Refractory Distal Ulcerative Colitis Responsive to 5-Aminosalicylate Enemas

Patients with distal ulcerative colitis may be refractory to standard drug therapy. 5-Aminosalicylate, the active moiety of sulfasalazine, is effective topically in new onset distal colitis. Six patients with distal colitis unresponsive to sulfasalazine and corticosteroids had a prompt and dramatic response to the administration of 5-aminosalicylate enemas with clinical, sigmoidoscopic, and histological improvement. Topical 5-aminosalicylate should be a useful addition to the current available therapies for some patients with refractory distal ulcerative colitis.     

Optimum dosage of 5-aminosalicylic acid as rectal enemas in patients with active ulcerative colitis.

5-Aminosalicylic acid (5-ASA), the active moiety of sulphasalazine (SASP), was given as a rectal enema to patients with mild to moderate distal ulcerative colitis to determine the minimum effective dosage. A double blind study was carried out using enemas containing 1, 2, or 4 g or 5-ASA or placebo for a one month treatment period. One hundred and thirteen patients with ulcerative colitis attending our outpatient clinic volunteered to participate. Clinical, sigmoidoscopic, and histological assessments were carried out at the beginning of the study and after 15 and 30 days of treatment. All patients who received 5-ASA enemas showed significantly better results than those who received a placebo enema (p less than 0.001) but no difference was detected among the patients receiving differing concentrations of 5-ASA. This study suggests that 1 g 5-ASA (in a 100 ml enema) is a sufficient dosage for patients with a mild to moderate attack of ulcerative colitis.     

Comparison of bismuth citrate and 5-aminosalicylic acid enemas in distal ulcerative colitis: a controlled trial.

An enema that contained a complex of bismuth citrate and polyacrylate was compared with 5-aminosalicylic acid (5-ASA) enemas for treatment of distal ulcerative colitis. The multicentre trial involving 63 patients was randomised and double blind with enemas given over four weeks; clinical, sigmoidoscopic, and histological assessments were made. Improvements were seen in both treatment groups. Clinical remission was seen in 18 of 32 patients treated with 5-ASA and 12 of 31 patients treated with bismuth citrate-carbomer (chi 2 1.94; p = 0.16). Sigmoidoscopic remission occurred in 20 of 32 patients in the 5-ASA group and 15 of 31 patients given bismuth (chi 2 1.27; p = 0.26). Improvement of rectal biopsy histology by at least one grade was seen in 16 of 32 patients in the 5-ASA group and 14 of 31 patients with bismuth (chi 2 0.15; p = 0.70). Analysis of covariance gave no significant difference between groups, although there was a trend favouring 5-ASA. There was no evidence of bismuth accumulation during the trial. Bismuth enemas may offer a new therapeutic option in distal ulcerative colitis.     

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.     

Failure of 5-Aminosalicylic acid enemas to improve chronic radiation proctitis

Radiation proctitis is a well-known complication of abdominal and pelvic radiation. Conventional medical and surgical treatment often is disappointing. 5-Aminosalicylic Acid (5-ASA)is the active component in sulfasalazine and is effective in the treatment of distal ulcerative colitis. Four patients with radiation proctitis were treated with 4 g 5-ASA by enema nightly for two to six months. Patients were seen monthly, interviewed, and a sigmoidoscopic exam performed. No change was seen in the degree of mucosal inflammation on follow-up sigmoidoscopic exams. Three patients noted no change in their symptoms of bleeding, pain, or tenesmus. One patient noted initial improvement, but this was not sustained. 5-ASA enemas do not appear to be effective in the treatment of radiation proctitis.     

5-Aminosalicylic acid enemas in treatment of distal ulcerative colitis and proctitis in Canada

The efficacy and safety of 4 g 5-aminosalicylic acid (5-ASA) enemas were assessed in 59 patients with ulcerative colitis involving up to 50 cm of their distal colon. Twenty-nine patients received 5-ASA and 30 received a placebo. There were 12 dropouts (five in the active and seven in the placebo group) during the study because of insufficient efficacy. After six weeks of therapy, 63% of the patients receiving the 5-ASA were considered to be “much improved” by the study physician compared to 20% patients on placebo (P<0.0001). A disease activity index (DAI), based upon patient symptoms and sigmoidoscopic appearance, was used to assess efficacy. Mean DAI declined 75% for patients on 5-ASA enemas and 32% for patients on placebo (P<0.05). The 5-ASA enemas are well tolerated and are of benefit in the treatment of ulcerative colitis confined to the distal colon.     

Topical treatment of refractory distal ulcerative colitis with 5-ASA and sodium butyrate

Nine patients with distal ulcerative colitis refractory to standard therapy were treated with intrarectal instillation of a sodium butyrate solution and 5-ASA. A marked clinical, endoscopical and, to a smaller extent, histological improvement was observed in seven of nine patients. The clinical improvement usually occurred within the second week of therapy, and thus earlier than in previous cases treated with butyrate alone. This preliminary experience suggests that the combined butyrate-5-ASA treatment may prove a useful therapeutic tool in refractory distal ulcerative colitis and possibly increase the effectiveness of the individual therapeutic regimens.     

5-Aminosalicylic Acid Enemas in Refractory Distal Ulcerative Colitis: Long-Term Results

In this trial, we examined the role of 4-g 5-aminosalicylic acid (5-ASA) enema in the long-term management of patients with previously refractory distal ulcerative colitis. Of 20 such patients treated with nightly 5-ASA enemas, 16 improved symptomatically, with 15 achieving clinical remission and 14 achieving sigmoidoscopic remission within 3 to 5 wk. An attempt was made to maintain clinical remission with 5-ASA enemas in these 16 by successively decreasing the frequency of administration to every other night and then every third night, as long as remission was maintained. Relapses were treated by reinstituting nightly 5-ASA enema administration followed by another attempt at tapering the frequency of administration. Follow-up has ranged from 5 to 16 months. Nine patients were rapidly tapered to every third night administration, but six relapsed. Of these six, four were brought into remission with reinitiation of nightly enemas and tapered to every three nights, whereas one ultimately required enemas every two nights for control and one required enemas nightly (with mild symptoms). Six other patients relapsed when the enemas were tapered to every two nights, and after retreatment on a nightly regimen, four could be maintained on an every third night regimen while two have required every second night administration. One patient has required nightly administration from the outset. Currently, one patient is off all medication, while eight are on an every third night, three are on an every second night, and three are on a nightly schedule. We conclude that in patients with distal ulcerative colitis refractory to conventional therapy but responsive to 5-ASA enemas, relapse is common as the frequency of 5-ASA enema administration is decreased, although some patients may be maintained on a less than nightly schedule. The optimal maintenance regimen remains to be determined.     

4-Aminosalicylic acid retention enemas in treatment of distal colitis

Forty-five of 47 patients with distal ulcerative colitis completed a two-week double-blind, randomized, controlled trial to determine if 4-aminosalicylic acid (4-ASA) enemas, 1 g bid or 2 g bid, were therapeutically effective compared to placebo. Forty-one patients enrolled because they were refractory to or had side effects during conventional therapy with sulfasalazine or corticosteroids. Proctoscopic examination was done before and after two weeks of treatment. Patients kept daily diaries assessing: (1) blood in stools, (2) mucus in stools, (3) tenesmus, (4) abdominal pain, (5) loss of appetite, (6) fatigue, (7) weight loss, and (8) malaise. Severity of each symptom ranged from 0 (absent) to 3 (severe). A total severity score was calculated from the above for each patient. At the end of the two-week study, 35 patients elected to take 4-ASA in an open-label trial for one year. 4-ASA enemas in the 1-g bid but not the 2-g bid dosage were significantly more effective in improving symptoms than placebo:P<-0.05. Neither dose of 4-ASA enema was better than placebo in improving the sigmoidoscopic appearance at the end of two-weeks. Forty-six percent of patients had complete resolution of all signs and symptoms in the open-label trial and 31% were better but still had sigmoidoscopic evidence of disease, a total response rate of 77%. Side effects were similar in the placebo and 4-ASA groups. We conclude that 4-ASA enemas in a dose of 1 g bid are safe and effective in the treatment of distal ulcerative colitis.Supported in part by Research Training Grant AM 07024 from the National Institutes of Health     

Practicality of 5-aminosalicylic suppositories for long-term treatment of inactive distal ulcerative colitis.

BACKGROUND/AIMS: Topical 5-aminosalicylic acid (5-ASA) is regarded as an effective form of therapy for distal ulcerative colitis. Unfortunately, experience about acceptability and tolerance of long-term treatment with 5-ASA suppositories is still meager. METHODOLOGY: We have evaluated the performance of 5-ASA suppositories as maintenance treatment in 34 patients with inactive distal colitis. Prior to entering the study, all patients were in clinical remission for 1-12 months. A single 500 mg 5-ASA suppository was administered nightly for 12 months in every patient and all other treatments were discontinued. Clinical evaluation was performed at 3, 6 and 12 months. RESULTS: Four patients withdrew from the study within the first 3 months because of local intolerance to the suppositories. Score of both comfort and tolerance was significantly higher in patients who continued treatment than in those who withdrew. Two patients who stayed in remission withdrew, one at 7 months because of thrombocytopenia and the other at 9 months for personal reasons. Of the 28 remaining patients, 7 relapsed and 21 remained in clinical remission at the end of the 12-month study period. Eleven of the 21 responder patients agreed to a sigmoidoscopic examination, that confirmed remission in all of them. Eight out of the 9 patients who had previously received 5-ASA enemas preferred suppositories to enemas. Apart from the 4 patients who did not tolerate suppositories, 26 patients considered this form of therapy quite comfortable. CONCLUSIONS: 5-ASA suppositories are generally well tolerated and considered comfortable for treatments of at least one year.     

A prospective randomized double blind trial comparing prednisolone and 4-aminosalicylic acid enemas in acute distal ulcerative colitis

A prospective double blind and randomized study was conducted to compare 4-aminosalicylic acid (4-ASA) and prednisolone-21-phosphate enemas in inducing remission in patients with acute distal ulcerative colitis. Patients with ulcerative colitis distal to the splenic flexure as assessed by flexible colonoscopy, barium enema and histology were included in the study. Of 40 consecutive patients, 20 were randomized to each of the two treatment groups. Clinical evaluation was done weekly; sigmoidoscopy and histology were performed at entry and at the end of 4 weeks. Therapy was discontinued in four patients treated with prednisolone enemas due to worsening of symptoms. The clinical improvement was significant in the remaining patients (P less than 0.001) and was similar in the two groups (P greater than 0.1). Sigmoidoscopic and histological improvement were better with 4-ASA than with prednisolone enemas. No adverse effects were observed in any of the patients treated. The present study suggests that 4-ASA is a safe and effective treatment for inducing remission in acute distal ulcerative colitis.     

Comparison of 5-aminosalicylic acid (3 g) and prednisolone phosphate sodium enemas (30 mg) in the treatment of distal ulcerative colitis. A prospective, randomized, double-blind trial

Twenty-nine patients with attacks of distal ulcerative colitis were treated randomly with 3 g 5-aminosalicylic acid (5-ASA) or 30 mg of prednisolone phosphate sodium (PP) enemas (40 ml). Endoscopic, clinical, and histologic improvement were comparable in the two treatment groups. Our study showed that topical treatment with 5-ASA is as efficacious as PP in improving distal ulcerative colitis.     

Putting rectal 5-aminosalicylic acid in its place: the role in distal ulcerative colitis

Oral aminosalicylates such as sulfasalazine and mesalamine are widely prescribed for the treatment of mild or moderately active distal ulcerative colitis. However, a critical review of the literature demonstrates that rectal 5-aminosalicylic acid (5-ASA) is the optimal therapy for this disease. Meta-analyses of published trials show that rectally delivered 5-ASA is superior to placebo and to conventional rectal corticosteroids in inducing remission of distal ulcerative colitis, whereas the combination of rectal 5-ASA with a rectal corticosteroid or oral aminosalicylate is superior to rectal 5-ASA alone. For maintaining remission of distal ulcerative colitis, rectal 5-ASA is significantly better than placebo and at least as effective as oral 5-ASA. The dosage forms available for rectal delivery include suppositories, foams, and liquid enemas, and selection among these preparations should be guided by the proximal extent of disease and patient preference. The efficacy of rectal 5-ASA is complemented by its low rate of reported adverse effects, which may reflect its reduced potential for systemic absorption. This review summarizes the evidence supporting the role of rectal 5-ASA as a first-line therapy for mild or moderately active distal ulcerative colitis, and offers guidelines for its use.     

The role of aminosalicylates in the treatment of ulcerative colitis

Aminosalicylates (5-ASA, sulfasalazine and mesalazine) play a central role in the treatment of ulcerative colitis (UC). For acute treatment of mild to moderate flares and in maintenance treatment, their efficacy has been established. Since ulcerative colitis is limited to the distal colon in two thirds of the patients, topical therapy also plays an important role. In mild/moderate active disease 5-ASA 4 g/d is as effective as oral corticosteroids. Ulcerative proctitis is treated with 2 x 500 mg or 1 x 1 g suppositories and proctosigmoiditis with 1 to 4 g enemas. Oral 5-ASA is also safe in maintenance treatment and is generally well tolerated. The risk of colorectal tumours is increased in patients with longstanding ulcerative colitis and epidemiological evidence indicates that chronic 5-ASA treatment reduces this risk. However, at present there is insufficient evidence to maintain patients on life-long 5-ASA maintenance treatment for this indication.     

5-ASA enemas for refractory distal ulcerative colitis. An open trial

We conducted an open trial of 5-ASA enemas to determine the role of this drug in idiopathic distal ulcerative colitis resistant to conventional therapeutic approaches. Fifty-one such refractory patients were given 4 g 5-ASA enemas once nightly for 2 weeks, and the response was then assessed clinically and sigmoidoscopically. Overall, 29 patients (57%) had an excellent response, 11 (21%) had a satisfactory response, and a further 11 (21%) had a poor outcome. Two patients developed adverse reactions. Of the 11 patients with a poor response, nine remained dependent on oral prednisone for remission of their colitis. Although the role of 5-ASA enemas in the treatment of refractory distal ulcerative colitis remains to be determined, it appears that the drug appears to be beneficial for only a minority of patients dependent on systemic corticosteroids.     

Therapeutic efficacy of 5-ASA molecules in idiopathic intestinal inflammatory diseases: critical review]

Sulfasalazine has been the most widely prescribed drug for patients with inflammatory bowel disease. Clinical trials have established its usefulness in treating patients with active ulcerative colitis and Crohn colitis and its important role in maintaining remissions in patients with ulcerative colitis. Despite its widespread acceptance, the usefulness of sulfasalazine has been limited by the occurrence of adverse reactions in about 10 to 20% of the patients. Now the aminosalicylates are emerging as a treatment for both ulcerative colitis and Crohn disease. We have critically reviewed the clinical trials assessing the efficacy of 5-ASA molecules. Therapeutic efficacy of 5-ASA appears to be as good as sulfasalazine but causing less adverse effects. In mild to moderate ulcerative colitis relapse, 2g 5-ASA is active while 1 g 5-ASA seems equivalent to 2g sulfasalazine for maintaining remission. 5-ASA enema in the treatment of distal ulcerative colitis is helpful and can replace topical cortisone administration. Administration of 1g 5-ASA enema a day seems to be the best regimen. In case of Crohn's disease, preliminary studies are encouraging but more date are required to define the indications as well as the regimen.     

Oral fluticasone propionate in active distal ulcerative colitis.

Fluticasone propionate is a new corticosteroid with low systemic bioavailability. This study reports the outcome of a double blind clinical trial comparing oral fluticasone propionate (5 mg four times daily) with placebo for the treatment of active distal ulcerative colitis. Sixty patients were treated for four weeks, with assessments at two and four weeks. One patient was withdrawn when she was found to have amoebiasis. Thus, results are presented for 29 patients who received placebo and 30 who received fluticasone propionate. The two groups were well matched for age, sex, length of history, and extent of disease. After four weeks of therapy the clinical, sigmoidoscopic, and histological responses were similar in the two groups. It is concluded that fluticasone propionate (5 mg four times daily) is not effective treatment for active distal ulcerative colitis.     

5-Aminosalicylic acid enema in the treatment of distal ulcerative colitis, proctosigmoiditis, and proctitis

The efficacy and safety of 4-g 5-aminosalicylic acid enemas were assessed in 153 patients with ulcerative colitis involving up to 50 cm of distal colon. Seventy-six patients received active medication and 77 received a placebo. There were 20 dropouts (6 in the active group and 14 in the placebo group) during the study because of insufficient efficacy. After 6 wk of therapy, 48 of the 76 patients (63%) receiving 5-aminosalicylic acid were considered to be "much improved" by the study physician compared to 22 of the 77 patients (29%) on placebo (p = 0.001). A disease activity index based on patient symptoms and sigmoidoscopic appearance was used to assess efficacy. Mean disease activity index declined 55% for patients on 5-aminosalicylic acid and 24% for patients on placebo (p = 0.0001). Analysis of subgroups indicated that patients most likely to respond were those with disease confined to the 20-40 cm from the anus. Response was not affected by concurrent sulfasalazine, but patients requiring concurrent oral steroids had a diminished response. Rapid onset of efficacy was shown by a significant reduction in rectal bleeding within 3 days of treatment initiation. 5-Aminosalicylic acid enemas are well tolerated and are of benefit in the treatment of ulcerative colitis confined to the distal colon.     

Treatment of distal ulcerative colitis (proctosigmoiditis) in relapse: comparison of hydrocortisone enemas and rectal hydrocortisone foam.

Thirty patients with distal colitis (proctosigmoiditis) in relapse were randonly allocated to twice daily treatment with traditional aqueous hydrocotrisone enemas (Cortenemas) or a suspension of hydrocortisone in an inert foam base (Colifoam). Each treatment contained the same amount of hydrocortisone. Clinical, sigmoidoscopic, and histological response was assessed after two weeks. Both agents were effective, and broadly similar in terms of objective improvement, but subjective improvement was greater with the foam preparation, and several patients expressed a preference to this mode of treatment.     

Sulfasalazine-induced abnormal sperm penetration assay reversed on changing to 5-aminosalicylic acid enemas

Sulfasalazine, a drug used in the treatment of inflammatory bowel disease, has been associated with male infertility, an effect attributed to sulfapyridine rather than to 5-aminosalicylic acid (5-ASA), the presumed therapeutically active component of sulfasalazine. Recently, the sperm penetration assay (SPA) has been found to be an accurate method of quantitating male fertilization potential. We report the case of a man with ulcerative colitis in whom infertility and a markedly abnormal SPA were demonstrated while he was taking sulfasalazine. Shortly after discontinuing sulfasalazine and initiating treatment with 5-ASA enemas, his SPA became normal and his wife became pregnant. The SPA is a useful screening test for sulfasalazine-induced male infertility. On the other hand, 5-ASA enemas do not appear to be associated with an abnormal SPA.