糖尿病视网膜病变的生化机制与药物治疗

糖尿病视网膜病变是导致不可逆性视力丧失的首要原因。由于糖尿病发病率正随着人们生活方式的改变而上升，加之人类寿命的延长，视网膜病变正成为新世纪所面临的严峻挑战。对于视网膜病变目前还没有有效的药物。良好的血糖控制可以在很大程度上阻止糖尿病视网膜病变的进展。激光治疗仍是现在最可令人接受的一种治疗方法。高血糖可以产生多种生化缺陷，影响许多细胞信号的表达，包括对视网膜病变相关的生长因子的刺激作用。因此，将来有可能会出现一种新的治疗方法来治疗视网膜病变。目前可以特异性改善视网膜病变生化缺陷的治疗药物均未上市，正在研究之中的如蛋白激酶C抑制剂、血管内皮生长因子抑制剂、色素上皮源性因子及许多其它的因子也许会被证实可作为新的治疗手段，有效地对视网膜病变不同阶段进行治疗。本文对视网膜病变复杂的生化机制及与之相关的药物作一介绍。     

糖尿病视网膜病变的影响因素及药物治疗研究进展

糖尿病视网膜病变(DR)是糖尿病微血管病变在眼底独特环境中的表现,是糖尿病最常见、最主要的微血管并发症之一,已经成为当前全球致盲的重要原因,发病率高达30%,其影响因素很多,发病机制非常复杂。现将糖尿病视网膜病变的影响因素及药物治疗的研究进展综述如下。     

糖尿病视网膜病变的影响因素及药物治疗研究进展

糖尿病视网膜病变(DR)是糖尿病微血管病变在眼底独特环境中的表现,是糖尿病最常见、最主要的微血管并发症之一,已经成为当前全球致盲的重要原因,发病率高达30%,其影响因素很多,发病机制非常复杂.现将糖尿病视网膜病变的影响因素及药物治疗的研究进展综述如下.     

用于治疗糖尿病视网膜病变的抗血管新生药物

糖尿病视网膜病变是糖尿病的主要并发症,也是中老年人失明的重要原因之一。血管新生被普遍认为是糖尿病视网膜病变的治疗靶点。综述可用于治疗糖尿病视网膜病变的抗血管新生药物,包括抗血管内皮细胞生长因子药物、皮质类固醇激素、蛋白激酶C-β抑制剂和色素上皮衍生因子等的研究进展,为该类药物的深入开发和临床应用提供思路。     

非甾体抗炎药防治糖尿病视网膜病变的研究进展

糖尿病视网膜病变(DR)是糖尿病最严重和常见的微血管慢性并发症之一,其发病机制复杂,至今尚未完全阐明。大量资料表明,炎症参与了糖尿病视网膜病变的发生、发展,非甾体抗炎药(NSAIDs)通过抑制炎症因子或炎症介质的表达,控制视网膜炎症反应,可以减轻DR视网膜的损伤。如今,NSAIDs已经成为研究药物治疗DR的热点之一。     

糖尿病视网膜病变相关检测指标与药物治疗

糖尿病视网膜病变是糖尿病患者较为严重的并发症．糖尿病病程越长其发生率越高。糖尿病一但确诊,眼底检查应定期进行,以利于尽早发现糖尿病视网膜病变．同时,相关检测指标如维生素D水平、游离脂肪酸水平、血清视黄醇结合蛋白4水平、D-二聚体水平等指标．更应及早筛查．这些指标的检测对于糖尿病视网膜病变的监控、判断轻重、用药防治及分析愈后都有着十分重要的意义。基于糖尿病视网膜病变的发病机制及患者体内检测指标的改变．人们已经研发出治疗药物．用于患者针对性治疗或辅助性治疗,取得了较好的临床疗效。     

糖尿病视网膜病变的治疗及护理

糖尿病视网膜病变(DR)是导致成人致盲的主要原因,严重影响糖尿病患者生存质量。随着激光光凝术技术及方式的日臻完善,对糖尿病视网膜病变进展机制及防治研究的不断深入,相关药物应用及防治措施的实施,糖尿病视网膜病变进展将得到有效控制。     

胱抑素C与2型糖尿病视网膜病变的相关性研究

<正>糖尿病视网膜病变(diabetic retinopathy,DR)是糖尿病患者最常见的微血管并发症之一,严重者可导致失明,其发生机制尚不完全清楚。我国糖尿病住院患者中并发视网膜病变者占35.7%[1]。如何早期发现糖尿病视网膜病变且给予及时有效的诊治是该病防治的重点,然而目前尚缺乏有效的早期诊断糖尿病视网膜病变的生物学指标。胱抑素C(cystatin C,Cys C)也称半胱氨酸蛋白酶抑制剂C,广泛存在于各种组织     

糖尿病视网膜病变的临床治疗现状及研究进展

糖尿病视网膜病变(DR)为长期高血糖导致的糖尿病患者视网膜局部微血管病变, 可造成不同程度的视功能损害, 是致盲的主要原因。DR的发生与多种因素有关, 其发病机制也十分复杂。目前临床上DR的治疗方式多种多样, 但疗效各异。随着DR发病机制研究的不断深入, 多种治疗该病的方法被不断提出。本文结合既往的研究报道对DR的发病机制和临床治疗现状进行综述, 旨在为临床提供参考。     

常见糖尿病慢性并发症的药物研发进展

糖尿病慢性并发症是由糖尿病病变转化而来的一系列慢性疾病,常见的主要包括糖尿病肾病、糖尿病视网膜病变和糖尿病神经病变等,严重影响着人们的生活。目前直接治疗糖尿病慢性并发症的药物很少,为了研发出治疗这些病的药物,各国的科研人员正在做不懈的努力。将对糖尿病肾病、糖尿病视网膜病变和糖尿病神经病变三大慢性并发症的药物研发进展进行综述。     

糖尿病视网膜病的药物治疗进展

对糖尿病视网膜病发病机制的研究是其药物治疗的基础。从抑制蛋白非酶糖基化终末产物、蛋白激酶C信号通路、细胞因子，抗氧化和对抗肾素-血管紧张素系统，内皮素受体拮抗剂等方面介绍了糖尿病视网膜病的治疗药物及研究思路。     

Pigment epithelium-derived factor Met72Thr polymorphism in patients with diabetic microangiopathy

Pigment epithelium-derived factor (PEDF) has recently been shown to be the most potent inhibitor of angiogenesis in the mammalian eye. We, along with others, have very recently found that loss of PEDF is involved in the development and progression of diabetic retinopathy. However, there are no studies on the allelic effects of PEDF gene polymorphism in diabetic retinopathy. In this study, we investigated whether a functional amino acid change, a methionine to threonine polymorphism (Met72Thr polymorphism) of the PEDF gene, is associated with microangiopathy in 143 patients with diabetes. We found that there were no significant associations between PEDF Met72Thr gene polymorphism and diabetic microangiopathy. These observations suggest that these genetic variants might not be involved in the mechanism of diabetic microangiopathy in patients with diabetes.     

Ruboxistaurin (Eli Lilly)

Eli Lilly & Co is developing the protein kinase C (PKC)-b inhibitor ruboxistaurin, the lead compound from a series of 14-membered macrocycles, for the potential treatment of diabetic retinopathy, diabetic peripheral neuropathy and macular edema.     

Effects of arctiin on streptozotocin-induced diabetic retinopathy in sprague-dawley rats

Diabetic retinopathy is one of the most common and severe complications of diabetes mellitus. Arctiin, a bioactive compound isolated from the dry seeds of Arctium lappa L., has been reported to have antidiabetic activity. In this study, we investigated the effect of arctiin on the serum glucose and HBA1c levels, the blood viscosity, and VEGF expression in the retinal tissues of rats with diabetic retinopathy. We first extracted arctiin from Fructus Arctii and then investigated its chemopreventive effect on streptozotocin-induced diabetic retinopathy in male Sprague-Dawley rats. After the induction of diabetes using streptozotocin (30 mg/kg, i. p.), the rats were randomly divided into five groups (n = 20 per group) and treated with intragastric doses of 30, 90, or 270 mg/kg/d wt of arctiin, 100 mg/kg/d wt of calcium dobesilate, or 0.5 % CMC-Na. Twenty nondiabetic sham-treated rats were treated with 0.5 % CMC-Na. The occurrence of diabetic retinopathy did not differ dramatically among the groups. However, at week 16, the glycosylated haemoglobin (HBA1c) level was significantly decreased in all of the arctiin-treated groups when compared with the control group, and the serum glucose level was also decreased in the rats treated with the highest dose of arctiin. In addition, treatment with arctiin ameliorated retinal oedema, detachment of the retina, and VEGF expression in the retina, as detected using histological and immunochemical examinations. Finally, arctiin increased the viability of retinal microvascular endothelial cells in vitro. Together, these findings demonstrate that arctiin decreases the severity of diabetic complications, demonstrating the importance of this compound as an inhibitor of diabetic retinopathy.     

Vascular protection of DPP-4 inhibitors in retinal endothelial cells in in vitro culture

People with diabetes are at high risk of developing diabetes-related eye disease, termed as diabetic retinopathy, due damage being caused to the blood vessels in the retina. An efficient medical treatment to reduce diabetic retinopathy can improve the quality of life for diabetes patients. In our study, we show that linagliptin, a commercially available DPP-4 inhibitor, plays a protective role in retinal vascular endothelial cells. The presence of linagliptin protects retinal endothelial cells against TNF-α-induced cytotoxicity and enhances their viability. Linagliptin treatment suppresses TNF-α-induced production of reactive oxygen species and improves mitochondrial membrane potential. Moreover, linagliptin suppresses TNF-α-induced production of pro-inflammatory and pro-adhesive vascular cytokines including IL-6, IL-8, ICAM-1, and VCAM-1. The presence of linagliptin in cell media can reduce the number of THP-1 cells that adhere to retina endothelial cells. Mechanistically, linagliptin potently suppresses TNF-α-induced accumulation of NF-κB nuclear protein p65 and activation of NF-κB promoter. Our data indicate that linagliptin is an anti-inflammatory diabetic agent, with the potential to be applied as a treatment for diabetic retinopathy.     

From peptides to peptidomimetics: rational design of potential PKC-β II inhibitors

Chronic hyperglycaemia is a major initiator of diabetic cardiovascular complications and microvascular complications such as retinopathy, neuropathy and nephropathy. Experimental results reveal liaison between cardiovascular disease and diabetic complications. Of the various targets, PKCs were identified to be specifically involved in diabetic complications, of which PKCβII isoform was found to play a significant role. Although the benefit of PKCβII is immense, not a single molecule has been approved yet for diabetic treatment. Because protein kinases share a high degree of similarity in both structure and functions, developing a highly specific inhibitor has been a challenging task. In this study, we have designed peptidomimetics based on autoinhibitory domain as this domain has a recognition motif specific for each isoform to resolve the specificity issue and validated the designed peptidomimetics by molecular docking. This study has provided useful insights into molecules that may be useful for diabetic complications.     

Advanced glycation and advanced lipoxidation: possible role in initiation and progression of diabetic retinopathy

Diabetic retinopathy remains the most common microvascular complication suffered by diabetic patients and is the leading cause of registerable blindness in the working population of developed countries. The clinicopathological lesions of diabetic retinopathy have been well characterised and although a multitude of pathogenic mechanisms have been proposed, the underlying dysfunctional biochemical and molecular pathways that lead to initiation and progression of this complication remain largely unresolved. There is little doubt that the pathogenesis of diabetic retinopathy is highly complex and there is a pressing need to establish new therapeutic regimens that can effectively prevent or limit retinal microvascular cell dysfunction and death which is characteristic of the vasodegenerative stages of diabetic retinopathy. The formation and accumulation of advanced glycation endproducts (AGEs) and/or advanced lipoxidation endproducts (ALEs) are among several pathogenic mechanisms that may contribute to diabetic retinopathy. AGEs/ALEs can form on the amino groups of proteins, lipids and DNA through a number of complex pathways including non-enzymatic glycation by glucose and reaction with metabolic intermediates and reactive dicarbonyl intermediates. These reactions not only modify the structure and function of proteins, but also cause intra-molecular and intermolecular cross-link formation. AGEs/ALEs are known to accumulate in the diabetic retina where they may have important effects on retinal vascular cell function, as determined by a growing number of in vitro and in vivo studies. Evidence now points towards a pathogenic role for advanced glycation/lipoxidation in the initiation and progression of diabetic retinopathy and this review will examine the current state of knowledge of AGE/ALE-related pathology in the diabetic retina at a cellular and molecular level. It will also outline how recent pharmaceutical strategies to inhibit AGE/ALE formation or limit their pathogenic influence during chronic hyperglycaemia may play a significant role in the treatment of diabetic retinopathy.     

EGFR inhibitor,AG1478, inhibits inflammatory infiltration and angiogenesis in mice with diabetic retinopathy

Diabetic retinopathy (DR) is one of the most frequently occurring microvascular complications of diabetes. Recent evidence indicates that epidermal growth factor receptors (EGFRs) are critical pathogenic players in non‐neoplastic diseases, including diabetic cardiomyopathy and DR. However, the precise pathogenic mechanism of EGFR in DR has yet to be fully understood. In this study, we developed a type 1 diabetic early‐stage retinopathy mouse model using injections of streptozotocin and an oxygen‐induced end‐stage diabetic retinopathy (OIR) model characterized by hypoxia‐induced revascularization. We tested the hypothesis that the pathogenesis of DR can be reduced by the classic EGFR inhibitor, AG1478, in the mouse models. Our data indicated that treatment of AG1478 prevented retinal dysfunction, and reduced impairment of retinal structures as well as mitochondrial structures in retinal blood vessels in diabetic mice. Furthermore, AG1478 reduced neovascular tufts formation but had no effects on revascularization at the avascular sites when compared to untreated littermates in the OIR model. Our findings provide strong evidence that EGFR critically promoted retinal dysfunction, retinal structural impairment, and retinal vascular abnormalities in models of DR. We conclude that EGFR can be a potential important therapeutic target for treatment of DR.     

Ruboxistaurin: LY 333531

Ruboxistaurin, an orally active protein kinase C beta (PKC beta) inhibitor, is a macrocyclic bisindolylmaleimide compound under development by Eli Lilly with potential as a therapy for diabetic macular oedema and other diabetic angiopathies, including diabetic retinopathy, diabetic peripheral neuropathy and diabetic nephropathy. Ruboxistaurin is awaiting approvals in the US and Europe for the treatment of diabetic retinopathy. Eli Lilly and Alcon entered into a long-term agreement to co-promote ruboxistaurin in the US and Puerto Rico for diabetic retinopathy. The agreement is subject to the US FDA's approval of the agent for this indication. Under the terms of the agreement, Alcon will assume primary responsibility for promotion to eye specialists including retinal specialists and general ophthalmologists, while Eli Lilly will be targeting endocrinologists and physicians. Subject to approval in the US, Eli Lilly will receive milestone and marketing payments from Alcon. Alcon in turn will receive compensation based on product sales. In December 2003, Eli Lilly signed a joint development and co-marketing agreement with Takeda Chemical Industries for ruboxistaurin in the Japanese market. Under the terms of the agreement, Eli Lilly Japan and Takeda will jointly develop ruboxistaurin in Japan, will file an NDA for diabetic peripheral neuropathy and diabetic retinopathy, and subsequently will market the drug in Japan. Ruboxistaurin was submitted for approval in Europe in the second quarter of 2006. The agent is also in phase II studies for the treatment of diabetic maculopathy (macular retinopathy) in Japan. Data from a phase III, 3-year study of ruboxistaurin in patients with moderate to severe diabetic retinopathy showed that ruboxistaurin markedly reduced the risk of sustained vision loss compared with placebo. This multicentre, randomised study, named PKC-DRS2 (Protein Kinase C-Diabetic Retinopathy Study 2), was conducted at 70 clinical sites and involved 685 patients with diabetic retinopathy. The agent is also in a phase II study in the US, Canada and Europe in patients with clinically significant macular oedema. The trial (B7A-MC-MBCU), which will evaluate oral administration of the drug using optical coherence tomography over a period of 18 months, is expected to enrol approximately 220 patients. This randomised, double-blind, placebo-controlled study was initiated in August 2005 and is expected to be completed in March 2008. Previously, results of the PKC-Diabetic Retinopathy Study (PKC-DRS) showed that ruboxistaurin at a dose of 32 mg/day has potential to reduce the risk of moderate vision loss especially in patients with diabetic macular oedema. This phase III, randomised, double-blind, multidose study in 252 patients with type 1 and type 2 diabetes receiving ruboxistaurin or placebo for 3-4 years evaluated the safety of the agent and its effect on progression of diabetic retinopathy, moderate vision loss and sustained moderate vision loss. The study was conducted at Joslin Diabetes Center and at centres in the US, Canada, Denmark, The Netherlands and the UK. In 2004, Eli Lilly presented new analysis of previously reported data for ruboxistaurin in diabetic macular oedema indicating that ruboxistaurin has the potential to decrease the progression of diabetic macular oedema involving the center of the macula. Positive results from the PKC Beta Inhibitor Diabetic Macular Edema (PKC-DMES) trial were reported in 2003. Eli Lilly expected to file for approval of ruboxistaurin for the treatment of diabetic peripheral neuropathy in the US and Europe in 2005. However, no development was reported for this indication. On 15 March 2007, Eli Lilly withdrew its marketing authorisation application for ruboxistaurin for diabetic retinopathy filed with EMEA in May 2006. Its current development status in the EU is unclear at this stage.     

Ruboxistaurin

Ruboxistaurin is a potent and specific inhibitor of the beta isoform of protein kinase C. Overactivation of protein kinase C has been demonstrated in patients with type 2 diabetes, and is postulated to play a major role in the pathogenesis of diabetic microvascular complications, which include diabetic retinopathy, neuropathy and nephropathy. The role of protein kinase C in promoting tissue injury in patients with diabetes, and the pharmacologic and clinical studies illustrating the potential of ruboxistaurin to reduce the burden of diabetic microvascular complications will be discussed in this article.