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Current Directions in IBD Therapy: What Goals Are Feasible With Biological Modifiers?

Inflammatory Bowel Disease Clinic, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota 55905, USA.
Gastroenterology (Impact Factor: 13.93). 11/2008; 135(5):1442-7. DOI: 10.1053/j.gastro.2008.09.053
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    • "e conventional treatments of IBD include corticosteroids and aminosalicylates. However, only 50% of patients achieve sustained remission with the conventional drugs which can raise many side effects [12]. Recently, many novel drugs have been developed for clinical IBD management, and among them, TNF neutralization by monoclonal antibodies $MJOJDBM 6TF PG *OëJYJNBC GPS *#% 5SFBUNFOU "
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    ABSTRACT: The pathogenesis and treatment of inflammatory bowel disease (IBD) have been recently advanced, while it is still challenged with high morbidity and poor prognosis. Infliximab, a monoclonal antibody of tumor necrosis factor (TNF), has emerged as an efficient treatment with many clinical benefits such as quick disease activity reduction and IBD patient life quality improvement. However, the biological effects of infliximab on IBD need to be elucidated. This paper reviewed the clinical use and recently advanced biological action of infliximab on IBD. By forming the stable complex with the soluble or the membrane form of TNF in fluid environment or on cell surface of immune cell, fibroblast, endothelium, and epithelium, infliximab quenches TNF activity and performs the important biological actions which lead to amelioration and remission of immune responses. The mechanisms of infliximab treatment for IBD were intensively discussed. The recent advances on two topics including predictors and side effects of infliximab treatment were also reviewed.
    01/2013; 2013:581631. DOI:10.1155/2013/581631
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    • "PER3 polymorphisms have been associated with circadian disruption , and disruption of body circadian rhythmicity has been linked with immune system dysregulation and altered secretion of several cytokines, including tumor necrosis factor (TNF)-α, interferon (IFN)-γ, interleukin (IL)-6, and IL-l, which can lead to chronic inflammation (Guess et al., 2009). Crohn's disease (CD) and ulcerative colitis (UC) are the two most common phenotypes of inflammatory bowel disease (IBD), characterized by recurrent flares of diarrhea, abdominal pain, and weight loss (Sandborn, 2008). Over the last decade, strong progress has been made towards understanding the genetic basis of IBD by means of linkage and association studies using positional mapping and candidate gene approaches (Anderson et al., 2011; Hugot et al., 2001; Franke et al., 2010; Kohr et al., 2011). "
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    ABSTRACT: Altered body rhythmicity and deregulated clock gene expression may cause circadian disruption, which can lead to immune dysregulation and chronic inflammatory diseases. PERIOD3 (PER3) polymorphisms have been associated with circadian disruption and changed secretion of cytokines involved in chronic inflammation. Crohn's disease (CD) and ulcerative colitis (UC) are multifactorial diseases resulting from complex interaction among environmental/microbial factors and the intestinal immune system, triggering an abnormal immune response in genetically susceptible individuals. We evaluated the influence of a polymorphism of the clock gene PER3 on susceptibility and behavior of these inflammatory bowel diseases. The rs2797685 variant of the PER3 gene was assessed in 1082 CD and 972 UC patients, 754 of whom had been diagnosed <18 yrs of age, and 1311 unrelated healthy controls. Allele and genotype frequencies of rs2797685 were significantly increased in both CD (p = 1.6 × 10(-4), odds ratio [OR] = 1.38, 95% confidence interval [CI]: 1.17-1.63) and UC (p = .012, OR = 1.25, 95% CI: 1.05-1.48) patients. Difference between frequency distributions remained statistically significant after stratifying the cohort according to age at diagnosis for CD, but not for UC. Statistically significant association was found between PER3 polymorphism and use of immunosuppressive drugs in pediatric CD patients (p < .001) and with stricturing and fistulizing disease behavior in adult CD patients (p = .031). In conclusion, results of this association study suggest a possible role of PER3 polymorphism in determining susceptibility to CD and UC and phenotypic characteristics of CD. In particular, the rs2797685 variant of the PER3 gene is associated with a more aggressive form of CD, highlighted by higher use of immunosuppressants and more frequent stricturing and fistulizing disease behaviors, as well as early onset of CD. This is a descriptive study, and functional data are needed to prove a causal relationship; nonetheless, involvement of the clock gene machinery in the susceptibility and the behavior of inflammatory bowel diseases may suggest new pathophysiological mechanisms and new therapeutic approaches. (Author correspondence: g.mazzoccoli@ operapadrepio.it ).
    Chronobiology International 08/2012; 29(8):994-1003. DOI:10.3109/07420528.2012.705935 · 2.88 Impact Factor
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    • "They are also among the most targeted proinflammatory cytokines in the development of biologic therapies for IBD [48] [49]. Currently, the most effective and extensively evaluated biologic drugs in treatment of IBD are TNFαneutralizing agents, including infliximab, adalinumab and cetolizumab pegol [48] [50]. Furthermore, Ustekinumab, a humanized monoclonal IgG1 antibody against IL-12/p40 subunit, which is shared by both IL-12 and IL-23 signaling , simultaneously targets two major diseasecausing inflammatory pathways, Th1 and Th17 Figure 6. "
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    ABSTRACT: Inflammatory Bowel Disease (IBD) is a chronic and frequently disabling inflammatory disorder of the intestine. New developments in IBD therapy are primarily focused on biologic treatments; however, they are both expensive and associated with significant side effects. Here, we provide the first preclinical evidence that YunNan BaiYao (YNBY), a well-known traditional Chinese herbal remedy frequently used for treating hemorrhages and wounds, can effectively alleviate experimental colitis. Oral administration of YNBY in drinking water significantly reduced the disease activities of both DSS- and TNBS-induced experimental colitis. Mechanistic studies revealed that the effectiveness of YNBY was not due to an anti-bacterial function since YNBY had no effect on E. coli growth. Rather, it exhibited an anti-inflammatory or immunosuppressive function: In the DSS colitis model, YNBY treatment decreased the levels of several pro-inflammatory cytokines in colonic mucosa, including TNFα, IL-12p40, and IL-17. Similar cytokine changes were also observed in mouse serum, suggesting that systemic changes in general reflect the changes in the affected colon. Significant down-regulation of IL-12p40 and IL-17, in addition to IFNγ, was also seen in TNBS-colitis model. Another potential mechanism for the anti-inflammatory effects of YNBY involves the selective suppression of pro-inflammatory immune cells: YNBY effectively suppressed the growth of multiple T- and B-lymphocytes, including Molt-4, Jurkat, and EBV-transformed human B-lymphocytes, more potently than 6-mecaptopurine (6-MP) and 5-aminosalicylic acid (5-ASA), two of the most commonly used first-line drugs in IBD therapy. In sharp contrast, YNBY exhibited no cytotoxicity to colonic epithelial cells (Caco-2 cells), even at the concentration 10-fold higher than that used in the lymphocyte model; and instead promoted cell spreading and wound healing. These results strongly suggest that YNBY not only has effective anti-inflammatory properties through suppressing lymphocyte growth and pro-inflammatory cytokine expression, but also can promote intestinal epithelial wound-healing and repair. Therefore, YNBY demonstrates strong potential as an alternative herbal therapy for IBD.
    International Journal of Clinical and Experimental Medicine 01/2011; 4(4):309-19. · 1.42 Impact Factor
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