眼部新生血管与抗血管内皮生长因子治疗

眼部新生血管性病变是致盲的主要原因之一,可见于多种眼底疾病,其确切的发病机制尚不完全清楚.大量的研究证据表明血管内皮生长因子(VEGF)是新生血管形成的关键调控因子.本文对VEGF的特性、VEGF在眼部新生血管形成中的作用和抗VEGF治疗进行综述.     

可溶性血管内皮生长因子受体-2及其对眼新生血管抑制作用的研究进展

新生血管形成是很多重要眼部疾病的共同病理改变,血管内皮生长因子（vascularendo-thelialgrowthfactor,VEGF）是血管生成重要的促进因子。近年来,可溶性血管内皮生长因子受体-2（solubleVEGFreceptor-2,sVEGFR-2）被证实为一种VEGF促血管生成信号转导通路的天然抑制剂。有研究表明,它与眼部新生血管的发生发展密切相关,可作为新生血管性眼病的抑制因子及其血清标志物而具有临床应用价值。本文就sVEGFR-2在抗眼部新生血管中作用的研究进展予以综述。     

血管内皮生长因子与眼内新生血管

眼内新生血管是多种致盲眼病的病理生理基础,新生血管形成受多种因子调控,其中血管内皮生长因子(VEGF)是最重要的细胞因子。它与特异性受体结合后通过复杂机制促进血管内皮细胞增殖、迁移和通透性增加。缺氧可诱导VEGF表达,VEGF通过NO的介导作用发挥促血管新生的作用。还有多种抑制和促进血管因子共同作用于血管内皮细胞。目前,人们通过基因手段抑制VEGF及其受体达到抑制血管新生的作用,为眼内新生血管性疾病开辟前景。     

血管内皮生长因子及其受体在眼科的应用研究进展

眼部新生血管的形成是一个及其复杂的病理生理过程,受多种因子的调节,目前血管内皮生长因子（vascular endothelial growth factor,VEGF）被认为是新生血管形成过程中关键性因子之一.已发现的血管内皮生长因子包括：VEGF-A、VEGF-B、VEGF-C、VEGF-D、VEGF-E、VEGF-F以及胎盘生长因子（placenta growth factor,PIGF）;VEGF受体（VEGF receptor,VEGFR）包括：VEGFR-1、VEG-FR-2、VEGFR-3.各受体可被不同或相同的VEGF激活、调控着不同的生理功能,其中对VEGF-A及其受体的研究最为深入.基于VEGF-A及其受体对新生血管不同作用位点和方式的研究,各种药物应运而生,使临床针对眼部新生血管性疾病的用药和治疗方案也发生了革命性的改变.但随着对VEGF家族及其受体的深入研究,逐渐发现VEGF家族中的其他成员,如：VEGF-B等与VEGF-A的作用靶器官及作用机制有很大差别.本文就VEGF家族中各成员及其受体的作用机制和功能以及目前抗VEGF的相关药物的种类、临床应用和研究进展进行综述.     

血管内皮生长因子抑制剂在角膜新生血管治疗中的研究进展

正常角膜是无血管、完全透明的组织,是眼部重要的屈光介质,但许多眼部疾病均可破坏抗血管生成因子与促血管生成因子之间的平衡,导致病理性角膜新生血管(CNV)的形成.大量研究表明,CNV的形成与血管内皮生长因子(VEGF)信号通路的激活密切相关.通过多靶点多途径阻断该信号通路可以有效抑制新生血管的形成,为CNV的治疗带来了希望.目前,针对新生血管性眼病的新型靶向治疗策略主要包括VEGF抑制剂和以微小RNA(miRNA)为核心的基因治疗,前者主要包括抗VEGF单克隆抗体、核酸适体、VEGFtrap、VEGF受体(VEGFR)酪氨酸激酶抑制剂等.本文将对具有代表性的抗VEGF药物和基因治疗的作用机制、用药疗效、药物安全性及研究现状进行综述.     

VEGF家族及其受体与视网膜新生血管形成

视网膜新生血管形成是眼部多种疾病共有的病理改变,其造成的眼部广泛损害已成为致盲的重要原因。VEGF家族（包括VEGF—A,VEGF—B,VEGF—C,VEGF—D,VEGF—E和胎盘生长因子）作为新生血管生成中必不可少的关键因子,通过刺激血管内皮细胞的有丝分裂、迁徙、增加血管的通透性、诱导毛细血管腔的形成。本文对VEGF家族理化特性及受体、在视网膜新生血管形成中的作用和针对其作用机制采取相应防治措施进行综述。     

血管内皮生长因子-B与眼部新生血管性疾病

异常的新生血管会导致多种眼部疾病,而血管内皮生长因子（VEGF）在新生血管的发生及发展中起重要作用.VEGF-B作为VEGF家族的一员,对血管生成和血管通透性无显著影响,但可通过血管生存作用和细胞凋亡作用对新生血管的生长进行调控,从而抑制新生血管的发生和发展.同时,VEGF-B对心脏和神经元等具有保护作用.抗VEGF治疗作为目前明确有效的治疗新生血管的方法,一直受到广泛关注,而因VEGF-B的两面性,对于抗VEGF-B的药物在治疗眼科新生血管性疾病方面的作用尚需进一步研究.就VEGF-B对机体血管、细胞、神经元及心脏所起的作用及其在眼部新生血管性疾病治疗中的应用进行综述.     

血管内皮生长因子抑制剂在糖尿病性视网膜病变中的应用

眼部新生血管是糖尿病性视网膜病变致盲的主要病理改变,而血管内皮生长因子（vascular endothelial growth factor,VEGF）在新生血管形成过程中起关键性刺激作用。VEGF抑制剂主要通过与VEGF结合并阻断其生物活性而起作用,从而达到抑制眼部新生血管生成的目的,在糖尿病性视网膜病变血管渗漏及新生血管形成的治疗中取得了显著的成绩。Bevacizumab（Avastin）是VEGF抑制剂之一,属于重组人源化单克隆抗体,因其疗效良好、价格低廉已被广泛应用于临床。现将VEGF抑制剂（尤其是Avastin）治疗糖尿病性视网膜病变的相关应用进展作一综述。     

血管内皮生长因子抑制剂治疗视网膜新生血管性疾病

视网膜新生血管性疾病是致盲的主要病因,早期预防、控制视网膜新生血管的发生发展显得尤为重要。目前,关于视网膜新生血管性疾病的确切发病机制尚不清楚,但对血管内皮生长因子(vascular endothelial growth factor,VEGF)在其形成过程中起关键作用已达成共识,现在已有多种VEGF抑制剂被用于治疗眼部新生血管性疾病。现将治疗视网膜新生血管性疾病的最新几种VEGF抑制剂作一综述。     

β肾上腺素能受体拮抗剂治疗眼部新生血管疾病的研究进展

眼部新生血管形成是糖尿病视网膜病变、早产儿视网膜病变、视网膜中央静脉阻塞和老年性黄斑变性等多种眼部疾病的病理学改变, 严重影响患者视力。β受体在结膜、角膜上皮细胞、角膜内皮细胞、眼外肌、小梁网、睫状肌、晶状体和视网膜中均有表达。β肾上腺素能受体拮抗剂与β受体结合, 通过抑制血管内皮生长因子(VEGF)、缺氧诱导因子-1、白细胞介素-6等促血管生成细胞因子, 降低巨噬细胞相关炎症反应, 增加抗血管生成因子表达来发挥抗血管生成作用。其在治疗角膜新生血管、脉络膜新生血管、早产儿视网膜病变时, 可显著减少新生血管面积, 延缓疾病进展, 联合应用抗VEGF药物可减少抗VEGF药物的给药频率。在有效的治疗浓度下, β肾上腺素能受体拮抗剂表现出良好的耐受性;且其较抗VEGF药物有更广泛的靶点, 为角膜、脉络膜和视网膜新生血管等眼部新生血管性疾病提供了新的治疗策略。     

Bevacizumab眼科应用新进展

Bevacizumab是世界上首个批准上市的血管内皮因子抑制剂，用于治疗肿瘤性疾病，由于其强大的抗新生血管作用，在眼科新生血管性疾病治疗中有广泛的应用前景。其使用方法包括静脉注射和玻璃体注射，初步结果显示具有显著疗效，相比与同类药物有一定的优势。本文对其作用机理、应用范围、方法和副作用进行论述。     

贝伐单抗治疗角膜新生血管的研究现况

贝伐单抗(bevacizumab)(商品名Avastin)是一种重组人源化单克隆IgG抗体,它与血管内皮生长因子(vascular endothelial growth factor,VEGF)高亲合力结合,抑制新生血管的生成,最初用于直肠癌的治疗,近几年用于眼部新生血管的治疗。我们对Avastin治疗角膜新生血管的基础研究及临床应用作一综述。     

贝伐单抗在虹膜新生血管治疗中的应用

虹膜新生血管是眼内新生血管的一种表现,血管内皮生长因子(vascular endothelial growth factor,VEGF)是迄今为止鉴定出来最重要的血管生成因子,与新生血管形成和通透性紧密相关。贝伐单抗是人源化的抗VEGF重组鼠单克隆抗体,可与所有已知VEGF异构体结合,通过抑制其生物学活性来抑制新生血管的生成。临床研究此药治疗虹膜新生血管在短期内取得了良好的疗效、且安全可靠。本文就最近几年国内外有关治疗虹膜新生血管疾病的研究进行综述,评估其在虹膜新生血管治疗方面的应用前景。     

Successful treatment of choroidal neovascular membrane in retinitis pigmentosa with intravitreal bevacizumab

We report a rare association of choroidal neovascularization (CNV) with retinitis pigmentosa and note its resolution by intravitreal injection of the anti-vascular endothelial growth factor (VEGF), bevacizumab. A classic choroidal neovascular membrane was seen in the right eye (RE) of a patient with sector retinitis pigmentosa. Bevacizumab 1.25 mg in 0.05 ml was injected intravitreally. The choroidal neovascular membrane was seen to regress following this single intravitreal bevacizumab injection with formation of a scar. CNV has very rarely been seen in association with retinitis pigmentosa. Anti-VEGF drugs have been shown to have a beneficial role in CNV with other causes; in this case their effectiveness in CNV associated with retinal dystrophies, for example retinitis pigmentosa, has been demonstrated.     

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.     

Induction of vascular endothelial growth factor receptor expression in human umbilical vein endothelial cells after repeated bevacizumab treatment in vitro

AIM: To investigate the mechanism underlying the loss of responsiveness to anti-vascular endothelial growth factor (VEGF) treatment after repeated injections for choroidal neovascularization, VEGF and VEGF receptor (VEGFR) expressions were evaluated following repeated bevacizumab treatments in hypoxic human umbilical vein endothelial cells (HUVECs) in vitro. METHODS: HUVECs were incubated under hypoxic conditions in two media of different bevacizumab concentrations (1.0 or 2.5 mg/mL) for 17h, and then in a new medium without bevacizumab for 7h. This procedure was repeated twice more. A culture with an identical volume of excipients served as the control. Cytotoxicity and cell proliferation were assessed using 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide and Ki-67 assays, respectively. Levels of VEGF and VEGFR were assessed using enzyme-linked immunosorbent assay and Western blot respectively. RESULTS: Cytotoxic effects were not reported for either bevacizumab concentration. Cell proliferation was not reduced after anti-VEGF treatments. VEGF level after single treatment was significantly higher than that of the control and after repeated treatments. Phosphorylated VEGFR-2 expression increased significantly after single and repeated bevacizumab treatments compared with the control. The 1.0 mg/mL bevacizumab induced significantly higher expressions of VEGFR-2 than the 2.5 mg/mL in single and repeated treatment groups. CONCLUSION: Bevacizumab treatment of HUVECs elevated VEGFR expression in both single and repeated treatments, indicating a mechanism for the reduced efficacy of anti-VEGF therapy in ocular neovascular disorders.     

从贝伐单抗应用的窘境议医疗管理政策的瓶颈

贝伐单抗（Avastin）和雷珠单抗（Lucentis）是同一公司研发的有效的抗血管内皮生长因子制剂,前者被用于治疗肿瘤,后者被用于治疗湿性年龄相关性黄斑变性（AMD）,但前者价格低于后者数十倍。近年的研究表明,两者在治疗AMD等新生血管性眼病的效果与安全性相似,眼科医师试图用其治疗新生血管性眼病,但有＂超适应证用药＂的困惑及风险。本文介绍了国外眼科界对＂超适应证用药＂的观点、国内执业医师法的相关规定及世界银行建议中国基本药物的仿制药战略。期望人们认识到,医师与患者在医疗过程中有着共同的立场、愿望及风险。