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

基本信息

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
项目类别：
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

项目摘要

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）：周围神经病变是糖尿病最常见的并发症，目前患有该疾病的 2500 万美国人中有一半以上会受到周围神经病变的影响。目前还没有 FDA 批准的治疗方法可以逆转许多新诊断的糖尿病患者中已经存在的远端退行性神经病变，并且随着时间的推移，这种病变会逐渐恶化。最近的临床和实验研究表明，小感觉轴突的外周末端从皮肤表皮回缩是糖尿病神经病变的早期特征。这提供了在神经元死亡发生之前停止或逆转外周末梢死亡的机会。我们的临床前研究表明，结构多样的毒蕈碱受体拮抗剂，如哌仑西平、VU0255035、MT-7和奥昔布宁可在体外促进成年大鼠感觉神经元的轴突生长，并且此类药物还可以防止表皮内神经纤维的损失（IENF））以及 1 型和 2 型糖尿病啮齿动物模型神经病变的其他特征。因此，成年周围神经元似乎处于轴突生长的持续内源性胆碱能约束之下。这一知识的实际应用是，毒蕈碱受体拮抗剂可能是逆转早期糖尿病神经病变的可行且新颖的疗法。 FDA 最近批准使用毒蕈碱受体拮抗剂奥昔布宁 (Gelnique 3%TM) 作为膀胱过度活动症的日常局部治疗。该药物每天以凝胶形式应用于皮肤区域，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来说是可以预见的。由于奥昔布宁是我们发现的可以预防糖尿病啮齿动物 IENF 耗竭的药物之一，因此我们现在提议进行一项试点临床试验，以确定在研究者发起的研究中超说明书使用的 Gelnique 3%TM 是否可以促进糖尿病啮齿动物中 IENF 的重新生长。一组已确诊周围神经病变的 2 型糖尿病受试者。我们将利用我们之前使用临床试验设计的经验，成功地证明了药物治疗在改善 2 型糖尿病受试者 IENF 密度方面的功效，为研究提供适当的动力，并重点关注易于恢复的神经病变终点。我们还将通过在患有 2 型糖尿病和已确诊周围神经病变的受试者中进行双盲、安慰剂对照研究来增强早期设计，该研究将测量每日将 Gelnique 3%TM 应用于近端之前和之后 20 周收集的皮肤活检中的 IENF 密度腿作为主要终点。次要终点是皮肤血流量、定量感官测试值和生活质量评分。我们还将包括一项关于催汗功能和汗腺神经支配的探索性研究，该研究将提供有关自主神经病变的数据，并协助针对糖尿病神经病变这一尚未充分研究的方面开发和验证新的生物标志物。我们进行这项试点临床试验的目的是为了说明一种治疗方法是从集中治疗中出现的临床前药物发现计划可以快速转化为在患有周围神经病变的糖尿病受试者中显示出明显的疗效。目标是提供概念验证数据，以支持（或反驳）毒蕈碱拮抗剂作为糖尿病神经病变的新型安全治疗方法的进一步开发。