Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0022104 (irritable bowel syndrome)
 8,033 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The better understanding of the mechanisms of inflammatory bowel disease has driven our progress into the development of new biological therapies targeting specific molecules. Anti-TNF-alpha biologic compounds have shown great efficacy particularly in Crohn's disease. Infliximab (an IgG1 mouse/human chimeric monoclonal anti-TNF-alpha antibody fragment) is the most efficacious compound in induction and maintenance therapy of active and fistulizing Crohn's disease, being at present the only biological compound approved for therapy, but with the limit of the immunogenicity; CDP-571 (a humanized anti-TNF-alpha antibody) and CDP-870 (a PEGylated anti-TNF-alpha antibody) are less immunogenic, showed some efficacy in induction therapy in Crohn's disease but a rapid loss of response in maintenance therapy. Etanercept and onercept (soluble human recombinant TNF-alpha receptors fusion proteins) seem not to be efficacious in Crohn's disease demonstrating no class-effect for anti-TNF-alpha compounds. In preliminary study, adalimumab (an IgG1 humanized monoclonal anti-TNF-alpha antibody) offers good perspective of efficacy and safety also in infliximab-resistant or allergic patients. Inhibition of lymphocyte trafficking to the gut, through anti-adhesion molecules specific therapies (natalizumab, MLN-02, alicaforsen), has shown promising results: unfortunately, natalizumab, the most effective drug of this class, has recently been suspected to favour serious neurological complications. Other biologic therapies are under evaluation but at present seem to be less promising than infliximab; they consist of antiinflammatory cytokines, inhibitors of proinflammatory cytokines, hormones and growth factors: anti-IL12-antibody, interferon-alpha, interferon-beta, G-CSF, GM-CSF, EGF, growth hormone, anti-interferon-gamma, anti-IL-18, anti-IL-2-receptor and anti-CD3 antibodies. The evaluation of other biological drugs has been suspended for severe side effects as happened for anti-CD40L antibody causing thromboembolism and anti-CD4 antibody causing ly.mphopenia. Other compounds as IL-10 and IL-11 have been proven to be ineffective even if an oral formulation of IL-11 is under evaluation. Among the MAP kinases inhibitors BIRB-796 and RDP58 showed to be ineffective while CNI-1493 is under evaluation. The effort in identifying specific patients features predicting therapy response and the possible combination of different biological therapies represent undoubtedly a very promising perspective. Aim of this article is to review the biological compounds and their efficacy in IBD.
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PMID:Biological therapies for inflammatory bowel disease: research drives clinics. 1684 27

The CD40-CD154 pathway is important in the pathogenesis of inflammatory bowel disease. Here we show that injection of an agonistic CD40 mAb to T and B cell-deficient mice was sufficient to induce a pathogenic systemic and intestinal innate inflammatory response that was functionally dependent on tumor necrosis factor-alpha and interferon-gamma as well as interleukin-12 p40 and interleukin-23 p40 secretion. CD40-induced colitis, but not wasting disease or serum proinflammatory cytokine production, depended on interleukin-23 p19 secretion, whereas interleukin-12 p35 secretion controlled wasting disease and serum cytokine production but not mucosal immunopathology. Intestinal inflammation was associated with IL-23 (p19) mRNA-producing intestinal dendritic cells and IL-17A mRNA within the intestine. Our experiments identified IL-23 as an effector cytokine within the innate intestinal immune system. The differential role of IL-23 in local but not systemic inflammation suggests that it may make a more specific target for the treatment of IBD.
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PMID:Differential activity of IL-12 and IL-23 in mucosal and systemic innate immune pathology. 1692 Jun 36