The Potential of the Alpha4 Beta7 Integrin Inhibitors as Treatment for Inflammatory Bowel Diseases and Related Disorders.

The thioguanine derivative, azathioprine, is a prodrug of 6-mercaptopurine that is further metabolized by various enzymes present in the liver and gut. Azathioprine and 6-mercaptopurine have been used in the treatment of inflammatory bowel disease, i.e. ulcerative colitis and Crohn's disease, for more than 30 years. However, widespread use of azathioprine or 6-mercaptopurine in inflammatory bowel disease is of more recent origin, the primary reason being a long-standing debate on the efficacy of these agents in inflammatory bowel disease. Both drugs are slow acting, which is why clinical efficacy cannot be expected until several weeks or even months of treatment have elapsed. Consequently, azathioprine and 6-mercaptopurine have no place as monotherapy in the treatment of acute relapsing inflammatory bowel disease. Today, azathioprine and 6-mercaptopurine are the most commonly used immunomodulatory drugs in the treatment of inflammatory bowel disease. Their clinical effects are probably identical, although their exact mode of action is still unknown. The mode of action of azathioprine is thought to be multifactorial, including conversion to 6-mercaptopurine (which acts as a purine antimetabolite), possible blockade of thiol groups by alkylation, inhibition of several pathways in nucleic acid biosynthesis (preventing proliferation of cells involved in the determination and amplification of the immune response) and damage to DNA through the incorporation of thiopurine analogues. However, 6-thioguanine nucleotides may accumulate in toxic doses in myeloid precursor cells, resulting in life-threatening myelosuppression. Azathioprine and 6-mercaptopurine are further known to alter lymphocyte function, reduce the number of lamina propria plasma cells and affect natural killer cell function. The purpose of this comprehensive review is to suggest guidelines for the application of azathioprine and 6-mercaptopurine in the treatment of inflammatory bowel disease.

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Inflammatory bowel disease is a chronic inflammatory disease of which the etiology is unknown. Ulcerative colitis and Crohn's disease are the two main entities of inflammatory bowel disease that are challenging clinicians. In addition to tumor necrosis factor blockers, this overview summarizes current and future new drugs, in the treatment of inflammatory bowel disease according to their goals. The infiltration of lymphocytes into the intestinal lining is a target for therapeutic purposes in inflammatory bowel disease. The vascular cell adhesion molecule-1 and the mucosal addressin cell adhesion molecule-1 are a family of integrins for the alpha4 that are specifically expressed in the alimentary canal on vascular endothelial cells. In Crohn's disease, the alpha4beta7 integrin, and its endothelial receptor, the mucosal addressin cell adhesion molecule-1, have proven to be a relevant factor in the development of chronic intestinal inflammation. New biological and chemical drugs are emerging, with additional molecules pending approval.

Inflammatory bowel disease part I: Nature and pathogenesis