Computational repositioning of the anticonvulsant topiramate for inflammatory bowel disease.
Computational repositioning of the anticonvulsant topiramate for inflammatory bowel disease.
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DOI：
10.1126/scitranslmed.3002648
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发表时间：
2011-08-17
影响因子：
17.1
通讯作者：
Butte AJ
中科院分区：
文献类型：
--
作者：
Dudley JT;Sirota M;Shenoy M;Pai RK;Roedder S;Chiang AP;Morgan AA;Sarwal MM;Pasricha PJ;Butte AJ
炎症性肠病(IBD)是一种慢性胃肠道炎症性疾病，长期治疗和疾病维持几乎没有安全有效的治疗选择。在这项研究中，我们应用计算方法，使用公开的分子数据测量IBD样本和164个小分子药物化合物的基因表达，在电子计算机中发现治疗IBD的新药物疗法。在我们的方法预测的治疗IBD的顶级化合物中，有强的松龙，一种已知用于治疗IBD的皮质类固醇，以及托吡酯，一种以前没有被描述为对IBD或任何相关的炎症或胃肠道疾病有效的抗惊厥药物。我们使用三硝基苯磺酸(TNBS)诱导的IBD啮齿动物模型，在体内实验验证了托吡酯的预测。实验结果表明，在TNBS诱导的IBD啮齿动物模型中，口服托吡酯能显著减少大体病理征象和原发病变结肠组织的显微损伤。这些发现表明托吡酯可能作为人类IBD的一种新的治疗选择，并支持使用公共分子数据和计算方法来发现IBD的新治疗选择。
Inflammatory Bowel Disease (IBD) is a chronic inflammatory disorder of the gastrointestinal tract for which there are few safe and effective therapeutic options for long-term treatment and disease maintenance. In this study, we applied a computational approach to discover novel drug therapies for IBD in silico using publicly available molecular data measuring gene expression in IBD samples and 164 small-molecule drug compounds. Among the top compounds predicted to be therapeutic for IBD by our approach were prednisolone, a corticosteroid known to treat IBD, and topiramate, an anticonvulsant drug not previously described to demonstrate efficacy for IBD or any related disorders of inflammation or the gastrointestinal tract. We experimentally validated our topiramate prediction in vivo using a trinitrobenzenesulfonic acid (TNBS) induced rodent model of IBD. The experimental results demonstrate that oral administration of topiramate is able to significantly reduce gross pathological signs and microscopic damage in primary affected colon tissue in a TNBS-induced rodent model of IBD. These finding suggest that topiramate might serve as a novel therapeutic option for IBD in humans, and support the use of public molecular data and computational approaches to discover novel therapeutic options for IBD.
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影响因子：
14.8
作者：
Wirtz, Stefan;Neufert, Clemens;Neurath, Markus F.
通讯作者：
Neurath, Markus F.
DOI：
10.1073/pnas.091062498
发表时间：
2001-04-24
影响因子：
11.1
作者：
Tusher, VG;Tibshirani, R;Chu, G
通讯作者：
Chu, G
影响因子：
--
作者：
Scheiffele, Frank;Fuss, Ivan J
通讯作者：
Fuss, Ivan J
DOI：
10.1073/pnas.0915139107
发表时间：
2010-02-09
影响因子：
11.1
作者：
Bhat, Roopa;Axtell, Robert;Steinman, Lawrence
通讯作者：
Steinman, Lawrence
影响因子：
56.9
作者：
Lamb, Justin;Crawford, Emily D.;Golub, Todd R.
通讯作者：
Golub, Todd R.