Pegaptanib for the treatment of age-related macular degeneration

Although neovascular (wet) age-related macular degeneration (AMD) only accounts for 10-20% of all AMD, the majority (about 90%) of severe vision loss associated with AMD is due to this form. Results from recent studies have implied that vascular endothelial growth factor (VEGF), particularly VEGF(165), plays a predominant role in the development of ocular neovascularization and vascular leakage secondary to AMD. Thus VEGF is an important therapeutic target in neovascular AMD. Pegaptanib, an anti-VEGF aptamer, can selectively bind with VEGF(165) and inhibit both the growth of blood vessels and vascular leakage, and was approved by the Food and Drug Administration in the United States as the therapy for the treatment of all subtypes of neovascular AMD in December 2004. This review summaries the mechanism, preclinical and clinical studies, and adverse events of pegaptanib treatment.     

Targeting angiogenesis, the underlying disorder in neovascular age-related macular degeneration

Angiogenesis has a causal role in many diseases, including neovascular age-related macular degeneration (AMD). Identification of key regulators of angiogenesis, including vascular endothelial growth factor (VEGF), fibroblast growth factor 2, pigment epithelium-derived growth factor, angiopoietins and extracellular matrix molecules, has facilitated the development of novel therapeutic agents that target the underlying pathological angiogenic process. Among these, VEGF serves as a "master switch" for many ocular neovascular conditions through its promotion of endothelial cell proliferation and survival, vascular permeability and ocular inflammation. Two anti-VEGF agents are now clinically available: bevacizumab, an antibody for metastatic colorectal cancer, and pegaptanib sodium, an aptamer for neovascular AMD. Unlike bevacizumab, which binds all VEGF isoforms, pegaptanib targets only VEGF165, the isoform responsible for pathological ocular neovascularization and thus an ideal target for treatment of AMD. Although other therapies targeting angiogenesis in AMD are in clinical development, to date, pegaptanib is the only therapy approved by the Food and Drug Administration of the United States for the treatment of all neovascular AMD and represents a valuable addition to the hitherto limited options available for patients.     

Clinical implications of vascular growth factors in proliferative retinopathies

Angiogenesis is a fundamental component of normal development and pathologic processes within the eye. Complications due to abnormal ocular neovascularization remain the leading cause of visual loss throughout the world today. Neovascularization and the associated increase in vascular permeability are the underlying threats to vision in such diverse conditions as diabetic retinopathy, retinal vein occlusion, retinopathy of prematurity, exudative age-related macular degeneration, sickle cell retinopathy, radiation retinopathy, and numerous others. Although it has been appreciated for nearly one-half century that the clinical findings associated with ocular neovascularization suggest an etiology involving the elaboration of growth factors, the exact molecules involved and their mechanisms of action have remained incompletely understood. Recent developments in this rapidly evolving field have begun to elucidate the major factors responsible for modulating the neovascularization common to these conditions and have significant theoretic implications for the development of novel, nondestructive, pharmacologic treatment modalities.     

色素上皮细胞衍生因子基因治疗视网膜及脉络膜新生血管性疾病研究进展

色素上皮细胞衍生因子（pigment epithelium—derived factor，PEDF）是一种相对分子质量为50000的分泌蛋白，属于丝氨酸超家族的一员。近年来研究发现PEDF具有多种生物学功效，包括抗新生血管，神经营养及神经保护功能。PEDF是最有效的内源性眼部新生血管抑制物。PEDF对于治疗血管增生性疾病及视网膜变性性疾病具有广阔的前景，基因转移为眼内组织治疗药物的持续传递提供了有效途径。就近年来关于PEDF基因治疗视网膜及脉络膜疾病的研究进展给以综述。     

Clinical experience with the surgical removal of subfoveal neovascular membranes. Short-term postoperative results.

BACKGROUND: Severe visual loss occurs in the presumed ocular histoplasmosis syndrome (POHS) and in age-related macular degeneration (ARMD) from subfoveal neovascularization. Although laser photocoagulation has recently been recommended for this complication in ARMD, treatment is inevitably associated with a loss of central vision. In an attempt to restore and/or preserve central vision, the authors undertook surgical removal of subfoveal neovascular membranes in these diseases. METHODS: Patients with POHS and ARMD with reduced Snellen visual acuity to 20/80 or less were selected if there was angiographic evidence of a neovascular membrane beneath the fovea. Modern vitreoretinal techniques were used to remove the subfoveal neovascular complex. RESULTS: The authors' first 15 patients with POHS and 19 patients with ARMD were followed for an average of 4 months postoperatively. Snellen visual acuity improved by 2 lines or more in 8 of 15 (53%) cases of POHS. Although similar improvements in Snellen visual acuity were not observed in cases of ARMD, 14 of 19 (74%) cases showed either slight improvement or stabilization of their vision postoperatively. Complications included recurrent neovascularization in 2 of 15 (13%) and 3 of 19 (16%) eyes with POHS and ARMD, respectively. No retinal detachment or preretinal proliferation was observed. CONCLUSIONS: These results suggest that subfoveal neovascularization can be successfully removed with preservation of foveal vision in POHS and stabilization in ARMD, at least for the short term. Visual improvement was observed in POHS even after 6 months of decreased vision. Finally, visual prognosis is most dependent on the integrity of the subfoveal RPE after removal of the membrane.     

干扰素诱导蛋白-10与新生血管性眼病关系的研究进展

干扰素诱导蛋白-10(IP-10)属于EL-CXC类趋化因子,是目前研究较多的一个分子,其唯一的受体是CXCR3.IP-10与其受体特异性结合后,可以发挥抑制新生血管的形成及抗纤维化的作用,该生物学功能也参与新生血管性眼病的发病进程.研究证实,IP-10与亚临床慢性炎症紧密相关,参与年龄相关性黄斑变性(AMD)的发病过程,可能成为一项AMD发病的临床检测指标;表达于脉络膜新生血管内皮细胞上的IP-10/CXCR3信号通路有抑制脉络膜新生血管的作用;此外,IP-10在AMD患眼病灶内的高表达可能与血管内皮生长因子表达升高,反馈性诱导负性调控因子(IP-10等)生成相关.IP-10参与糖尿病视网膜病变(DR)的发病过程中,可用于临床检测DR病情的严重程度及预后评估的新指标,以及可能具有使增生性DR(PDR)患者活动期新生血管生成中止、促进新生血管纤维化的作用,从而抑制PDR的发展.IP-10可通过下调炎症细胞促血管生成因子表达的间接作用以及通过抑制血管内皮细胞迁移和管腔形成的作用直接减少角膜新生血管的生成.IP-10可能参与早产儿视网膜病变和脉络膜息肉样病变的发病过程.鉴于其独特的生物学功能,有望运用IP-10作为靶点进行临床靶向治疗达到抑制新生血管性眼病的目的.本文就近年来IP-10与几种常见新生血管性眼病关系的研究进展进行综述.     

Intraokulare Bevacizumab-Injektionen bei seltenen Indikationen – zwei Kasuistiken

Intravitreal anti-VEGF injections are currently the most effective treatment option for neovascular age-related macular degeneration. The anti-VEGF treatment of other, more common ocular diseases, such as diabetic retinopathy and vascular occlusions with neovascularization and retinal edema, is currently described in numerous studies and cases. Rare neovascular ocular diseases, such as Eales disease, presumed ocular histoplasmosis syndrome (POHS), retinopathy of prematurity, and idiopathic telangiectasia, may be future areas for anti-VEGF therapy. In our case report we describe intravitreal bevacizumab (Avastin) therapy for central serous chorioretinopathy and for pseudoxanthoma elasticum with angioid streaks and choroidal neovascularization. In both cases the intravitreal injection resulted in morphological and functional rehabilitation.     

Laser prophylaxis for age-related macular degeneration

BACKGROUND: Age-related macular degeneration (AMD) is the most common cause of severe and irreversible vision loss among people 50 years of age or older in many Western countries. Most of the available treatments for AMD are intended for the late stage, specifically for choroidal neovascularization (CNV). Effective preventive treatments could have an even greater impact on the vision of the millions of people at risk for vision loss from AMD. Drusen are typically the earliest lesions seen in patients with AMD and precede the development of CNV. In 1973, Gass noted the disappearance of drusen in eyes that received laser photocoagulation, which led to the hypothesis that laser-induced drusen reduction could alter the natural course of AMD. METHODS: We reviewed relevant articles found through a search of MEDLINE through February 2005 by means of the following key words, alone or in combination: drusen, laser, photocoagulation, age-related macular degeneration, macula and choroidal neovascularization. RESULTS: Reports ranging from individual cases and case series to randomized controlled pilot studies have described various laser treatment protocols and their effects on eyes with high-risk drusen but no neovascular changes. These reports provide evidence that laser photocoagulation can induce drusen reduction. Although some investigators have reported a corresponding improvement in visual function, others have found no change or even worsening. The results in several of the larger randomized controlled studies suggest that CNV may occur at an increased rate in laser-treated eyes with high-risk drusen in patients who have neovascular AMD in the other eye. The long-term effects of laser treatment in patients with high-risk drusen in both eyes and no neovascular changes have yet to be determined. INTERPRETATION: The outcome of clinical trials such as the Prophylactic Treatment of Age-Related Macular Degeneration and the Complications of Age-Related Macular Degeneration Prevention Trial will help to determine the role of laser prophylaxis in patients with AMD.     

The results of wet AMD treatment by intravitreal injections--preliminary report

Age-related macular degeneration (AMD) is the leading cause of irreversible, severe loss of vision in the developed countries. One of the modern methods of treatment in neovascular form of AMD are repeated intravitreal injections of ranibizumab (Lucentis). Ranibizumab is a recombinant, humanized, monoclonal antibody that neutralizes all biologically active forms of vascular endothelial growth factor A (VEGF-A). The aim of the study was to analyze the results of intravitreal ranibizumab injections in wet AMD patients. There were 57 patients enrolled in the study. 87% of them avoided any loss of visual acuity and 47.3% gained at least one line at visual acuity chart. Authors conclude that treatment with repeated intravitreal injections of ranibizumab is effective in neovascular form of AMD.     

Angiogenesis and retinal diseases

Angiogenesis is the process involving the growth of new blood vessels from preexisting vessels which occurs in both physiologic and pathological settings. It is a complex process controlled by a large number of modulating factors, the pro-and antiangiogenic factors. The underlying cause of vision loss in proliferative retinal diseases, such as age-related macular degeneration and proliferative diabetic retinopathy, are increased vascular permeability and choroidal neovascularization, and vascular endothelial growth factor (VEGF) plays a central role in this process. VEGF is produced in the eye by retinal pigment epithelium (RPE) cells and is upregulated by hypoxia. There are four major biologically active human isoforms, of which VEGF165 is the predominant in the human eye and appears to be the responsible for pathological ocular neovascularization. Besides being a potent and specific mitogen for endothelial cells, VEGF increases vascular permeability, inhibits endothelial cells apoptosis, and is a chemoattractant for endothelial cell precursors. VEGF is not the only growth factor involved in ocular neovascularization. Basic fibroblast growth factor (bFGF), angiopoietins, pigment epithelium-derived factor (PEDF), and adhesion molecules also play a role in the pro- and antiangiogenic balance. Advances in the understanding of the bases of pathological ocular angiogenesis and identification of angiogenesis regulators have enabled the development of novel therapeutic agents. Anti-VEGF antibodies have been developed for intravitreal use, and other approaches are currently under investigation. These new drugs may be powerful tools for the treatment of the leading causes of irreversible blindness in people over age 65.     

抗VEGF药物在视网膜血管性疾病围手术期的应用

血管内皮生长因子（VEGF）与新生血管性眼病密切相关,是有效的治疗靶点.抗VEGF药物能减少新生血管形成,降低血管通透性,为新生血管性眼病的治疗带来重大变革.目前雷珠单抗在国内已被批准用于湿性年龄相关性黄斑变性的治疗,在美国被批准用于糖尿病性黄斑水肿和视网膜静脉阻塞后黄斑水肿的治疗.抗VEGF药物也作为适应证外治疗药物用于其他新生血管性眼病的治疗,如增生性糖尿病视网膜病变、其他视网膜血管性疾病和新生血管性青光眼等.抗VEGF药物辅助手术治疗显示出明显的疗效,可减少术中、术后的并发症和疾病的复发率.就贝伐单抗和雷珠单抗等抗VEGF药物在视网膜血管性疾病围手术期的应用情况进行综述.     

Use of intravitreal injection of triamcinolone acetonide in the treatment of age-related macular degeneration

Age-related macular degeneration (AMD) is now considered an important and leading cause of blindness among elderly patients in developed and developing countries. AMD has two forms, dry and wet; both can lead to visual loss. However, occurrence of subfoveal choroidal neovascular (CNV) membrane in the wet form results in severe visual impairment. Treatment options for choroidal neovascularization are available in order to maintain and in some cases improve vision. Photodynamic therapy (PDT) has been used to treat both classic and occult membranes. It has known to cause choroidal hypoperfusion and production of vascular endothelial growth factor. Intravitreal steroid can possibly reduce the damage caused due to these undesirable effects. In the recent past, intravitreal injection of triamcinolone acetonide (IVTA) has been used extensively as an adjunct to PDT in AMD in order to reduce the number of PDT sessions and evaluate possible beneficial effects on vision. This article reviews the pharmacological attributes of triamcinolone, available evidence of its use as monotherapy or combination therapy to treat AMD, ocular side-effects thereof and ongoing clinical trials on IVTA.     

Age-related macular degeneration and risk factors for the development of choroidal neovascularization in the fellow eye

Age-related macular degeneration (AMD) is one of the leading causes of blindness in the world. Most of the severe vision loss associated with AMD is due to the development of choroidal neovascularization (CNV). The specific causes of AMD and in particular, its neovascular phase, remain uncertain. During the past two decades a number of large prospective clinical trials, observational epidemiologic studies, and population-based cohort studies have furthered our understanding of this blinding ocular condition. The Macular Photocoagulation Study has received praise for its many contributions in the laser treatment of neovascular complications of AMD; however, these trials have made other significant contributions by helping to better define the natural history of AMD, and in particular, risk factors for the development of CNV in eyes with non-neovascular disease. This type of information may provide significant clues for researchers regarding disease pathogenesis and identify a high-risk group in whom to target new treatment strategies. For patients currently diagnosed with macular degeneration, this information can lead to a better understanding of their condition and a more accurate prognosis of their ocular health and vision status. This article reviews information from a variety of sources to investigate incidence rates and risk factors for the development of CNV in the fellow eye of patients with AMD and unilateral neovascular maculopathy.     

抗VEGF药物治疗血管源性眼病的基础与临床研究进展

许多人类血管源性眼病均与血管内皮生长因子(VEGF)有关.近年来玻璃体腔注射抗VEGF药物治疗血管源性眼病逐渐应用于临床,就maeugen,hcentis和avastin三种抗VEGF药物的基础研究、临床应用进展及不良反应情况进行综述,从生物学特性、临床疗效及应用前景等方面分析比较三种药物的共同点与特异性.     

Pegaptanib治疗湿性年龄相关性黄斑变性的临床研究

年龄相关性黄斑变性(age-relatedmaculardegeneration,AMD)是发达国家老年人的主要致盲眼病,脉络膜新生血管(choroidalneovascularization,CNV)的形成是湿性AMD患者丧失视力的主要原因。CNV的发生机制尚不清楚,已证实血管内皮生长因子(vascularendothelialgrowthfac-tor,VEGF)是诱发CNV的关键因素之一。Pegaptanib作为眼科领域应用的第一种VEGF抑制剂,通过抑制CNV形成和血管渗漏,对湿性AMD已初步显示出较传统疗法更优越的治疗效果。随着对CNV发生机制的深入研究,针对病因进行治疗,将有可能更加有效的防治湿性AMD等CNV相关疾病。     

neovascular age-related macular degeneration: Natural History and Treatment Outcomes

BACKGROUND: This review summarizes the data reported in peer-reviewed literature and presents current knowledge on differentiation, natural history, and therapeutic outcomes of neovascular age-related macular degeneration (AMD). METHODS: The MEDLINE database was searched to review natural history of neovascular AMD and therapeutic effects of available treatments. RESULTS: The search produced>7,000 articles. Research suggests that fluorescein angiographic characterization of location, composition, and size of neovascular lesions may be important in prognosis and should be considered for evaluation of treatment benefits in conjunction with evidence of recent disease progression for lesions not composed of predominantly classic choroidal neovascularization (CNV). Laser photocoagulation, photodynamic therapy with verteporfin, and administration of pegaptanib sodium reduce the risk of vision loss in selected cases of neovascular AMD, while submacular surgery can reduce the risk of severe visual acuity loss in selected cases of predominantly hemorrhagic CNV; further approaches are under investigation. CONCLUSION: Visual prognosis of neovascular AMD is variable according to lesion location, composition, and size. Often, lesions have a poor prognosis, resulting in rapid and progressive loss of visual acuity and contrast sensitivity. Such losses have a profound effect on patients' quality of life and ability to perform everyday tasks. Reducing the risk of further loss of visual acuity and contrast sensitivity might enable patients with neovascular AMD to maintain better functional abilities.     

The role of vascular endothelial growth factor and other endogenous interplayers in age-related macular degeneration

Age-related macular degeneration (AMD) is a multifaceted disease characterized by early subclinical changes at the choroidea-retinal pigment epithelium interface. Both the causal and formal pathogenesis of the disease is still puzzling. Similarly, the reason for progression into two distinct late forms which are "geographic atrophy" and "choroidal neovascularization" remains enigmatic. Late changes are usually responsible for the dramatic loss in central function that has a devastating effect on quality of life. In industrialized countries the disease is a major cause for visual disability among persons over 60 years of age. Due to demographic right-shift and increased life expectancy, AMD is not only a medical problem but will have a pronounced socio-economic effect. Neovascular AMD with the development of choroidal neovascularization in the macular area accounts for 80% of the severe loss of visual acuity due to AMD. In the last decades, treatment modes were merely based on the destruction or surgical removal of the neovascular complex. In the present, however, the philosophical approach to treat the disease is changing to a pathology modifying manner. Intelligent targeting of the involved relevant factors and pathways should stop disease progression, reduce complications and improve vision. The first step into this new era has been accomplished with the introduction of antiangiogenic agents. The new agents act either directly on vascular endothelial growth factor (VEGF) or indirectly on its functional cascade. VEGF makes a fundamental contribution to neovascular processes but it also acts in physiological pathways. The main purpose of this review is to summarize its physiological role especially within the eye, the role in the development of AMD and to understand and foresee both the benefits and potential side-effects of the anti-VEGF-based therapy.     

Age-related macular degeneration

Age-related macular degeneration (AMD) is a major cause of visual loss. The atrophic form is more frequent but accounts for only 20% of severe visual loss. The neovascular form accounts for 80% of severe visual loss. The Macular Photocoagulation Study demonstrated that prompt argon laser photocoagulation can significantly reduce the risk of severe visual loss for patients with neovascular membranes outside the fovea. For patients with both atrophic and neovascular forms of AMD, low vision aids may be of great benefit.     

湿性年龄相关性黄斑变性治疗方法的新选择

湿性年龄相关性黄斑变性(AMD)是导致AMD患者视力丧失的主要原因,抗血管内皮生长因子(VEGF)的药物治疗可达到提高患者视力、减少AMD致盲率的目的,目前已成为治疗湿性AMD的一线用药.但在AMD的发病和进展过程中,脉络膜新生血管(CNV)的形成是复杂的、综合的病理过程,单纯的抗VEGF治疗并不能达到治愈所有湿性AMD的目的,因此对CNV形成各个信号途径的靶向治疗药物已进入各期临床试验阶段.除此之外,小干扰RNA技术、基因组学技术也被用于湿性AMD的治疗,其中基因治疗和干细胞治疗更值得关注,这些新的治疗手段无疑为湿性AMD的治疗提供了新的选择.     

康柏西普在眼部新生血管性疾病中的应用进展

康柏西普是中国自主研发的一种抗血管内皮生长因子新药。自从2013年被中国国家食品药品管理总局批准用于临床,康柏西普在治疗湿性年龄相关性黄斑变性、脉络膜新生血管、黄斑水肿等眼部新生血管性疾病过程中显示出可靠的安全性和疗效。针对不同的疾病,康柏西普的治疗策略有所不同。本文就近年来康柏西普在湿性年龄相关性黄斑变性、糖尿病性黄斑水肿、病理性近视脉络新生血管、新生血管性青光眼、未成熟儿视网膜病变、角膜新生血管等眼部新生血管性疾病中的应用进展进行综述,总结探讨康柏西普的用药适应证、给药方案和治疗效果。期待康柏西普的用药适应证会更广,给药方案会更多,为眼部新生血管性疾病的治疗带来新的思路。