Abstract
Purpose
The cytotoxic and immunosuppressive effects of azathioprine, which mitigate the disease activity in inflammatory bowel disease, may compromise the healing of intestinal anastomoses leading to an increased risk of anastomotic leakage. The effect of azathioprine treatment on intestinal healing was tested.
Methods
In an experimental study, rats were randomly given one oral dose of azathioprine (5 mg or 20 mg/kg body weight per day) or placebo. After 28 days of treatment, a left colonic anastomosis was performed. After three days of healing, the breaking strengths of the anastomoses were tested, along with measurements of azathioprine major metabolite concentrations: 6-thioguanine and 6-methyl-mercaptopurine.
Results
There were no significant differences in the anastomotic breaking strength between the three groups.
Conclusions
Daily treatment for four weeks with high or low azathioprine doses has no inhibitory effect on colonic healing in rats.
Similar content being viewed by others
References
Pearson DC, May GR, Fick GH, Sutherland LR. Azathioprine and 6-mercaptopurine in Crohn’s disease. A meta-analysis. Ann Intern Med 1995;123:132–42.
Marion JF, Present DH. The modern medical management of acute, severe ulcerative colitis [review]. Eur J Gastroenterol Hepatol 1997;9:831–5.
Sandborn WJ. Azathioprine: state of the art in inflammatory bowel disease [review]. Scand J Gastroenterol Suppl 1998;225:92–9.
Lennard L. The clinical pharmacology of 6-mercaptopurine [review]. Eur J Clin Pharmacol 1992;43:329–39.
Dervieux T, Boulieu R. Simultaneous determination of 6-thioguanine and methyl 6-mercaptopurine nucleotides of azathioprine in red blood cells by HPLC. Clin Chem 1998;44:551–5.
George J, Present DH, Pou R. 6-Mercaptopurine for the treatment of ulcerative colitis. Am J Gastroenterol 1996;91:1711–4.
Mahadevan U, Loftus EV Jr, Tremaine WJ, et al. Azathioprine or 6-mercaptopurine before colectomy for ulcerative colitis is not associated with increased postoperative complications. Imflamm Bowel Dis 2002;8:311–6.
Belliveau P, Truel J, Vasilevsky CA, Stein B, Gordon PH. Ileoanal anastomosis with reservoirs: complications and long-term results. Can J Surg 1999;42:345–52.
Meagher AP, Farouk R, Dozois RR, Kelly KA, Pemberton JH. J ileal pouch-anal anastomosis for chronic ulcerative colitis: complications and long-term outcome in 1310 patients. Br J Surg 1998;85:800–3.
Hurst RD, Finco C, Rubin M, Michelassi F. Prospective analysis of preoperative morbidity in one hundred consecutive colectomies for ulcerative colitis. Surgery 1995;118:748–55.
Anonymous. Report of validation study of assessment of direct immunotoxicity in the rat. International Collaborative Immunotoxicity Study. The ICICIS Group Investigators. Toxicology 1998;125:183–201.
Pedersen BK, Beyer JM. A longitudinal study of the influence of azathioprine on natural killer cell activity. Allergy 1986;41:286–9.
Institoris L, Siroki O, Desi I, et al. Extension of the protocol of OECD guideline 407 (28-day repeated dose oral toxicity test in the rat) to detect potential immunotoxicity of chemicals. Hum Exp Toxicol 1998;17:206–11.
Hendriks T, Mastboom WJ. Healing of experimental intestinal anastomoses. Parameters for repair [review]. Dis Colon Rectum 1990;33:891–901.
Jonsson T, Hogstrom H. Neutrophil-dependent decrease in early wound margin strength. Arch Surg 1991;126:1423–6.
Christensen H, Chemnitz J, Christensen BC, Oxlund H. Collagen structure organization of healing colonic anastomoses and the effect of growth hormone treatment. Dis Colon Rectum 1995;38:1200–5.
Eisinger DR, Sheil AG. A comparison of the effects of cyclosporin A and standard agents on primary wound healing in the rat. Surg Gynecol Obstet 1985;160:135–8.
Lima O, Cooper JD, Peters WJ, et al. Effects of methylprednisolone and azathioprine on bronchial healing following lung autotransplantation. Thorac Cardiovasc Surg 1981;82:211–5.
Kiyama T, Onda M, Tokunaga A, Efron DT, Barbul A. Effect of matrix metalloproteinase inhibition on colonic anastomotic healing in rats. J Gastrointest Surg 2001;5:303–11.
Jiborn H. Healing of left colonic anastomoses. An experimental study in the rat [thesis]. Malmö: University of Lund, 1978.
Oxlund H, Christensen H, Seyer-Hansen M, Andreassen TT. Collagen deposition and mechanical strength of colon anastomoses and skin incisional wounds of rats. J Surg Res 1996;66:25–30.
Fielding LP, Steward-Brown S, Blesovsky L, Kearney G. Anastomotic integrity after operations for large bowel cancer: a multicenter study. Br Med J 1980;281:411–4.
Sandborn WJ, Tremaine WJ, Wolf DC, et al. Lack of effect of intravenous administration on time to respond to azathioprine for steroid-treated Crohn’s disease. North American Azathioprine Study Group. Gastroenterology 1999;117:527–35.
Dubinsky MC, Lamothe S, Yang HY, et al. Pharmacogenomics and metabolite measurement for 6-mercaptopurine therapy in inflammatory bowel disease. Gastroenterology 2000;118:705–13.
Belaiche J, Desager JP, Horsmans Y, Louis E. Therapeutic drug monitoring of azathioprine and 6-mercaptopurine metabolites in Crohn’s disease. Scand J Gastroenterol 2001;36:71–6.
Author information
Authors and Affiliations
Additional information
Supported by the Institute for Experimental Clinical Research at Århus University and The Danish Colitis-Crohn Association. The azathioprine compound was provided by GlaxoWellcome Research and Development.
About this article
Cite this article
Stolzenburg, T., Ljungmann, K. & Christensen, H. The Effect of Azathioprine on Anastomotic Healing: An Experimental Study in Rats. Dis Colon Rectum 50, 2203–2208 (2007). https://doi.org/10.1007/s10350-007-9010-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10350-007-9010-9