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| 1 | Plecanatide and dolcanatide, novel guanylate cyclase-C agonists, ameliorate gastrointestinal inflammation in experimental models of murine colitis显示文摘AIM: To evaluate the effect of orally administeredplecanatide or dolcanatide, analogs of uroguanylin, on amelioration of colitis in murine models.METHODS: The cyclic guanosine monophosphate(cG MP) stimulatory potency of plecanatide and dolcanatide was measured using a human colon carcinoma T84 cellbased assay. For animal studies all test agents were formulated in phosphate buffered saline. Sulfasalazine or 5-amino salicylic acid(5-ASA) served as positive controls. Effect of oral treatment with test agents on amelioration of acute colitis induced either by dextran sulfate sodium(DSS) in drinking water or by rectal instillation of trinitrobenzene sulfonic(TNBS) acid, was examined in BALB/c and/or BDF1 mice. Additionally, the effect of orally administered plecanatide on the spontaneous colitis in T-cell receptor alpha knockout(TCRα-/-) mice was also examined. Amelioration of colitis was assessed by monitoring severity of colitis, disease activity index and by histopathology. Frozen colon tissues were used to measure myeloperoxidase activity.RESULTS: Plecanatide and dolcanatide are structurally related analogs of uroguanylin, which is an endogenous ligand of guanylate cyclase-C(GC-C). As expected from the agonists of GC-C, both plecanatide and dolcanatide exhibited potent cG MP-stimulatory activity in T84 cells. Once-daily treatment by oral gavage with either of these analogs(0.05-0.5 mg/kg) ameliorated colitis in both DSS and TNBS-induced models of acute colitis, as assessed by body weight, reduction in colitis severity(P < 0.05) and disease activity index(P < 0.05). Amelioration of colitis by either of the drug candidates was comparable to that achieved by orally administered sulfasalazine or 5-ASA. Plecanatide also effectively ameliorated colitis in TCRα-/- mice, a model of spontaneous colitis. As dolcanatide exhibited higher resistance to proteolysis in simulated gastric and intestinal juices, it was selected for further studies. CONCLUSION: This is the first-ever study reporting the therapeutic utility of GC-C agonists as a new class of orally delivered and mucosally active drug candidates for the treatment of inflammatory bowel diseases. | Kunwar Shailubhai Vaseem Palejwala Krishna Priya Arjunan Sayali Saykhedkar Bradley Nefsky John A Foss Stephen Comiskey Gary S Jacob Scott E Plevy | 2015 | World Journal of Gastrointestinal Pharmacology and Therapeutics2015，6，4： | 5 |
| 2 | The role of the maerophage in sentinel responses in intestinal immunity 显示文摘 | Sheikh S Z Plevy S E | 2010 | Curt Opin Gastroenterol2010，26，6： | 1 |
| 3 | Selective leukocyte apheresis for the treatment of inflammatory bowel disease显示文摘 | Abreu MT Plevy S Sands BE | 2007 | J Clin Gastro- enterol2007，41，10： | 1 |
| 4 | A phase I study of visilizumab, a humanized anti-CD3 monoclonal antibody, in severe steroid-refractory ulcerative colitis显示文摘 | Plevy S Salzberg B Van Assche G et at | 2007 | Gastroenterology2007，133，5： | 1 |
| 5 | Future therapeutic approaches for inflam- matory,bowel diseases显示文摘 | Plevy S E Targan S R | 2011 | Gastroenterology2011，140，6： | 1 |
| 6 | Combined serological, ge- netic, and ittflammatory markers differentiate norr-IBD, Crohn' s dis- ease, and ulcerative colitis patients 显示文摘 | Plevy S Si|verberg MS Lockton S | 2013 | Inflamm Bowel Dis2013，19，6： | 1 |
| 7 | Infliximab for hospitalized patients with severe ulcerative colitis显示文摘 | Regueiro M Curtis J Plevy S | 2006 | J Clin Gastroenterol2006，40，： | 1 |
| 8 | Combined serological, genetic, and inflammatory markers differentiate non-IBD, Crohn's disease, and ulcerative colitis patients 显示文摘 | Plevy S Silverberg M S Lockton S | 2013 | Inflamm Bowel Dis2013，19，6： | 1 |
| 9 | A phase Ⅰ study of visilizumab,a humanized anti-CD3 monoclonal antibody,in severe steroid-refractory ulcerative colitis显示文摘 | Plevy S Salzberg B Van Assche G | 2007 | Gastroenterolo gy2007，133，： | 1 |
| 10 | A phase Ⅰ study of visilizumab,a humanized anti-CD3 monoclonal antibody,in severe steroid-refractoryulcerative colitis显示文摘 | Plevy S Salzberg B Van AG | | 0，，5： | 1 |
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