Targeting Inflammation with Salsalate as a Novel Therapy for Diabetic Neuropathy

 描述(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。糖尿病肾病是一种进行性疾病，导致严重的发病率和惊人的医疗费用(220亿美元/年www.diabetes.org)。患者由于疼痛、感觉丧失导致平衡不良、摔倒以及最终足部畸形，溃疡和截肢率较高，生活质量较差。虽然心血管自主神经病变(CAN)的诊断不像糖尿病肾病那样常见，但它的发病率与经历直立不稳、心律失常和过早死亡的患者相同。在实验和临床研究中，有证据表明低度炎症在糖尿病肾病和CAN的发病机制中起着重要作用。我们最近完成了一系列来自稳定和进展性糖尿病肾病患者的腓肠神经活检组织的微阵列分析，发现进展性糖尿病肾病患者“炎症反应”基因的表达显著增加。水杨酸盐是一种高效的抗炎疗法，安全边际大，成本低。在概念的先验证明中 先导性研究(R03 DK 094499)，我们获得了使用水杨酸盐的IND(IND 113650)，并完成了8名T1 DM和糖尿病肾病患者的临床和安全性评估，用3克/天的水杨酸盐治疗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糖尿病肾病和CAN的基于机制的疗法。这里的目的是确定水杨酸盐是否是治疗糖尿病肾病和CAN的有效和安全的方法。我们的中心假设是炎症在糖尿病肾病和慢性肾病的发生和发展中起作用，用水杨酸盐阻断炎症可以积极地影响疾病的进展。提出这项研究的理由是，一项水杨酸盐疗法的试点临床试验将：1)测试炎症在糖尿病肾病和CAN中的作用，2)允许为这两种疾病开发生物标记物，以及3)提供水杨酸盐治疗糖尿病肾病和CAN的大规模临床试验的合理性。我们计划通过追求两个具体目标来检验我们的中心假设，从而实现这一应用的目标：目标1：检查3克/天的水杨酸盐对T1 DM和轻度糖尿病患者12个月的糖尿病肾病和CAN的疗效；目标2：确定3克/天的水杨酸盐对T1 DM和轻度糖尿病患者的安全性。

 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.