Spread and distribution of 5-ASA colonic foam and 5-ASA enema in patients with ulcerative colitis

Rectal treatment with enemas, foams, and suppositories is the most efficient method of delivering an adequate quantity of locally active drugs to the distal colon. In a pilot study carried out by colonoscopy in four patients, it was observed that 4 g 5-ASA in 20 ml foam spread up or beyond the splenic flexure and more extensively than 2 g 5-ASA in 10 ml foam. Therefore we have undertaken a study in order to compare by scintigraphy the colonic distribution of 4 g 5-ASA foam versus 4 g 5-ASA in 100 ml liquid enemas in 10 patients with ulcerative colitis using a crossover randomized design. Both preparations were labeled with 100 MBq [^99mTc] sulfur colloid before administration. Anterior scans were taken at intervals for 4 hr. Activity, expressed as a percentage of total radioactivity, was measured in the rectum, sigmoid, descending, transverse, and ascending colon. Six patients had the same extent of spread with the two formulations; in three patients with foam and in one patient with enema a greater spread was observed. the foam reached the upper limit of disease in all cases, while enema failed in two cases. The maximum spread with foam was observed within 30 min in nine of 10 patients compared with seven of 10 after enema. Compared to enema, foam distributes more uniformly and seems to persist longer in the descending and sigmoid colon. The 5-ASA colonic foam shows some more favorable characteristics than enema for the local treatment of left-sided ulcerative colitis.This work was supported in part by Bracco S.p.A (Milan, Italy).Part of this study was presented at the 92th Annual Meeting of The American Gastrointestinal Association, May 18–24, 1991, in New Orleans, Louisiana.     

Retrograde distribution of a new 5-aminosalicylic acid enema in patients with ulcerative colitis.

Retrograde colonic distribution of a new 4 g 5-aminosalicylic acid enema (mesalazine) was investigated in seven patients with ulcerative colitis, five of whom were in remission. The enema was labeled with 99m-technetium and imaged by a gamma camera. A median of 86 percent (range 57-90) of the enema had spread beyond the rectum during the first two hours after administration. In four of the five examined patients with left-sided ulcerative colitis, the diseased mucosa was covered within the first 4 hours. In the fifth patient, with involvement of the descending colon, the enema did not spread beyond the very tortuous sigmoid colon 4 or even 8 hours after enema administration.     

A new oral delivery system for 5-ASA: preliminary clinical findings for MMx

BACKGROUND: Multi-matrix (MMx), a new delivery system for mesalazine, seems to release 5-aminosalicyclic acid (5-ASA) preferentially in the sigmoid colon. This study had 2 objectives: (1) to evaluate the therapeutic response to MMx in patients with active left-sided disease and (2) to gain additional insights as to how the therapy would compare with topical 5-ASA. METHODS: Patients received either 1.2 g of 5-ASA MMx three times per day plus placebo enema or 4 g of 5-ASA enema plus placebo tablets for 8 weeks. The primary endpoint was clinical remission (clinical activity index < or =4) at 8 weeks. Secondary endpoints were endoscopic and histologic remissions. RESULTS: Seventy-nine patients were enrolled. Clinical remission rates at 4 and 8 weeks were 57.5% and 60.0% for patients treated with MMx and 68.4% and 50.0% for patients randomized to 5-ASA enemas, respectively (95% confidence interval for the difference at 8 weeks, -12 to +32). Endoscopic remission was achieved by 45.0% of patients on 5-ASA MMx and by 36.8% of those on enema, whereas 15.0% and 8% of patients, respectively, showed histologic remission. Compliance was 97.0% for oral and 87.5% for topical therapy. In the enema group, compliance was 88.0% for the patients in remission and 65.5% for those with active disease. CONCLUSIONS: Preliminary studies suggest that similar rates for induction of remission can be expected from 5-ASA enemas and MMx for patients with left-sided ulcerative colitis.     

Clinical guidelines for the medical management of left-sided ulcerative colitis and ulcerative proctitis: summary statement

There are few published guidelines for the treatment of inflammatory bowel disease. Physicians choose therapy based on evidence-based data, peer and expert opinion, and personal experience. This article provides treatment guidelines for the induction and maintenance of ulcerative proctitis and left-sided colitis and the management of disease refractory to 5-aminosalicylic acid (5-ASA) compounds and corticosteroids The guidelines are derived from evidence-based data and, when lacking, expert opinion or the authors' experience. The comprehensive review of the literature is presented in the accompanying article, "The Medical Management of Left-Sided Ulcerative Colitis and Ulcerative Proctitis: Critical Evaluation of Therapeutic Trials". Rectally administered 5-ASA and corticosteroid suppositories are effective treatment for most ulcerative proctitis patients. Corticosteroid and 5-ASA enemas, which reach the splenic flexure of the colon, are recommended for patients with left-sided ulcerative colitis. The combination of rectally administered 5-ASA enemas and oral 5-ASA agents may afford better treatment of left-sided colitis and possibly prevent proximal extension of disease. Patients refractory to 5-ASAs and corticosteroids may require an immunomodulator or biological response modifier therapy. Those who have ongoing signs and symptoms of ulcerative proctitis and left-sided ulcerative colitis despite maximal medical therapy require a proctocolectomy.     

5-Aminosalicylic Acid Enemas in Refractory Distal Ulcerative Colitis: A Randomized, Controlled Trial

5-Aminosalicylic acid (5-ASA), the presumed active moiety of sulfasalazine, has shown clinical efficacy when administered per rectum as initial therapy to patients with distal ulcerative colitis. We report the results of a randomized double-blind trial comparing nightly retention of a 4-g 5-ASA enema with continued administration of hydrocortisone enemas in 18 patients with persistent active distal ulcerative colitis after at least a 3-wk course of treatment with 100-mg hydrocortisone enemas with or without oral sulfasalazine. Continuation of hydrocortisone enemas rather than placebo was used in the control group to reflect the realistic alternative therapy likely to be employed in current practice. Response to therapy was assessed after 3 wk by comparing pretreatment and posttreatment point scores of clinical, sigmoidoscopic, and histological severity. Improvement in clinical score was achieved in seven of nine 5-ASA enema-treated patients versus one of nine hydrocortisone enema-treated patients (p less than 0.05). Sigmoidoscopic and histological improvement generally paralleled clinical improvement. We conclude that in patients with distal ulcerative colitis unresponsive to standard therapy, treatment with 5-ASA enemas results in significant short-term clinical and sigmoidoscopic improvement in a majority of cases. Moreover, a significantly greater number of refractory patients improve when switched to 5-ASA enemas than when continued on standard therapy.     

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.     

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.     

Distribution of Dysplasia in Ulcerative Colitis

Epithelial dysplasia was found in the large intestine of 8 of 15 patients with ulcerative colitis operated on between 1980 and 1982. In six of eight patients, dysplasia was found in the cecum and ascending colon, in one of eight in the descending or sigmoid colon, and in four of eight in the rectum. None of the five carcinomas in three patients were located in the sigmoid colon or rectum. The age of onset was much lower. 19 ± 7 years, and the duration of colitis longer, 15 ± 7 years, for the group with dysplasia compared with that without dysplasia, 37 ± 18 and 4 ± 3 years, respectively. Our study indicates that malignant transformation may frequently occur in the proximal colon and emphasizes the need for total colonoscopy with multiple biopsies in the evaluation of patients with long-standing ulcerative colitis.     

Measurement of colonic mucosal concentrations of 5-aminosalicylic acid is useful for estimating its therapeutic efficacy in distal ulcerative colitis: comparison of orally administered mesalamine and sulfasalazine

OBJECTIVES: Oral 5-aminosalicylic acid (5-ASA) preparations have been used frequently in the treatment of ulcerative colitis. However, there have been few reports investigating the relationship between colonic mucosal concentrations of 5-ASA and its clinical efficacy when oral sulfasalazine or 5-ASA compounds were administered. The aim of this study is to compare the mucosal concentrations of 5-ASA ensured by sulfasalazine or mesalamine, and to define the clinical significance of the measurement of 5-ASA concentrations in the treatment of distal ulcerative colitis. MATERIALS AND METHODS: Biopsies were taken from the rectum and sigmoid colon of the oral sulfasalazine group (n = 13) and the slow-release 5-ASA (mesalamine) group with (n = 5) or without (n = 11) rectal administration of 5-ASA. High-pressure liquid chromatography was used to measure the tissue concentrations of 5-ASA and its metabolites. We compared the 5-ASA concentrations of the sulfasalazine group with the mesalamine group. Furthermore, we analyzed the relationship between tissue 5-ASA concentrations and the Disease Activity Index (DAI). RESULTS: The concentrations of 5-ASA and acetyl-5-ASA in the sulfasalazine group were higher than those in the group taking oral mesalamine alone (p < 0.01). The concentration of 5-ASA was much higher in the patients who received oral and rectal mesalamine in an enema than in the patients who had oral mesalamine alone. There was a significant inverse correlation between the DAI and concentrations of 5-ASA in the rectum (r = 0.712, p < 0.001). CONCLUSIONS: We demonstrated that the colonic mucosal concentration of 5-ASA was significantly higher in the sulfasalazine group than in the mesalamine group. Furthermore, the concentrations of mucosal 5-ASA may be a good marker for the estimation of its efficacy in the treatment of ulcerative colitis.     

Retrograde spread of 5-aminosalicylic acid enemas in patients with active ulcerative colitis

In an attempt to know the exact retrograde spread of high-dosage 5-aminosalicylic acid enemas, we have studied eight patients with active left-sided colitis, by adding a small amount of barium sulfate to the enemas and by checking the spread radiologically after 15 minutes, 1 hour, and 6 hours. Four grams of 5-aminosalicylic acid in 100-ml enemas and 4 gm in 200-ml enemas were used. The same experiment was repeated in a subsequent attack, with enemas labeled with technetium-99m and checked by scintiscans in five of these patients. We always have observed a volume-dependent spread of enemas but, interestingly, in the patients studied with technetium-99m there was always a wider spread than that which was detected with barium enemas. In all five patients, 100-ml enemas reached the splenic flexure. In two patients with total colitis, a progression of 100-ml technetium-99m enemas was performed in the transverse colon, but the maximum opacity remained in the left side. We can conclude that 4 gm of 5-aminosalicylic acid in 100-ml enemas can be suitable for treating patients with left-sided colitis, and will represent a valid addition for patients with more extensive colitis.     

Distribution of dysplasia in ulcerative colitis

Epithelial dysplasia was found in the large intestine of 8 of 15 patients with ulcerative colitis operated on between 1980 and 1982. In six of eight patients, dysplasia was found in the cecum and ascending colon, in one of eight in the descending or sigmoid colon, and in four of eight in the rectum. None of the five carcinomas in three patients were located in the sigmoid colon or rectum. The age of onset was much lower, 19 +/- 7 years, and the duration of colitis longer, 15 +/- 7 years, for the group with dysplasia compared with that without dysplasia, 37 +/- 18 and 4 +/- 3 years, respectively. Our study indicates that malignant transformation may frequently occur in the proximal colon and emphasizes the need for total colonoscopy with multiple biopsies in the evaluation of patients with long-standing ulcerative colitis.     

Medical management of ulcerative proctitis, proctosigmoiditis, and left-sided colitis.

Ulcerative colitis distal to the splenic flexure includes disease confined to the rectum (proctitis), rectosigmoid (proctosigmoiditis or distal colitis), or extending to the descending colon or splenic flexure (left-sided colitis). These subtypes represent up to 60% to 80% of newly presenting cases of ulcerative colitis. Although these conditions are defined by the extent of colon that is affected, they also share the characteristic of being amenable to topical therapy. In general, the course of disease is milder and symptoms are less severe than in patients with more extensive colonic involvement. Nonetheless, symptoms may significantly impair patients' health-related quality of life. Treatment options include the oral and/or rectal 5-aminosalicylate (5-ASA) preparations. Rectal therapy delivering higher concentrations of active medication (5-ASA or glucocorticoids) directly to the inflamed mucosa while minimizing systemic absorption provides a highly effective and safe treatment. Oral glucocorticoids are indicated in patients who are resistant to or intolerant of 5-ASA therapy. Immunomodulators have an important role in individuals with glucocorticoid dependent or glucocorticoid refractory disease. This article reviews the clinical diagnosis and current medical management of ulcerative proctitis, proctosigmoiditis, and left-sided ulcerative colitis, including patients resistant to conventional medical therapy.     

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.     

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 ulcerative colitis. Doubleblind study between beclomethasone dipropionate and mesalazine

Fifty-nine patients with ulcerative colitis localised in the rectum, sigmoid and colon entered the trial. Thirty were treated with BDP and twenty-nine with 5-Aminosalicylic (enemas and suppositories) for 8 weeks, in a doubleblind, controlled study. Clinical, endoscopic and histological assessment was carried out before and after 4 and 8 weeks of treatment. It is concluded that BDP is a new important treatment for mild and moderate activity ulcerative colitis.     

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.     

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.     

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.     

Long-term use of mesalamine enemas to induce remission in ulcerative colitis

The courses of 90 patients with left-sided ulcerative colitis that was unresponsive or intolerant to conventional therapy were retrospectively reviewed. They had been treated with 5-aminosalicylic acid enemas (mesalamine) on a long-term basis. After an initial 12-week course of treatment, 87% of the patients had improved by at least one grade of inflammation (improvement), and 54% of these were asymptomatic with normal colonic mucosa (remission). Overall, there was an 80% remission rate by 34 weeks. Remission rate was not affected by extent of sigmoid or left-sided colon disease before treatment or prior medication use for ulcerative colitis. Treatment with mesalamine enemas allowed patients to decrease or discontinue glucocorticoid treatment. Patients treated for relapse episodes responded as well as they did to the first course of treatment, whether the relapse occurred after discontinuation of mesalamine or during a tapering of the dose. In conclusion, extending mesalamine treatment to at least 34 weeks was beneficial in inducing a complete remission in 80% of patients unresponsive to conventional therapy.     

5-ASA in ulcerative colitis： Improving treatment compliance

5-aminosalicylic acid （5-ASA） compounds are a highly effective treatment for ulcerative colitis （UC）. While UC patient compliance in clinical studies is over 90%, only 40% of patients in every day life take their prescribed therapy. Adherence to medication has been emphasized recently by a Cochrane meta-analysis that has suggested that future trials of 5-ASA in UC should look at patient compliance rather than drug efficacy. Better compliance can be obtained by reducing the number of tablets and times of administration. Given that the 5-ASA formulations have different delivery systems that split the active moiety in various regions of the intestine, it is particularly important that an adequate dose of the drug arrives at the inflamed part of the colon. 5-ASA Multi matrix （MMx） is a novel, high strength （1.2 g）, oral formulation designed for oncedaily dosing. It releases the active moiety throughout the colon. Different studies with this compound have shown that it is as effective as 5-ASA enema in the treatment of mild-to-moderate, left-sided UC, and is comparable to a pH-dependent, delayed release 5-ASA （Asacol）, even if given once daily. Recently, the effectiveness in the acute phase of UC has been confirmed also in maintenance. In conclusion, at present, 5-ASA MMx seems theoretically the best agent for maintaining patient compliance, and consequently, treatment effectiveness.