5-aminosalicylic Acid Enemas Research Articles

An updated review on the treatment for diversion colitis and pouchitis, with a focus on the utility of autologous fecal microbiota transplantation and its relationship with the intestinal microbiota.

Diversion colitis (DC) is characterized by mucosal inflammation in the defunctioned segment of the colon following a colostomy or ileostomy. The major causes of DC are an increase in the number of aerobic bacteria, a lack of short-chain fatty acids (SCFAs), and immune disorders in the diverted colon. However, its exact pathogenesis remains unknown. Various treatment strategies for DC have been explored, although none have been definitively established. Treatment approaches such as SCFAs, 5-aminosalicylic acid enemas, steroid enemas, and irrigation with fibers have been attempted, yielding various degrees of efficacies in mitigating mucosal inflammation. However, only individual case reports demonstrating the limited effect of the following therapies have been published: leukocytapheresis, dextrose (hypertonic glucose) spray, infliximab, an elemental diet, and coconut oil. The usefulness of probiotics for treating DC has recently been reported. Furthermore, fecal microbiota transplantation (FMT) has emerged as a promising treatment for DC. This review provides an update on the treatment strategies of DC, with a particular focus on FMT and its relationship with the intestinal microbiota. FMT may become the first choice of treatment for some patients in the future because of its low medical costs, ease of use, and minimal side effects. Furthermore, FMT can also be used for postoperative DC prophylaxis.

Fecal Microbial Transplantation versus Mesalamine Enema for Treatment of Active Left-Sided Ulcerative Colitis-Results of a Randomized Controlled Trial.

Background and Aims: Ulcerative colitis (UC) is a chronic inflammatory disease. Fecal microbial transplantation (FMT) is a promising alternative treatment. Methods: This multicenter, open-label, noninferiority trial randomized patients with active left-sided UC (Mayo score 4–10) equally to FMT or 5-aminosalicylic acid (5-ASA) enemas. FMT enemas were administered five times in the first week and then once weekly for 5 weeks. 5-ASA enemas were administered daily for 2 weeks and then every other day. The primary study endpoint was clinical remission, with a total Mayo score ≤2 at week 12 with no subscore >1. Results: Sixty-one patients were screened; 45 were enrolled and randomized to FMT (n = 23) or 5-ASA (n = 22). Twenty-one FMT and 22 5-ASA patients completed at least the week 4 study visit and were included in the mITT analysis. Twelve FMT (57%) and eight 5-ASA patients achieved the primary study endpoint. FMT noninferiority with 10% margin was confirmed (95% CI: −7.6%, 48.9%). Adverse events occurred in 12 FMT (57%) and 13 5-ASA (59%) patients. Increased microbial diversity persisted 3 months after FMT. Conclusion: FMT is an effective treatment for left-sided UC and increased recipient microbiome diversity. Targeted microbiome modification may improve FMT efficacy. Further investigation is needed to guide donor and patient selection.

Predictive factors for achievement of mucosal healing by budesonide 2-mg foam in ulcerative colitis: a pooled analysis of data from two clinical trials.

Background/AimsMucosal healing (MH) of distal lesions in ulcerative colitis (UC) has recently been confirmed with budesonide 2-mg foam (BF) treatment in 2 clinical trials; however, few studies have investigated the predictive factors for complete MH.MethodsWe conducted a post hoc analysis using pooled data from phase II and III clinical trials evaluating the efficacy and safety of BF for UC. Additionally, we analyzed the relationships between complete MH and baseline factors and clinical symptoms from baseline to week 6.ResultsAmong the 291 Japanese patients from the 2 pooled clinical studies, 119 patients in the BF twice a day group and 117 in the placebo group were included in the full analysis set. The proportion of patients with a rectal bleeding (RB) subscore of 0 was significantly higher in the BF group than in the placebo group after a 5-day treatment (P<0.05). After a 2-day treatment, significantly more patients in the BF group had a stool frequency (SF) subscore of 0 than patients in the placebo group (P<0.05). Multivariate analysis showed that complete MH at week 6 was influenced by baseline SF subscore and 5-aminosalicylic acid (5-ASA) enema or suppository use (P=0.0086 and P=0.0015, respectively). The relationship between complete MH at week 6 and RB subscore after week 2 was also confirmed.ConclusionsNormal SF at baseline, history of 5-ASA topical product use, and elimination of RB after week 2 are suggested predictors of complete MH at week 6 with twice-daily BF treatment.

Endoscopic management of chronic radiation proctitis

Chronic radiation proctopathy occurs in 5%-20% of patients following pelvic radiotherapy. Although many cases resolve spontaneously, some lead to chronic symptoms including diarrhea, tenesmus, urgency and persistent rectal bleeding with iron deficiency anemia requiring blood transfusions. Treatments for chronic radiation proctitis remain unsatisfactory and the basis of evidence for various therapies is generally insufficient. There are very few controlled or prospective trials, and comparisons between therapies are limited because of different evaluation methods. Medical treatments, including formalin, topical sucralfate, 5-amino salicylic acid enemas, and short chain fatty acids have been used with limited success. Surgical management is associated with high morbidity and mortality. Endoscopic therapy using modalities such as the heater probe, neodymium:yttrium-aluminium-garnet laser, potassium titanyl phosphate laser and bipolar electrocoagulation has been reported to be of some benefit, but with frequent complications. Argon plasma coagulation is touted to be the preferred endoscopic therapy due to its efficacy and safety profile. Newer methods of endoscopic ablation such as radiofrequency ablation and cryotherapy have been recently described which may afford broader areas of treatment per application, with lower rate of complications. This review will focus on endoscopic ablation therapies, including such newer modalities, for chronic radiation proctitis.

The role of endoscopy in patients with anorectal disorders

The role of endoscopy in patients with anorectal disorders

Clinical trial: randomized‐controlled clinical study comparing the efficacy and safety of a low‐volume vs. a high‐volume mesalazine foam in active distal ulcerative colitis

Rectally administered mesalazine (mesalamine; 5-aminosalicylic acid) is the first-line therapy for treatment of distal ulcerative colitis. Recently, a high-volume 5-aminosalicylic acid foam has been shown to be as effective and safe as standard 5-aminosalicylic acid enema. To study the efficacy and safety of a low-volume vs. a high-volume 5-aminosalicylic acid foam. In this investigator-blinded study, patients with active distal ulcerative colitis [Clinical Activity Index (CAI) > 4, Endoscopic Index > or = 4] were randomized to receive 2 x 1 g/30 mL low-volume (n = 163) or 2 x 1 g/60 mL high-volume 5-aminosalicylic acid foam (n = 167) for 42 days. Primary end point was clinical remission (CAI < or = 4) at the final/withdrawal visit (per-protocol). 330 patients were evaluable for efficacy and safety by intention-to-treat, 290 for per-protocol analysis. Clinical remission rates at week 6 (per-protocol) were 77% on low-volume foam vs. 77% on high-volume foam (P = 0.00002 for non-inferiority). The low-volume foam was associated with a lower frequency of severe discomfort, pain and retention problems. Low-volume 5-aminosalicylic acid foam is as effective and safe as a high-volume 5-aminosalicylic acid foam in the treatment of active distal ulcerative colitis, but offers compliance advantages compared to the high-volume preparation.

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

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. 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. 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). 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.

A Meta-Analysis of the Placebo Rates of Remission and Response in Clinical Trials of Active Ulcerative Colitis

Knowledge of the placebo outcomes and understanding specific study features that influence these outcomes is important for designing future clinical trials evaluating therapy of ulcerative colitis (UC). The aims of this study were to estimate the placebo rates of remission and response in placebo-controlled, randomized clinical trials for active UC and to identify factors influencing these rates. We performed a systematic review and meta-analysis of placebo-controlled, randomized clinical trials evaluating therapies for active UC identified from MEDLINE from 1966 through 2005. Forty studies met the inclusion criteria. The pooled estimates of the placebo rates of remission and response were 13% (95% confidence interval, 9%-18%; range, 0%-40%; median, 12%) and 28% (95% confidence interval, 23%-33%; range, 0%-67%; median, 30%), respectively, both with significant heterogeneity. Studies that used more stringent definitions of outcomes had lower placebo rates of remission and response. Study duration, number of study visits, disease duration, baseline composite and rectal bleeding scores of the disease activity index, and inclusion of endoscopic mucosal healing as the remission definition all were associated with the placebo remission rate. Rates of remission in the placebo arm of UC clinical trials ranges from 0% to 40%. The placebo remission rates are influenced by the trial length, number of study visits, use of stricter remission definitions, and design features that enroll patients with more active disease. These factors should be considered when designing future placebo-controlled clinical trials in patients with active UC.

Once-Daily, High-Concentration MMX Mesalamine in Active Ulcerative Colitis

SPD476 (LIALDA in the US; MEZAVANT in the EU; otherwise known as MMX mesalamine; Shire Pharmaceuticals Inc., Wayne, PA, under license from Giuliani SpA, Milan, Italy) is a novel, once-daily, high-strength (1.2 g/tablet) formulation of mesalamine, utilizing MMX Multi Matrix System (MMX) technology designed to deliver the active drug throughout the colon. We performed a double-blind, multicenter study, comparing MMX mesalamine vs placebo for the treatment of active ulcerative colitis. A delayed-release oral mesalamine (ASACOL; Procter & Gamble, Cincinnati, OH) reference arm was included. Three hundred forty-three patients with active, mild-to-moderate ulcerative colitis received MMX mesalamine 2.4 g/day or 4.8 g/day given once daily, ASACOL 2.4 g/day given in 3 divided doses, or placebo for 8 weeks. The primary end point was the proportion of patients in clinical and endoscopic remission (modified ulcerative colitis disease activity index of < or =1 with rectal bleeding and stool frequency scores of 0, no mucosal friability, and a > or =1-point reduction in sigmoidoscopy score from baseline). A significantly greater proportion of patients receiving MMX mesalamine 2.4 g/day given once daily (40.5%; P = .01) and 4.8 g/day given once daily (41.2%; P = .007) achieved clinical and endoscopic remission at week 8, vs placebo (22.1%). The clinical and endoscopic remission rate for ASACOL (32.6%; P = .124) was not significantly superior to placebo. All active treatments were well-tolerated. Once-daily MMX mesalamine was efficacious and well-tolerated for the induction of clinical and endoscopic remission. MMX mesalamine offers effective and convenient mesalamine therapy, potentially improving treatment compliance.

Trichuris suis therapy for active ulcerative colitis: A randomized controlled trial

Ulcerative colitis is most common in Western industrialized countries. Inflammatory bowel disease is uncommon in developing countries where helminths are frequent. People with helminths have an altered immunological response to antigens. In animal models, helminths prevent or improve colitis by the induction of regulatory T cells and modulatory cytokines. This study determined the efficacy and safety of the helminth Trichuris suis in therapy of ulcerative colitis. This was a randomized, double blind, placebo-controlled trial conducted at the University of Iowa and select private practices. Trichuris suis ova were obtained from the US Department of Agriculture. The trial included 54 patients with active colitis, defined by an Ulcerative Colitis Disease Activity Index of > or =4. Patients were recruited from physician participants and were randomly assigned to receive placebo or ova treatment. Patients received 2500 Trichuris suis ova or placebo orally at 2-week intervals for 12 weeks. The primary efficacy variable was improvement of the Disease Activity Index to > or =4. After 12 weeks of therapy, improvement according to the intent-to-treat principle occurred in 13 of 30 patients (43.3%) with ova treatment compared with 4 of 24 patients (16.7%) given placebo (P = .04). Improvement was also found with the Simple Index that was significant by week 6. The difference in the proportion of patients who achieved an Ulcerative Colitis Disease Activity Index of 0-1 was not significant. Treatment induced no side effects. Ova therapy seems safe and effective in patients with active colitis.

Diversion Colitis.

Management of the patient with diversion colitis is dependent upon both patient and disease-related factors. Patients in whom diversion is not permanent, who desire stoma closure, and who have an acceptable surgical risk should undergo re-establishment of intestinal continuity. Asymptomatic, high-risk surgical candidates need only undergo periodic, regular endoscopic surveillance of both the functional and nonfunctional large bowel according to currently accepted screening guidelines. Most symptomatic patients in whom the diversion is permanent can be treated successfully with steroid enemas, 5-aminosalicylic acid enemas or suppositories, or short-chain fatty acid enemas. If diversion is permanent, medical treatment is unsuccessful, and symptoms persist, acceptable surgical candidates should undergo resection of the excluded bowel.

A Case Study of Ulcerative Colitis Effectively Treated with 5-Aminosalicylic Acid Enema

潰瘍性大腸炎（UC）の治療は，従来，ステロイド剤やサラゾピリンなどを中心とした薬物療法が一般的であるが，その治療および緩解の維持には難渋するものも少なくない。今回，5アミノサリチル酸（5-ASA）注腸療法が奏効したUCの1例を経験したので，内視鏡所見を中心に報告する。症例は19歳，男性で，全大腸型UCに対し，約1年にわたってステロイド療法，メサラジン内服療法などを繰り返すも，直腸からS状結腸に大腸炎が持続し，副腎機能低下症などを併発したため，当科を紹介された。5-ASA注腸療法を開始したところ，持続していたUCが軽快し，ステロイドの使用を中止でき，さらに副腎機能の回復をみた。現在，患者は外来にて5-ASA注腸療法を継続し，経過良好である。5-ASA注腸療法は大量の長期投与でも安全で，とくに今回の結果では病変部が下部大腸に限局している軽～中等度のUC症例に対して有効性が認められた。

Budesonide in inflammatory bowel disease

Due to its immunomodulatory and anti-inflammatory properties glucocorticosteroids have proved to be highly efficacious in patients with inflammatory bowel disease. However, because of the risk of side-effects, the dose and duration of therapy with systemically acting glucocorticosteroids have to be restricted. Recently the use of topically acting glucocorticosteroids has attracted great interest. Among the various topically acting glucocorticosteroids budesonide has emerged as the most promising. Budesonide is highly potent, is readily water-soluble and has low systemic bioavailability, thus reducing the risk of corticosteroid-related side-effects. When given as enema to patients with proctitis or proctosigmoiditis, the efficacy of budesonide is greater than that of placebo and equal to that of prednisolone or 5-aminosalicylic acid enemas. In an enteric-coated formulation budesonide is more effective than placebo in achieving and maintaining remission in patients with ileocecal Crohn's disease. Although corticosteroidrelated side-effects are rare, some suppression of the hypothalamic-pituitary-adrenal axis may occur.

5-Aminosalicylic acid enemas to maintain remission in left-sided ulcerative colitis: a meta- and economic analysis.

The efficacy of 5-aminosalicylic acid (5-ASA) enemas for maintaining remission in left-sided ulcerative colitis is controversial because clinical trials conducted thus far have given conflicting results (1–7). To further investigate this issue, we undertook a meta-analysis of the published studies.

Combined therapy with 5-aminosalicylic acid tablets and enemas for maintaining remission in ulcerative colitis: Results at 12 months

Combined therapy with 5-aminosalicylic acid tablets and enemas for maintaining remission in ulcerative colitis: Results at 12 months

Budesonide for the Treatment of Inflammatory Bowel Disease

While corticosteroids are the most effective treatment for the symptomatic management of patients with inflammatory bowel disease (IBD), they cause serious side effects. Budesonide is a nonhalogenated glucocorticosteroid structurally related to 16 alpha-hydroxyprednisolone that possesses high topical anti-inflammatory activity and low systemic activity compared with the conventional steroids prednisone and prednisolone. This favourable activity ratio is achieved because a high affinity to the steroid receptor is coupled with rapid hepatic conversion to metabolites with minimal or no biological activity. Controlled trials in patients with distal ulcerative colitis indicate that budesonide enemas have equivalent or superior efficacy compared with 5-aminosalicylic acid (5-ASA) enemas, prednisolone disodium phosphate enemas or methylprednisolone enemas, without causing significant depression of endogenous cortisol levels. Two controlled trials investigating the efficacy of an oral controlled-ileal release form of hudesonide for active Crohn’s disease have recently been completed. In the first trial, after eight weeks’ treatment budesonide 9 mg daily caused clinical remission in 51% of patients, compared with 20% of patients receiving placebo. Budesonide caused a dose-related reduction of plasma cortisol responses to adrenocorticotropic hormone stimulation, but was not associated with clinically important corticosteroid-related symptom or other toxicity. In a second trial, budesonide 9 mg daily was as effective as prednisolone for induction of remission in active ileocecal Crohn’s disease. Budesonide is a potentially promising new therapeutic agent for the management of patients with IBD.

Intermittent therapy with high-dose 5-aminosalicylic acid enemas maintains remission in ulcerative proctitis and proctosigmoiditis

The aim of this study was to compare the efficacy of intermittent therapy with mesalazine enemas and continuous oral mesalazine to maintain remission of distal ulcerative colitis or proctitis. Thirty-eight patients with distal ulcerative colitis (n = 17) or ulcerative proctitis (n = 21) in clinical, endoscopic, and histologic remission were randomly assigned to receive either oral mesalazine (0.5 g three times/day, Eudragit L coating, n = 19) or intermittent therapy with mesalazine enemas (4 g of 5-aminosalicylic acid enema every third night, n = 19). Both groups were comparable in regard to sex, age, age at disease onset, extent and duration of disease, number and mode of treatment of previous attacks, and time in remission. Patients were reviewed at the beginning of the study and, subsequently, at two-month intervals for 24 months or until a relapse occurred. At each visit, diaries were reviewed and clinical and laboratory assessments were performed. Sigmoidoscopy was carried out and biopsies were obtained by a blinded observer. Histology was assessed without knowledge of the patient's clinical state or treatment category. At the end of the study, 6 of 19 patients on oral mesalazine (32 percent) and 14 of 19 patients on mesalazine enemas (74 percent) were still in full remission (log rank test: 15.28, P < 0.001). Differences in relapse rates between groups were significant even when data were stratified by extent of disease (P < 0.01). In the oral group, six and seven patients relapsed at 12 and 24 months, respectively. In the enema group, three and two relapses occurred in the first and second year of the study, respectively. All patients complied with the treatment satisfactorily and there were no dropouts. These results suggest that intermittent therapy with mesalazine enemas is more effective than continuous oral mesalazine in maintaining remission in patients with distal ulcerative colitis and proctitis.

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.

Distribution of Mesalamine Enemas in Patients With Active Distal Ulcerative Colitis

Mesalamine (5-aminosalicylic acid), a topically administered anti-inflammatory agent, is effective treatment by enema for distal ulcerative colitis; it lacks many of the side effects of orally administered sulfasalazine. In this study, we determined the colonic distribution of a 60-ml mesalamine enema in eight patients (five women and three men, 18 to 48 years old) with active distal ulcerative colitis that ranged from 12 to 40 cm proximal to the anal verge. On 3 consecutive days, each patient self-administered a 4-g (60-ml) 5-aminosalicylic acid enema that contained 3.7 MBq of [99mTc]technetium-sulfur colloid. Anterior and posterior images were obtained at 0, 30, 60, 120, and 240 minutes. During the 4-hour study period, all patients retained the enemas. The enemas spread to the sigmoid region in 24 of 24 studies, to the splenic flexure region in 22 of 24, and to the transverse colon in 1 of 24. Most of the enema was retained in the sigmoid colon. Therefore, we conclude that a 60-ml enema, when administered as recommended clinically, routinely flows retrograde as far as the splenic flexure but rarely spreads beyond this point. These results support the use of intrarectally administered 5-aminosalicylic acid for segmental colitis of the descending colon.

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 coloni cmucosa (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.