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Ultra-high dose of mesalamine to treat steroid-dependent ulcerative colitis
Journal of Crohn's and Colitis (2014) 8, 1745–1746
Available online at www.sciencedirect.com
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LETTER TO THE EDITOR Ultra-high dose of mesalamine to treat steroid-dependent ulcerative colitis
To the Editor:
To the best of our knowledge, the use of ultra-high doses of mesalamine to treat ulcerative colitis (UC) has not been previously reported. We are reporting a UC patient whose treatment with an ultra-high dose of mesalamine resulted in the ability to eliminate steroid-dependence. A 25 year old male presented in another city with bloody diarrhea, and was diagnosed with ulcerative pan-colitis. He was initially treated with a cortico-steroid and mesalamine (Salofalk, Mesalamine Delayed Release Tablets USP, Aptalis Pharma Canada Inc.) 4.0 g/day. Because of steroid dependency, azathioprin was added. After being steroid-dependent for 6 months on triple therapy (prednisone 20–30 mg/day, mesalamine 4 g/day, and azathioprine 150 mg/day), he was advised to start anti-TNF therapy. He declined, and sought another opinion. The second gastroenterologist switched him from Salofalk tablets to mesalamin (MezavantR, 1.2 g Delayed-and Extended-Release Tablets, Shire Canada Inc.). The patient assumed that the dosing regimen was the same, and took 4.8 g BID. Soon after the 5-ASA therapy was increased to the ultra-high dose of 9.6 g/day, he was able to taper and stop prednisone for the first time since his diagnosis, and remain in clinical remission. At that time he moved to Toronto, and was referred to us for ongoing management. When we first encountered the patient, he had been on the ultra-high dose of 5-ASA for 6 months. We did not observe any adverse effects of this ultra-high dose of mesalamine. He was tolerating the ultra-high dose of mesalamine very well, and his urinalysis, complete blood count, liver and kidney profiles were all within the normal range. Thiopurine metabolite levels were therapeutic. While some studies have shown that higher doses of delayed-release mesalamine produced greater mucosal healing and faster colitis improvement versus lower doses 1, other trials have not shown the same results for doses ranging from 1.6 to 4.8 g 2. It has been shown that standard high oral doses of 5-ASA (from 2.4 to 4.8 g/day) can be effective in reducing or eliminating
steroids in up to 50% of patients with steroid-dependent UC 3. Studies have shown that the colonic mucosal concentrations of 5-ASA are significantly higher in patients receiving combined oral and topical formulations compared to oral therapy alone, and that there is an inverse relationship between mucosal concentrations of 5-ASA and colitis disease activity, as measured by histological or endoscopic evaluations 4. We believe that an ultra-high dose of mesalamine should result in higher colonic mucosal concentrations of 5-ASA, hence a greater chance of effective disease control. Since mesalamine has not been reported to have dose-related side effects 5, one might anticipate that other patients would be able to tolerate ultra-high doses of mesalamine. In conclusion, using higher than recommended doses of mesalamine may have an important role in achieving clinical remission in selected ulcerative colitis patients. Further clinical studies are needed to examine the potential benefits and risks of an ultra-high dose of mesalamine in UC patients.
Grant support Nil.
Conflict of interest No conflict of interest for any of the authors.
Specific authors' contributions Conception and design: Fred Saibil, Soleiman B Kashkooli; acquisition of data, initial drafting: Soleiman B Kashkooli, Mehrdad Rouhani; preparation of the final transcript: Soleiman B Kashkooli; critical revision of the transcript and supervision: Fred Saibil. All authors read and approved the final version of the transcript.
References 1. Lichtenstein GR, Ramsey D, Rubin DT. Randomised clinical trial: delayed-release oral Mesalazine 4.8 g/day vs. 2.4 g/day in endoscopic mucosal healing — ASCEND I and II combined analysis. Aliment Pharmacol Ther 2011;33:672–8.
http://dx.doi.org/10.1016/j.crohns.2014.08.007 1873-9946/Crown Copyright © 2014 Published by Elsevier B.V. on behalf of European Crohn's and Colitis Organisation. All rights reserved.
1746 2. Hanauer S, Sandborn W, Kornbluth A, et al. Delayed-release oral mesalamine at 4.8 g/day (800 mg tablet) for the treatment of moderately active ulcerative colitis: the ASCEND II trial. Am J Gastroenterol 2005;100:2478–85. 3. Tremaine WJ, Schroeder KW, Ilstrup DM. The corticosteroid-sparing effect of oral 5-aminosalycilic acid for chronic ulcerative coltis. Gastroenetrology 1987:92A1673. 4. D'Incà R, Paccagnella M, Cardin R, et al. 5-ASA colonic mucosal concentrations resulting from different pharmaceutical formulations in ulcerative colitis. World J Gastroenterol 2013 September 14;19(34):5665–70. 5. Brimblecombe R. Mesalazine: a global safety evaluation. Scand J Gastroenterol Suppl 1990;172:66.
LETTER TO THE EDITOR Soleiman B. Kashkooli Mehrdad Rouhani Fred Saibil* Division of Gastroenterology, Sunnybrook Health Sciences Centre, Department of Medicine, University of Toronto, Toronto, Canada ⁎Corresponding author at: Division of Gastroenterology, Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, Room HG-52, Toronto, Ontario M4N 3M5, Canada. Tel.: +1 416 480 4727; fax: +1 416 480 5977. E-mail address: [email protected] (F. Saibil). 10 August 2014
Available online at www.sciencedirect.com
ScienceDirect
LETTER TO THE EDITOR Ultra-high dose of mesalamine to treat steroid-dependent ulcerative colitis
To the Editor:
To the best of our knowledge, the use of ultra-high doses of mesalamine to treat ulcerative colitis (UC) has not been previously reported. We are reporting a UC patient whose treatment with an ultra-high dose of mesalamine resulted in the ability to eliminate steroid-dependence. A 25 year old male presented in another city with bloody diarrhea, and was diagnosed with ulcerative pan-colitis. He was initially treated with a cortico-steroid and mesalamine (Salofalk, Mesalamine Delayed Release Tablets USP, Aptalis Pharma Canada Inc.) 4.0 g/day. Because of steroid dependency, azathioprin was added. After being steroid-dependent for 6 months on triple therapy (prednisone 20–30 mg/day, mesalamine 4 g/day, and azathioprine 150 mg/day), he was advised to start anti-TNF therapy. He declined, and sought another opinion. The second gastroenterologist switched him from Salofalk tablets to mesalamin (MezavantR, 1.2 g Delayed-and Extended-Release Tablets, Shire Canada Inc.). The patient assumed that the dosing regimen was the same, and took 4.8 g BID. Soon after the 5-ASA therapy was increased to the ultra-high dose of 9.6 g/day, he was able to taper and stop prednisone for the first time since his diagnosis, and remain in clinical remission. At that time he moved to Toronto, and was referred to us for ongoing management. When we first encountered the patient, he had been on the ultra-high dose of 5-ASA for 6 months. We did not observe any adverse effects of this ultra-high dose of mesalamine. He was tolerating the ultra-high dose of mesalamine very well, and his urinalysis, complete blood count, liver and kidney profiles were all within the normal range. Thiopurine metabolite levels were therapeutic. While some studies have shown that higher doses of delayed-release mesalamine produced greater mucosal healing and faster colitis improvement versus lower doses 1, other trials have not shown the same results for doses ranging from 1.6 to 4.8 g 2. It has been shown that standard high oral doses of 5-ASA (from 2.4 to 4.8 g/day) can be effective in reducing or eliminating
steroids in up to 50% of patients with steroid-dependent UC 3. Studies have shown that the colonic mucosal concentrations of 5-ASA are significantly higher in patients receiving combined oral and topical formulations compared to oral therapy alone, and that there is an inverse relationship between mucosal concentrations of 5-ASA and colitis disease activity, as measured by histological or endoscopic evaluations 4. We believe that an ultra-high dose of mesalamine should result in higher colonic mucosal concentrations of 5-ASA, hence a greater chance of effective disease control. Since mesalamine has not been reported to have dose-related side effects 5, one might anticipate that other patients would be able to tolerate ultra-high doses of mesalamine. In conclusion, using higher than recommended doses of mesalamine may have an important role in achieving clinical remission in selected ulcerative colitis patients. Further clinical studies are needed to examine the potential benefits and risks of an ultra-high dose of mesalamine in UC patients.
Grant support Nil.
Conflict of interest No conflict of interest for any of the authors.
Specific authors' contributions Conception and design: Fred Saibil, Soleiman B Kashkooli; acquisition of data, initial drafting: Soleiman B Kashkooli, Mehrdad Rouhani; preparation of the final transcript: Soleiman B Kashkooli; critical revision of the transcript and supervision: Fred Saibil. All authors read and approved the final version of the transcript.
References 1. Lichtenstein GR, Ramsey D, Rubin DT. Randomised clinical trial: delayed-release oral Mesalazine 4.8 g/day vs. 2.4 g/day in endoscopic mucosal healing — ASCEND I and II combined analysis. Aliment Pharmacol Ther 2011;33:672–8.
http://dx.doi.org/10.1016/j.crohns.2014.08.007 1873-9946/Crown Copyright © 2014 Published by Elsevier B.V. on behalf of European Crohn's and Colitis Organisation. All rights reserved.
1746 2. Hanauer S, Sandborn W, Kornbluth A, et al. Delayed-release oral mesalamine at 4.8 g/day (800 mg tablet) for the treatment of moderately active ulcerative colitis: the ASCEND II trial. Am J Gastroenterol 2005;100:2478–85. 3. Tremaine WJ, Schroeder KW, Ilstrup DM. The corticosteroid-sparing effect of oral 5-aminosalycilic acid for chronic ulcerative coltis. Gastroenetrology 1987:92A1673. 4. D'Incà R, Paccagnella M, Cardin R, et al. 5-ASA colonic mucosal concentrations resulting from different pharmaceutical formulations in ulcerative colitis. World J Gastroenterol 2013 September 14;19(34):5665–70. 5. Brimblecombe R. Mesalazine: a global safety evaluation. Scand J Gastroenterol Suppl 1990;172:66.
LETTER TO THE EDITOR Soleiman B. Kashkooli Mehrdad Rouhani Fred Saibil* Division of Gastroenterology, Sunnybrook Health Sciences Centre, Department of Medicine, University of Toronto, Toronto, Canada ⁎Corresponding author at: Division of Gastroenterology, Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, Room HG-52, Toronto, Ontario M4N 3M5, Canada. Tel.: +1 416 480 4727; fax: +1 416 480 5977. E-mail address: [email protected] (F. Saibil). 10 August 2014