therapy for mildly to moderately acute disease as well as for the long-term maintenance treatment in the patient with ulcerative colitis.     

奥沙拉嗪联合地塞米松保留灌肠治疗溃疡性结肠炎的疗效评价

[目的]评价奥沙拉嗪联合地塞米松保留灌肠治疗溃疡性结肠炎(ulcerative colitis,UC)的疗效及安全性.[方法]50例UC患者随机分为观察组(26例,采用奥沙拉嗪联合地塞米松保留灌肠)、对照组(24例,采用柳氮磺嘧啶联合地塞米松保留灌肠),比较2组治疗前及治疗1个月、2个月后患者疾病活动指数(disease activity index,DAI),治疗2个月后总有效率及不良反应发生情况.[结果]2组患者治疗前DAI差异无统计学意义(P＞0.05);治疗1个月后,2组患者DAI均较治疗前降低(P＜0.05),而2组间比较差异无统计学意义(P＞0.05);治疗2个月后,2组DAI均较治疗前下降显著(P＜0.01),观察组优于对照组,差异有统计学意义(P＜0.05).治疗2个月后,观察组总有效率为92.3％,对照组为75.0％,2组比较差异有统计学意义(P＜0.05).[结论]奥沙拉嗪联合地塞米松保留灌肠治疗UC患者安全有效,值得临床推广.     

Disposition of 5-aminosalicylic acid by olsalazine and three mesalazine preparations in patients with ulcerative colitis: comparison of intraluminal colonic concentrations, serum values, and urinary excretion.

To compare the disposition of 5-aminosalicylic acid (5-ASA) and its acetylated metabolite during treatment with olsalazine and mesalazine, 14 patients with inactive ulcerative colitis were randomly assigned to olsalazine (1 g twice daily) and the mesalazines, Asacol (800 + 400 + 800 mg daily), Pentasa (750 + 500 + 750 mg daily), and Salofalk (750 + 500 + 750 mg daily) in a crossover design trial so that all received each drug for seven days. Intraluminal colonic concentrations of 5-ASA were estimated after five days by the method of equilibrium in vivo dialysis of faeces. A predose serum sample and a 24 hour urine collection were obtained on day seven. The 5-ASA and acetyl-5-aminosalicylic acid (Ac-5-ASA) values were determined by high performance liquid chromatography. Olsalazine almost doubled the colonic concentrations (mean 23.7 (SEM) (1.9) mmol/l) of its therapeutically active ingredient (5-ASA) compared with equimolar doses of Pentasa (12.6 (2.2) mmol/l; p less than 0.0003) and Salofalk (15.0 (2.0) mmol/l; p less than 0.003). At the same time, olsalazine treatment was associated with lower serum concentrations and urinary excretions (p less than 0.05) of 5-ASA and Ac-5-ASA compared with the mesalazine preparations. The low systemic load of 5-ASA provided by olsalazine reduces the potential risk of nephrotoxicity during long term treatment.     

Influence of olsalazine on gastrointestinal transit in ulcerative colitis.

The effect of olsalazine on stool output and the transit of a solid radiolabelled meal through the stomach, small intestine and colon was studied in six patients with ulcerative colitis intolerant of sulphasalazine. Olsalazine 250 mg four times daily significantly accelerated gastric emptying (mean +/- SD; 45.3 +/- 24.2 min v 67.3 +/- 33.1 min, p less than 0.05), mouth to caecum transit time (242 +/- 41 min v 325 +/- 33 min, p less than 0.02) and whole gut transit time (60.5 +/- 26 h v 37.8 +/- 17.8 h, p less than 0.05). No significant changes were seen in mean daily stool weight (215 +/- 41 g v 162 +/- 62 g) and mean daily stool frequency (2.2 +/- 0.6 v 2.4 +/- 1.8). None of these patients developed diarrhoea, but acceleration of gastric and intestinal transit may be responsible for the diarrhoea reported in some patients taking this drug.     

Effect of long-term therapy with sulphasalazine, levamisole, corticosteroids and ascorbic acid and of disease activity on polymorphonuclear leukocyte function in patients with ulcerative colitis

Adhesion, random migration and chemotactic migration, phagocytosis, and spontaneous nitroblue tetrazolium-dye reduction (NBT) capacity of polymorphonuclear leukocytes (PMNs) were analysed in 38 patients with ulcerative colitis before and during therapy with sulphasalazine (12 months), corticosteroids (6 months), levamisole (12 months), ascorbic acid (6 months) and sulphasalazine plus levamisole (12 months). Remission was achieved by levamisole in as many patients as by sulphasalazine and by sulphasalazine and levamisole used together. Nevertheless, the only function of PMNs affected by levamisole therapy was a depression of chemotaxis, whereas other functions as well as chemotaxis were altered by sulphasalazine, whether used alone or in combination with levamisole. Of patients treated with corticosteroids, all were in remission at 6 months and the most marked decrease in chemotaxis was seen. No clinical benefits were observed after 6 months of treatment with ascorbic acid and PMNs function was unaltered. The depression of chemotaxis occurred whether or not remission was achieved, suggesting a direct drug-induced effect. The apparent discrepancies of the "in vivo" drug effects in comparison with previously reported findings may reflect abnormal reactivity of PMNs in UC.     

A controlled therapeutic trial of long-term maintenance treatment of ulcerative colitis with sulphasalazine (Salazopyrin)

Sixty-four patients with proven ulcerative colitis who had been maintained on sulphasalazine as their sole form of treatment for a minimum period of one year were entered into a controlled trial of sulphasalazine versus dummy tablets for a period of six months. All the patients admitted were not only symptom-free but also showed no evidence of inflammation on sigmoidoscopy and rectal biopsy. A patient was judged to have relapsed when there was a recurrence of colitic symptoms accompanied by sigmoidoscopic and histological evidence of inflammation.The patients who received dummy tablets had more than four times the relapse rate of those receiving sulphasalazine. The results were similar in patients who had been on maintenance treatment with sulphasalazine for less than three years before entry into the trial and in those who had been on this treatment for more than three years.It is concluded that maintenance treatment of ulcerative colitis with sulphasalazine should be continued indefinitely unless contraindicated by side effects.     

Prophylactic effects of olsalazine v sulphasalazine during 12 months maintenance treatment of ulcerative colitis. The Danish Olsalazine Study Group.

In a Danish multicentre trial we compared the relapse preventing effects of olsalazine and sulphasalazine in patients with ulcerative colitis over a 12 month treatment period. Two hundred and twenty seven patients (118 men) with at least two previous attacks of ulcerative colitis were randomly allocated according to a prearranged treatment schedule to olsalazine 500 mg bd or sulphasalazine 1 g bd in a double blind, double dummy fashion. One hundred and ninety seven patients completed the trial. The relapse rate after 12 month in the olsalazine group was 46.9% v 42.4% in the sulphasalazine group with a 95% confidence interval for the difference in proportions of -9% to 18%. Seven per cent of the patients were withdrawn from the trial because of adverse drug reactions and these were equally distributed between the two groups.     

Optimum dose of olsalazine for maintaining remission in ulcerative colitis.

To evaluate the optimum dose of olsalazine for maintaining remission in ulcerative colitis, 198 patients in remission for more than three months were randomly assigned to receive 0.5 g, 1.0 g, or 2.0 g/day for 12 months. A dose-ranging effect was detected in the per protocol analysis, with remission rates of 60% (0.5 g), 70% (1.0 g), and 78% (2.0 g) (p = 0.03, trend in proportions). The higher dose was most effective in patients with proctitis (90% remission on 2 g/day, p = 0.03) or those in remission for less than 12 months before the trial (88% remission on 2 g/day, p = 0.0006). There was little dose-ranging effect in patients with extensive colitis or those in remission for more than 12 months. Diarrhoea necessitated treatment withdrawal in 12%. The optimal dose of olsalazine for maintaining remission in ulcerative colitis is 1 g/day. For patients with proctitis or recent relapse, 2 g/day may be preferable, although the dose seems to be less important in patients with more extensive disease or those in long term remission.     

Bilateral pulmonary infiltrates in a patient with ulcerative colitis receiving mesalazine

A 36-year-old woman presented with a 2-month history of dry cough, bilateral pain in the upper chest, and low-grade fever. She had a 1-year history of ulcerative colitis (UC), which was treated with mesalazine. Cultures of sputum and bronchoalveolar lavage (BAL) fluid were negative. Chest radiograph and a computed tomography (CT) scan showed dense bilateral subpleural infiltrates in both upper lobes. A c-ANCA test was positive in a 1:1280 titer, and further specification showed antibodies against proteinase-3 antigen. Due to the possibility of mesalazine toxicity, this medication was stopped. Within 2 weeks, the patient's symptoms markedly improved, together with the chest roentgenogram.     

美沙拉嗪联合培菲康对溃疡性结肠炎患者免疫功能及炎性因子的影响

目的探究美沙拉嗪联合培菲康对溃疡性结肠炎(UC)患者免疫功能及炎性因子的影响。方法选取2015年1月至2016年1月接受治疗的UC患者80例,按随机数字法分为对照组和研究组,每组40例。对照组服用美沙拉嗪,研究组在对照组基础上加服培菲康,比较两组临床疗效、血清免疫球蛋白IgA、IgG、IgM、肿瘤坏死因子-α(TNF-α)、白细胞介素-10(IL-10)水平及不良反应发生情况。结果研究组治疗后的总有效率显著高于对照组(P0.05)。治疗后两组的临床症状评分均显著下降(P0.05),且研究组下降幅度更大,两组差异有统计学意义(P0.05)。治疗前两组的IgA、IgG、IgM水平差异无统计学意义(P0.05),而治疗后两组的IgA、IgG水平均显著下降(P0.05),且研究组下降幅度更大,两组差异有统计学意义(P0.05)。治疗前两组的TNF-α、IL-10水平差异无统计学意义(P0.05),而治疗后两组的TNF-α水平均显著下降,IL-10则显著上升(P0.05),且研究组变化幅度更大,两组差异有统计学意义(P0.05)。两组的不良反应发生情况的差异无统计学意义(P0.05)。结论美沙拉嗪联合培菲康治疗UC患者较单用美沙拉嗪的疗效更显著,不良反应少,安全有效,临床上值得推广。     

Clinical course and long-term prognosis of Japanese patients with ulcerative colitis

The course and prognosis of 308 patients with ulcerative colitis who visited Tohoku University Hospital during the period from 1954 to 1987 were investigated. Based these investigations, the following results were obtained. 1) In 27.6% of patients with proctitis, extension to the proximal colon developed during the observation period. 2) Surgical intervention was necessary in 33.9% of patients with total colitis and in 9.7% of those with left-sided colitis. 3) Of 1,566 patient-years in which the course was observed, 988 (63.1%) were active-years. When the course of ulcerative colitis was analyzed according to the duration and extent of involvement, the frequency of the attack-years in patients with proctitis or left-sided colitis steadily decreased with time. However, that of total colitis was constant, 65-85%, regardless of the follow-up period. Patients younger than age 20 at onset were prone to relapse during their course, compared with patients older than 20. 4) Ten patients died from causes related to ulcerative colitis in our hospital: 5 of them due to postoperative complications. Two patients developed colorectal cancer accompanying ulcerative colitis. 5) With respect to the cumulative survival rate, the 95% confidence limits of the observed curve was lower than the expected curve during the first 2 years and 12-16 years after the onset. The main causes of death were postoperative complications in the former and unrelated deaths of older patients in the latter. This work was partly supported by a grant from the Investigation and Research Committee for Intractable Inflammatory Bowel Diseases, organized by Japanese Ministry of Public Welfare.     

Clinical course and long-term prognosis of Japanese patients with ulcerative colitis

The course and prognosis of 308 patients with ulcerative colitis who visited Tohoku University Hospital during the period from 1954 to 1987 were investigated. Based these investigations, the following results were obtained. 1) In 27.6% of patients with proctitis, extension to the proximal colon developed during the observation period. 2) Surgical intervention was necessary in 33.9% of patients with total colitis and in 9.7% of those with left-sided colitis. 3) Of 1,566 patient-years in which the course was observed, 988 (63.1%) were active-years. When the course of ulcerative colitis was analyzed according to the duration and extent of involvement, the frequency of the attack-years in patients with proctitis or left-sided colitis steadily decreased with time. However, that of total colitis was constant, 65-85%, regardless of the follow-up period. Patients younger than age 20 at onset were prone to relapse during their course, compared with patients older than 20. 4) Ten patients died from causes related to ulcerative colitis in our hospital: 5 of them due to postoperative complications. Two patients developed colorectal cancer accompanying ulcerative colitis. 5) With respect to the cumulative survival rate, the 95% confidence limits of the observed curve was lower than the expected curve during the first 2 years and 12-16 years after the onset. The main causes of death were postoperative complications in the former and unrelated deaths of older patients in the latter.