Oral beclometasone dipropionate in the treatment of active ulcerative colitis: a double-blind placebo-controlled study

AIM: To evaluate efficacy and safety of oral beclometasone dipropionate (BDP) when added to 5-ASA in the treatment of patients with active ulcerative colitis. METHODS: In a 4-week, placebo-controlled, double-blind study, patients with extensive or left-sided mild to moderate active ulcerative colitis were randomized to receive oral 5-ASA (3.2 g/day) plus BDP (5 mg/day) or placebo. Clinical, endoscopic and histologic features, and haematochemical parameters were recorded at baseline and at the end of the study. RESULTS: One hundred and nineteen patients were enrolled and randomly treated with BDP plus 5-ASA (n = 58) or placebo plus 5-ASA (n = 61). Both treatment groups showed a statistically significant decrease of disease activity index (DAI) and histology score at the end of treatment (P = 0.001, each). DAI score was lower in the BDP group than in the placebo group (P = 0.014), with more patients in clinical remission in the BDP group (58.6% vs. 34.4%, P = 0.008). Serum cortisol levels significantly decreased in BDP group vs. baseline (P = 0.002), but without signs of pituitary-adrenal function depletion. A low incidence of adverse events was observed in both groups. CONCLUSIONS: Oral BDP in combination with oral 5-ASA is significantly more effective than 5-ASA alone in the treatment of patients with extensive or left-sided active ulcerative colitis.     

Meta-analysis: the efficacy of rectal beclomethasone dipropionate vs. 5-aminosalicylic acid in mild to moderate distal ulcerative colitis

BACKGROUND: Beclomethasone dipropionate (BDP) is a second-generation steroid with topical effects and minimal systemic activity for patients with ulcerative colitis (UC). AIM: To review all available literature to assess the efficacy of enema/foam BDP compared with enema/foam 5-aminosalicylic acid (5-ASA) in the control of left-sided mild-moderate UC. METHODS: We selected randomized controlled trials of enema/foam BDP compared with enema/foam 5-ASA treatment in patients with UC. Two reviewers assessed trial quality and extracted data independently. RESULTS: Four trials involving 428 UC patients, 209 treated with 5-ASA (1-4 g o.d.) and 219 with BDP (3 mg o.d.), were included. Intention-to-treat analysis showed that 5-ASA induced improvement/remission of UC in 146 (69.9%) patients, while BDP in 143 (65.3%). The test for heterogeneity (Cochran Q) was not significant and Mantel-Haenszel pooled estimate of odds ratio was 1.23 (95% CI = 0.82-1.85). The results did not change when analysis was performed on a per-protocol basis. CONCLUSION: The randomized controlled trials identified in this review showed that rectal BDP has equal effect as 5-ASA to control symptoms in UC.     

Review article: treatment of mild to moderate ulcerative colitis and pouchitis

The meta-analyses of published trials have shown topical therapy with 5-aminosalicylic acid (5-ASA) to be the treatment of choice in active distal ulcerative colitis. Oral aminosalicylates are effective for both distal and extensive ulcerative colitis, but in distal colitis the rates of improvement and remission are usually lower than those reported for rectal 5-ASA therapy. An alternative to 5-ASA therapy is represented by the new steroids; budesonide and beclometasone dipropionate (BDP) enemas, the most extensively studied, have been shown to be as effective as conventional steroids but with a significantly lower inhibition of plasma cortisol. Patients who do not respond to 5-ASA or new steroids should be treated with oral steroids. Azathioprine or 6-mercaptopurine may be effective in patients who do not respond or cannot be weaned off steroids. Treatment of pouchitis is largely empirical and few controlled studies have been carried-out. Antibiotics are the treatment of choice and most patients make a good response to metronidazole or ciprofloxacin. Chronic refractory pouchitis may benefit from a prolonged course of a combination of antibiotics. Highly concentrated probiotics (VSL#3) are effective both for the prevention of pouchitis onset and the prevention of relapses.     

Treatment of mild to moderate ulcerative colitis and pouchitis

The meta-analyses of published trials have shown topical therapy with 5-aminosalicylic acid (5-ASA) to be the treatment of choice in active distal ulcerative colitis. Oral aminosalicylates are effective for both distal and extensive ulcerative colitis, but in distal colitis the rates of improvement and remission are usually lower than those reported for rectal 5-ASA therapy. An alternative to 5-ASA therapy is represented by the new steroids; budesonide and beclometasone dipropionate (BDP) enemas, the most extensively studied, have been shown to be as effective as conventional steroids but with a significantly lower inhibition of plasma cortisol. Patients who do not respond to 5-ASA or new steroids should be treated with oral steroids. Azathioprine or 6-mercaptopurine may be effective in patients who do not respond or cannot be weaned off steroids. Treatment of pouchitis is largely empirical and few controlled studies have been carried-out. Antibiotics are the treatment of choice and most patients make a good response to metronidazole or ciprofloxacin. Chronic refractory pouchitis may benefit from a prolonged course of a combination of antibiotics. Highly concentrated probiotics (VSL#3) are effective both for the prevention of pouchitis onset and the prevention of relapses.     

Systemic availability of 5-aminosalicylic acid: comparison of delayed release and an azo-bond preparation

Aim: To determine the systemic uptake of 5-aminosalicylic acid (5-ASA) and acetyl-5-ASA (Ac-5-ASA) at steady state during treatment with either an azo-bond preparation, olsalazine, or a delayed-release mesalazine.
Methods: In an open cross-over trial with randomized sequence, 15 patients with ulcerative colitis in remission were given 7-day courses of olsalazine (Dipentum 1.0 g daily) and of mesalazine (Asacol 1.6 g daily). Plasma and urine were collected on days 6 and 7 of each course and concentrations of 5-ASA and Ac-5-ASA were determined by high-performance liquid chromatography (HPLC).
Results: Mean steady-state plasma concentrations of 5-ASA and Ac-5-ASA were significantly higher after treatment with mesalazine than with olsalazine ( P < 0.0001). Total urinary excretion of 5-ASA and Ac-5-ASA as a percentage of the given dose was significantly higher on mesalazine than on olsalazine ( P <0.01).
Only two patients experienced, during the first 3 days of treatment with olsalazine, transient watery diarrhoea which resolved spontaneously. No unexpected or major changes in haematology or biochemistry were detected during the study.
Conclusion: As 5-ASA acts locally, the lower systemic load provided by olsalazine may increase efficacy and reduce the potential risk of nephrotoxicity during long-term maintenance treatment of ulcerative colitis.     

Infliximab in the treatment of steroid-dependent ulcerative colitis

BACKGROUND AND OBJECTIVES: Infliximab has proven efficacious in the treatment of Crohn's disease. Limited and contrasting data are available on effectiveness of anti-TNF alpha therapy in ulcerative colitis. We evaluated the efficacy of infliximab in the management of steroid-dependent ulcerative colitis. METHODS: We report preliminary data from a randomized, open-label, methylprednisolone-controlled trial of infliximab in the induction and maintenance of remission of patients with moderate to severe steroid-dependent ulcerative colitis. Twenty patients received either three infusion of infliximab (5 mg/kg) at 0, 2 and 6 weeks and thereafter every 8 weeks (group A) or methylprednisolone (0,7-1 mg/kg) daily for one week followed by a tapering regimen up to the minimal dose to maintain a symptom-free condition (group B). Clinical remission was defined as a DAI score less than 3. RESULTS: Ten patients in group A (DAI: 8.9+/-1.4) achieved remission after the first infusion (DAI: 1.6+/-0,7; p = 0.005) and steroids were progressively discontinued. At present (mean follow-up: 9.8+/-1.1 months), 9 out of 10 patients maintain clinical remission, while one patient relapsed at 3 months. Ten patients in group B (DAI: 8.7+/-1.4) reached clinical remission at one week (DAI: 1.9+/-0.3; p = 0.005). Eight out of 10 patients were maintained at a minimal steroid dosage without any relapse at 9.7+/-1.0 months follow-up. Two patients relapsed at 6 and 8 months, respectively. CONCLUSIONS: Infliximab seems to be as effective as steroids in the management of moderate to severe steroid-dependent ulcerative colitis. These preliminary data suggest the potential efficacy of repeated treatment with infliximab for short-term maintenance of remission and steroid withdrawal in glucocorticoid-dependent ulcerative colitis.     

Once daily MMX mesalazine for the treatment of mild-to-moderate ulcerative colitis: a phase II, dose-ranging study

Background SPD476 (MMX? mesalazine), is a novel, once daily, high‐strength mesalazine formulation (1.2 g/tablet) that utilizes Multi Matrix System? (MMX) technology to delay and extend delivery of the active drug throughout the colon. Aim To assess the safety and efficacy of MMX mesalazine in patients with mild‐to‐moderately active ulcerative colitis, in a pilot, phase II, randomized, multicentre, double‐blind, parallel‐group, dose‐ranging study (SPD476‐202). Methods Thirty‐eight patients with mild‐to‐moderately active ulcerative colitis were randomized to MMX mesalazine 1.2, 2.4 or 4.8 g/day given once daily for 8 weeks. Remission ulcerative colitis‐disease activity index (UC‐DAI) ≤1, a score of 0 for rectal bleeding and stool frequency, and ≥1‐point reduction in sigmoidoscopy score from baseline was the primary end point. Results Week 8 remission rates were 0%, 31% and 18% of patients receiving MMX mesalazine 1.2, 2.4 and 4.8 g/day respectively. No statistically significant difference in remission was observed between treatment groups. MMX mesalazine 2.4 and 4.8 g/day groups demonstrated greater improvement in overall UC‐DAI and component scores from baseline, compared with the 1.2 g/day group. Conclusion MMX mesalazine given as 2.4 or 4.8 g/day once daily is well tolerated and effective for the treatment of mild‐to‐moderately active ulcerative colitis.     

Randomised clinical trial: the efficacy and safety of propionyl-L-carnitine therapy in patients with ulcerative colitis receiving stable oral treatment

Aliment Pharmacol Ther 2011; 34: 1088–1097

Summary

Background Ulcerative colitis (UC) is characterised by impaired fatty‐acid oxidation; l ‐carnitine has a key role in fatty‐acid metabolism and short‐chain fatty acids such as butyrate and propionate are important energy source for intestinal epithelial cells. Aim To evaluate efficacy and safety of colon‐release propionyl‐l ‐carnitine (PLC) in patients with mild‐to‐moderate UC receiving stable oral aminosalicylate or thiopurine therapy. Methods In a multicentre, phase II, double‐blind, parallel‐group trial, patients were randomised to receive PLC 1 g/day, PLC 2 g/day or placebo. Main inclusion criteria were as follows: age 18–75; disease activity index (DAI) score 3–10 inclusive, be under oral stable treatment with aminosalicylate or thiopurine. The primary endpoint was clinical/endoscopic response, defined as a decrease in DAI score ≥ 3 points or remission, defined as a DAI score ≤ 2 with no individual sub‐score > 1. Results Of 121 patients who were randomised, 57 of 79 (72%) patients receiving PLC (combined 1 g and 2 g cohort) had a clinical/endoscopic response vs. 20 of 40 (50%) receiving placebo (P = 0.02). Specifically, in PLC 1 g/day group, 30 of 40 (75%) patients had clinical/endoscopic response (P = 0.02 vs. placebo) and 27 of 39 (69%) in the PLC 2 g/day group (P = 0.08 vs. placebo). Rates of remission were 22/40 (55%), 19/39 (49%), 14/40 (35%) in the PLC 1 g, PLC 2 g, and placebo groups, respectively. PLC had a similar safety profile to placebo; the most common adverse events were gastrointestinal. Conclusion Propionyl‐l ‐carnitine 1 g/day should be investigated further as a co‐treatment for mild‐to‐moderate ulcerative colitis (NCT‐01026857).     

Comparative efficacy of coated, oral 5-aminosalicylic acid (Claversal) and sulphasalazine for maintaining remission of ulcerative colitis. International Study Group

The safety and efficacy of Claversal (coated, oral 5-aminosalicylic acid (5-ASA) 0.75 g/day) and sulphasalazine 1.5-2.0 g/day were compared for the maintenance treatment of ulcerative colitis in a 1-year double-blind trial. Three hundred and thirty-four patients, whose disease was controlled on a stable dose of sulphasalazine (1.5-2.0 g/day) for a 1-month pre-trial, entered the study. On entry, patients were assigned in a random manner to continue sulphasalazine or to switch to coated 5-ASA. One hundred and thirty-one patients in the coated 5-ASA group and 142 on sulphasalazine were analysed for efficacy. No significant difference was observed between treatments with respect to the cumulative rate of relapse. Over the 12 months, 30 (28%) of the coated 5-ASA patients versus 29 (23%) of those treated with sulphasalazine had an exacerbation of their disease (log rank test P = 0.7011). The incidence of drug-related adverse events and subsequent withdrawals was similar. The high incidence of side-effects usually associated with sulphasalazine was not observed, probably due to the fact that this population was tolerant of sulphasalazine pre-trial. Of the 37 patients who reported adverse events with previous sulphasalazine therapy, however, only two (8%) of the 24 experienced those events when randomized to coated 5-ASA while five (38%) of the 13 who continued on sulphasalazine reported those same events. Coated 5-ASA is a safe, effective therapy for maintaining ulcerative colitis in remission.     

Beclomethasone dipropionate versus budesonide inhalation suspension in children with mild to moderate persistent asthma

Inhaled steroids are the most effective long-term treatment of persistent asthma but many children are unable to use correctly the available inhalers. Administration of nebulized corticosteroids has some advantages over the administration with pressurised metered-dose inhalers (pMDls). The objective of this multicenter randomised study was to compare the efficacy and tolerability of nebulized corticosteroids in paediatric patients with asthma. 127 patients aged > or = 6 and < or = 14 years with a diagnosis of mild to moderate persistent asthma (PEFR % predicted > 50% and < 85%) and positive response to the reversibility test were randomized. The patients were assigned by randomisation to one of the two treatment groups (4 weeks): beclomethasone dipropionate (BDP) 800 microg/daily b.i.d. (n = 66) or budesonide (BUD) 1000 microg/daily b.i.d. (n = 61) both administered by nebulizer. The primary efficacy end point was the final mean of PEFR measured at clinical visit (clinic PEFR). In the BDP group clinic PEFR increased from 177.5 +/- 80 L/min to 246.6 +/- 84.2 L/min (p < 0.001 vs baseline), while in the BUD group the increase was from 180.4 +/- 77.8/min to 260.9 +/- 84.1 L/min (p < 0.001 vs baseline) (NS between treatments). FEV1 (% predicted) increased from 77.8% to 92.7% (p < 0.001 vs baseline) and from 74.1% to 95.9% (p < 0.001 vs baseline) in BDP and BUD group respectively (NS between treatments). Patients reduced the use of salbutamol rescue medication by 76% and 81% in BDP and BUD group respectively (p < 0.001 vs baseline, NS between treatments). 4 patients in the BDP group and 2 in the BUD group reported adverse events (AEs). AEs were mild to moderate and never there was the need to discontinue the treatments. In conclusion the results of this study demonstrate that both BDP (800 microg/daily) and BUD (1000 microg/daily) administered by nebulization are effective and with a acceptable safety and tolerability profile.     

The systemic load and efficient delivery of active 5-aminosalicylic acid in patients with ulcerative colitis on treatment with olsalazine or mesalazine

BACKGROUND: There have been reports of nephrotoxic reactions in patients with ulcerative colitis treated with 5-aminosalicylic acid (5-ASA) preparations. AIM: To compare the efficacy in delivery of active 5-ASA to the colon and the systemic load as the basis for potential long-term toxicity during treatment with olsalazine or mesalazine in patients with ulcerative colitis in remission. PATIENTS AND METHODS: Fifteen patients with ulcerative colitis were treated with olsalazine or mesalazine, each for 7 days in an open, randomized, crossover design study. 5-ASA and acetyl-5-ASA (Ac-5-ASA) in plasma and urine were measured by high performance liquid chromatography. RESULTS: The plasma concentration of 5-ASA was 1.2 +/- 0.1 micromol/L (mean +/- S.E.M.) for olsalazine and 8.0 +/- 1.9 micromol/L for mesalazine, while the plasma concentration of Ac-5-ASA was 2.8 +/- 0.2 micromol/L for olsalazine and 10.8 +/- 1.6 micromol/L for mesalazine. The amount of 5-ASA excreted in the urine was 68 +/- 30 micromol/24 h for olsalazine and 593 +/- 164 micromol/24 h for mesalazine. The amount of Ac-5-ASA in the urine was 1260 +/- 102 micromol/24 h for olsalazine and 3223 +/- 229 micromol/24 h for mesalazine. The urinary recovery of total 5-ASA plus Ac-5-ASA (as a percentage of the given dose) was 23 +/- 2.1% for olsalazine and 39 +/- 3.6% for mesalazine. The ratio between the plasma concentrations of mesalazine and olsalazine differed significantly both for 5-ASA (5.1) and Ac-5-ASA (3.6); for 5-ASA (9. 9) and Ac-5-ASA (2.6) in urine, and for the urinary recovery of total 5-ASA plus Ac-5-ASA (1.7). Moreover, in the mesalazine group there was a large variation in the individual plasma concentrations of 5-ASA and Ac-5-ASA, with maximal values 5-6-fold higher than that in the olsalazine group. CONCLUSION: The systemic load of active 5-ASA is significantly higher for mesalazine than for olsalazine, when based on the dosages given and when calculated on an equimolar basis. Some of the patients in the mesalazine group showed unexpected high levels of plasma and urinary 5-ASA concentrations, a finding which may have long-term safety implications.     

Rectal aminosalicylate therapy for distal ulcerative colitis: a meta-analysis

Background: To summarize and quantify the evidence supporting rectal 5- or 4-aminosalicylate (ASA) therapies for disease exacerbation or remission maintenance in distal ulcerative colitis, we performed a meta-analysis. Methods: All randomized, double-blind controlled trials involving aminosalicylate therapy were retrieved from a MEDLINE search, review articles on ulcerative colitis therapy or their bibliographies. Of 55 studies retrieved, 19 met the inclusion criteria. Appraisal and data extraction were performed by two observers and scoring disagreements were resolved by consensus. Results: Eleven trials tested 5-ASA and three tested 4-ASA in active ulcerative colitis. 5-ASA was superior to placebo for inducing remission or symptomatic improvement in active ulcerative colitis with a pooled odds ratio of 7.36 (95% Confidence interval (CI): 4.72–11.47). In four trials the pooled odds ratio for endoscopic improvement was 10.04 (95 % CI: 5.72–17.61) and for histological improvement 10.31 (95% CI: 5.85–18.18). Studies evaluating 4–ASA suggest a benefit similar to prednisolone in treating active disease. Five trials assessed remission maintenance with 5-ASA, and when compared to placebo gave a pooled odds ratio of 16.22 (95% CI: 4.71–55.92). No dose-response relationship was observed. ASA compounds were not therapeutically superior to other treatments. Conclusions: We conclude that rectal 5-ASA is effective therapy for active distal ulcerative colitis. More trials are needed to assess 4-ASA, dose-response effects and the ideal regimen for remission maintenance.     

Review: new aminosalicylic acid derivatives for the treatment of inflammatory bowel disease

Up to 20-30% of patients treated with sulphasalazine experience a variety of adverse effects, principally due to the carrier moiety sulphapyridine. In the last decade there has been a major drive to develop a new generation of 5-aminosalicylic acid (5-ASA) and 5-ASA-related drugs which not only have a high efficacy but are also devoid of the unwanted side-effects of sulphapyridine. Various forms of 5-ASA have been evaluated in ulcerative colitis and appear to be effective orally in preventing relapse and topically in the treatment of active distal colitis. More recently, topical 4-ASA has been found to be useful for the treatment of distal colitis with the advantage of better stability and lower cost compared with 5-ASA. In the foreseeable future it seems likely that these new aminosalicylic acid derivatives will become the drugs of choice in the treatment of inflammatory bowel disease and largely replace sulphasalazine.     

Comparison of budesonide and 5-aminosalicylic acid enemas in active distal ulcerative colitis

Background: Budesonide is a new corticosteroid with high topical anti-inflammatory activity but little systemic effect. The aim of the present study was to compare the efficacy and safety of budesonide enema (2 mg/100 mL) and 5-ASA enema (mesalazine 1 g/ 100 mL) given for 4 weeks in the treatment of active distal ulcerative colitis and proctitis. Methods: Ninety-seven patients were studied in a multicentre single-blind randomized group-comparative trial. The primary efficacy variables were endoscopy and histopathology scores obtained at 0, 2 and 4 weeks. Clinical symptoms were the secondary efficacy variables. Haematology, chemistry and adverse events were the safety variables. Results: Budesonide and 5-ASA enemas both resulted in a significant improvement in endoscopy and histopathology scores but no difference could be demonstrated between the two treatment groups. There was also a significant improvement of symptoms (number of bowel movements per day, quality of stools, presence of blood and mucus, and state of well-being) within both groups but no difference between the two treatment groups. The clinical remission rate at 4 weeks was, however, 38% for patients treated with budesonide enema but 60% for those treated with 5-ASA enema (P= 0.03). No adverse events attributed to the study drugs were recorded in either of the groups. Conclusions: Budesonide enema 2 mg/100 mL appears to be as efficient and well-tolerated as 5-ASA enema in the treatment of active distal ulcerative colitis and proctitis.     

5-Aminosalicylic acid in patients with an ileo-rectal anastomosis

Summary The pharmacokinetics of 5-aminosalicylic acid (5-ASA) from sulphasalazine (SASP) and the slow-release 5-ASA preparation Pentasa was investigated in a cross-over study in 9 otherwise healthy patients with an ileo-rectal anastomosis. The 24-hour recoveries of the drugs were 90.5% and 84.7%, respectively. The median release of 5-ASA from SASP was 50% and from Pentasa 75%. Equal amounts of 5-ASA (18.0% vs 17.9%) were found in the faeces, and a significantly larger amount (4.4% vs 28.9%) of the metaboliteN-acetyl-5-aminosalicylic acid (ac-5-ASA) was found in faeces following Pentasa. A larger amount of 5-ASA was absorbed and subsequently excreted in the urine, mainly as the metabolite (2.5% vs 20.5%) from Pentasa. This confirms previous results in ileostomized patients treated with Pentasa. The present findings also demonstrate that bacterial azo-reduction of SASP in patients with ileorectal anastomosis may be an adequate way to deliver 5-ASA in this type of patient. Both treatments may be used in these patients during a flare up of ulcerative colitis, but randomized studies are needed.     

Discovery and preclinical development of a novel prodrug conjugate of mesalamine with eicosapentaenoic acid and caprylic acid for the treatment of inflammatory bowel diseases

Mesalamine (5-ASA) is one of the drugs indicated as first line therapy in ulcerative colitis for induction and maintenance of remission. Sulfasalazine and formulations of 5-ASA (pH-dependent and controlled release formulations) were developed to minimize the systemic absorption and maximize the delivery of the mesalamine to colon. Although, its efficacy and safety is well documented there are approximately 30% nonresponders to 5-ASA therapy. This necessitates the need for novel therapeutic options to improve the efficacy and safety of the currently available 5-ASA therapy. CLX-103 is a novel, patented prodrug molecular conjugate of mesalamine, eicosapentaenoic acid and caprylic acid designed to offer incremental benefits over the currently approved 5-ASA formulations. Results of in vitro and in vivo studies showed that CLX-103, was stable in simulated gastric fluid, but undergoes enzymatic hydrolysis in the small/large intestines to release the active moiety. Our data also showed that the active moiety is retained in the targeted intestinal tissues (ileum and colon) over a longer period of time in relation to sulfasalazine. The in vitro data supports the observed in vivo plasma kinetics of 5-ASA characterized by longer T_max, low C_max after the oral administration of CLX-103. Efficacy study of CLX-103 in acute dextran sodium sulfate (DSS) mouse colitis model showed improved potency measured as Disease Activity Index (DAI) and histological scores in the colon as compared to sulfasalazine. These findings indicate that CLX-103 could offer a differentiated drug product which is more efficacious and safer than the currently approved 5-ASA formulations in the treatment of inflammatory bowel diseases.     

Is 5-ASA still the treatment of choice for ulcerative colitis?

5-Amino-salacylic acid (5-ASA) is up to now the treatment of choice in the induction and maintenance of remission of mild-to-moderate ulcerative colitis (UC). Sulfasalazine, despite similar efficacy, is hampered by more side effects, but in presence of peripheral arthopaties it remains the treatment of choice. The new delayed release MMX formulation seems to be promising in reducing compliance problems, but further studies are warranted to show the superiority of new MMX formulation compared with the older formulations of 5-ASA. Some trials evaluated also the efficacy and safety of once-daily dosing of older 5-ASA formulations in maintenance of remission, finding a greater adherence to therapy in the group given the once daily regimen, compared with the classic twice daily groups. Regarding the efficacy of alternative treatment such us probiotics and antibiotics, the current data are not sufficient to promote their use in clinical practice. Clinical evidence supports the use of topical 5-ASA in active mild to moderate distal UC showing superior ef?cacy to placebo, topical corticosteroids, and oral 5-ASA. A combination of oral and rectal 5-ASA produces additional ef?cacy in both limited and extensive UC. Topical 5-ASA formulations are effective also for the maintenance of remission, however long term treatment may not be acceptable to many patients. Other topical drugs (E. Coli Nissle, propionyl-L-carnitine, butyrate, tacrolimus, rosiglitazone) have been investigated with conflicting results. The possible chemopreventive role of long term treatment with 5-ASA strengthens the indication to the long term use of 5-ASA.     

Evaluation of renal function following treatment with 5-aminosalicylic acid derivatives in patients with ulcerative colitis

BACKGROUND: A number of cases of nephrotoxicity have been reported in patients with inflammatory bowel disease taking oral 5-aminosalicylic acid (5-ASA). AIM: To evaluate the effects of 9 months of therapy with mesalazine or olsalazine on renal function in patients with ulcerative colitis in remission. METHODS: Forty patients with ulcerative colitis in complete remission for 6 months were randomized to either olsalazine (n=20) or mesalazine (n=20 for nine months). Thirty-six of the 40 patients were on prior salicylate therapy. Disease activity was the measure ofclinical efficacy and was assessed by the Harvey-Bradshaw Index (HBI). Laboratory efficacy measurements included glomerular filtration rate (GFR), microalbuminuria, urinary gluthathione S-transferase (GST) and serum C-reactive protein (CRP). Safety analysis consisted of documentation of adverse events and laboratory values. RESULTS: There was no significant reduction in the GFR overall on therapy. The levels of GFR adjusted for baseline were similar in the two treatment groups after 3, 6 and 9 months. A significantly higher percentage of mesalazine-treated patients experienced drug related adverse events, all of a minor nature. The incidence of adverse events causing early withdrawal was similar in the two treatment groups. CONCLUSION: Treatment with mesalazine or olsalazine for 9 months had no significant impact on GFR.     

Impact on the composition of the faecal flora by a new probiotic preparation: preliminary data on maintenance treatment of patients with ulcerative colitis

BACKGROUND: Although 5-aminosalicylic acid (5-ASA) oral compounds are the standard maintenance treatment for ulcerative colitis in remission, some patients cannot use them because of side-effects. Clinical and experimental observations have suggested the potential role of probiotics in inflammatory bowel disease therapy. AIM: To evaluate the effects on intestinal microflora and the clinical efficacy of a new probiotic preparation in patients with ulcerative colitis in remission. PATIENTS AND METHODS: Twenty patients with ulcerative colitis, intolerant or allergic to 5-ASA, have been treated with a new probiotic preparation (VSL#3, CSL, Milan, Italy) containing 5x10(11) cells/g of 3 strains of bifidobacteria, 4 strains of lactobacilli and 1 strain of Streptococcus salivarius ssp. thermophilus. Two doses of 3 g were administered o.d. for 12 months. Faecal samples for stool culture were obtained from the patients at the beginning of the trial and after 10, 20, 40, 60, 75, 90 days, 12 months and at 15 days after the end of the treatment. The following bacterial groups have been evaluated in the faeces: total aerobic and anaerobic bacteria, enterococci, Streptococcus thermophilus, lactobacilli, bifidobacteria, Bacteroides, clostridia, coliforms. Patients were assessed clinically every two months, and assessed endoscopically at 6 and 12 months or in relapse. RESULTS: Faecal concentrations of Streptococcus salivarius ssp. thermophilus, lactobacilli and bifidobacteria increased significantly in all patients, compared to their basal level, from the 20th day of treatment (P<0.05) and remained stable throughout the study. Concentrations of Bacteroides, clostridia, coliforms, total aerobic and anaerobic bacteria did not change significantly during treatment (P = N.S.). Fifteen of 20 treated patients remained in remission during the study, one patient was lost to follow up, while the remaining relapsed. No significant side-effects have been reported. CONCLUSIONS: These results show that this probiotic preparation is able to colonize the intestine, and suggest that it may be useful in maintaining the remission in ulcerative colitis patients intolerant or allergic to 5-ASA. Controlled trials are warranted to confirm these preliminary results.     

Review article: new developments in the use of 5-aminosalicylic acid in patients with inflammatory bowel disease

Sulphasalazine is composed of sulphapyridine and mesalazine (5-aminosalicylic acid, 5-ASA or mesalazine) joined by an azo bond. Sulphasalazine has been used clinically for 40 years but less than 10 years ago it was recognized that the active moiety is 5-ASA. Sulphapyridine appears to act only as a carrier molecule to deliver mesalazine to the bowel, yet it is the sulphapyridine which appears to be responsible for many of the adverse effects observed with sulphasalazine. Normally, mesalazine is rapidly absorbed from the upper gastrointestinal tract. Since the action of mesalazine is thought to be locally at the site of disease in the intestine, the 5-ASA must be 'protected' to ensure its release in the terminal ileum and colon, the site of bowel inflammation in patients with Crohn's disease or ulcerative colitis. Recent clinical studies have confirmed the efficacy of topical (suppositories and enemas) therapy for ulcerative proctitis and left-sided colitis; oral mesalazine has been proven to be useful for the treatment of acute ulcerative colitis and for the maintenance of remission. There is preliminary evidence for the clinical usefulness of mesalazine in acute Crohn's disease as well as for the maintenance of remission.