Muscarinic receptor antagonists as a therapy for diabetic neuropathy

毒蕈碱受体拮抗剂治疗糖尿病神经病变

• 批准号: 8684643
• 负责人: NIGEL A. CALCUTT
• 金额: $ 22.95万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8684643
• 关键词: Adult; Adverse effects; Afferent Neurons; Aftercare; American; Anti-Cholinergics; Axon; Back; Biological Assay; Biological Markers; Biopsy; Blood flow; Cessation of life; Cholinergic Agents; Clinical Research; Clinical Trials; Clinical Trials Design; Complications of Diabetes Mellitus; Contralateral; Data; Development; Diabetes Mellitus; Diabetic Neuropathies; Discrimination; Disease; Distal; Double-Blind Method; Drug Formulations; Epidermis; Evaluation; FDA approved; Feasibility Studies; Fiber; Future; Gel; Goals; Growth; In Vitro; Insulin-Dependent Diabetes Mellitus; Ipsilateral; Knowledge; Label; Leg; Limb structure; Measurement; Measures; Muscarinic Acetylcholine Receptor; Muscarinic Antagonists; Natural regeneration; Nerve; Nerve Fibers; Nerve Regeneration; Neurons; Neuropathy; Newly Diagnosed; Non-Insulin-Dependent Diabetes Mellitus; Overactive Bladder; Patients; Peripheral; Peripheral Nerves; Peripheral Nervous System Diseases; Pharmaceutical Preparations; Pharmacotherapy; Pilot Projects; Pirenzepine; Placebo Control; Preparation; Process; Quality of life; Randomized; Rattus; Recovery; Research; Research Personnel; Rodent; Rodent Model; Safety; Schedule; Sensory; Skin; Structure; Surveys; Sweat Glands; Testing; Therapeutic; Time; Topical application; Toxic effect; Translating; Translations; Treatment Efficacy; Validation; Xerostomia; arm; autonomic nerve; autonomic neuropathy; axon growth; cholinergic; density; design; diabetic; diabetic patient; drug discovery; experience; foot; improved; in vivo; indexing; nerve supply; novel therapeutic intervention; novel therapeutics; oxybutynin; placebo controlled study; practical application; pre-clinical; preclinical efficacy; preclinical study; prevent; programs; public health relevance; research study; treatment site; type I and type II diabetes

DESCRIPTION (provided by applicant): Peripheral neuropathy is the most common complication of diabetes and will afflict over half of the 25 million Americans who currently suffe from the disease. There is no FDA-approved therapy to reverse the distal degenerative neuropathy that is already present in many newly diagnosed diabetic patients and which gets progressively worse over time. Recent clinical and experimental studies have demonstrated that the retraction of peripheral terminals of small sensory axons from the epidermis of the skin is an early feature of diabetic neuropathy. This offers an opportunity to halt or reverse the dying-back of peripheral terminals before neuronal death occurs. Our preclinical studies have demonstrated that structurally diverse muscarinic receptor antagonists such as pirenzepine, VU0255035, MT-7 and oxybutynin promote axonal growth from sensory neurons of adult rats in vitro and that this class of drugs also prevents loss of intra-epidermal nerve fibers (IENF) and other features of neuropathy in rodent models of type 1 and type 2 diabetes. It therefore appears that adult peripheral neurons are under constant endogenous cholinergic constraint of axonal growth. The practical application of this knowledge is that muscarinic receptor antagonists may be viable and novel therapeutics for reversing early diabetic neuropathy. The FDA has recently approved use of the muscarinic receptor antagonist oxybutynin (Gelnique 3%TM) as a daily topical therapy for overactive bladder. The drug is applied daily to a region of the skin as a gel and has a good safety profile, the main side effect being dry mouth, which is predictable for an anti-cholinergic drug. As oxybutynin is one of the drugs that we found to prevent IENF depletion in diabetic rodents, we now propose a pilot clinical trial to determine whether Gelnique 3%TM, used off label in an investigator initiated study, can promote re-growth of IENF in a group of type 2 diabetic subjects with established peripheral neuropathy. We will take advantage of our prior experience using a clinical trial design that successfully showed efficacy of drug therapy in improving IENF density in type 2 diabetic subjects, to power the study appropriately and focus on neuropathy end points that are amenable to recovery. We will also enhance the earlier design by performing a double blind, placebo controlled study in subjects with type 2 diabetes and established peripheral neuropathy that will measure IENF density in skin biopsies collected before and 20 weeks after daily application of Gelnique 3%TM to the proximal leg as the primary end point. Secondary end points will be skin blood flow, quantitative sensory test values and quality of life score. We will also include an exploratory study of sudomotor function and sweat gland innervation that will provide data on autonomic neuropathy and assist development and validation of new biomarkers for this understudied aspect of diabetic neuropathy. Our intent in performing this pilot clinical trial is to illustrate that a therapeutic emerging from a focused preclinical drug discovery program can be rapidly translated to show demonstrable efficacy in diabetic subjects with peripheral neuropathy. The goal is to provide proof-of-concept data to support (or refute) the further development of muscarinic antagonists as a new and safe treatment for diabetic neuropathy.

描述（由申请人提供）：周围神经病是糖尿病最常见的并发症，将折磨于目前从该疾病中获得的2500万美国人中的一半以上。没有FDA批准的疗法可以扭转许多已诊断出的糖尿病患者已经存在的远端退化性神经病，并且随着时间的流逝逐渐恶化。最近的临床和实验研究表明，从皮肤表皮中缩回小感觉轴突的外围末端是糖尿病神经病的早期特征。这提供了一个机会，可以在神经元死亡发生之前停止或扭转周围终端的垂死。 Our preclinical studies have demonstrated that structurally diverse muscarinic receptor antagonists such as pirenzepine, VU0255035, MT-7 and oxybutynin promote axonal growth from sensory neurons of adult rats in vitro and that this class of drugs also prevents loss of intra-epidermal nerve fibers (IENF) and other features of neuropathy in rodent models of type 1 and 2型糖尿病。因此，似乎成年周围神经元处于轴突生长的恒定内源性胆碱能约束之下。这种知识的实际应用是，毒蕈碱受体拮抗剂可能是可行的，可用于逆转早期糖尿病神经病的新型治疗剂。 FDA最近批准使用毒蕈碱受体拮抗剂羟丁酸（Gelnique 3％TM）作为过度活跃膀胱的日常局部疗法。该药物每天用作凝胶的皮肤区域，并具有良好的安全性，主要副作用是口干，这对于抗胆碱能药物是可预测的。由于羟丁酰蛋白是我们发现糖尿病啮齿动物中IENF耗竭的药物之一，因此我们现在提出一项试验临床试验，以确定在研究人员发起的研究中使用标签的Gelnique 3％TM是否可以促进IENF的IENF重新增长，其中包括2型糖尿病患者，具有固定的近神经疗法。我们将使用临床试验设计利用我们先前的经验，该设计成功地表明了药物治疗在改善2型糖尿病患者中IENF密度的功效，适当地为研究供电，并专注于可恢复的神经病终点。我们还将通过在患有2型糖尿病的受试者和已建立的周围神经病的受试者中进行双盲，安慰剂对照研究来增强早期的设计，该研究将在每天在每天将Gelnique 3％TM应用于近端腿上收集到的皮肤活检中的IENF密度。次要终点将是皮肤血流，定量感觉测试值和生活质量评分。我们还将包括一项探索性研究的探索性研究和汗腺神经支配，该研究将提供有关自主神经病的数据，并为糖尿病神经病的这一研究不足的方面提供了新生物标志物的开发和验证。我们执行这项试验临床试验的目的是说明从聚焦 可以快速翻译临床前药物发现计划，以表现出在周围神经病的糖尿病患者中表现出明显的功效。目的是提供概念验证数据，以支持（或驳斥）毒蕈碱拮抗剂作为糖尿病神经病的一种新的安全治疗。