Targeting Inflammation with Salsalate as a Novel Therapy for Diabetic Neuropathy

使用双水杨酸靶向炎症作为糖尿病神经病变的新疗法

• 批准号: 9221315
• 负责人: RODICA BUSUI (POP-BUSUI)
• 金额: $ 58.83万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-03-01 至 2021-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9221315
• 关键词: Address; Affect; Amputation; Anti-Inflammatory Agents; Anti-inflammatory; Arrhythmia; Biopsy; Cardiovascular system; Cessation of life; Chronic; Clinical; Clinical Research; Clinical Trials; Clinical Trials Design; Complications of Diabetes Mellitus; Degenerative polyarthritis; Development; Diabetes Mellitus; Diabetic Neuropathies; Diagnosis; Disease; Disease Progression; Electrophysiology (science); Equilibrium; FDA approved; Foot Deformities; Future; Generic Drugs; Genes; Goals; Health Care Costs; Hypoglycemia; Individual; Inflammation; Inflammatory Response; Insulin-Dependent Diabetes Mellitus; LDL Cholesterol Lipoproteins; Life; Link; Measures; Mediator of activation protein; Microarray Analysis; Mission; Morbidity - disease rate; Nerve; Nerve Fibers; Neuropathy; Non-Insulin-Dependent Diabetes Mellitus; Numbness; Orthostasis; Outcome; Pain; Pathogenesis; Patients; Pattern; Peripheral Nerves; Pharmaceutical Preparations; Physically Handicapped; Pilot Projects; Placebo Control; Prodrugs; Progressive Disease; Public Health; Quality of life; Randomized; Renal function; Reporting; Research; Role; Safety; Salicylic Acids; Series; Serum; Symptoms; Testing; Treatment Efficacy; Ulcer; United States National Institutes of Health; Urine; Work; autonomic neuropathy; base; biomarker development; chemokine; clinical efficacy; cost; cytokine; density; design; experience; experimental study; falls; inflammatory marker; innovation; insight; mortality; novel therapeutics; patient oriented; pilot trial; premature; public health relevance; salicylsalicylic acid; specific biomarkers; sural nerve; treatment effect

 DESCRIPTION (provided by applicant): Diabetic neuropathy (DN) is the most common chronic complication of diabetes, affecting up to 50% of individuals with type 1 diabetes (T1DM). DN is a progressive disease, leading to severe morbidity and staggering health care costs ($22 billion/year www.diabetes.org). Patients experience poor quality of life due to pain, loss of sensation leading to poor balance, falls and eventual foot deformities with high rates of ulcerations and amputations. While not as commonly diagnosed as DN, cardiovascular autonomic neuropathy (CAN) carries equal morbidity with patients experiencing orthostasis, arrhythmias and premature death. Evidence for an important role of low-grade inflammation in the pathogenesis of DN and CAN is emerging from both experimental and clinical studies. We recently completed a series of microarray analyses of sural nerve biopsies from subjects with stable versus progressive DN and discovered a highly significant increase in the expression of "inflammatory response" genes in subjects with progressive DN. Salsalate is highly effective anti- inflammatory therapy, with a large margin of safety and low cost. In a prior proof of concept pilot study (R03 DK 094499), we obtained the IND (IND 113650) for the use of salsalate and completed clinical and safety assessments in 8 subjects with T1DM and DN, treated with 3 gram/day salsalate for 3 months, with evidence of early clinical efficacy and drug safety. Our long-term goal is to identify mechanism based therapies for the treatment of DN and CAN. The objective here is to determine if salsalate is an effective and safe therapy for DN and CAN. Our central hypothesis is that inflammation has a role in the development and progression of DN and CAN and that blocking inflammation with salsalate can positively affect disease progression. The rationale for the proposed research is that a pilot clinical trial of salsalate therapy will: 1) test the role of inflammation in DN and CAN, 2) allow for biomarker development for both disorders, and 3) provide the justification for a large scale clinical trial of salsalate n the treatment of DN and CAN. We plan to test our central hypothesis, and thereby accomplish the objective of this application, by pursuing two specific aims: Aim 1: Examine the therapeutic efficacy of 3 gram/day salsalate for 12 months on measures of DN and CAN in subjects with T1DM and mild DN Aim 2: Determine the safety profile of 3 gram/day salsalate in patients with T1DM and mild DN.

 描述（由申请人提供）：糖尿病神经病变 (DN) 是糖尿病最常见的慢性并发症，影响高达 50% 的 1 型糖尿病 (T1DM) 患者。 DN 是一种进行性疾病，会导致严重的发病率和惊人的医疗费用（每年 220 亿美元 www.diabetes.org）。由于疼痛、感觉丧失导致平衡不良、跌倒以及最终的足部畸形以及溃疡和截肢率高，患者的生活质量很差。虽然不像 DN 那样常见，但心血管自主神经病 (CAN) 的发病率与直立性停滞、心律失常和过早死亡的患者相同。实验和临床研究均显示低度炎症在 DN 和 CAN 发病机制中发挥重要作用的证据。我们最近完成了对稳定与进展性 DN 受试者的腓肠神经活检进行的一系列微阵列分析，发现进展性 DN 受试者的“炎症反应”基因表达显着增加。水杨酸是高效的抗炎疗法，具有很大的安全性和低成本。在先前的概念验证中 在试点研究（R03 DK 094499）中，我们获得了双水杨酸使用的 IND（IND 113650），并在 8 名 T1DM 和 DN 受试者中完成了临床和安全性评估，接受 3 克/天双水杨酸治疗 3 个月，有早期临床疗效和药物安全性的证据。我们的长期目标是找到治疗 DN 和 CAN 的基于机制的疗法。这里的目的是确定双水杨酸是否是治疗 DN 和 CAN 的有效且安全的疗法。我们的中心假设是炎症在 DN 和 CAN 的发生和进展中发挥作用，并且用双水杨酸阻断炎症可以积极影响疾病进展。拟议研究的基本原理是，双水杨酸疗法的试点临床试验将：1）测试炎症在 DN 和 CAN 中的作用，2）允许开发这两种疾病的生物标志物，3）为双水杨酸治疗 DN 和 CAN 的大规模临床试验提供理由。我们计划通过追求两个具体目标来测试我们的中心假设，从而实现本申请的目标： 目标 1：检查 3 克/天水杨酸 12 个月对 T1DM 和轻度 DN 受试者的 DN 和 CAN 测量的治疗效果 目标 2：确定 3 克/天水杨酸对 T1DM 和轻度 DN 患者的安全性。