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5-Lipoxygenase inhibitors for the treatment of inflammatory bowel disease

  • Experimental Aspects of Gastrointestinal Inflammation New Approaches to Therapy of Gastrointestinal Inflammation General Inflammation Research Topics 3rd Meeting on Side Effects of Anti-Inflammatory Drugs and 13th European Workshop on Inflammation Verona, Italy
  • New Approaches to Therapy of Gastrointestinal Inflammation
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Abstract

The unique role of the enzyme 5-lipoxygenase (5-LO) in the production of leukotrienes (LTs) makes it a likely target for biochemical manipulation. The rationale for using 5-LO inhibitors for the treatment of inflammatory bowel disease (IBD) is based on the increased generation of LTs in the inflamed mucosa, LTB4 being the most potent chemotactic and chemokinetic metabolite of arachidonic acid. Furthermore, conventional drugs, such as corticosteroids, sulphasalazine, and 5-aminosalicylic acid, inhibit LT production and specific 5-LO inhibition accelerates healing in animal models of acute colitis. The compounds identified as 5-LO inhibitors can be divided into antioxidants, substrate-analogous, and a large miscellaneous group of inhibitors, where hydroxamic acids are potent and more selective inhibitors of 5-LO. The benzothiophene hydroxyurea, zileuton, is the first selective 5-LO inhibitor evaluated for the treatment of patients with IBD. An 800-mg oral dose of zileuton was shown to reduce LTB4, but not prostaglandin E2, concentrations by 75–85% in rectal dialysates from patients with active ulcerative colitis. The clinical efficacy of zileuton 800 mg b.i.d. has also been tested in a randomized, double-blind, placebo-controlled trial in similar patients. Zileuton significantly improved the symptom scores and the histology score, but not the sigmoidoscopy score, compared to pretreatment conditions and with response to placebo, the beneficial effects being most pronounced in patients not receiving concomitant sulphasalazine treatment. The mean inhibition of LTB4 in the target tissue of inflammation was 70%. The proof that any putative 5-LO inhibitor is blocking LT production is an important stage in assessing any such drug. The main disadvantage of existing new LT inhibitors relates to the high potency of LTs, and unless a higher level of inhibition can be achieved, endogenous LTs may still be present in sufficient amounts to produce their effects.

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  1. Department of Medicine G, Bispebjerg Hospital, University of Copenhagen, DK-2400, Copenhagen, Denmark

    J. Rask-Madsen

  2. Department of Biochemistry and Nutrition, Technical University of Denmark, Denmark

    K. Bukhave

  3. Department of Medical Gastroenterology, Odense University Hospital, Denmark

    L. S. Laursen & K. Lauritsen

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Rask-Madsen, J., Bukhave, K., Laursen, L.S. et al. 5-Lipoxygenase inhibitors for the treatment of inflammatory bowel disease. Agents and Actions 36 (Suppl 1), C37–C46 (1992). https://doi.org/10.1007/BF01991022

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