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. 2016 May 9;2016(5):CD000544.
doi: 10.1002/14651858.CD000544.pub4.

Oral 5-aminosalicylic acid for maintenance of remission in ulcerative colitis

Yongjun Wang  1 , Claire E Parker, Brian G Feagan, John K MacDonald
Affiliations

Oral 5-aminosalicylic acid for maintenance of remission in ulcerative colitis

Yongjun Wang et al. Cochrane Database Syst Rev. .

Update in

Abstract

Background: Oral 5-aminosalicylic (5-ASA) preparations were intended to avoid the adverse effects of sulfasalazine (SASP) while maintaining its therapeutic benefits. Previously, it was found that 5-ASA drugs were more effective than placebo but had a statistically significant therapeutic inferiority relative to SASP. This updated review includes more recent studies and evaluates the effectiveness, dose-responsiveness, and safety of 5-ASA preparations used for maintenance of remission in quiescent ulcerative colitis.

Objectives: The primary objectives were to assess the efficacy, dose-responsiveness and safety of oral 5-ASA compared to placebo, SASP, or 5-ASA comparators for maintenance of remission in quiescent ulcerative colitis. A secondary objective was to compare the efficacy and safety of once daily dosing of oral 5-ASA with conventional (two or three times daily) dosing regimens.

Search methods: A literature search for relevant studies (inception to 9 July 2015) was performed using MEDLINE, EMBASE and the Cochrane Library. Review articles and conference proceedings were also searched to identify additional studies.

Selection criteria: Studies were accepted for analysis if they were randomized controlled trials with a minimum treatment duration of six months. Studies of oral 5-ASA therapy for treatment of patients with quiescent ulcerative colitis compared with placebo, SASP or other 5-ASA formulations were considered for inclusion. Studies that compared once daily 5-ASA treatment with conventional dosing of 5-ASA and 5-ASA dose ranging studies were also considered for inclusion.

Data collection and analysis: The primary outcome was the failure to maintain clinical or endoscopic remission. Secondary outcomes included adherence, adverse events, withdrawals due to adverse events, and withdrawals or exclusions after entry. Trials were separated into five comparison groups: 5-ASA versus placebo, 5-ASA versus sulfasalazine, once daily dosing versus conventional dosing, 5-ASA versus comparator 5-ASA formulation, and 5-ASA dose-ranging. Placebo-controlled trials were subgrouped by dosage. Once daily versus conventional dosing studies were subgrouped by formulation. 5-ASA-controlled trials were subgrouped by common 5-ASA comparators (e.g. Asacol and Salofalk). Dose-ranging studies were subgrouped by 5-ASA formulation. We calculated the risk ratio (RR) and 95% confidence intervals (95% CI) for each outcome. Data were analyzed on an intention-to-treat basis.

Main results: Forty-one studies (8928 patients) were included. The majority of included studies were rated as low risk of bias. Ten studies were rated at high risk of bias. Seven of these studies were single-blind and three studies were open-label. However, two open-label studies and four of the single-blind studies utilized investigator performed endoscopy as an endpoint, which may protect against bias. 5-ASA was significantly superior to placebo for maintenance of clinical or endoscopic remission. Forty-one per cent of 5-ASA patients relapsed compared to 58% of placebo patients (7 studies, 1298 patients; RR 0.69, 95% CI 0.62 to 0.77). There was a trend towards greater efficacy with higher doses of 5-ASA with a statistically significant benefit for the 1 to 1.9 g/day (RR 0.65; 95% CI 0.56 to 0.76) and the > 2 g/day subgroups (RR 0.73, 95% CI 0.60 to 0.89). SASP was significantly superior to 5-ASA for maintenance of remission. Forty-eight per cent of 5-ASA patients relapsed compared to 43% of SASP patients (12 studies, 1655 patients; RR 1.14, 95% CI 1.03 to 1.27). A GRADE analysis indicated that the overall quality of the evidence for the primary outcome for the placebo and SASP-controlled studies was high. No statistically significant differences in efficacy or adherence were found between once daily and conventionally dosed 5-ASA. Twenty-nine per cent of once daily patients relapsed over 12 months compared to 31% of conventionally dosed patients (8 studies, 3127 patients; RR 0.91, 95% CI 0.82 to 1.01). Eleven per cent of patients in the once daily group failed to adhere to their medication regimen compared to 9% of patients in the conventional dosing group (6 studies, 1462 patients; RR 1.22, 95% CI 0.91 to 1.64). There does not appear to be any difference in efficacy among the various 5-ASA formulations. Forty-four per cent of patients in the 5-ASA group relapsed compared to 41% of patients in the 5-ASA comparator group (6 studies, 707 patients; RR 1.08, 95% CI 0.91 to 1.28). A pooled analysis of two studies showed no statistically significant difference in efficacy between Balsalazide 6 g and 3 g/day. Twenty-three per cent of patients in the 6 g/day group relapsed compared to 33% of patients in the 3 g/day group (216 patients; RR 0.76; 95% CI 0.45 to 2.79). One study found Balsalazide 4 g to be superior to 2 g/day. Thirty-seven per cent of patients in the 4 g/day Balsalazide group relapsed compared to 55% of patients in the 2 g/day group (133 patients; RR 0.66; 95% CI 0.45 to 0.97). One study found a statistically significant difference between Salofalk granules 3 g and 1.5 g/day. Twenty-five per cent of patients in the Salofalk 3 g/day group relapsed compared to 39% of patients in the 1.5 g/day group (429 patients; RR 0.65; 95% CI 0.49 to 0.86). Common adverse events included flatulence, abdominal pain, nausea, diarrhea, headache, dyspepsia, and nasopharyngitis. There were no statistically significant differences in the incidence of adverse events between 5-ASA and placebo, 5-ASA and SASP, once daily and conventionally dosed 5-ASA, 5-ASA and comparator 5-ASA formulations and 5-ASA dose ranging studies. The trials that compared 5-ASA and SASP may have been biased in favour of SASP because most trials enrolled patients known to be tolerant to SASP which may have minimized SASP-related adverse events.

Authors' conclusions: 5-ASA was superior to placebo for maintenance therapy in ulcerative colitis. However, 5-ASA had a statistically significant therapeutic inferiority relative to SASP. Oral 5-ASA administered once daily is as effective and safe as conventional dosing for maintenance of remission in quiescent ulcerative colitis. There does not appear to be any difference in efficacy or safety between the various formulations of 5-ASA. Patients with extensive ulcerative colitis or with frequent relapses may benefit from a higher dose of maintenance therapy. High dose therapy appears to be as safe as low dose and is not associated with a higher incidence of adverse events.

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Conflict of interest statement

Yongjun Wang: None known

Claire E Parker: None known

Brian G Feagan has received fees from Abbott/AbbVie, Amgen, Astra Zeneca, Avaxia Biologics Inc., Bristol‐Myers Squibb, Celgene, Centocor Inc., Elan/Biogen, Ferring, JnJ/Janssen, Merck, Nestles, Novartis, Novonordisk, Pfizer, Prometheus Laboratories, Protagonist, Salix Pharma, Takeda, Teva, TiGenix, Tillotts Pharma AG and UCB Pharma for Scientific Advisory Board membership; fees from Abbott/AbbVie, Actogenix, Akros, Albireo Pharma, Amgen, Astra Zeneca, Avaxia Biologics Inc., Avir Pharma, Axcan, Baxter Healthcare Corp., Biogen Idec, Boehringer‐Ingelheim, Bristol‐Myers Squibb, Calypso Biotech, Celgene, Elan/Biogen, EnGene, Ferring Pharma, Roche/Genentech, GiCare Pharma, Gilead, Given Imaging Inc., GSK, Ironwood Pharma, Janssen Biotech (Centocor), JnJ/Janssen, Kyowa Kakko Kirin Co Ltd., Lexicon, Lilly, Lycera BioTech, Merck, Mesoblast Pharma, Millennium, Nektar, Nestles, Novonordisk, Pfizer, Prometheus Therapeutics and Diagnostics, Protagonist, Receptos, Salix Pharma, Serono, Shire, Sigmoid Pharma, Synergy Pharma Inc., Takeda, Teva Pharma, TiGenix, Tillotts, UCB Pharma, Vertex Pharma, VHsquared Ltd., Warner‐Chilcott, Wyeth, Zealand, and Zyngenia for consultancy; payment for lectures from Abbott/AbbVie, JnJ/Janssen, Takeda, Warner‐Chilcott, UCB Pharma; his institution has received grants/grants pending from Abbott/AbbVie, Amgen, Astra Zeneca, Bristol‐Myers Squibb (BMS), Janssen Biotech (Centocor), JnJ/Janssen, Roche/Genentech, Millennium, Pfizer, Receptos, Santarus, Sanofi, Tillotts, and UCB Pharma

John K MacDonald: None known

Figures

1
1
Study flow diagram.
2
2
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
1.1
1.1. Analysis
Comparison 1 5‐ASA versus placebo, Outcome 1 Failure to Maintain Clinical or Endoscopic Remission.
1.2
1.2. Analysis
Comparison 1 5‐ASA versus placebo, Outcome 2 Development of Any Adverse Event.
1.3
1.3. Analysis
Comparison 1 5‐ASA versus placebo, Outcome 3 Development of Any Adverse Event (Sensitivity analysis).
1.4
1.4. Analysis
Comparison 1 5‐ASA versus placebo, Outcome 4 Withdrawal from Study due to Adverse Event.
1.5
1.5. Analysis
Comparison 1 5‐ASA versus placebo, Outcome 5 Withdrawal from Study due to Adverse Event (Sensitivity analysis).
1.6
1.6. Analysis
Comparison 1 5‐ASA versus placebo, Outcome 6 Exclusion/Withdrawal after Entry (not due to relapse).
2.1
2.1. Analysis
Comparison 2 5‐ASA versus sulfasalazine, Outcome 1 Failure to Maintain Clinical or Endoscopic Remission.
2.2
2.2. Analysis
Comparison 2 5‐ASA versus sulfasalazine, Outcome 2 Failure to Maintain Remission (trials without olsalazine).
2.3
2.3. Analysis
Comparison 2 5‐ASA versus sulfasalazine, Outcome 3 Development of Any Adverse Event.
2.4
2.4. Analysis
Comparison 2 5‐ASA versus sulfasalazine, Outcome 4 Withdrawal from Study due to Adverse Event.
2.5
2.5. Analysis
Comparison 2 5‐ASA versus sulfasalazine, Outcome 5 Exclusion/Withdrawal after Entry (not due to relapse).
3.1
3.1. Analysis
Comparison 3 Once daily versus conventional dosing, Outcome 1 Failure to Maintain Clinical or Endoscopic Remission at 6 months.
3.2
3.2. Analysis
Comparison 3 Once daily versus conventional dosing, Outcome 2 Failure to Maintain Clinical or Endoscopic Remission at 12 months.
3.3
3.3. Analysis
Comparison 3 Once daily versus conventional dosing, Outcome 3 Failure to adhere to study medication regimen at study endpoint.
3.4
3.4. Analysis
Comparison 3 Once daily versus conventional dosing, Outcome 4 Failure to adhere to study medication regimen (Sensitivity analysis ‐ excluding outliers).
3.5
3.5. Analysis
Comparison 3 Once daily versus conventional dosing, Outcome 5 Development of Any Adverse Event.
3.6
3.6. Analysis
Comparison 3 Once daily versus conventional dosing, Outcome 6 Withdrawal due to adverse event.
3.7
3.7. Analysis
Comparison 3 Once daily versus conventional dosing, Outcome 7 Exclusion/Withdrawal after Entry (not due to relapse).
4.1
4.1. Analysis
Comparison 4 5‐ASA versus comparator 5‐ASA, Outcome 1 Failure to Maintain Clinical or Endoscopic Remission at 12 months.
4.2
4.2. Analysis
Comparison 4 5‐ASA versus comparator 5‐ASA, Outcome 2 Development of Any Adverse Event.
4.3
4.3. Analysis
Comparison 4 5‐ASA versus comparator 5‐ASA, Outcome 3 Withdrawal from Study due to Adverse Event.
4.4
4.4. Analysis
Comparison 4 5‐ASA versus comparator 5‐ASA, Outcome 4 Exclusion/Withdrawal after Entry (not due to relapse).
5.1
5.1. Analysis
Comparison 5 5‐ASA (dose ranging), Outcome 1 Failure to Maintain Clinical or Endoscopic Remission.
5.2
5.2. Analysis
Comparison 5 5‐ASA (dose ranging), Outcome 2 Development of Any Adverse Event.
5.3
5.3. Analysis
Comparison 5 5‐ASA (dose ranging), Outcome 3 Withdrawal from Study due to Adverse Event.
5.4
5.4. Analysis
Comparison 5 5‐ASA (dose ranging), Outcome 4 Exculsion/Withdrawal after Entry (not due to relapse).
See this image and copyright information in PMC

Update of

References

References to studies included in this review

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Pica 2012 {published data only}
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Prantera 2009 {published data only}
    1. Kohn A, Prantera C, Caprilli R, Campieri M, Cottone M, Pallone F, et al. Maintenance treatment of ulcerative colitis with 5‐aminosalicylic acid (5‐ASA): results from the Italian population of a one year, randomized, multinational study comparing MMx® with Asacol®. Gastroenterology 2009;136(5 Suppl 1):390.
    1. Prantera C, Kohn A, Campieri M, Caprilli R, Cottone M, Pallone F, et al. Clinical trial: ulcerative colitis maintenance treatment with 5‐ASA: a 1‐year, randomized multicentre study comparing MMX with Asacol. Alimentary Pharmacology and Therapeutics 2009;30(9):908‐18. - PubMed
Rijk 1992 {published data only}
    1. Rijk MCM, Lier HJJ, Tongerson JHM. Relapse‐preventing effect and safety of sulfasalazine and olsalazine in patients with ulcerative colitis in remission: prospective, double‐blind, randomized multicenter study. American Journal of Gastroenterology 1992;87:438‐42. - PubMed
    1. Rijk MCM, Tongersen JHM. The relapse preventing effect and safety of sulphasalazine and olsalazine in patients with ulcerative colitis in remission. Gastroenterology 1991;100(5 Part 2):A243.
Riley 1988 {published data only}
    1. Riley SA, Mani V, Goodman MJ, Herd ME, Dutt S, Turnberg LA. Comparison of delayed‐release 5‐aminosalicylic acid (mesalazine) and sulfasalazine as maintenance treatment for patients with ulcerative colitis. Gastroenterology 1988;94:1383‐9. - PubMed
    1. Riley SA, Mani V, Goodman MJ, Turnberg LA. A comparison of delayed‐release 5‐ASA and sulfasalazine as maintenance treatment in ulcerative colitis [abstract]. Gastroenterology 1987;92:A1596. - PubMed
    1. Riley SA, Mani V, Goodman MJ, Turnberg LA. A comparison of delayed‐release 5‐aminosalicylic acid (5‐ASA) and sulfasalazine (SSZ) as maintenance treatment of ulcerative colitis (UC) [abstract]. Gut 1987;28:1390.
Rutgeerts 1989 {published data only}
    1. Rutgeerts P. Comparative efficacy of coated, oral 5‐aminosalicylic acid (Claversal) and sulphasalazine for maintaining remission of ulcerative colitis. Alimentary Pharmacology and Therapeutics 1989;3:183‐91. - PubMed
Sandberg‐Gertzen 1986 {published data only}
    1. Jarnerot G, Sandberg‐Gertzen H. Azodisal sodium, (ADS), Dipentum, as relapse prevention in ulcerative colitis (UC). a double‐blind placebo controlled study. Gastroenterology 1985;88(5 Part 2):A1432.
    1. Sandberg‐Gertzen H, Jarnerot G, Kraaz W. Azodisal sodium in the treatment of ulcerative colitis: a study of tolerance and relapse prevention properties. Gastroenterology 1986;90:1024‐30. - PubMed
Sandborn 2010 {published data only}
    1. Sandborn W, Kane S, Korzenik J, Lashner B, Leighton J, Mahadevan U, et al. Once daily dosing of delayed‐release oral mesalamine for maintenance of remission of ulcerative colitis (the QDIEM trial): 6 and 12 month results. Inflammatory Bowel Diseases 2009;15:S15.
    1. Sandborn WJ, Korzenik J, Lashner B, Leighton JA, Mahadevan U, Marion JF, et al. Once‐daily dosing of delayed‐release oral mesalamine (400‐mg tablet) is as effective as twice‐daily dosing for maintenance of remission of ulcerative colitis. Gastroenterology 2010;138(4):1286‐96. - PubMed
Travis 1994 {published data only}
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Watanabe 2013 {published data only}
    1. Watanabe M, Hanai H, Nishino H, Yokoyama T, Terada T, Suzuki Y. Comparison of QD and TID oral mesalazine for maintenance of remission in quiescent ulcerative colitis: a double‐blind, double‐dummy, randomized multicenter study. Inflammatory Bowel Diseases 2013;19(8):1681‐90. - PubMed
Wright 1993 {published data only}
    1. Wright JP, O'Keefe EA, Cuming L, Jaskiewicz K. Olsalazine in maintenance of clinical remission in patients with ulcerative colitis. Digestive Diseases and Sciences 1993;38:1837‐42. - PubMed
    1. Wright JP, O'Keefe EA, Cuming L, Jaskiewicz K. Olsalazine in the maintenance of remission in patients with ulcerative colitis [abstract]. Gastroenterology 1992;102:A714. - PubMed

References to studies excluded from this review

Bardazzi 1994 {published data only}
    1. Bardazzi G, d'Albasio G, Bonanomi AG, Trallori G, Messori A, Amorosi A, et al. Intermittent versus continuous 5‐aminosalicylic acid treatment for maintaining remission in ulcerative colitis. Italian Journal of Gastroenterology 1994;26(7):334‐7. - PubMed
d'Albasio 1997 {published data only}
    1. d'Albasio G, Pacini F, Camarri E, Messori A, Trallori G, Bonanomi AG, et al. Combined therapy with 5‐aminosalicylic acid tablets and enemas for maintaining remission in ulcerative colitis: a randomized double‐blind study. American Journal of Gastroenterology 1997;92(7):1143‐7. - PubMed
Dew 1982b {published data only}
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Eliakim 1990 {published data only}
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Ewe 1996 {published data only}
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Fernández‐Bañares 1999 {published data only}
    1. Fernández‐Bañares F, Hinojosa J, Sánchez‐Lombraña JL, Navarro E, Martínez‐Salmerón JF, García‐Pugés A, et al. Randomized clinical trial of Plantago ovata seeds (dietary fiber) as compared with mesalamine in maintaining remission in ulcerative colitis. Spanish Group for the Study of Crohn's Disease and Ulcerative Colitis (GETECCU). American Journal of Gastroenterology 1999;94(2):427‐33. - PubMed
Frieri 2005 {published data only}
    1. Frieri G, Pimpo M, Galletti B, Palumbo G, Corrao G, Latella G, et al. Long‐term oral plus topical mesalazine in frequently relapsing ulcerative colitis. Digestive and Liver Disease 2005;37(2):92‐6. - PubMed
Giaffer 1992b {published data only}
    1. Giaffer MH, O'Brien CJ, Holdsworth CD. Clinical tolerance to three 5‐aminosalicylic acid releasing preparations in patients with inflammatory bowel disease intolerant or allergic to sulphasalazine. Alimentary Pharmacology and Therapeutics 1992;6(1):51‐9. - PubMed
Gionchetti 1990 {published data only}
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Gionchetti 1996 {published data only}
    1. Gionchetti P, Campieri M, Venturi A, Rizzello F, Ferretti M, Brignola C, et al. Systemic availability of 5‐aminosalicylic acid: comparison of delayed release and an azo‐bond preparation. Alimentary Pharmacology and Therapeutics 1996;10(4):601‐5. - PubMed
Green 2004 {published data only}
    1. Green JR, Swan CH, Gibson JA, Kerr GD, Swarbrick ET, Thornton PC. Patient‐led variable dosing with balsalazide as long‐term therapy for maintenance in ulcerative colitis: a 3‐year prospective observational study. Alimentary Pharmacology and Therapeutics 2004;19(4):435‐42. - PubMed
Hanauer 2009 {published data only}
    1. Hanauer SB, Lichtenstein GR, Kamm MA, Sandborn WJ, Lees KH, Barrett K, et al. MMX mesalamine for induction and maintenance therapy in mild‐to‐moderate ulcerative colitis. Gastroenterology and Hepatology 2009;5(7):494‐500. - PMC - PubMed
Karamanolis 1996 {published data only}
    1. Karamanolis DG, Papatheodoridis GV, Xourgias V. Systemic absorption of 5‐aminosalicylic acid in patients with inactive ulcerative colitis treated with olsalazine and mesalazine. European Journal of Gastroenterology and Hepatology 1996;8(11):1083‐8. - PubMed
Kruis 1997 {published data only}
    1. Kruis W, Schütz E, Fric P, Fixa B, Judmaier G, Stolte M. Double‐blind comparison of an oral Escherichia coli preparation and mesalazine in maintaining remission of ulcerative colitis. Alimentary Pharmacology and Therapeutics 1997;11(5):853‐8. - PubMed
Kruis 2004 {published data only}
    1. Kruis W, Fric P, Pokrotnieks J, Lukas M, Fixa B, Kascak M, et al. Maintaining remission of ulcerative colitis with the probiotic Esherichia coli Nissle 1917 is as effective as with standard mesalazine. Gut 2004;53(11):1617‐23. - PMC - PubMed
Mani 1994 {published data only}
    1. Mani V, Gotch P. Comparison of pharmacokinetics and colonic transit time in quiescent ulcerative colitis on mesalazine and olsalazine ‐ A cross over study [abstract]. Gut 1994;35(Suppl 4):A124.
Mantzaris 2004 {published data only}
    1. Mantzaris GJ, Sfakianakis M, Archavlis E, Petraki K, Christidou A, Karagiannidis A, et al. A prospective randomized observer‐blind 2‐year trial of azathioprine monotherapy versus azathioprine and olsalazine for the maintenance of remission of steroid‐dependent ulcerative colitis. American Journal of Gastroenterology 2004;99(6):1122‐8. - PubMed
Odes 1997 {published data only}
    1. Odes HS. 5‐Aminosalicylic acid, 1,000‐mg caplets versus 500‐mg tablets, in maintenance of remission in ulcerative colitis. Journal of Clinical Gastroenterology 1997;24(4):287‐8. - PubMed
Osterman 2014 {published data only}
    1. Osterman MT, Aberra F, Cross R, Liakos S, McCabe RP, Shafran I, et al. A randomized controlled trial of mesalamine dose escalation for ulcerative colitis in remission. Gastroenterology 2014;146(5 Suppl 1):S149. - PMC - PubMed
Paoluzi 2002 {published data only}
    1. Paoluzi P, D'Albasio G, Pera A, Bianchi Porro G, Paoluzi OA, Pica R, et al. Oral and topical 5‐aminosalicylic acid (mesalazine) in inducing and maintaining remission in mild‐moderate relapse of ulcerative colitis: one‐year randomised multicentre trial. Digestive and Liver Disease 2002;34(11):787‐93. - PubMed
Papatheodoridis 1995 {published data only}
    1. Papatheodoridis GV, Xourgias V, Sdonas T, Triantoafyllou M, Tzouvaia M, Karamanolis DG. Systematic load of 5‐ASA in patients with inactive ulcerative colitis treated with olsalazine and mesalazine [abstract]. Gut 1995;37(Suppl 2 Pt 2):A54.
Pelech 1998 {published data only}
    1. Pelech T, Fric P, Fixa B, Komarkova O. Comparison of Mutaflor and mesalazine in the maintenance treatment of inactive ulcerative colitis. Prakticky Lekar 1998;78(10):556‐8.
Staerk Laursen 1990 {published data only}
    1. Staerk Laursen L, Stokholm M, Bukhave K, Rask‐Madsen J, Lauritsen K. Disposition of 5‐aminosalicylic acid by olsalazine and three mesalazine preparations in patients with ulcerative colitis: Comparison of intraluminal colonic concentrations, serum values, and urinary excretion. Gut 1990;31:1271‐6. - PMC - PubMed
Stoa‐Birketvedt 1999 {published data only}
    1. Florholmen J. The systemic load and efficient delivery of active 5‐ASA in patients with ulcerative colitis on treatment with Dipentum (Olsalazine) and Mesasael (Mesalazine) [abstract]. Gut 1994;35(Suppl 4):A121. - PubMed
    1. Stoa‐Birketvedt G, Florholmen J. The systemic load and efficient delivery of active 5‐aminosalicylic acid in patients with ulcerative colitis on treatment with olsalazine or mesalazine. Alimentary Pharmacology and Therapeutics 1999;13:357‐61. - PubMed
Tragnone 1996 {published data only}
    1. Tragnone A, Elmi G, Tagliente C, Bazzocchi G, Dina R, Euseb V, et al. Oral 5‐aminosalicylic acid therapy for the prevention of relapse in patients with ulcerative colitis (UC) during remission: a new therapeutical approach by using 5‐ASA tablets 800 mg. A multicenter controlled randomized trial [abstract]. Gastroenterology 1996;110:A1030.
Tzivras 1997 {published data only}
    1. Archimandritis A, Hatzis G, Konstandinidis A, Paraskeva K, Tjivras M, Skandalis N. Disposition of 5‐ASA by olsalazine (Dipentum) and mesalazine (Asacol) in patients with ulcerative colitis in remission [abstract]. Gut 1996;39(Suppl 3):A75.
    1. Tzivras M, Konstandinidis A, Hatzis G, Paraskeva K, Skandalis N, Archimandritis A. Systemic absorption of 5‐aminosalicylic acid in patients with inactive ulcerative colitis treated with olsalazine and mesalazine. European Journal of Gastroenterology and Hepatology 1997;9(7):729‐30. - PubMed
Yokoyama 2007 {published data only}
    1. Yokoyama H, Takagi S, Kuriyama S, Takahashi S, Takahashi H, Iwabuchi M, et al. Effect of weekend 5‐aminosalicylic acid (mesalazine) enema as maintenance therapy for ulcerative colitis: results from a randomized controlled study. Inflammatory Bowel Diseases 2007;13(9):1115‐20. - PubMed
Zocco 2006 {published data only}
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References to other published versions of this review

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