Abstract
Despite limited understanding of therapeutic aetiopathogenesis of ulcerative colitis and Crohn’s disease, there is a strong evidence base for the efficacy of pharmacological and biological therapies. It is equally important to recognise toxicity of the medical armamentarium for inflammatory bowel disease (IBD).
Sulfasalazine consists of sulfapyridine linked to 5-aminosalicylic acid (5-ASA) via an azo bond. Common adverse effects related to sulfapyridine ‘intolerance’ include headache, nausea, anorexia, and malaise. Other allergic or toxic adverse effects include fever, rash, haemolytic anaemia, hepatitis, pancreatitis, paradoxical worsening of colitis, and reversible sperm abnormalities.
The newer 5-ASA agents were developed to deliver the active ingredient of sulfasalazine while minimising adverse effects. Adverse effects are infrequent but may include nausea, dyspepsia and headache. Olsalazine may cause a secretory diarrhoea. Uncommon hypersensitivity reactions, including worsening of colitis, pancreatitis, pericarditis and nephritis, have also been reported.
Corticosteroids are commonly prescribed for treatment of moderate to severe IBD. Despite short term efficacy, corticosteroids have numerous adverse effects that preclude their long term use. Adverse effects include acne, fluid retention, fat redistribution, hypertension, hyperglycaemia, psycho-neurological disturbances, cataracts, adrenal suppression, growth failure in children, and osteonecrosis. Newer corticosteroid preparations offer potential for targeted therapy and less corticosteroid-related adverse effects.
Azathioprine and mercaptopurine are associated with pancreatitis in 3 to 15% of patients that resolves upon drug cessation. Bone marrow suppression is dose related and may be delayed.
The adverse effects of methotrexate include nausea, leucopenia and, rarely, hypersensitivity pneumonia or hepatic fibrosis. Common adverse effects of cyclosporin include nephrotoxicity, hypertension, headache, gingival hyperplasia, hyperkalaemia, paresthesias, and tremors. These adverse effects usually abate with dose reduction or cessation of therapy. Seizures and opportunistic infections have also been reported.
Antibacterials are commonly employed as primary therapy for Crohn’s disease. Common adverse effects of metronidazole include nausea and a metallic taste. Peripheral neuropathy can occur with prolonged administration. Ciprofloxacin and other antibacterials may be beneficial in those intolerant to metronidazole.
Newer immunosuppressive agents previously reserved for transplant recipients are under investigation for IBD. Tacrolimus has an adverse effect profile similar to cyclosporin, and may cause renal insufficiency. Mycophenolate mofetil, a purine synthesis inhibitor, has primarily gastrointestinal adverse effects.
Biological agents targeting specific sites in the immunoinflammatory cascade are now available to treat IBD. Infliximab, a chimeric antibody targeting tumour necrosis factor-α has been well tolerated in clinical trials and early postmarketing experience. Additional trials are needed to assess long term adverse effects.
Similar content being viewed by others
References
Schroder H, Campbell DES. Absorption, metabolism and excretion of salicylazosulfapyridine in man. Clin Pharm Ther 1972; 13: 359–1
Peppercorn MA. Sulfasalazine. Pharmacology, clinical use, toxicity and new drug development. Ann Int Med 1984; 101: 377–86
Greenfield SM, Punchard NA, Teare JP, et al. Review article: The mode of action of the aminosalicylates in inflammatory bowel disease. Aliment Pharmacol Ther 1993; 7: 369–83
Das KM, Eastwood MA. Acetylation polymorphism of sulfapyridine in patients with ulcerative colitis and Crohn’s disease. Clin Pharm Ther 1975; 18: 514–20
Ireland A, Priddle JD, Jewell DP. Acetylation of 5-aminosalicylic acid by isolated human colonic epithelial cells. Clin Science 1990; 78: 105–11
Klotz U. Clinical pharmacokinetics of sulphasalazine, its metabolites, and other prodrugs of 5-aminosalicylic acid. Clin Pharmacokinetics 1985; 10: 285–302
Azad-Khan AK, Piris J, Truelove SC. An experiment to determine the active therapeutic moiety of sulphasalazine. Lancet 1977; II: 892–5
Hanauer SB, Meyers S, Sachar DB. The pharmacology of anti-inflammatory drugs in inflammatory bowel disease. In: Kirsner JB, Shorter RG, editors. Inflammatory bowel disease. 4th ed. Baltimore (ML): Williams & Wilkins, 1995: 643–63
Sandberg-Gertzen H, Ryde M, Janerot G. Absorption, metabolism and excretion of a single 1gm dose of azodisal sodium in subjects with ileostomy. Scand J Gastroenterol 1983; 18: 107–111
McIntyre PB, Rodrigues CA, Leonard-Jones JE, et al. Balsalazide in the maintenance treatment of patients with ulcerative colitis, a double-blind comparison with sulphasalazine. Aliment Pharmacol Ther 1988; 2: 237–43
Rasmussen SN, Bondesen S, Hvidberg, et al. 5-Aminosalicylic acid in a slow-release preparation: Bioavailability, plasma level, and excretion in humans. Gastroenterology 1982; 83: 1062–70
Dew MJ, Ebden P, Kidwai NS, et al. Comparison of the absorption and metabolism of sulfasalazine and acrylic-coated 5-aminosalicylic acid in normal subjects and patients with ulcerative colitis. Br J Clin Pharmacol 1984; 17: 474–6
Hanauer SB, Stathopoulos G. Risk-benefit assessment of drugs used in treatment of inflammatory bowel disease. Drug Saf 1991; 6: 192–219
Laursen SL, Stokholm M, Bukhave K, et al. 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
Sutherland LR. Topical treatment of ulcerative colitis. Med Clin North Am 1990; 74: 119–31
Campieri M, Corbelli C, Gionchetti P, et al. Spread and distribution of 5-ASA colonic foam and 5-ASA enema in patients with ulcerative colitis. Dig Dis Sci 1992; 37: 1890–7
Gaginella TS, Walsh RE. Sulfasalazine: multiplicity of action. Dig Dis Sci 1992; 37: 801–12
Wahl C, Liptay S, Adler G, et al. Sulfasalazine: a potent and specific inhibitor of nuclear factor kappa B. J Clin Invest 1998; 101: 1163–74
Lauritsen K, Laursen S, Bukhave K, et al. Inflammatory intermediaries in inflammatory bowel disease. Int J Colorectal Dis 1989; 4: 75–90
Zimmerman MJ, Jewell DP. Cytokines and mechanisms of action of glucocorticoids and aminosalicylates in the treatment of ulcerative colitis and Crohn’s disease. Aliment Pharmacol Ther 1996; 10: 93–8
Bjarnason I, Hayllar J, MacPherson A, et al. Side effects of nonsteroidal anti-inflammatory drugs on the small and large intestine in humans. Gastroenterology 1993; 104: 1832–47
Rask-Madsen J, Burkhave K, Laursen LS, et al. 5-Lipoxygenase inhibitors for the treatment of inflammatory bowel disease. Agents Actions 1992; 37: 36–46
Grisham MB. Oxidants and free radicals in inflammatory bowel disease. Lancet 1994; 344: 859–61
Taffet SL, Das KM. Sulfasalazine: Adverse effects and desensitization. Dig Dis Sci 1983; 28: 833–42
Das KM, Eastwood MA, McManus JP, et al. Adverse reactions during salicylazosulfapyridine therapy and the relation with drug metabolism and acetylator phenotype. N Engl J Med: 1973; 289: 491–5
Nielsen OH. Sulfasalazine intolerance: a retrospective survey of the reasons for discontinuing treatment with sulfasalazine in patients with chronic inflammatory bowel disease. Scand J Gastroenterol 1982; 17: 389–93
Strom J. Toxic epidermal necrolysis (Lyell’s syndrome)-a report on four cases with three deaths. Scand J Infect Dis 1969; 1: 209–16
Griffiths MB, Kane MA. Sulphasalazine-induced lupus syndrome in ulcerative colitis. BMJ 1977; 2: 188–9
Reid J, Holt S, Housley E, et al. Raynaud’s phenomenon induced by sulphasalazine. Postgrad Med J 1980; 56: 106–7
Block MB, Genant HKI, Kirsner JB. Pancreatitis as an adverse reaction to salicylazosulfapyridine [letter]. N Engl J Med 1970; 282: 380
Hamadeh MA, Atkinson J, Smith LJ. Sulfasalazine-induced pulmonary disease [letter]. Chest 1992; 101: 1033
Jamshidi K, Arlander T, Garcia MC, et al. Azulfidine agranulocytosis with bone marrow megakaryocytosis, histiocytosis, plasmacytosis. Minn Med 1972; 55: 545–8
Davies G, Palek J. Selective erythroid and megakaryocytic aplasia after sulfasalazine administration [letter]. Arch Intern Med 1980; 140: 1122
Franklin JL, Rosenberg IH. Impaired folic acid absorption in inflammatory bowel disease: effects of salicylazosulfapyridine (azulfidine). Gastroenterology 1973; 64: 517–25
Schneider RE, Beeley L. Megaloblastic anemia associated with sulphasalazine treatment BMJ 1977; 1: 1638–9
Riley SA, Lecarpentier J, Mani V, et al. Sulphasalazine induced seminal abnormalities in ulcerative colitis: results of mesalazine substitution. Gut 1987; 28: 1008–12
Gaiffer 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. Aliment Pharm Ther 1992; 6: 51–9
Walker AM, Szneke P, Bianchi LA, et al. 5-Aminosalicylates, sulfasalazine, steroid use, and complications in patients with ulcerative colitis. Am J Gastroenterol 1997; 92: 816–20
Hautekeete ML, Bourgeois N, Potvin P, et al. Hypersensitivity with hepatotoxicity to mesalazine after hypersensitivity to sulfasalazine. Gastroenterology 1992; 103: 1925–7
Reinoso MA, Schroeder KW, Pisani RJ. Lung disease associated with orally administered mesalamine for ulcerative colitis. Chest 1992; 101: 1469–70
Kristensen KS, Hoegholm A, Bohr L, et al. Fatal myocarditis associated with mesalazine [letter]. Lancet 1990; I: 605
Abdullah AM, Scott RB, Martin SR. Acute pancreatitis secondary to 5-aminosalicylic acid in a child with ulcerative colitis. J Pediatr Gastroenterol Nutr 1993; 17: 441–4
Calvino JR, Romero J, Pintos E, et al. Mesalazine-associated tubulo-interstitial nephritis in inflammatory bowel disease. Clin Nephrol 1998; 49: 265–7
Elton E, Hanauer SB. Review article: the medical management of Crohn’s disease. Aliment Pharmacol Ther 1996; 10: 1–22
Raimundo AH, Patil DH, Frost PG, et al. Effects of olsalazine and sulphasalazine on jejunal and ileal water and electrolyte absorption in normal human subjects. Gut 1991; 32: 270–4
Korelitz BI. Inflammatory bowel disease and pregnancy. Gastro Clin North Am 1998; 27: 213–24
Jarnerot G, Into-Malberg MB. Sulphasalazine treatment during breast feeding. Scand J Gastroenterol 1979; 14: 869–71
Diav-Citrin O, Park Y, Veerasuntharam G, et al. The safety of mesalamine in human pregnancy: a prospective controlled cohort study. Gastroenterology 1998; 114: 23–8
Miller LG, Hopkinson JM, Motil KJ, et al. Disposition of olsalazine and metabolites in breast milk. J Clin Pharmacol 1993; 33: 703–6
Swartz SL, Dluhy RG. Corticosteroids: Clinical pharmacology and therapeutic use. Drugs 1978; 16: 238–55
Lewis GP, Jusko WJ, Burke CW, et al. Prednisone side effects and serum protein levels. Lancet 1971; II: 778–80
Boekenoogen SJ, Szefler SJ, Jusko WJ. Prednisolone disposition and protein binding in oral contraceptive users. J Clin Endocrinol Met 1983; 56: 702–9
Marshall JK, Irvine EJ. Rectal corticosteroids versus alternative treatments in ulcerative colitis: a meta-analysis. Gut 1997; 40: 775–81
Petitjean O. Pharmacokinetics and absolute rectal bioavailability of hydrocortisone acetate in distal colitis. Alim Pharm Ther 1992; 6: 351–7
Farmer RG, Schumacher OP. Treatment of ulcerative colitis with hydrocortisone enemas: relationship of hydrocortisone absorption, adrenal suppression and clinical response. Dis Colon Rectum 1970; 13: 355–61
Brattsand R, Linden M. Cytokine modulation by glucocorticoids: mechanisms and actions in cellular studies. Aliment Pharmacol Ther 1996; 10: 81–92
Hawthorne AB, Hawkey CJ. Immunosuppressive drugs in inflammatory disease: a review of their mechanisms of efficacy and place in therapy. Drugs 1989; 38: 267–88
Flower FJ, Blackwell CJ. Anti-inflammatory steroids induce biosynthesis of a phospholipase A2 inhibitor which prevents prostaglandin generation. Nature 1979; 278: 456–9
Lindmark B. Short and long-term steroid side effects: the importance for patients with inflammatory bowel disease. Res Clin Forums 1993; 15: 35
Hall RCW, Popkin MK, Stichney SK, et al. Presentation of steroid psychosis. J Ner Ment Disorder 1979; 167: 229–35
Nashel DJ. Is atherosclerosis a complication of long-term corticosteroid treatment? Am J Med 1986; 80: 925–9
Bar-Meir S, Chowers Y, Lavy A, et al. Budesonide versus prednisone in the treatment of active Crohn’s disease. Gastroenterology 1998; 115: 835–40
Tripathi RC, Kirshner BS, Kipp M, et al. Corticosteroid treatment for inflammatory bowel disease in pediatric patients increases intraocular pressure. Gastroenterology 1992; 102: 1957–61
Dujorne CA, Azarnoff DL. Clinical complications of corticosteroid therapy. Med Clin No Amer 1973; 57: 1331–42
Mandel S. Steroid myopathy: insidious cause of muscle weakness. Postgrad Med 1982; 72: 207–15
Conn HO, Blitzer BL. Non-association of adrenocorticosteroid therapy and peptic ulcer. N Engl J Med 1976; 294: 473–9
Nelp WB. Acute pancreatitis associated with steroid therapy. Arch Int Med 1961; 108: 702–10
Seyrig JA, Jian R, Modigliani R, et al. Idiopathic pancreatitis associated with inflammatory bowel disease. Dig Dis Sci 1989; 30: 1121–6
Issenman RM. Bone mineral metabolism in pediatric inflammatory bowel disease. Inflammatory Bowel Dis 1999; 5: 192–9
Sadeghi-Nejad A, Senior B. The treatment of ulcerative colitis in children with alternate-day corticosteroids. Pediatrics 1968; 43: 840–4
Olbricht T, Benker G. Glucocorticoid-induced osteoporosis: pathogenesis, prevention and treatment, with special regard to the rheumatic diseases. J Intern Med 1993; 234: 237–44
Valentine JF, Sninsky CA. Prevention and treatment of osteoporosis in patients with inflammatory bowel disease. Am J Gastroenterol 1999; 94: 877–83
Compston JE. Review article: osteoporosis, corticosteroids and inflammatory bowel disease. Aliment Pharmacol Ther 1995; 9 (3): 237–50
Lukert BP, Raisz LG. Glucocorticoid-induced osteoporosis. Rheum Dis Clin No Amer 1994; 20: 629–50
Vakil N, Sparberg M. Steroid-related osteonecrosis in inflammatory bowel disease. Gastroenterology 1989; 96: 62–6
Summers RW, Switz DM, Jr Sessions JT, et al. National Cooperative Crohn’s Disease Study (NCCDS): results of drug treatment. Gastroenterology 1979; 77: 847–69
Stuck AE, Minder CE, Frey FJ. Risk of infectious complications in patients taking glucocorticoids. Rev Infect Dis 1989; 6: 954–63
Schlaghecke R, Kornely E, Santen RT, et al. The effect of long-term glucocorticoid therapy on pituitary-adrenal responses to exogenous corticotropin-releasing hormone. N Engl J Med 1992; 326: 226–30
Christy NP. Pituitary-adrenal function during corticosteroid therapy. Learning to live with uncertainty. N Engl J Med 1992; 326: 265–7
Cook DM. Safe use of glucocorticoids. Postgrad Med 1992; 91: 145–54
Mogadam DM, Dobbins WO III, Korelitz BI, et al. Pregnancy in inflammatory bowel disease: effect of sulfasalazine and corticosteroids on fetal outcomes. Gastroenterology 1981; 80: 72–6
Barocco PJ, Korelitz BI. The influence of inflammatory bowel disease and its treatment on pregnancy and fetal outcome. J Clin Gastroenterol 1984; 6: 211–6
Hamedani R, Feldman RD, et al. Review article: drug development in inflammatory bowel disease: budesonide-a model of targeted therapy. Aliment Pharmacol Ther 1997; 11Suppl. 3: S98–S107
Stotland BR, Lichtenstein GR. Newer treatments for inflammatory bowel disease. Primary Care Clin No Am 1996; 23: 577–608
Hanauer SB, Robinson M, Pruitt R, et al. Budesonide enema for the treatment of active, distal ulcerative colitis and proctitis: a dose ranging study. Gastroenterology 1998; 115: 525–32
Campieri M, Ferguson A, Doe W, et al. Oral budesonide is as effective as oral prednisolone in active Crohn’s disease. Gut 1997; 41: 209–14
Kumana CR, Seaton T, Meghji M, et al. Beclomethasone dipropionate enamas for treating inflammatory bowel disease without producing Cushing’s syndrome or hypothalamic-pituitary-adrenal suppression. Lancet 1982; I: 579–83
Brogden RN, Heel RC, Speight TM, et al. Beclomethasone dipropionate: A reappraisal of its pharmacodynamic properties and therapeutic efficacy after a decade of use in asthma and rhinitis. Drugs 1984; 29: 99–126
Hanauer SB, Kirsner JB, Barrett WE. The treatment of left-sided ulcerative colitis with tixocortal pivalate [abstract]. Gastroenterology 1986; 90: A1449
Larochelle P, Du Sovich P, Bolte E, et al. Tixocortol pivalate, a corticosteroid with no systemic glucocorticoid effect after oral, intrarectal, and intranasal application. Clin Pharm Ther 1983; 3: 343–50
Hawthorne AB, Record CO, Holdsworth CD, et al. Double-blind trial of oral fluticasone-propionate versus prednisolone in the treatment of active ulcerative colitis. Gut 1993; 34: 125–8
Wright JP, Jaarnum S, Muckadell OS, et al. Oral fluticasone propionate compared with prednisolone in the treatment of active Crohn’s disease: a randomized double-blind multicenter study. Eur J Gasto Hepatol 1993; 5: 499–503
Van Scoik KG, Johnson CA, Porter WR. The pharmacology and metabolism of the thiopurine drugs 6-mercaptopurine and azathioprine. Drug Metab Rev 1985; 16: 157–74
Sandborn WJ. A review of immune modifier therapy for inflammatory bowel disease: azathioprine, 6-mercaptopurine, cyclosporine, and methotrexate. Am J Gastroenterol 1996; 91 (3): 423–33
Sandborn WJ. Azathioprine: state of the art in inflammatory bowel disease. Scand J Gastroenterol 1998; 225Suppl.: S92–S99
Zimm S, Collins JM, Riccardi R, et al. Variable bioavailability of oral mercaptopurine: is maintenance chemotherapy in acute lymphoblastic leukemia being optimally delivered? N Engl J Med 1983; 308: 1005–9
Langevin AM, Koren GT, Soldin SJ, et al. Pharmacokinetic case for giving 6-mercaptopurine maintenance doses at night. Lancet 1987; II: 505–6
Hanauer SB. Drug therapy: inflammatory bowel disease. N Engl J Med 1996; 334: 841–8
Szawlowski PWS, Al-Safi SA, Dooley T, et al. Azathioprine suppresses the mixed lymphocyte reaction of patients with Lesch-Nyhan syndrome. Br J Clin Pharm 1985; 20: 489–91
Chalmers AH. Studies on the mechanism of formation of 5-mercapto-1-methyl-4-imidazole: a metabolite of the immunosuppressive drug azathioprine. Biochem Pharm 1974; 23: 1891–901
Leman B, Shanahan F, Targan S. Serial study of immunologic alterations in patients with IBD on long-term treatment with 6-MP [abstract]. Gastroenterology 1988; 94: A255
Present DH, Korelitz BI, Wishc JL, et al. Treatment of Crohn’s disease with 6-mercaptopurine. N Engl J Med 1980; 302: 981–7
Marion JF. Toxicity of 6-mercaptopurine/azathioprine in patients with inflammatory bowel disease. Inflamm Bowel Dis 1998; 4: 117–8
Haber DJ, Meltzer SJ, Present DH, et al. Nature and course of pancreatitis caused by 6-mercaptopurine in the treatment of inflammatory bowel disease. Gastroenterology 1986; 91: 982–6
Singleton JW, Law DH, Kelley ML, et al. National Cooperative Crohn’s Disease Study: adverse reactions to study drugs. Gastroenterology 1979; 77: 870–82
Present DH, Meltzer SJ, Krumholz MP, et al. 6-mercaptopurine in the management of inflammatory bowel disease: short and long term toxicity. Ann Intern Med 1989; 111: 641–9
Baert F, Rutgeerts P. Immunomodulatory therapy in inflammatory bowel disease. Acta Clin Belgica 1997; 52: 251–7
Gross R, Scapa E. Hepatotoxicity of 6-mercaptopurine in Crohn’s disease. Am J Gastroenterol 1992; 87: 1885–6
Kirschner BS. Safety of azathioprine and 6-mercaptopurine in pediatric patients with inflammatory bowel disease. Gastroenterology 1998; 115: 813–21
Connell WR, Kamm MA, Ritchie JK, et al. Bone marrow toxicity caused by azathioprine in inflammatory bowel disease: 27 years of experience. Gut 1993; 34: 1081–5
Lennard L, van Loon J, Weinshilboum RM. Pharmacogenetics of acute azathioprine toxicity: relationship to thiopurine methyltransferase genetic polymorphism. Clin Pharmacol Ther 1989; 46: 149–54
Stolk JN, Boerbooms AMT, DeAbreu RA, et al. Reduced thiopurine methyltransferase activity and development of side effects of azathioprine treatment in patients with rheumatoid arthritis. Arthritis Rheum 1998; 41: 1858–66
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
Bradley PP, Warden GD, Maxwell JG, et al. Neutropenia and thrombocytopenia in renal allograft recipients treated with trimethoprim-sulfamethoxazole. Ann Int Med 1980; 93: 560–2
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. Gastroenterology 1999; 117: 527–35
Korelitz BI, Mirsky FJ, Fleisher MR, et al. Malignant neoplasms subsequent to treatment of inflammatory bowel disease with 6-mercaptopurine. Am J Gastroenterol 1999; 94: 3248–53
Greenstein AJ, Mullin GE, Strauchen JA, et al. Lymphoma in inflammatory bowel disease. Cancer 1992; 69: 1119–23
Kinlen LJ. Incidence of cancer in rheumatoid arthritis and other disorders after immunosuppressive treatment. Am J Med 1985; 78: 44–9
Leman M, Bonhomme P, Biton A, et al. Traitment de la maladie de Crohn’s par l’azathioprine ou la 6-mercaptopurine: etude retrospective chez 126 malades. Gastroenterol Clin Biol 1990; 14: 548–54
Larvol L, Soule JC, LeTourneau A. Reversible lymphoma in the setting of azathioprine therapy for Crohn’s disease. N Engl J Med 1994: 331: 883–4
Present D, Heizer WD, Peterson JL. Acute myeloblastic leukemia following prolonged treatment of Crohn’s disease with 6-mercaptopurine. Dig Dis Sci 1998; 43: 1791–3
Connell WR, Kamm MA, Dickson M, et al. Long-term neoplasia risk after azathioprine treatment in inflammatory bowel disease. Lancet 1994; 343: 1249–52
Merker HJ, Pospisil M, Mewes P. Cytotoxic effects of 6-mercaptopurine on the limb-bud blastemal cells of rat embryos. Teratology 1975; 11: 199–217
Williamson RA, Karp LE. Azathioprine teratogenicity: review of the literature and case report. Obstet Gynecol 1981; 58: 247–50
Hou S. Pregnancy in organ transplant recipients. Med Clin North Am 1989; 73: 667–83
Alstead EM, Ritchie RK, Lennard-Jones JE, et al. Safety of azathioprine in pregnancy in inflammatory bowel disease. Gastroenterology 1990; 99: 443–6
Marteau P, Tennenbaum R, Elefant E, et al. Drug treatment of inflammatory bowel disease during pregnancy. Res Clin Forums 1998; 20 (1): 57–64
Rajapakse RO, Korelitz BI, Zlatanic J, et al. Outcome of pregnancies when fathers are treated with 6-mercaptopurine for inflammatory bowel disease. Am J Gastroenterol 2000; 3: 683–8
Sandborn WJ. A review of immune modifier therapy for inflammatory bowel disease: azathioprine, 6-mercaptopurine, cyclosporine, and methotrexate. Am J Gastroenterol 1996; 91: 423–33
Jolivet J, Cowan KH, Curt GA, et al. The pharmacology and clinical use of methotrexate. N Engl J Med 1983; 309: 1094–104
Egan LJ, Snadborn WJ. Methotrexate for inflammatory bowel disease: pharmacology and preliminary results. May Clin Proc 1996; 71: 69–80
Feagan BG, Rochon J, Fedorak RN, et al. Methotrexate for the treatment Crohn’s disease. N Engl J Med 1995; 332: 292–7
Baron TH, Truss CD, Elson CO. Low-dose oral methotrexate in refractory inflammatory bowel disease. Dig Dis Sci 1993; 38: 1851–6
Kozorek RA, Patterson DJ, Gelfand MD, et al. Methotrexate induces clinical and histological remission in patients with refractory inflammatory bowel disease. Ann Intern Med 1989; 110: 353–6
Kremer JM, Lee JK. The safety and efficacy of the use of methotrexate in long-term therapy for rheumatoid arthritis. Arthritis Rheum 1986; 29: 822–31
Morgan SL, Baggott JE, Vaughn WH, et al. Supplementation with folic acid during methotrexate therapy for rheumatoid arthritis. Ann Intern Med 1994; 121: 833–41
Weinblatt ME. Methotrexate for chronic diseases in adults. N Engl J Med 1995; 332: 330–1
Al-Awadhi A, Dale P, McKendry RJ. Pancytopenia associated with low dose methotrexate therapy: a regional survey. J Rheum 1993; 20: 1121–5
Searles G, McKendry RJ. Methotrexate pneumonitis in rheumatoid arthritis: Potential risk factors. Four case reports and a review of the literature. J Rheumatol 1987; 14: 1164–71
Kamel OW, van de Rijn M, Weiss LM, et al. Brief report: reversible lymphomas associated with Epstein-Barr virus occurring during methotrexate therapy for rheumatoid arthritis and dermatomyositis. N Engl J Med 1993; 328: 1317–21
Alarcon GS, Goodman TA, Polisson RP. Methotrexate: adverse reactions and major toxicities. Rheumatic Dis Clin North Am 1994; 20: 513–28
Kremer JM, Alarcon GS, Lightfoot Jr RW, et al. Methotrexate for rheumatoid arthritis. Suggested guidelines for monitoring liver toxicity. Arthritis Rheum 1994; 37: 316–28
Roenigk Jr HH, Auebach R, Maibach HI, et al. Methotrexate in psoriasis: revised guidelines. J Am Acad Dermatol 1988; 19: 145–56
Te H, Schiano TD, Kuan SF, et al. Is long term methotrexate use hepatotoxic in IBD patients? [abstract]. Gastroenterology 1999; 116: A830
Goldenberg M, Bider D, Admon D, et al. Methotrexate therapy for tubal pregnancy. Hum Reprod 1993; 8: 660–6
Hess AD, Tutschka PJ, Santos GW. Effect of cyclosporin A on human lymphocyte response in vitro. J Immunol 1982; 128: 355–9
DiPavoda FE. Pharmacology of cyclosporine (sandimmune). Pharm reviews 1989; 41: 373–97
Flanagan WM, Corthesy B, Bram RJ, et al. Nuclear association of a T-cell transcription factor blocked by FK-506 and cyclosporin. Nature 1991; 352: 803–7
Sandborn WJ. A critical review of cyclosporine therapy in inflammatory bowel disease. Inflamm Bowel Dis 1995; 1: 48–63
Trull AK, Tan KKC, Uttridge J, et al. Cyclosporine absorption form microemulsion formulation in liver transplant recipient [letter]. Lancet 1993; 341: 433
Oppong K, Record CO. Neoral may be as effective as intravenous cyclosporine in the treatment of steroid-resistant ulcerative colitis. Am J Gastroenterol 1998; 93: 1188–9
Kornbluth A, Present DH, Lichteger S, et al. Cyclosporin for severe ulcerative colitis: a user’s guide. Am J Gastroenterol 1997; 92: 1424–8
Stein R, Cohen R, Hanauer S. Complications during cyclosporine therapy for inflammatory bowel disease. Gastroenterology 1997; 112: A1096
Sternthal M, George J, Kornbluth A, et al. Toxicity associated with the use of cyclosporin in patients with inflammatory bowel disease [abstract]. Gastroenterology 1996; 110: A1019
Brynskov J, Thomsen H, Nielsen SL. Renographic monitoring of renal function in patients with Crohn’s disease treated with low-dose cyclosporine: A controlled study. Br Med J 1990; 300: 1438–9
Feutren G and Mihatsch MJ. Thank you.] et al. Risk factors for cyclosporine-induced nephropathy in patients with autoimmune disease. N Engl J Med 1992; 326: 1654–60
Lorber MI, Van Buren CT, Flechner SM, et al. Hepatobiliary complications of cyclosporine therapy following renal transplantation. Transplant Proc 1987; 19: 1808–10
Scalzini A, Barni C, Stellini R, et al. Fatal invasive aspergillosis during cyclosporine and steroids treatment for Crohn’s disease [letter]. Dig Dis Sci 1995; 40: 528
Arellano F, Krupp P. Malignancies in rheumatoid arthritis patients treated with cyclosporin A. Br J Rheumatol 1993; 32: 72–5
Armenti VT, Ahlswede KM, Ahlswede BA, et al. National transplantation pregnancy registry: outcomes of 154 pregnancies in cyclosporine-treated female kidney transplant recipients. Transplantation 1994; 57: 502–6
Marion JF, Rubin PH, Lichtiger S, et al. Cyclosporine is safe for severe colitis complicating pregnancy [abstract]. Am J Gastroenterol 1996; 91: A1975
European FK-506 Multicentre Liver Study Group. Randomised trial comparing tacrolimus (FK-506) and cyclosporin in prevention of liver allograft rejection. Lancet 1994; 344: 423–8
Schreiber SL, Crabtree GR. The mechanism of action of cyclosporin A and FK-506. Immunol Today 1992; 13: 136–42
Aiko S, Conner EM, Fuseler JA, et al. Effects of cyclosporine or FK-506 in chronic colitis. J Pharm Exp Ther 1997; 280: 1075–6
Morris RE. Mechanisms of action of new immunosuppressive drugs. Ther Drug Monit 1995; 17: 564–9
Peters DH, Fitton A, Plosker GL, et al. Tacrolimus: a review of its pharmacology, and therapeutic potential in hepatic and renal transplantation. Drugs 1993; 46: 746–94
Fellerman K, Ludwig D, Stahl M, et al. Steroid-unresponsive acute attacks of inflammatory bowel disease. Immunomodulation by tacrolimus (FK-506). Am J Gastro 1998; 93: 1860–6
Sandborn WJ. Preliminary report on the use of oral tacrolimus (FK-506) in the treatment of complicated proximal small bowel and fistulizing Crohn’s disease. Am J Gastroenterol 1997; 92: 876–9
Florey HW, Gilliver K, Jennings MA, et al. Mycophenolic acid: an antibiotic from Penicillium brevicompactum. Lancet 1946; I: 46
Johnson HD, Swan SK, Heim-Duthoy KL, et al. The pharmacokinetics of a single oral dose of mycophenolate mofetil in patients with varying degrees of renal function. Clin Pharm Ther 1998; 63: 512–8
Fulton B, Markham A. Mycophenolate mofetil, a review of its pharmacodynamic and pharmocokinetic properties and clinical efficacy in renal transplantation. Drugs 1996; 51: 278–98
Smith KG, Isbel N, Catton MG, et al. Suppression of the humoral immune response by mycophenolate mofetil. Nephrol Dial Transplant 1998; 13: 160–4
Sollinger HW. Mycophenolate mofetil for the prevention of acute rejection in primary cadaveric renal allograft recipients. US Renal Transplant Mycophenolate Mofetil Study Group. Transplantation 1995; 60: 225–32
Florin THJ, Roberts RK, Watson MR. Treatment of steroid refractory inflammatory bowel disease (IBD) with mycophenolate mofetil (MMF). Aust NZ J Med 1998; 28: 344–5
Neurath MF, Wanitschke R, Krummenauer F, et al. Randomised trial of mycophenolate mofetil versus azathioprine for treatment of chronic active Crohn’s disease [abstract]. Gastroenterology 1998: 113: A491
Horgan K. Initial experience with mycophenolate mofetil in the treatment of severe inflammatory bowel disease [abstract]. Gastroenterology 1997; 112: A999
Roth D, Colona J, Burke GW, et al. Primary immunosuppression with tacrolimus and mycophenolate mofetil for renal allograft recipients. Transplantation 1998; 65: 248–52
Paterson DL, Singh N, Panebianco A, et al. Infectious complications occurring in liver transplant recipients receiving mycophenolate mofetil. Transplantation 1998; 66: 593–8
Ursing B, Alm T, Barany F, et al. A comparative study of metronidazole and sulfasalazine for active Crohn’s disease: The Cooperative Crohn’s disease study in Sweden. Gastroenterology 1982; 83: 550–62
Rutgeerts P, Hiele M, Geboes K, et al. Controlled trial of metronidazole for prevention of Crohn’s recurrence after ileal resection. Gastroenterology 1995; 108: 1617–21
Feagan B. Antibiotics are not effective for Crohn’s disease(time to remove coloured glasses). Inflamm Bowel Dis 1997; 3: 314–7
Peppercorn MA. Antibiotics are effective for Crohn’s disease. Inflamm Bowel Dis 1997; 3: 317–20
Duffy LF, Daum F, Fisher SE, et al. Peripheral neuropathy in Crohn’s disease patients treated with metronidazole. Gastroenterology 1985; 88: 681–4
Piper JM, Mitchel EF, Ray WA. Prenatal use of metronidazole and birth defects: no association. Obstet Gynecol 1993; 82: 348–52
Turunen UM, Farkkila MA, Hakala K, et al. Long-term treatment of ulcerative colitis with ciprofloxacin: a prospective, double-blind, placebo-controlled study. Gastroenterology 1998; 115: 1072–8
Greenbloom SL, Steinhart AH, Greenberg GR. Combination ciprofloxacin and metronidazole for active Crohn’s disease. Can J Gastroenterol 1998; 12: 53–6
Colombel JF, Lemann M, Cassagnou M, et al. Controlled trial comparing ciprofloxacin with mesalazine for the treatment of active Crohn’s disease. Groupe d’Etudes Therapeutiques des Affections Inflammatoires Digestives (GETAID) Am J Gastroenterol 1999; 94: 674–8
Sands BE. Biologic therapy for inflammatory bowel disease. Inflamm Bowel Dis 1997; 3: 95–113
Sandborn WE, Hanauer SB. Antitumor necrosis factor therapy for inflammatory bowel disease: a review of agents, pharmacology, clinical results, and safety. Inflamm Bowel Dis 1999; 5: 119–33
Targan SR, Hanauer SB, van Derventer SJH, et al. Ashort-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor alpha for Crohn’s disease. N Engl J Med 1997; 337: 1029–35
Present D, Mayer L, VanDerventer SJH, et al. Infliximab for the treatment of fistulas in patients with Crohn’s disease. N Engl J Med 1999; 1398–405
Bickston SJ, Lichtenstein GR, Arseneaus KO, et al. The relationship between infliximab treatment and lymphoma in Crohn’s disease. Gastroenterology 1999; 117: 433–7
Ehrenpreis ED, Kane SV, Cohen LB, et al. Thalidomide therapy for patients with refractory Crohn’s disease. An open label trial. Gastroenterology 1999; 117: 1271–7
Vasiliauskas EA, Kam LA, Abreau-Martin MT, et al. An open-label pilot study of low-dose thalidomide in chronically-active, steroid-dependent Crohn’s disease. Gastroenterology 1999; 117: 1278–87
Yacyshyn B, Woloschuk MB, Yacyshyn D, et al. Efficacy and safety of ISIS 2302 (ICAM antisense oligonucleotide) treatment of steroid dependent Crohn’s disease [abstract]. Gastroenterology 1997; 112: A1123
Sands BE, Bank S, Sninsky CA, et al. Preliminary evaluation of safety and activity of recombinant human interleukin 11 in patients with active Crohn’s disease. Gastroenterology 1999; 117: 58–64
van Derventer SJ, Elson CO, Fedorak RN, et al. Multiple doses of interleukin 10 in steroid refractory Crohn’s disease [abstract]. Gastroenterology 1997; 113: A383
Schreiber S, Fedorak RN, Nielsen OH, et al. A safety and efficacy study of recombinant human interleukin-10 (rhIL-10) treatment in 329 patients with chronic active Crohn’s disease [abstract]. Gastroenterology 1998; 114: A266
Evans RC, Wong VS, Morris AI, et al. Treatment of corticosteroid-resistant ulcerative colitis with heparin-a report of 16 cases. Aliment Pharmacol Ther 1997; 11: 1037–40
Kim YI. Short-chain fatty acids in ulcerative colitis. Nutr Rev 1998; 56; 17–24
Burke A, Lichtenstein GR, Rombeau JL. Nutrition and ulcerative colitis. Baillieres Clin Gastroenterol 1997; 11; 153–74
Thomas GAO, Rhodes J, Green JT. Inflammatory bowel disease and smoking-A review. Am J Gastroenterol 1998; 93: 144–9
Lashner BA, Hanauer SB, Silverstein MD. Testing nicotine gum for ulcerative colitis. Dig Dis Sci 1990; 35: 827–32
Pullan RD, Rhodes J, Ganesh S. Transdermal nicotine for active ulcerative colitis. N Engl J Med 1994; 330: 811–5
Sandborn WJ, Tremaine W, Offord K, et al. Arandomised, double-blind, placebo-controlled trial of transdermal nicotine for mildly to moderately active ulcerative colitis. Ann Intern Med 1997; 126: 364–71
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Stein, R.B., Hanauer, S.B. Comparative Tolerability of Treatments for Inflammatory Bowel Disease. Drug-Safety 23, 429–448 (2000). https://doi.org/10.2165/00002018-200023050-00006
Published:
Issue Date:
DOI: https://doi.org/10.2165/00002018-200023050-00006