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了从表面缺陷到全厚度上皮病变的角膜侵蚀/擦伤，并且这种病被称为糖尿病性角膜病。此外，角膜重新上皮化和持续性上皮缺陷/复发性侵蚀的困难与糖尿病患者的供体角膜的使用以及糖尿病个体中玻璃体切除术期间的角膜上皮切除有关。这种角膜上皮缺陷会导致感染性的角膜溃疡，次要疤痕和视力丧失。令人信服的证据表明，阿片类药物拮抗剂Naltrexone（NTX）封锁了阿片类药物受体相互作用，可恢复不受控制的糖尿病中角膜上皮伤口愈合。该赠款旨在使从长凳到床边的过渡，并探讨了以下假设：NTX的局部应用将预防和/或改善与1型糖尿病有关的角膜上皮伤口愈合并发症。一个由基本科学家，两名眼科医生和生物统计学家组成的多学科研究团队已经建立了伙伴关系，以便在细胞和分子生物学中达到这种进步的全部治疗潜力。在R21阶段（在R33阶段完成）中，该假设在良好控制的1型糖尿病的动物模型中进行了关于NTX在稳态（未调的）和受伤的角膜上皮的毒性和功效的动物模型。为了准备FDA要求，使用了两种动物：大鼠和兔子。该赠款利用了大鼠和兔子中角膜重新上皮化的有据可查且可靠的模型，通过注射链霉菌素（STZ）（大鼠）（大鼠）或Alloxan（兔）（兔子）和皮下胰岛素损伤来诱导1型糖尿病，以维持正常的胰岛素。 R21研究了NTX对大鼠的未受伤（特定目标＃1）和受伤（特定目标＃2）的影响（特定目标＃2）和未受伤的兔角膜上皮（特定的目标＃3）。 R33研究了NTX治疗在糖尿病兔中角膜擦伤中的安全性和功效（特定的目标＃1）。如果动物实验成功地显示出具有功效的无毒剂量，我们将根据食品和药物管理的指南进行尽职调查测试（具体目标＃2）。这些数据将用于确保IND数字以进行临床试验，并作为机构审查委员会批准进行I期临床试验的证据。 提议使用NTX的生物治疗是一种创新的方法，可以操纵患者自身的生长调节机制以纠正糖尿病并发症。

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