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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 | Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders显示文摘 | E Joanna Baxter Linda M Scott Peter J Campbell Clare East Nasios Fourouclas Soheila Swanton George S Vassiliou Anthony J Bench Elaine M Boyd Natasha Curtin Mike A Scott Wendy N Erber Anthony R Green | 2005 | The Lancet . 2005 (9464)2005，，： | 2 |
| 3 | Cesarean delivery for fetal distress: Rate and risk factors 显示文摘 | CHAUHAN S P MAGANN E F SCOTT J R | 2003 | Obstet Gynecol Surv2003，58，5： | 1 |
| 4 | Total synthesis of(+)-papulacandin D显示文摘 | Scott E Denmark Tetsuya Kobayashi Christopher S Re-gens | 2010 | Tetra-hedron2010，，66： | 1 |
| 5 | The relationship of personality to entrepreneurial intentions and performance : A meta - analytic review 显示文摘 | Zhao H Scott S E Lumpkin G T | 2010 | Journal of Management March2010，36，2： | 1 |
| 6 | Imaging taste responses in the fly brain reveals a functional map of taste category and behavior 显示文摘 | Marella S Fischler W Kong P Asgarian S Rueckert E Scott K | 2006 | Neuron2006，49，： | 1 |
| 7 | An ultra low-energy ADC for smart dust 显示文摘 | SCOTT M D BOSER B E KRISTOFER S J | 2003 | IEEE J Sol Sta Cire2003，38，7： | 1 |
| 8 | Inhibition of postharvest pathogens by vapor of citral and related compounds in cul- ture 显示文摘 | WURYATMO E KLIEBER A SCOTT E S | 2003 | J Agric Food Chom2003，51，9： | 1 |
| 9 | An ultralow-ener- gy ADC for smart dust显示文摘 | Scott M D Boser B E Pister K S J | 2003 | IEEE J Solid-State Cir- cuits2003，8，7： | 1 |
| 10 | Modeling the leaching of Pb,Cd, As, and Cr from cementitious waste using PHREEQC 显示文摘 | Halim C E Short S A Scott J A | 2005 | Journal of Hazardous Materials2005，125，13： | 1 |
| 11 | Acute endophthalmitis following intravitreal triamcinolone acetonide injection显示文摘 | Darius M Moshfeghi Peter K Kaiser Ingrid U Scott Jonathan E Sears Matthew Benz Juan P Sinesterra Richard S Kaiser Sophie J Bakri Raj K Maturi Jonathan Belmont Paul M Beer Timothy G Murray Hugo Quiroz-Mercado William F Mieler | 2003 | American Journal of Ophthalmology2003，，5： | 1 |
| 12 | Cover-and density-based vegetation classifications of the Sonoran Desert using Landsat TM and ERS-1 SAR imagery显示文摘 | Scott M S Stuart E M | 2004 | Remote Sensing of Environment2004，93，： | 1 |
| 13 | Low probability of choroplast movement from oilseed rape (Brassica napus) into wild Brassica rapa显示文摘 | Wilkinson M J | 1999 | Nature Biotechnol1999，17，： | 1 |
| 14 | Mineralogy,geochemistry and mineral chemistry of siliceous ore and altered footwall rock in the Uwamuki 2 and 4 deposits,Kosaka mine,Hokuroko district,Japan显示文摘 | Bryndzia L T Scott S D Farr J E | 1983 | Economic Geology(Monograph)1983，，5： | 1 |
| 15 | Chloropicrin as a soil fumigant in forest nunes显示文摘 | David B S William A C and Scott A E | 1997 | The Forestry Chronicle1997，73，4： | 1 |
| 16 | Cognitive Engagement with a Multimedia ERP Training Tool:Assessing Computer Self-efficacy and Technology Acceptance显示文摘 | Scott J E Walczak S | 2009 | Information&Management2009，46，4： | 1 |
| 17 | Inheritance to southern corn rust in maize populations显示文摘 | SCOTT G E KING S B ARMOUR J W | 1962 | Phytopatholgy1962，52，： | 1 |
| 18 | Adaptive sweeping techniques显示文摘 | Scott M A Earp M A Benzley S E | 2004 | Engineering with Computers2004，26，3： | 1 |
| 19 | Use of complementary and alternative medicine in cancer patients:a European survey显示文摘 | Molassiotis A Fernadez-Ortega P Pud D Ozden G Scott JA Panteli V Margulies A Browall M Magri M Selvekerova S Madsen E Milovics L Bruyns I Gudmundsdottir G Hummerston S Ahmad AM Platin N Keamey N Patiraki E | | 0，，04： | 1 |
| 20 | TACI and BAFF-R mediateisotype switching in B cells显示文摘 | Castigli E Wilson SA Scott S | 2005 | J Exp Med2005，201，1： | 1 |
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