Non Phamacologic Treatments for Diabetic Neuropathy

糖尿病神经病变的非药物治疗

• 批准号: 7848748
• 负责人: NIGEL A. CALCUTT
• 金额: $ 1.76万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-02-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7848748
• 关键词: Acute; Address; Adverse effects; Animals; Biochemical; Blood; Blood flow; Clinical; Clinical Research; Clinical Trials; Data; Detection; Development; Diabetic Angiopathies; Diabetic Neuropathies; Disease; Drug Design; Equilibrium; Erythropoietin; Evaluation; Event; FDA approved; Goals; Hypoxia; Hypoxia Inducible Factor; Insulin; Insulin Resistance; Insulin-Dependent Diabetes Mellitus; Investigation; Knowledge; Left; Life; Limb structure; Measures; Mediating; Modeling; Molecular; Muscle; Nature; Nerve; Nerve Degeneration; Neural Conduction; Neuropathy; Non-Insulin-Dependent Diabetes Mellitus; Organ; Pain; Patients; Peripheral Nerves; Pharmacologic Substance; Pharmacotherapy; Physiologic pulse; Physiological; Placebos; Prevention; Property; Protein Isoforms; Proteins; Rattus; Rest; Secondary to; Sensory; Streptozocin; Surveys; Therapeutic; Time; Tissues; Translations; Treatment Protocols; Ultrasonic Therapy; Ultrasonography; Vascular Endothelial Growth Factors; Vascularization; Vasodilation; Vasodilator Agents; Work; Wound Healing; angiogenesis; base; cost; diabetic patient; diabetic rat; efficacy testing; high risk; improved; indexing; interest; neurochemistry; non-drug; novel therapeutic intervention; pre-clinical; preclinical evaluation; prevent; public health relevance; response; type I and type II diabetes; vascular bed

DESCRIPTION (provided by applicant): Diabetic neuropathy is a widespread clinical problem, for which there is no FDA-approved, mechanistically based treatment. There is considerable interest in the hypothesis that neuropathy is secondary to microvascular disease in diabetic patients and drug therapies intended to induce vasodilation or angiogenesis in nerve are being explored in both pre-clinical and clinical studies. However, these systemic pharmaceutical approaches have not overcome the problem of how to target nerve blood flow without impacting vascular beds in other organs where increasing blood flow may be harmful to diabetic patients. We have therefore become interested in non-pharmacologic approaches to inducing local, rather than systemic, blood flow. Pulsed low intensity ultrasound increases local blood flow as part of its wound healing properties via both vasodilator and angiogenic mechanisms. To our knowledge, low intensity ultrasound has not undergone comprehensive preclinical evaluation of its potential to prevent or alleviate indices of diabetic neuropathy. We will address the general hypothesis that low intensity ultrasound treatment is capable of inducing biochemical and physiologic events in rat models of type and type 2 diabetes that prevent and reverse development of functional and structural indices of neuropathy via an ability to modulate local tissue blood flow. We have performed exploratory studies to investigate the effects of ultrasound treatment on nerve disorders in the streptozotocin-diabetic rat model of type 1 diabetes and found that it ameliorated nerve conduction slowing. We propose to undertake a comprehensive survey of the effects of low-intensity ultrasound on functional and structural nerve disorders in STZ-diabetic rats in both prevention and reversal paradigms and to extend optimal treatment regimens to the ZDF model of type 2 diabetes. This will be our primary goal and, while it represents a somewhat observational and high-risk approach, we believe that this is balanced by the potential for our findings to prompt an unusually rapid translation of positive preclinical observations to clinical use because of the non-invasive, non-systemic and non-drug based nature of the treatments. Our secondary goal will be to begin to investigate a potential mechanism of action, namely that ultrasound treatment induces HIF/VEGF/EPO-mediated reparative responses in the nerve in response to exaggerated nerve ischemic hypoxia induced by acute diversion of blood from nerve to muscle. By investigating a local, non-pharmacologic, approach to treating diabetic neuropathy we hope to avoid the side-effects, systemic effects and cost concerns that are inherent to current pharmaceutical-based approaches to ameliorating neuropathy in patients who are likely to require treatment for the rest of their lives. PUBLIC HEALTH RELEVANCE Our primary aim is to investigate the effect of low-intensity ultrasound to prevent and treat nerve damage in diabetic rats. Our secondary aim is to investigate whether the mechanism of action is related to induction of changes in blood flow local, without there being any general systemic effects. The goal is to determine whether this non-invasive, non-pharmaceutical, therapy has potential for rapid translation to use in patients suffering from diabetic neuropathy, for whom life-long treatment with systemic drugs designed to improve nerve blood flow may be costly and have harmful side-effects.

描述（由申请人提供）：糖尿病神经病变是一种普遍存在的临床问题，目前还没有 FDA 批准的基于机制的治疗方法。人们对神经病变继发于糖尿病患者微血管疾病的假设非常感兴趣，并且在临床前和临床研究中正在探索旨在诱导神经血管舒张或血管生成的药物疗法。然而，这些全身性药物方法尚未解决如何在不影响其他器官血管床的情况下靶向神经血流的问题，在其他器官中，增加血流量可能对糖尿病患者有害。因此，我们对诱导局部血流而非全身血流的非药物方法产生了兴趣。脉冲低强度超声波通过血管扩张和血管生成机制增加局部血流量，作为其伤口愈合特性的一部分。据我们所知，低强度超声尚未对其预防或减轻糖尿病神经病变指标的潜力进行全面的临床前评估。我们将提出一个普遍的假设，即低强度超声治疗能够在 2 型糖尿病和 2 型糖尿病大鼠模型中诱导生化和生理事件，通过调节局部组织血流的能力来预防和逆转神经病变的功能和结构指标的发展。我们进行了探索性研究，以调查超声治疗对 1 型糖尿病链脲佐菌素-糖尿病大鼠模型中神经紊乱的影响，并发现它可以改善神经传导减慢。我们建议在预防和逆转范式中对低强度超声对 STZ 糖尿病大鼠功能性和结构性神经紊乱的影响进行全面调查，并将最佳治疗方案扩展到 2 型糖尿病的 ZDF 模型。这将是我们的主要目标，虽然它代表了一种观察性和高风险的方法，但我们相信，我们的研究结果有可能促使积极的临床前观察异常快速地转化为临床使用，因为非-治疗的侵入性、非全身性和非药物性质。我们的第二个目标是开始研究潜在的作用机制，即超声治疗诱导神经中 HIF/VEGF/EPO 介导的修复反应，以应对血液从神经到肌肉的急性转移引起的过度神经缺血性缺氧。通过研究治疗糖尿病神经病变的局部非药物方法，我们希望避免目前以药物为基础的方法来改善可能需要治疗糖尿病神经病变的患者所固有的副作用、全身效应和成本问题。他们的余生。公共健康相关性我们的主要目的是研究低强度超声对预防和治疗糖尿病大鼠神经损伤的作用。我们的次要目的是研究作用机制是否与诱导局部血流变化有关，而不存在任何一般的全身效应。我们的目标是确定这种非侵入性、非药物疗法是否有潜力快速转化为糖尿病神经病变患者使用，对于这些患者来说，终身使用旨在改善神经血流的全身药物治疗可能成本高昂，而且效果不佳。有害的副作用。