NITROXIDE THERAPY FOR INFLAMMATORY BOWEL DISEASE

炎症性肠病的氮氧化物疗法

• 批准号: 6311264
• 负责人: Carleton Hsia
• 金额: $ 10万
• 依托单位: SYNZYME TECHNOLOGY, INC.
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-05-01 至 2001-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6311264
• 关键词: antioxidants; biotechnology; colitis; drug administration rate /duration; drug administration routes; drug design /synthesis /production; drug screening /evaluation; female; histology; inflammatory bowel diseases; laboratory mouse; nitrogen oxides; oxidative stress; pharmacokinetics; pharmacology; superoxides; tissue /cell preparation

DESCRIPTION (Adapted from the application): Free radicals play important roles in inflammatory bowel disease (IBD), and the reduction or elimination of the adverse effects of these oxidants could provide novel therapies. Antioxidants have been reported to reduce tissue injury in colitis models, but more potent, stable and bioavailable antioxidant compounds are required. This project will test a new class ofantioxidants based on polynitroxylation technology, or linkage of nitroxides (stable N-oxyl radicals) to biological macromolecules. In a preliminary study, polynitroxyl-starch (PNS) acted synergistically with the free (unbound) nitroxide compound Tempol to reduce oxidants (especially superoxide) and attenuate inflammation in TNBS-induced murine colitis. We hypothesize that TNBS colitis involves significant superoxide-mediated injury, and that PNS and Tempol can attenuate this injury. Specific aims are: (1) Produce PNS and characterize its antioxidant activity. (2) Pharmacokinetically define optimal dose and route of administration. (3) Define efficacy in TNBS-induced mouse colitis. If this is successful, Phase II will define mechanisms of action in animal models of IBD (including the IL-10-/- knockout mouse which spontaneously develops colitis) and other studies required for progression to clinical testing in IBD. PROPOSED COMMERCIAL APPLICATION: Inflammatory bowel disease is a significant health problem. If successful this research will lead to the development of a novel therapeutic agent(s) for the treatment of IBD. This would represent a significant commercial opportunity and provide substantial benefit to patients.

描述（改编自申请）：自由基发挥重要作用 炎症性肠病（IBD），以及减少或消除 这些氧化剂的副作用可以提供新的疗法。抗氧化剂 据报道可以减少结肠炎模型中的组织损伤，但更有效， 需要稳定且生物可利用的抗氧化剂化合物。该项目将 测试基于聚硝酰化技术的新型抗氧化剂，或 硝基氧（稳定的 N-氧基自由基）与生物大分子的连接。在 初步研究表明，聚硝酰淀粉 (PNS) 与 游离（未结合）硝基氧化合物 Tempol 可还原氧化剂（尤其是 超氧化物）并减轻 TNBS 诱导的小鼠结肠炎的炎症。我们 假设 TNBS 结肠炎涉及显着的超氧化物介导的损伤， PNS 和 Tempol 可以减轻这种损伤。具体目标是：（1） 产生三七总皂苷并表征其抗氧化活性。 (2)药代动力学 确定最佳剂量和给药途径。 (3) 定义功效 TNBS 诱导的小鼠结肠炎。如果成功，第二阶段将定义 IBD 动物模型中的作用机制（包括 IL-10-/- 敲除 自发发展结肠炎的小鼠）和其他所需的研究 进展至 IBD 临床测试。 拟议的商业应用： 炎症性肠病是一个重大的健康问题。 如果这项研究成功的话 导致治疗 IBD 的新型治疗剂的开发。 这会 代表着重要的商业机会，并为患者带来巨大的利益。