Medical therapy for ulcerative colitis

https://doi.org/10.1016/S0889-8553(01)00010-3Get rights and content

Section snippets

Aminosalicylates

Sulfasalazine (Azulfidine) and the newer aminosalicylates are first-line therapy for the treatment of UC. Sulfasalazine contains a 5-aminosalicylic acid (5-ASA) moiety that is linked to sulfapyridine by an azo bond and is delivered intact to the colon [43], [54], [137]. On entering the colon, the azo bond is cleaved by bacterial azo-reductase, releasing sulfapyridine and 5-ASA. The sulfapyridine is absorbed systemically and accounts for most of the drug's toxicity and intolerance [1]. The 5-ASA

Clinical efficacy

Sulfasalazine and the newer 5-ASA preparations are effective treatment for mild-to-moderate UC. Sulfasalazine controls disease activity and induces remission in approximately 70% of patients [134]. There is a dose response for sulfasalazine, and although the maximal recommended dose is 4 g/d, there are data showing increased efficacy at 6 g/d [72], [135]. The side effects are dose dependent, and many patients do not tolerate higher doses of sulfasalazine. The newer 5-ASA agents have similar

Topical therapy

Topical 5-ASA treatment is highly effective for the treatment of mild-to-moderate distal UC and proctitis [94]. The suppository preparations reach the upper rectum, whereas the enema formulations reach the splenic flexure and distal transverse colon [47]. The dose of mesalamine enema varies from 1 to 4 g/d, but in contrast to the dose response with the oral 5-ASA agents, there is no proven benefit of topical doses greater than 1 g/d [136]. Rectal formulations are superior to oral medications

Drug toxicity

Aminosalicylates generally are well tolerated for mild-to-moderate disease, but because of the possibility of exacerbating disease, they should not be initiated as monotherapy for severe UC. Approximately 30% of patients are intolerant to sulfasalazine and develop nausea, vomiting, anorexia, or headaches [59], [62], [154]. The sulfapyridine moiety also may cause hypersensitivity reactions, including rash, fever, agranulocytosis, pancreatitis, nephritis, hepatitis, and transient male infertility

Mechanism of action

Systemic corticosteroids are effective treatment for moderate-to-severe UC and for controlling acute exacerbations. Topical corticosteroids are delivered rectally and are effective treatment for distal colitis. Corticosteroids are potent anti-inflammatory and immunosuppressive agents that inhibit the production of arachidonic acid, alter leukocyte function, and decrease the expression of proinflammatory cytokines (e.g., IL-1, IL-2, IL-4, IL-5, IL-6, IL-8, and interferon-γ) [10], [48], [49], [64]

Antibiotics

Intestinal flora and microbial superinfection have been implicated as possible triggering factors in the cascade of immunoinflammatory events leading to inflammatory bowel disease [128]. Antibiotics may inhibit chemotactic peptides released by luminal bacteria and have been shown to prevent inflammation in animal models of colitis [113], [127]. In contrast to Crohn's disease, antibiotics have not been proved effective for the treatment of UC. Vancomycin, tobramycin, and metronidazole have been

Azathioprine and 6-mercaptopurine

Azathioprine (AZA) and 6-mercaptopurine (6-MP) are immunomodulators that are effective for the treatment of steroid-dependent UC. On absorption, AZA is nonenzymatically converted to 6-MP, which then is metabolized to the active end product, 6-thioguanine nucleotide [59], [86]. The 6-thioguanine nucleotides are purine analogues that inhibit ribonucleotide synthesis and exhibit antiproliferative effects on activated lymphocytes [17]. These agents have a direct anti-inflammatory effect that is due

Nicotine

Several epidemiologic studies have shown a reduced risk of developing UC in cigarette smokers compared with nonsmokers [15], [56], [140]. The precise mechanism by which nicotine controls inflammation in UC is unclear but is likely due to the inhibition of proinflammatory cytokines, IL-2, IL-8, and IL-10, and increased production of the protective mucus layer of the colon [8], [91], [146], [155]. The observation that cigarette smoking is protective against the development of UC has led to

Summary

Although newer therapeutic agents are being developed for the treatment of inflammatory bowel disease, aminosalicylates and corticosteroids remain the mainstay of treatment for UC (Table 2, Table 3, Table 4, Table 5). Patients who do not respond to these agents or become steroid dependent require immunomodulatory therapy or curative surgery. Cyclosporine represents the greatest treatment advance for UC in 10 years. The role of nicotine, heparin, antibiotics, probiotics, and SCFA in the

First page preview

First page preview
Click to open first page preview

References (156)

  • S. Hanauer et al.

    Long-term use of mesalamine (Rowasa) suppositories in remission and maintenance of ulcerative proctitis

    Am J Gastroenterol

    (2000)
  • H. Kaplan et al.

    A controlled evaluation of intravenous adrenocorticotropic hormone and hydrocortisone in the treatment of acute colitis

    Gastroenterology

    (1975)
  • B. Korelitz et al.

    Shingles during the course of treatment with 6-mercaptopurine for inflammatory bowel disease

    Am J Gastroenterol

    (1999)
  • B. Korelitz et al.

    Malignant neoplasms subsequent to treatment of inflammatory bowel disease with 6-mercaptopurine

    Am J Gastroenterol

    (1999)
  • R. Lofberg et al.

    Oral budesonide versus prednisolone in patients with active extensive and left-sided ulcerative colitis

    Gastroenterology

    (1996)
  • J. Marshall et al.

    Putting rectal 5-aminosalicylic acid in its place: The role in distal ulcerative colitis

    Am J Gastroenterol

    (2000)
  • S. Meyers et al.

    Corticotrophin versus hydrocortisone in the intravenous treatment of ulcerative colitis: A prospective, randomized, double-blind clinical trial

    Gastroenterology

    (1983)
  • S. Meyers et al.

    Systemic corticosteroid therapy in ulcerative colitis

    Gastroenterology

    (1985)
  • J. Misiewicz et al.

    Controlled trial of sulphasalazine in maintenance therapy for ulcerative colitis

    Lancet

    (1965)
  • A.K. Aazad Khan et al.

    An experiment to determine the active moiety of sulphasalazine

    Lancet

    (1977)
  • G. Actis et al.

    Efficacy and efficiency of oral microemulsion cyclosporin versus intravenous and soft gelatin capsule cyclosporin in the treatment of severe steroid-refractory ulcerative colitis: An open-label retrospective trial

    Inflamm Bowel Dis

    (1998)
  • G. Actis et al.

    Oral microemulsion cyclosporin to reduce steroids rapidly in chronic active ulcerative colitis

    Eur J Gastroenterol Hepatol

    (1999)
  • D. Adler et al.

    The therapeutic efficacy of 6-mercaptopurine in refractory ulcerative colitis

    Am J Gastroenterol

    (1990)
  • S. Ardizzone et al.

    Mesalazine foam (salofalk foam) in the treatment of active distal ulcerative colitis: A comparative trial vs Salofalk enema. The SAF–3 study group

    Ital J Gastroenterol Hepatol

    (1999)
  • J. Baron et al.

    Outpatient treatment of ulcerative colitis: Comparison between three doses of oral prednisone

    BMJ

    (1962)
  • T. Baron et al.

    Low-dose oral methotrexate in refractory inflammatory bowel disease

    Dig Dis Sci

    (1993)
  • M. Bhatti et al.

    Inflammatory bowel disease IL-8 production and tissue expression is modulated by nicotine and crude tobacco extract

    Gut

    (1997)
  • W. Bleyer

    The clinical pharmacology of methotrexate: New applications of an old drug

    Cancer

    (1978)
  • R. Brattsand et al.

    Cytokine modulation by glucocorticoids: Mechanisms and actions in cellular studies

    Aliment Pharmacol Ther

    (1996)
  • F. Brazier et al.

    Treatment of ulcerative colitis with heparin

    Gastroenterology

    (1996)
  • R. Breuer et al.

    Short-chain fatty acid rectal irrigation for left-sided ulcerative colitis: A randomised, placebo controlled trial

    Gut

    (1997)
  • D. Burke et al.

    The efficacy of tobramycin in the treatment of ulcerative colitis

    Aliment Pharmacol Ther

    (1990)
  • D. Burke et al.

    Ulcerative colitis and E. coli with adhesive properties

    J Clin Pathol

    (1987)
  • B. Calkins

    A meta-analysis of the role of smoking in inflammatory bowel disease

    Dig Dis Sci

    (1989)
  • F. Casellas et al.

    Practicality of 5-aminosalicylic suppositories for long-term treatment of inactive distal ulcerative colitis

    Hepatogastroenterology

    (1999)
  • G. Chan et al.

    Azathioprine metabolism: Pharmacokinetics of 6-mercaptopurine, 6-thiouric acid and 6-thioguanine nucleotides in renal transplant patients

    J Clin Pharmacol

    (1990)
  • M. Chapman et al.

    Butyrate oxidation is impaired in the colonic mucosa of sufferers of quiescent ulcerative colitis

    Gut

    (1994)
  • R. Chapman et al.

    Controlled trial of intravenous metronidazole as an adjunct to corticosteroids in severe ulcerative colitis

    Gut

    (1986)
  • T. Colonna et al.

    The role of leukopenia in the 6-mercaptopurine-induced remission of refractory Crohn's disease

    Am J Gastroenterol

    (1994)
  • G. D'Albasio et al.

    Combined therapy with 5-aminosalicylic acid tablets and enemas for maintaining remission in ulcerative colitis: A randomized double blind study

    Am J Gastroenterol

    (1997)
  • A. D'Arienzo et al.

    Beclomethasone diproprionate (3 mg) enemas combined with oral 5-ASA (2.4 g) in the treatment of ulcerative colitis not responsive to 5-ASA alone

    Ital J Gastroenterol Hepatol

    (1998)
  • K.M. Das et al.

    Acetylation polymorphism of sulfapyridine in patients with ulcerative colitis and Crohn's disease

    Clin Pharmacol Ther

    (1972)
  • G. D'Haens et al.

    Intravenous cyclosporine versus intravenous corticosteroids as a single therapy for severe attacks of ulcerative colitis

    Gastroenterology

    (2000)
  • A. Dick et al.

    Controlled trial of sulphasalazine in the treatment of ulcerative colitis

    Gut

    (1964)
  • R. Dickinson et al.

    Double blind controlled trial of oral vancomycin as adjunctive treatment in acute exacerbations of idiopathic colitis

    Gut

    (1985)
  • F. Di Pavoda

    Pharmacology of cyclosporine (Sandimmune): Pharmacologic effects on immune function: In vitro studies

    Pharmacol Rev

    (1989)
  • R. Eliakim et al.

    Potential mediators of inflammatory bowel disease

    Gastroenterol Int

    (1992)
  • E. Evans et al.

    Treatment of corticosteroid-resistant ulcerative colitis with heparin—a report of 16 cases

    Aliment Pharmacol Ther

    (1997)
  • R. Fabia et al.

    Impairment of bacterial flora in human ulcerative colitis and experimental colitis in the rat

    Digestion

    (1993)
  • B. Feagan

    Methotrexate for the treatment of Crohn's disease

    N Engl J Med

    (1995)
  • Cited by (42)

    • Jiaolong capsule protects SD rats against 2,4,6-trinitrobenzene sulfonic acid induced colitis

      2021, Journal of Ethnopharmacology
      Citation Excerpt :

      Drugs such as anti-inflammatory (Steroids and non-steroidal), immunomodulation, and antibiotics are being mainly used to relieve the symptoms. The adverse drug reactions, however, have limited their long-term use (Jani and Regueiro, 2002; Lakatos and Lakatos, 2008). An effective strategy to treat the disease, therefore, is urgently needed.

    • Alternative drug delivery approaches for the therapy of inflammatory bowel disease

      2008, Journal of Pharmaceutical Sciences
      Citation Excerpt :

      Besides the approved 6-mercaptopurine and its prodrug azathioprine, cyclosporine, and methotrexate,10–12 newer immunosuppressive agents such as mycophenolate and tacrolimus are also starting to attract attention.13 Antibiotics, especially metronidazole and ciprofloxacine have been used to induce remission of CD but are ineffective in UC.10,14 Deeper insights into pathogenesis offered the opportunity to develop treatment options on the basis of antibody engineering.

    • Inflammatory Bowel Disease in the Pediatric Patient

      2007, Surgical Clinics of North America
      Citation Excerpt :

      Lichtiger and colleagues [22] demonstrated that cyclosporine, an immunomodulator, is a viable therapeutic option for severe UC that is refractory to corticosteroids. Although efficacious, there are serious side effects of cyclosporine, which include renal insufficiency, Pneumocystis carinii infections, seizures, tremor, gingival hyperplasia, and hypertension [23,24]. Despite the risk of complications from cyclosporine, it remains a safe viable option for acute therapy [25].

    View all citing articles on Scopus
    View full text