Shailubhai Kunwar, Palejwala Vaseem, Arjunan Krishna Priya, Saykhedkar Sayali, Nefsky Bradley, Foss John A, Comiskey Stephen, Jacob Gary S, Plevy Scott E
Kunwar Shailubhai, Vaseem Palejwala, John A Foss, Stephen Comiskey, R and D Center, Synergy Pharmaceuticals Inc., Doylestown, PA 18902, United States.
World J Gastrointest Pharmacol Ther. 2015 Nov 6;6(4):213-22. doi: 10.4292/wjgpt.v6.i4.213.
To evaluate the effect of orally administered plecanatide or dolcanatide, analogs of uroguanylin, on amelioration of colitis in murine models.
The cyclic guanosine monophosphate (cGMP) stimulatory potency of plecanatide and dolcanatide was measured using a human colon carcinoma T84 cell-based 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.
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.
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.
评估口服尿鸟苷素类似物普卡那肽或多卡那肽对改善小鼠模型结肠炎的效果。
使用基于人结肠癌T84细胞的检测方法测定普卡那肽和多卡那肽的环磷酸鸟苷（cGMP）刺激活性。在动物研究中，所有受试药物均用磷酸盐缓冲盐水配制。柳氮磺胺吡啶或5-氨基水杨酸（5-ASA）作为阳性对照。在BALB/c和/或BDF1小鼠中，检测受试药物口服治疗对改善饮用水中葡聚糖硫酸钠（DSS）诱导或直肠灌注三硝基苯磺酸（TNBS）诱导的急性结肠炎的效果。此外，还检测了口服普卡那肽对T细胞受体α敲除（TCRα(-/-)）小鼠自发性结肠炎的影响。通过监测结肠炎严重程度、疾病活动指数和组织病理学评估结肠炎的改善情况。使用冷冻结肠组织测量髓过氧化物酶活性。
普卡那肽和多卡那肽是尿鸟苷素的结构相关类似物，尿鸟苷素是鸟苷酸环化酶-C（GC-C）的内源性配体。正如GC-C激动剂所预期的那样，普卡那肽和多卡那肽在T84细胞中均表现出强大的cGMP刺激活性。通过口服灌胃每天一次给予这些类似物中的任何一种（0.05-0.5mg/kg），均可改善DSS和TNBS诱导的急性结肠炎模型中的结肠炎，通过体重、结肠炎严重程度降低（P<0.05）和疾病活动指数（P<0.05）进行评估。两种候选药物对结肠炎的改善效果与口服柳氮磺胺吡啶或5-ASA相当。普卡那肽还可有效改善TCRα(-/-)小鼠（一种自发性结肠炎模型）的结肠炎。由于多卡那肽在模拟胃液和肠液中对蛋白水解的抗性更高，因此被选用于进一步研究。
这是首次报道GC-C激动剂作为一类新型口服给药且具有黏膜活性的候选药物治疗炎症性肠病的治疗效用的研究。
