Oroileal transit of slow release 5-aminosalicylic acid.

The predominant active anti-inflammatory moiety in chronic inflammatory bowel disease is 5-aminosalicylic acid (5-ASA). As unprotected 5-ASA is rapidly absorbed in the upper gastrointestinal tract several slow release preparations have been developed to permit passage of 5-ASA to the lower small bowel and to the colon. To investigate luminal kinetics and extent of the release of 5-ASA intraluminal concentrations and loads of this compound together with that of its main metabolite acetyl-5-aminosalicylic acid (ac-5-ASA) were studied, over 15 hours after giving the slow release preparation Salofalk at a dose of 500 mg orally together with a test meal. Plasma concentrations and urinary excretion were also measured. Six healthy volunteers swallowed an 11 lumen oroileal tube, which allowed marker perfusion, aspiration of luminal content from the duodenum, mid-jejunum, and ileum, and recording of intestinal motility. Emptying of 5-ASA into the duodenum started after emptying of the meal, together with the first phase III of interdigestive motility. Mean luminal concentrations of 5-ASA and ac-5-ASA increased continuously from duodenum (both: 15 to 30 micrograms/ml) to ileum (60 to 110 micrograms/ml and 80 to 150 micrograms/ml respectively) over three hours and decreased over the next three hours. During 10 hours after eating, 30% of the total dose passed the ileum in solution and another 10% were excreted in urine. Thus about 60% reached the colon unreleased from tablets and another 30% were in solution. The ratio of 5-ASA and ac-5-ASA in solution was about 1:1 in the duodenum and 1:1.5 to 1:2 in the more distal small intestine. The data suggest that the large quantities of intraluminal ac-5-ASA are generated in the intestinal mucosa and reach the lumen by back diffusion. The results show that most of the 5-ASA from this slow release preparation is delivered into the colon, which explains its effectiveness in ulcerative colitis. The considerable luminal concentrations already present in the distal ileum might justify therapeutic trials in Crohn's disease.     

Double blind, controlled trial of 4-aminosalicylic acid and prednisolone enemas in distal ulcerative colitis.

Corticosteroid or 5-aminosalicylic acid enemas are the treatment of choice for distal ulcerative colitis but up to one third of patients may be unresponsive. As an alternative therapy might be advantageous, the efficacy of six weeks' treatment with 2 g 4-aminosalicylic acid (4-ASA) (n = 24) and 20 mg prednisolone enemas (n = 21) were compared in a double blind, randomised trial in patients with acute distal (less than 30 cm from the anus) ulcerative colitis. Baseline demography and clinical severity were similar in both groups. Five of 24 patients receiving 4-ASA and 4 of 21 receiving prednisolone did not complete the trial because of deteriorating symptoms, failure to improve, or side effects. At the time of leaving the trial, 24 hour stool frequency, the presence of blood in the stools, and histological and sigmoidoscopic appearances were similar in both groups. Symptomatic improvement occurred in 17 of 24 patients receiving 4-ASA compared with 11 of 21 receiving prednisolone (chi 2 = 1.62, NS). Complete symptomatic improvement occurred in 9 of 24 patients receiving 4-ASA compared with 5 of 21 receiving prednisolone (chi 2 = 0.98, NS). Histological improvement was seen in 9 of 24 patients on 4-ASA compared with 7 of 21 on prednisolone (chi 2 = 0.08, NS). One patient receiving 4-ASA was considered to have an idiosyncratic reaction to the drug but other side effects were not considered to be drug related. Thus, 4-ASA, previously used in the treatment of tuberculosis (para-aminosalicyclic acid), is as good as prednisolone in the treatment of distal ulcerative colitis and should be considered in patients unresponsive to steroids or in whom steroid treatment is undesirable.     

Oral 5-aminosalicylic acid (Asacol) in the maintenance treatment of Crohn's disease. The Italian IBD Study Group.

A randomized, placebo-controlled multicenter trial was conducted to evaluate the efficacy and safety of a delayed-release formulation of 5-aminosalicylic acid (5-ASA) (Asacol; Giuliani & Bracco, Milan, Italy) for prevention of clinical relapse in 125 patients with inactive Crohn's disease. Patients in remission [Crohn's Disease Activity Index (CDAI) less than 150] between 3 months and 2 years were randomly allocated to receive either 800 mg 5-ASA three times daily (n = 64) or placebo (n = 61) for up to 12 months or until relapse of symptoms. Relapse was defined by a CDAI greater than 150, with a minimum increase of 100 points over the baseline value. The cumulative relapse rates were 12% in the 5-ASA group and 22% in the placebo group at 3 months [95% confidence interval (CI) for the difference, -4 to 24]; 28% and 41%, respectively, at 6 months (95% CI, -4 to 30); and 34% and 55%, respectively, at 12 months (95% CI, 3-39; P = 0.02, log rank test). Significant decrease in the risk of relapse was found in patients with ileitis, in those with previous bowel resection and, in those with prolonged prestudy remission. Eight patients (5 on 5-ASA, 3 on placebo) withdrew from the study because of adverse reactions, but no major clinical or laboratory adverse effect was observed. It is concluded that oral 5-ASA coated with Eudragit S (Rohn Pharma GmbH, Wieterstadt, Germany), 2.4 g daily, is safe and seems superior to placebo in preventing or delaying clinical relapse in Crohn's disease, especially in milder cases and in ileal disease.     

Bioavailability of 5-aminosalicylic acid from slow release 5-aminosalicylic acid drug and sulfasalazine in normal children

The bioavailability of a controlled release 5-aminosalicylic acid preparation (Pentasa) was investigated in nine healthy children after a medication period of six days (1000 mg/day) and compared with sulfasalazine (Salazopyrin) (2000 mg/day). The local bioavailability in the distal gut lumen, reflected by the 5-aminosalicylic acid concentration in the fecal water, showed comparable values after Pentasa (4.44 mmol/liter) and Salazopyrin (6.25 mmol/liter). The concentration ofN-acetyl-5-ASA was significantly higher after Pentasa, reflecting the more proximal release of 5-aminosalicylic acid compared with Salazopyrin. No relation was found between the 5-aminosalicylic acid fecal water concentration and the 5-aminosalicylic acid dose per kilogram of body weight. The urinary excretion of 5-aminosalicylic acid andN-acetyl-5-aminosalicylic acid was higher after Pentasa than after Salazopyrin (32% vs 25%). Dose interval plasma concentration curves showed low values after both preparations. Based on the concept that the fecal water concentration is decisive for the efficacy of 5-aminosalicylic acid in distal inflammatory bowel disease, Pentasa treatment offers a relevant alternative in cases of Salazopyrin intolerance or allergy in children. The higher systemic bioavailability from Pentasa warrants monitoring of the renal function.     

Oral 5-aminosalicylic acid preparations in treatment of inflammatory bowel disease an update

Therapeutic efficacy of 5-aminosalicylic acid (5-ASA) preparations is reviewed. In the acute treatment of Crohn's disease, Pentasa and Salofalk seem to be more effective than placebo. When it is given in an equimolar 5-ASA regimen, Salofalk appears to be at least as effective as sulfasalazine (SAS) in the treatment of both Crohn's disease and ulcerative colitis. Asacol and SAS are equally effective in maintenance therapy of ulcerative colitis. Dipentum was more efficient than placebo. There was only a low incidence of side effects from oral 5-ASA preparations, but larger-scale trials may be needed for a more accurate profile of adverse reactions.     

Double blind, randomised, placebo controlled study of leflunomide in the treatment of active ankylosing spondylitis

OBJECTIVE: To assess the efficacy and safety of leflunomide in active ankylosing spondylitis (AS) compared with placebo in a 24 week pilot study. METHODS: In a single centre randomised, double blind, placebo controlled study, 45 patients with active AS were randomised to either leflunomide 20 mg daily (n=30) or placebo (n=15). Active disease was defined as a score of >or=4 on the Bath ankylosing spondylitis disease activity index (0-10), and pain of >or=4 on a visual analogue scale (0-10). The primary efficacy variable at week 24 was the 20% response rate, as recommended by the Assessments in Ankylosing Spondylitis (ASAS) working group. Secondary outcome variables included general wellbeing, metrology index, swollen joint count, erythrocyte sedimentation rate, and C reactive protein. RESULTS: In all, 13 women and 32 men were studied. Demographic and disease indices were comparable between the two treatment groups at baseline. The rate of ASAS 20% responders was not significantly different: 27% in the leflunomide treated patients and 20% in the placebo group (95% confidence interval, -32% to 19%). No significant differences were found between the treatment groups in mean changes of the secondary outcome variables. Eleven patients were withdrawn prematurely from the study because of adverse events (7), lack of efficacy (3), and non-compliance (1). Most frequently adverse events were gastrointestinal side effects and skin disorders. CONCLUSIONS: In this placebo controlled study, leflunomide treatment did not result in a significant improvement of the ASAS 20% response in active ankylosing spondylitis. No unexpected or severe adverse events occurred.     

Endotoxaemia in active Crohn's disease. Treatment with whole gut irrigation and 5-aminosalicylic acid.

Endotoxins in plasma were monitored during treatment in 18 patients hospitalised for acute exacerbation of Crohn's disease: systemic endotoxaemia was found on admission in all but one. The patients were randomly divided into two groups: one receiving treatment with total parenteral nutrition and steroids. To decrease the absorbable endotoxin pool, the other group was additionally treated with whole gut irrigation and 5-aminosalicylic acid was added to the lavage fluid. In most of these patients endotoxaemia cleared after intestinal lavage and they needed shorter hospitalisation. Earlier improvement was also indicated by a faster decrease of the Crohn's disease activity index and vanHees index. In the group receiving conservative treatment alone, endotoxaemia was controlled within three weeks. We conclude that endotoxaemia occurs in most patients suffering from active Crohn's disease. Control of endotoxaemia after intestinal lavage suggests that systemic endotoxaemia is caused by absorption of endotoxins from the gut. Earlier improvement after whole gut irrigation indicates its beneficial effect in active Crohn's disease.     

A controlled double blind study of azathioprine in the management of Crohn's disease.

While immunosuppressive agents are used widely in the management of Crohn's disease, their efficacy has not been well established in randomised controlled trials. This study was designed to examine whether azathioprine increases remission rate when used in conjunction with a diminishing dose regimen of prednisolone over a period of 12 weeks. It further examined whether azathioprine offers any therapeutic advantage over placebo in the maintenance of remission in Crohn's disease over a period of 15 months. Sixty three patients with active Crohn's disease were treated with a 12 weeks diminishing dose of prednisolone and at the same time entered into a randomised, double blind 15 month trial of either azathioprine (2.5 mg/kg) or placebo. Remission rates between the two groups were compared at 12 weeks and at 15 months. There was no significant difference in the proportion of patients who had achieved and maintained remission by week 12 but at 15 months there was a highly significant difference in the proportion of patients in remission (42% receiving azathioprine v 7% receiving placebo), p = 0.001. Using life tables this beneficial effect was reflected as the difference in the median number of days on the trial (p = 0.02). There were significantly greater decreases over the trial period in the median erythrocyte sedimentation rate, C reactive protein, and leucocyte count in the azathioprine group. There were no cases of severe bone marrow suppression or clinical pancreatitis. In conclusion, azathioprine offers a therapeutic advantage over placebo in the maintenance of remission in Crohn's disease.     

国产5-氨基水杨酸肠溶片治疗溃疡性结肠炎多中心临床研究

目的　评价国产 5 氨基水杨酸 (5 ASA)肠溶片治疗溃疡性结肠炎 (UC)的疗效和安全性及该药的口服吸收情况。方法　采用多中心、随机、双盲、双模拟和对照方案 ,将 1 2 9例UC患者随机分为5 ASA肠溶片试验组 (6 5例 ,2 .4 g/d)和水杨酸偶氮磺胺吡啶 (SASP)对照组 (6 4例 ,4 .0g/d) ,疗程均为6周。治疗第 8天 ,随机抽取试验组 1 3例和对照组 1 2例UC患者血清 ,应用高效液相色谱分析法检测血清 5 ASA及其代谢产物Ac 5 ASA的稳态血药浓度。对两组患者治疗前后的临床症状、粪便检查和肠镜检查的情况进行比较 ,并记录治疗过程中的不良反应。结果　实际完成研究者 1 2 0例 (5 ASA组 6 1例 ,SASP组 5 9例 ) ,两组各有 4例失访 ,SASP组有 1例因严重胃肠道不良反应中途退出。 5 ASA肠溶片组和SASP组治疗UC的总有效率分别为 70 .0 5 %和 6 7.79% ,两组间差异无显著性 (P >0 .0 5 ) ,5 ASA肠溶片的完全缓解率明显高于SASP (2 9.5 1 %比 1 3.31 % ,P <0 .0 5 )。 5 ASA肠溶片组和SASP组的不良反应分别为 1 1 .4 8%和 2 3.33%。 5 ASA组和SASP组的血清 5 ASA浓度分别为 (0 .0 32± 0 .0 0 8) μg/ml和 (0 .0 4 1± 0 .0 0 5 ) μg/ml(P >0 .0 5 )。 结论　 5 ASA肠溶片治疗UC总有效率与SASP相仿 ,但对UC的完     

Double blind, placebo controlled study of metronidazole as a disease modifying agent in the treatment of rheumatoid arthritis.

Anecdotal reports suggest that metronidazole may have disease modifying activity in the treatment of rheumatoid arthritis. To assess possible beneficial effects a double blind, comparative trial of metronidazole and placebo was performed. Fifty patients with active rheumatoid arthritis were randomly allocated to receive active drug (n = 24) or placebo (n = 26) and reviewed at weeks 0, 1, 4, 8, 12, 16, and 24. Detailed assessment of drug safety, biochemical and haematological parameters, and efficacy was made at these dates. Dose regimen was 400 mg twice daily from weeks 0 to eight, increasing to 400 mg three times a day from weeks nine to 24 provided that no adverse effects were recorded. Most patients were unable to tolerate metronidazole because of side effects or lack of efficacy, with only five (21%) continuing to take the drug at 24 weeks. For those patients attaining 12 weeks of treatment an overall improvement in articular index and morning stiffness was found. No improvement in laboratory indices of disease activity was seen, however. In this study metronidazole did not have disease modifying properties and was unacceptably toxic.     

5-fluorouracil in the treatment of scleroderma: a randomised, double blind, placebo controlled international collaborative study.

A six month controlled study of 5-fluorouracil in the treatment of scleroderma showed a modest benefit in skin scores, Raynaud's phenomenon, and patients' global assessment. Visceral organ and hand function were unaffected. Mild to moderate toxicity was common in the 5-fluorouracil treated patients but usually responded to dose reduction. Two patients receiving 5-fluorouracil died from causes seemingly unrelated to treatment. Significant clinical improvement in scleroderma was not noted in the first six months of treatment with 5-fluorouracil.     

Incompletely and completely healed duodenal ulcers' outcome in maintenance treatment: a double blind controlled study.

A six month, double blind, controlled study was performed in 107 asymptomatic duodenal ulcer patients who, after short term cimetidine treatment, showed complete or incomplete endoscopic healing. Patients were stratified according to the type of healing and randomly allocated to cimetidine (200 mg at lunch, 400 mg at bedtime) or placebo. Endoscopic examinations were carried out after six months or when symptoms recurred. Eighty seven patients completed the maintenance trial. Of the 56 patients admitted to the study with complete healing, 30 were placed on cimetidine and 26 on placebo. Of the 31 patients admitted with incomplete healing, 15 were placed on cimetidine, and 16 on placebo. Results showed that, regardless of maintenance treatment, patients with incompletely healed ulcers had a higher ulcer crater recurrence rate, than patients with complete healing (71% vs 34%; p less than 0.005). A significantly higher ulcer crater recurrence was observed in incompletely healed ulcer patients, even when cimetidine or placebo treatment groups were considered separately. Irrespective of the type of healing, ulcer crater recurrence was more frequent in placebo treated patients than in those treated with cimetidine (67% vs 29%; p less than 0.001). We conclude that, in order to prevent a high ulcer recurrence rate, maintenance treatment should start only after the assessment of a complete endoscopic healing of duodenal ulcers.     

Efficacy of 5-aminosalicylic acid enemas versus hydrocortisone enemas in ulcerative colitis

A controlled trial has been carried out in order to compare the efficacy of enemas containing a high dosage of 5-ASA (4g) versus enemas containing hydrocortisone 100 mg. The trial was conducted on 86 patients, 44 of whom received 5-ASA and 42 received hydrocortisone. The results were favorable in terms of clinical, sigmoidoscopic, and histologic criteria for 5-ASA treatment. Other aspects have been investigated, such as retrograde spread of enemas which have been shown to reach the left colon. No nephrotoxicity was detected. The long term experience confirmed the preliminary positive results.     

Effect of weekend 5-aminosalicylic acid (mesalazine) enema as maintenance therapy for ulcerative colitis: results from a randomized controlled study

BACKGROUND: 5-aminosalicylic acid (5-ASA) is known to be effective in the treatment of active ulcerative colitis (UC). The aim of the current study was to investigate the effect of 5-ASA enemas, as a maintenance therapy for UC, when administered twice weekly as a weekend treatment regimen, compared to daily oral 5-ASA alone. We hypothesized that the weekend enema therapy would be better tolerated by patients who worked or attended school. METHODS: Between January 2004 and August 2005, patients with UC, in whom remission of the condition had just been induced, were randomly assigned to either: the weekend 5-ASA enema group (n=11), who received 1 g 5-ASA enemas twice a week on Saturday and Sunday plus oral 5-ASA 3 g/day for 7 days, or to the daily oral 5-ASA use only group (n=13), who received only oral 5-ASA 3 g/day for 7 days. The primary endpoint of the study was defined as the incidence of relapse. The study was stopped after 24 patients had been enrolled because an interim analysis showed a significant benefit of the weekend 5-ASA enema group. RESULTS: In the weekend enema group, 2 patients (18.2%) had relapses compared with 10 (76.9%) in the oral 5-ASA only group. The multivariate hazard ratio of relapse associated with weekend 5-ASA enema, relative to the oral alone group, was 0.19 (95% confidence interval, 0.04-0.94). CONCLUSIONS: This study demonstrated the beneficial effects of adding weekend 1 g 5-ASA enema to daily 3 g oral 5-ASA as maintenance therapy for UC.     

Randomised controlled trial of azathioprine and 5-aminosalicylic acid for treatment of steroid dependent ulcerative colitis

BACKGROUND AND AIMS: There are limited evidence based data concerning the use of azathioprine in ulcerative colitis. We aimed to compare the efficacy of azathioprine and oral 5-aminosalicylic acid in inducing remission of steroid dependent ulcerative colitis. METHODS: Seventy two patients with steroid dependent ulcerative colitis were admitted to this investigator-blind study. Steroid dependence was defined as a requirement for steroid therapy > or =10 mg/day during the preceding six months, with at least two attempts to discontinue the medication. The disease had to be clinically and endoscopically active at study entry, and all patients were taking systemic prednisolone (40 mg/day). Patients were randomised to receive azathioprine 2 mg/kg/day or oral 5-aminosalicylic acid 3.2 g/day, for a six month follow up period. The outcome of the treatment was defined as (1) success, indicating induction of clinical and endoscopic remission and steroid discontinuation, or (2) failure, indicating the absence of clinical and endoscopic remission and therefore the need for at least one further cycle of systemic steroids to control symptoms, apart from the initial one, or colectomy. RESULTS: Significantly more patients in the azathioprine than in the 5-aminosalicylic acid group had clinical and endoscopic remission, and discontinued steroid therapy, both in the intention to treat (azathioprine v 5-aminosalicylic acid: 19/36 patients (53%) v 7/36 (21%); odds ratio (OR) 4.78 (95% confidence interval (CI) 1.57-14.5)) and per protocol (azathioprine v 5-aminosalicylic acid: 19/33 patients (58%) v 7/34 (21%); OR 5.26 (95% CI 1.59-18.1)) analysis. CONCLUSIONS: Azathioprine is significantly more effective than 5-aminosalicylic acid in inducing clinical and endoscopic remission and avoiding steroid requirement in the treatment of steroid dependent ulcerative colitis.