Abstract | AIM: METHODS: 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 cGMP-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.
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Authors | Kunwar Shailubhai, Vaseem Palejwala, Krishna Priya Arjunan, Sayali Saykhedkar, Bradley Nefsky, John A Foss, Stephen Comiskey, Gary S Jacob, Scott E Plevy |
Journal | World journal of gastrointestinal pharmacology and therapeutics
(World J Gastrointest Pharmacol Ther)
Vol. 6
Issue 4
Pg. 213-22
(Nov 06 2015)
ISSN: 2150-5349 [Print] United States |
PMID | 26558155
(Publication Type: Journal Article)
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