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  • Title: Alpha4-integrin antagonism--an effective approach for the treatment of inflammatory diseases?
    Author: Davenport RJ, Munday JR.
    Journal: Drug Discov Today; 2007 Jul; 12(13-14):569-76. PubMed ID: 17631252.
    Abstract:
    Inhibition of leucocyte trafficking by antagonism of the alpha4 (alpha4)-integrin has now been validated as a therapeutic approach for the treatment of inflammatory diseases such as multiple sclerosis (MS) and inflammatory bowel disease (IBD). This validation has been overshadowed by three incidences of progressive multifocal leucoencaphalopathy (PML) in patients receiving natalizumab (Tysabri), a therapeutic monoclonal IgG antibody directed against alpha4-integrins. This led to the initial removal of natalizumab from the market. Following a safety review, it was reintroduced for the treatment of relapsing-remitting MS patients (with restrictions). This has led to a refocus on alpha4-integrins as a therapeutic target across the pharmaceutical industry. Recent advances in small molecule development are worth reviewing. New understanding of pharmacokinetics and selectivity will potentially contribute to the development of alpha4 antagonist with greater clinical efficacy and safety.
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