Naltrexone as a Novel Treatment for Diabetic Keratopathy

纳曲酮作为糖尿病角膜病的新型治疗方法

• 批准号: 6954645
• 负责人: IAN S ZAGON
• 金额: $ 36.08万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-30 至 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6954645
• 关键词: corneal epithelium; diabetes mellitus therapy; diabetic ophthalmopathy; dosage; drug screening /evaluation; eye disorder chemotherapy; insulin dependent diabetes mellitus; keratitis; laboratory rabbit; laboratory rat; naltrexone; nonhuman therapy evaluation; wound healing

DESCRIPTION (provided by applicant): Corneal erosions/abrasions ranging from superficial defects to full thickness epithelial lesions are found in 50% of diabetic patients, and this condition is termed diabetic keratopathy. Moreover, difficulty with corneal re-epithelialization and persistent epithelial defects/recurrent erosions is associated with the use of donor corneas from diabetic patients, and with corneal epithelial removal during vitrectomy in diabetic individuals. Such corneal epithelial defects can result in infectious corneal ulcers, secondary scarring, and loss of vision. Compelling evidence shows that blockade of opioid-receptor interactions by the opioid antagonist, naltrexone (NTX), restores corneal epithelial wound healing in uncontrolled diabetes. This grant is designed to make the transition from bench to bedside and explores the hypothesis that topical application of NTX will prevent and/or ameliorate corneal epithelial wound healing complications related to Type 1 diabetes. A multi-disciplinary research team consisting of a basic scientist, two ophthalmologists, and a biostatistician have formed a partnership in order to reach the full therapeutic potential of this advance in cell and molecular biology. In the R21 phase (with completion in the R33 phase), this hypothesis is tested in animal models of well-controlled Type 1 diabetes as to the toxicity and efficacy of NTX in the homeostatic (unwounded) and injured corneal epithelium. In order to prepare for FDA requirements, two species of animals are utilized: rat and rabbit. The grant utilizes a well-documented and reliable model of corneal re-epithelialization in the rat and rabbit, induction of Type 1 diabetes by injection of streptozotocin (STZ) (rats) or alloxan (rabbits), and subcutaneous insulin pellets to maintain normoglycemia. The R21 studies the effects of NTX on uninjured (Specific Aim #1) and injured (Specific Aim #2) corneal epithelium of rats, and the uninjured rabbit corneal epithelium (Specific Aim #3). The R33 investigates the safety and efficacy of NTX treatment in corneal abrasions in the diabetic rabbit (Specific Aim #1). If the animal experiments successfully show a non-toxic dose with efficacy, we will perform due diligence testing under the guidelines of the Food and Drug Administration (Specific Aim #2). These data will be used to secure an IND number in order to pursue clinical trials, and as evidence for Institutional Review Board approval to conduct Phase I clinical trials. The proposed use of biotherapy with NTX is an innovative approach whereby the patient's own growth regulatory mechanisms are manipulated to correct complications from diabetes.

描述（由申请人提供）： 在50%的糖尿病患者中发现角膜糜烂/擦伤，范围从表面缺陷到全层上皮病变，这种病症被称为糖尿病性角膜病变。此外，角膜再上皮化的困难和持续的上皮缺陷/复发性糜烂与使用来自糖尿病患者的供体角膜以及糖尿病个体的玻璃体切除术期间的角膜上皮去除相关。这种角膜上皮缺陷可导致感染性角膜溃疡、继发性瘢痕形成和视力丧失。令人信服的证据表明，阿片类药物拮抗剂纳洛酮（NTX）阻断阿片类药物-受体相互作用，可恢复不受控制的糖尿病患者的角膜上皮伤口愈合。该补助金旨在从实验室过渡到床边，并探索NTX的局部应用将预防和/或改善与1型糖尿病相关的角膜上皮伤口愈合并发症的假设。由一名基础科学家，两名眼科医生和一名生物统计学家组成的多学科研究团队已经建立了合作伙伴关系，以充分发挥细胞和分子生物学这一进步的治疗潜力。在R21阶段（在R33阶段完成），在良好控制的1型糖尿病的动物模型中测试了该假设，关于NTX在稳态（未受伤）和受伤的角膜上皮中的毒性和功效。为了满足FDA要求，使用了两种动物：大鼠和家兔。该资助利用了一个有充分记录的和可靠的模型，在大鼠和兔子的角膜上皮再生，诱导1型糖尿病的注射链脲佐菌素（STZ）（大鼠）或四氧嘧啶（兔子），皮下胰岛素丸，以维持正常。R21研究了NTX对大鼠未损伤（特定目标#1）和损伤（特定目标#2）角膜上皮以及未损伤兔角膜上皮（特定目标#3）的影响。R33研究了NTX治疗糖尿病兔角膜擦伤的安全性和有效性（具体目标#1）。如果动物实验成功显示无毒剂量有效，我们将根据美国食品药品监督管理局的指导原则（具体目标#2）进行尽职调查测试。这些数据将用于获得IND编号，以便进行临床试验，并作为机构审查委员会批准进行I期临床试验的证据。 建议使用NTX生物疗法是一种创新方法，通过操纵患者自身的生长调节机制来纠正糖尿病并发症。

项目成果

Corneal safety of topically applied naltrexone.

局部应用纳曲酮的角膜安全性。

• DOI: 10.1089/jop.2006.22.377
• 发表时间: 2006
• 期刊: Journal of ocular pharmacology and therapeutics : the official journal of the Association for Ocular Pharmacology and Therapeutics
• 作者: Zagon,IanS;Klocek,MatthewS;Sassani,JosephW;Mauger,DavidT;McLaughlin,PatriciaJ
• 通讯作者: McLaughlin,PatriciaJ

Adaptation of homeostatic ocular surface epithelium to chronic treatment with the opioid antagonist naltrexone.

稳态眼表上皮对阿片类拮抗剂纳曲酮长期治疗的适应。

• DOI: 10.1097/01.ico.0000224646.66472.aa
• 发表时间: 2006
• 期刊: Cornea
• 影响因子: 2.8
• 作者: Zagon,IanS;Sassani,JosephW;McLaughlin,PatriciaJ
• 通讯作者: McLaughlin,PatriciaJ

Dry eye reversal and corneal sensation restoration with topical naltrexone in diabetes mellitus.

• DOI: 10.1001/archophthalmol.2009.270
• 发表时间: 2009-11
• 期刊: ARCHIVES OF OPHTHALMOLOGY
• 作者: Zagon, Ian S.;Klocek, Matthew S.;Sassani, Joseph W.;McLaughlin, Patricia J.
• 通讯作者: McLaughlin, Patricia J.

Naltrexone accelerates healing without compromise of adhesion complexes in normal and diabetic corneal epithelium.

纳曲酮可加速愈合，而不损害正常和糖尿病角膜上皮中的粘附复合物。

• DOI: 10.1016/j.brainresbull.2006.12.007
• 发表时间: 2007
• 期刊: Brain research bulletin
• 影响因子: 3.8
• 作者: Zagon,IanS;Sassani,JosephW;Myers,RolandL;McLaughlin,PatriciaJ
• 通讯作者: McLaughlin,PatriciaJ