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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 | An electrophoretic ink for all-printed reflective electronic displays显示文摘 | Barrett Comiskey Albert J D Hidekazu Yoshizawa | 1998 | Nature1998，394，： | 2 |
| 3 | Investment decisions and the equity accounting standards显示文摘 | Comiskey E and Mulford C W | 1986 | The Accounting Review1986，61，3： | 1 |
| 4 | 显示文摘 | Comiskey B Albert J Yoshizawa H | 1998 | Nature1998，394，6690： | 1 |
| 5 | 显示文摘 | Comiskey B Albert J D Yoshizawa H | 1998 | Nature1998，394，： | 1 |
| 6 | 显示文摘 | Comiskey B Albert J D Yoshizawa H | 1998 | Nature1998，394，： | 1 |
| 7 | T cell-mediated pathology in two models of experiment colitis depends predominantly on the interleukine 12/signal transducer and activator of transcription (stat)-4 pathway,but is not conditional on interferon gamma expression by T cells显示文摘 | Shah S Comiskey M | 1998 | J Exp Med1998，187，： | 1 |
| 8 | An electrphoretic ink for all-printed reflective electronic displays 显示文摘 | Comiskey B Albert J Yoshizawa H | 1998 | Nature1998，394，： | 1 |
| 9 | An electrophoretic ink for all-printed reflective electronic displays显示文摘 | Comiskey B Albert J Yoshizawa H | 1998 | Nature1998，394，： | 1 |
| 10 | A study of bone mineral density in adults with disability 显示文摘 | Smith EM Comiskey CM Carroll AM | 2009 | Arch Phys Med Rehabil2009，90，： | 1 |
| 11 | 显示文摘 | Comiskey B Albert J Yoshizawa H | 1998 | Nature1998，394，： | 1 |
| 12 | An electrphoretic ink for all -printed reflective electronic displays显示文摘 | Comiskey B Albert J Yoshizawa H | 1998 | Nature1998，394，： | 1 |
| 13 | An electrophoretic ink for all-printed reflective electronic displays显示文摘 | Comiskey B Albert J D Hidekazu Yoshizawa | 1998 | Nature1998，394，16： | 1 |
| 14 | Small vectors for expression based on dominant drug resistance with direct multicopy selection显示文摘 | Higgins D R Busser K Comiskey J | 1998 | Mol Biol1998，103，： | 1 |
| 15 | An electrophoretic ink for all-printed reflective electronic displays显示文摘 | Comiskey B Albert J Yoshizawa H | 1998 | Nature1998，394，： | 1 |
| 16 | Is negative goodwill valued by investors? 显示文摘 | Comiskey E E J E Clarke C W Mulford | 2010 | Accounting Hori- zons2010，9，： | 1 |
| 17 | An electrophoretie ink for all-printed reflective electronic displays 显示文摘 | COMISKEY B ALBERT J D YOSHIZAWA H | 1998 | Nature1998，394，： | 1 |
| 18 | An electrophoretic ink for all-printed reflective electronic displays显示文摘 | Comiskey B Albert J D Yoshizawa H Jacobson J | 1998 | Nature 19981998，，： | 1 |
| 19 | An electrophoretic ink for all-printed reflective electronic displays显示文摘 | Comiskey B Albert J D Yoshizawa H et ol | 1998 | Nature1998，394，： | 1 |
| 20 | An electrophoretic ink for all-printed reflective electronic displays 显示文摘 | COMISKEY B ALBERT J D YOSHIZAWA H JACOBSON J | 1998 | Nature1998，，394： | 1 |
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