Targeting Inflammation with Salsalate as a Novel Therapy for Diabetic Neuropathy

 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（T1 DM）患者。DN是一种进行性疾病，导致严重的发病率和惊人的医疗保健费用（220亿美元/年）。www.diabetes.org由于疼痛、感觉丧失导致平衡差、福尔斯和最终的足部畸形，患者的生活质量差，溃疡和截肢率高。虽然不像DN那样常见，但心血管自主神经病变（CAN）的发病率与发生体位性、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的发病机制中起重要作用。我们最近完成了一系列的微阵列分析腓肠神经活检从受试者与稳定与进行性DN和发现一个高度显着增加的“炎症反应”基因的表达与进行性DN。双水杨酯是一种高效的抗炎治疗药物，安全性高，成本低.在先前的概念验证中 在初步研究（R 03 DK 094499）中，我们获得了使用双水杨酯的IND（IND 113650），并在8例T1 DM和DN受试者中完成了临床和安全性评估，这些受试者接受了3 g/天双水杨酯治疗3个月，有早期临床疗效和药物安全性的证据。我们的长期目标是确定治疗DN和CAN的机制为基础的疗法。本研究的目的是确定双水杨酯是否是治疗DN和CAN的有效和安全的治疗方法。我们的中心假设是炎症在DN和CAN的发展和进展中起作用，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，双水杨酯治疗的试点临床试验将：1）测试炎症在DN和CAN中的作用，2）允许两种疾病的生物标志物开发，以及3）为双水杨酯治疗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检验我们的中心假设，从而实现本申请的目的：目标1：检查3克/天双水杨酸酯持续12个月对患有T1 DM和轻度DN的受试者的DN和CAN测量的治疗功效目标2：确定3克/天双水杨酸酯在患有T1 DM和轻度DN的患者中的安全性特征。

 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.