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）：糖尿病神经病是一个广泛的临床问题，没有FDA批准的基于机械的治疗。在糖尿病患者中神经病是继发于微血管疾病的假设和旨在诱导神经血管生成或血管生成的药物疗法的假设引起的兴趣。但是，这些系统性的药物方法尚未克服如何靶向神经血流而不会影响其他器官中血液流量增加可能对糖尿病患者有害的问题。因此，我们已经对诱导局部而不是系统性血流的非药物方法感兴趣。脉冲低强度超声可以通过血管扩张器和血管生成机制增加局部血流，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指数的潜力进行全面的临床前评估。我们将解决以下一般假设：低强度超声处理能够在类型和2型糖尿病的大鼠模型中诱导生化和生理事件，从而通过调节局部组织血流来预防和逆转神经病功能和结构性指标的发育。我们已经进行了探索性研究，以研究超声处理对1型糖尿病链霉菌素糖尿病大鼠模型中神经疾病的影响，并发现它可以改善神经传导的减慢。我们建议对预防和逆转范式中STZ糖尿病大鼠中低强度超声对功能和结构神经疾病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，尽管它代表了一种有点观察和高风险的方法，但我们认为，这是由于我们的发现的潜力平衡，因为我们的发现，临床使用的积极临床前观察会异常快速地翻译为临床使用，因为非侵入性，非肠肠脉络性和非毒品基于治疗的性质的性质。我们的次要目标是开始研究一种潜在的作用机制，即超声处理会导致神经中的HIF/VEGF/EPO介导的修复反应，从而响应急性血液从神经到肌肉的急性转移而引起的夸张的神经缺血性缺氧。通过研究一种局部非药物治疗糖尿病神经病的方法，我们希望避免避免副作用，全身效应和成本问题，这些副作用，成本问题是当前基于药物的基于药物的神经病的固有方法，以改善可能需要治疗余生的患者的患者。公共卫生相关性我们的主要目的是研究低强度超声检查以预防和治疗糖尿病大鼠神经损伤的影响。我们的次要目的是研究作用机理是否与局部血流变化的诱导有关，而没有任何一般的系统性影响。目的是确定这种非侵入性，非药物的治疗是否有可能快速翻译用于患有糖尿病神经病的患者，该患者用旨在改善神经血流的全身药物治疗，旨在改善神经血流的终身治疗可能是昂贵的，并且具有有害的副作用。