A Phase II Randomized, Double Blind, Placebo Controlled, Parallel Group,Multi-centre Study to Evaluate the Efficacy, Safety and Tolerability ofTRC160334 as an Add-on to Mesalamine in Subjects with Mild to Moderately Active Ulcerative Colitis - HEAL

开始日期2019-07-15

申办/合作机构

Torrent Pharmaceuticals Ltd.

100 项与 TRC-160334 相关的临床结果

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100 项与 TRC-160334 相关的转化医学

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100 项与 TRC-160334 相关的专利（医药）

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项与 TRC-160334 相关的文献（医药）

2012-01-01·American Journal of Nephrology3区 · 医学

Treatment with a Novel Hypoxia-Inducible Factor Hydroxylase Inhibitor (TRC160334) Ameliorates Ischemic Acute Kidney Injury

3区 · 医学

Article

作者: Jamadarkhana, Prashant ; Deshpande, Shailesh ; Gupta, Rameshchandra ; Dubey, Amita ; Chhipa, Laxmikant ; Chaudhary, Anita ; Mohanan, Anookh

Background: Hypoxia-inducible factor (HIF) transcriptional system plays a central role in cellular adaptation to low oxygen levels. Preconditional activation of HIF and/or expression of its individual target gene products leading to cytoprotection have been well established in hypoxic/ischemic renal injury. Increasing evidence indicate HIF activation is involved in hypoxic/ischemic postconditioning of heart, brain and kidney. Very few studies evaluated the potential benefits of postischemia HIF activation in renal injury employing a pharmacological agent. We hypothesized that postischemia augmentation of HIF activation with a pharmacological agent would protect renal ischemia/reperfusion injury. For this, TRC160334, a novel HIF hydroxylase inhibitor, was used. Methods: TRC160334, a novel HIF hydroxylase inhibitor, was synthesized. Ability of TRC160334 for stabilization of HIF-α and consequent HIF activation was evaluated in Hep3B cells. Efficacy of TRC160334 was evaluated in a rat model of ischemia/reperfusion-induced AKI. Two different treatment protocols were employed, one involved treatment with TRC160334 before onset of ischemia, the other involved treatment after the reperfusion of kidneys. Results: TRC160334 treatment results in stabilization of HIF-α leading to HIF activation in Hep3B cells. Significant reduction in renal injury was observed by both treatment protocols and remarkable reduction in serum creatinine (23 and 71% at 24 and 48 h, respectively, p < 0.01) was observed with TRC160334 treatment applied after reperfusion. Urine output was significantly improved up to 24 h by both treatment protocols. Conclusion: The data presented here provide pharmacologic evidence for postischemia augmentation of HIF activation by TRC160334 as a promising and clinically feasible strategy for the treatment of renal ischemia/reperfusion injury.

Clinical and Experimental Gastroenterology

Therapeutic treatment with a novel hypoxia-inducible factor hydroxylase inhibitor (TRC160334) ameliorates murine colitis

Article

作者: Chaudhary, Anita R ; Chauthaiwale, Vijay ; Jadhav, Avinash V ; Shah, Binita N ; Dutt, Chaitanya ; Gupta, Ram ; Deshpande, Shailesh ; Zambad, Shitalkumar P ; Gupta, Ramesh Chandra

BACKGROUND AND AIMMucosal healing in inflammatory bowel disease (IBD) can be achieved by improvement of intestinal barrier protection. Activation of hypoxia-inducible factor (HIF) has been identified as a critical factor for barrier protection during mucosal insult and is linked with improvement in symptoms of colitis. Although prophylactic efficacy of HIF hydroxylase inhibitors in murine colitis have been established, its therapeutic efficacy in clinically relevant therapeutic settings have not been established. In the present study we aim to establish therapeutic efficacy of TRC160334, a novel HIF hydroxylase inhibitor, in animal models of colitis.METHODSThe efficacy of TRC160334 was evaluated in two different mouse models of colitis by oral route. A prophylactic efficacy study was performed in a 2,4,6-trinitrobenzene sulfonic acid-induced mouse model of colitis representing human Crohn's disease pathology. Additionally, a therapeutic efficacy study was performed in a dextran sulfate sodium-induced mouse model of colitis, a model simulating human ulcerative colitis.RESULTSTRC160334 treatment resulted in significant improvement in disease end points in both models of colitis. TRC160334 treatment resulted into cytoprotective heatshock protein 70 induction in inflamed colon. TRC160334 successfully attenuated the rate of fall in body weight, disease activity index, and macroscopic and microscopic scores of colonic damage leading to overall improvement in study outcome.CONCLUSIONOur findings are the first to demonstrate that therapeutic intervention with a HIF hydroxylase inhibitor ameliorates IBD in disease models. These findings highlight the potential of TRC160334 for its clinical application in the treatment of IBD.

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