Medical therapy for ulcerative colitis
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
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