抗血管内皮生长因子在眼科实验室及临床应用中的进展

抗血管内皮生长因子( anti-VEGF )药物在眼科应用广泛,主要适应证为湿性年龄相关性黄斑变性( wAMD )通
　　过检索国内外相关文献,我们得出很多抗VEGF药物在眼科实验室及临床其他疾病的应用个案报道及研究进展,部分为超适应证应用研究,为我们拓展了思维,但到临床应用阶段仍有差距。抗VEGF药物应用前景广阔,需更多研究以进一步发掘和明确。     

和血明目片联合雷珠单抗治疗湿性年龄相关性黄斑变性的临床效果

 目的 观察和血明目片联合抗血管内皮生长因子(vascular endothelial growth factor, VEGF)药物雷珠单抗治疗湿性年龄相关性黄斑变性(wet age-related macular degeneration, wAMD)的临床效果。方法 选择2016-06至2018-06收治的96例(96只眼)wAMD患者,按照随机数字表法分为治疗组和对照组,每组48例(48只眼)。治疗组给予雷珠单抗球内注射联合和血明目片口服治疗,对照组仅给予雷珠单抗球内注射治疗。两组均连续治疗3个月,治疗结束后随访3个月,观察最佳矫正视力(best corrected visual acuity,BCVA)、黄斑区视网膜中央厚度(central retinal thickness,CRT)、黄斑出血面积、渗出面积及累积损伤面积等情况,随访结束后黄斑水肿复发情况,并进行统计学评价。结果 (1)BCVA:治疗3个月后,两组均比治疗前升高(t=8.320,t=4.689,P＜0.01),且治疗组高于对照组(t=2.509,P＜0.01);随访3个月后,两组均比治疗前高,差异有统计学意义(t=7.909,t=3.808,P＜0.01),且治疗组高于对照组(t=3.164,P＜0.01)。(2)CRT:治疗3个月后,两组均低于治疗前(t=16.864,t=14.175,P＜0.01),但两组间差异无统计学意义(t=1.402);随访3个月后,两组均低于治疗前,差异有统计学意义(t=14.478,P＜0.01),且治疗组低于对照组(t=2.687,P＜0.05)。(3)治疗后3个月,两组眼底出血、渗出及总的累积损伤面积均较治疗前明显缩小(P均＜0.05),且治疗组眼底出血面积(t=2.893,P＜0.05)和累积损伤面积缩小幅度(t=2.164,P＜0.05)较对照组更明显,均有统计学意义。(4)两组复发率比较,差异有统计学意义(χ²=4.937,P＜0.05)。结论 抗VEGF球内注射联合和血明目片治疗wAMD的临床疗效肯定,联合治疗在控制黄斑出血及水肿复发方面有优势。     

Fluorescein angiography of retinal vascular involution after intravitreal injection of ranibizumab for retinopathy of prematurity

AIM: To describe the involution patterns of vessel growth of retina through fluorescein angiography (FA) of children, who had been under treatment up to 1y previously intravitreal ranibizumab (IVR) as monotherapy for retinopathy of prematurity (ROP). METHODS: This is a retrospective study. The medical information and FA of 17 children (34 eyes) whose area of avascular retina from the ora serrata was more than two disc diameters (DD) were analyzed. RESULTS: Among 34 eyes, all were the presence of finger-shaped vessels and arteriolar-venular shunts (100%, 34/34 eyes). Popcorn abnormalities were found in most of the eyes (94.1%, 32/34 eyes). Furthermore, in many cases (23.5%, 8/34 eyes), there were leakage persisting in the region of the junction between avascular and vascular retina. In contrast, just 2 eyes (5.9%) showed damage of retinal capillary bed and 3 eyes (8.8%) showed large area of retinal pigment epithelium (RPE) atrophy. CONCLUSION: Although IVR can be very effective in ROP, we should remain cautious as infants may remain avascular peripheral retinas and abnormal vessel. FA allows accurate visualization of vessel abnormalities in eyes with ROP, which will be helpful to affect assessment of disease activity and therapeutic effect.     

Modifying Choroidal Neovascularization Development with a Nutritional Supplement in Mice

We examined the effect of nutritional supplements (modified Age Related Eye Disease Study (AREDS)-II formulation containing vitamins, minerals, lutein, resveratrol, and omega-3 fatty acids) on choroidal neovascularization (CNV). Supplements were administered alone and combined with intravitreal anti-VEGF in an early-CNV (diode laser-induced) murine model. Sixty mice were evenly divided into group V (oral vehicle, intravitreal saline), group S (oral supplement, intravitreal saline), group V + aVEGF (oral vehicle, intravitreal anti-VEGF), and group S + aVEGF (oral supplement, intravitreal anti-VEGF). Vehicle and nutritional supplements were administered daily for 38 days beginning 10 days before laser. Intravitreal injections were administered 48 h after laser. Fluorescein angiography (FA) and flat-mount CD31 staining evaluated leakage and CNV lesion area. Expression of VEGF, MMP-2 and MMP-9 activity, and NLRP3 were evaluated with RT-PCR, zymography, and western-blot. Leakage, CNV size, VEGF gene and protein expression were lower in groups V + aVEGF, S + aVEGF, and S than in V (all p < 0.05). Additionally, MMP-9 gene expression differed between groups S + aVEGF and V (p < 0.05) and MMP-9 activity was lower in S + aVEGF than in V and S (both p < 0.01). Levels of MMP-2 and NLRP3 were not significantly different between groups. Nutritional supplements either alone or combined with anti-VEGF may mitigate CNV development and inhibit retinal disease involving VEGF overexpression and CNV.     

Pegaptanib sodium for the treatment of neovascular age-related macular degeneration

This article reviews pegaptanib sodium, a compound developed by Eyetech Pharmaceuticals Inc. and Pfizer Inc., for the treatment of neovascular age-related macular degeneration (AMD). Traditional treatment approaches to neovascular AMD have included destructive therapies such as thermal laser photocoagulation and photodynamic therapy; the use of pegaptanib sodium heralds a new treatment approach that is a non-destructive therapy based on the inhibition of vascular endothelial growth factor activity in the eye. This diminishes the neovascular drive in the pathologically hyperpermeable state of the diseased eye. Pegaptanib sodium is one of the first therapeutics belonging to the class of compounds known as aptamers. The chemistry, mechanism of action, pharmacokinetics and rationale for the clinical use of the drug are reviewed. The article highlights and summarises the results of the multi-centre, randomised, sham-controlled clinical trials with pegaptanib sodium to treat subfoveal choroidal neovascularisation in AMD. In addition, the safety profile is reviewed.     

Transpupillary thermotherapy (TTT) for age-related macular degeneration

Purpose. To review the results of transpupillary thermotherapy (TTT) on choroidal neovascular membranes associated with age-related macular degeneration (AMD). Materials and Methods. 35 eyes of 35 patients with AMD and choroidal neovascularization and exudation were treated with TTT and had fundus photographs and fluorescein angiography (FA) before and at least six months after TTT. 28 eyes had predominantly occult lesions as seen on FA, while 7 demonstrated primarily classic lesions. All were treated with 650 mw power or less using the 810 nm diode laser (3000 micron spot, duration of 60 seconds). Visual acuity, lesion size, and amount of subretinal fluid were determined by results of examination and review of photographs and fluorescein angiograms. Results. A 50% reduction in subretinal fluid was achieved in 67% of treated eyes overall, with stabilization of vision (less than three lines of visual acuity lost) in 86%. Complications from treatment were infrequent (9%) and involved hemorrhage noted in the region of treatment upon follow-up. Conclusion. TTT promotes resolution of subretinal fluid and appears to stabilize visual acuity in patients with exudative AMD.     

VEGF is important for early liver regeneration after partial hepatectomy

BACKGROUND: The aim of the study was to determine the role of Vascular Endothelial Growth Factor (VEGF) on the microvasculature and on angiogenetic gene expression after partial hepatectomy (PH) in the rat model. METHODS: To determine the effect of exogenous and endogenous VEGF after PH, rats were subjected to 70% PH and treated either with VEGF, anti-VEGF or NaCl. Postoperatively (3-168 h), vessel density (VD), vessel diameter (VDi), and intersinusoidal space, liver body weight ratio (LBR), hepatic proliferation and biochemical markers were assessed. To further elucidate the underlying molecular mechanisms hepatic gene expression was determined by customized cDNA arrays and quantitative RT-PCR. RESULTS: In the VEGF group, VD, VDi, and LBR were significantly increased compared with anti-VEGF or controls. Blockage of endogenous VEGF led to a marked increase of biochemical markers. Anti-VEGF almost completely suppressed and VEGF markedly enhanced hepatic proliferation in the first 24 h after surgery. This was associated with a modulation of cell cycle control genes (PC4, Gadd45a, Tis21/BTG2), v-jun, and CD14 by VEGF. CONCLUSIONS: VEGF plays an important role in liver regeneration and this may be due in part through its effects on neovascularization. Whether it may, when given therapeutically, represent a strategy to optimize liver regeneration in problematic patients needs to be clarified.     

Emerging drugs for age-related macular degeneration

Age-related macular degeneration (AMD) is a leading cause of blindness that until recently had no recognised drug treatment. In wet AMD, choroidal neovascularisation (CNV) causes a profound loss of central vision. CNV is a complex process in which tissue ischaemia and/or inflammation is thought to trigger production of angiogenic signal molecules. The release of VEGF appears to be particularly important. Verteporfin photodynamic therapy was the first drug therapy to be licensed for the treatment of some types of wet AMD. Other treatments directly targeting VEGF or other aspects of angiogenesis, such as pegaptanib, ranibizumab and anecortave acetate, have either recently been licensed or are in the advanced stages of development. These and other promising treatment options such as combination strategies are reviewed.     

Systemic thromboembolic adverse events in patients treated with intravitreal anti-VEGF drugs for neovascular age-related macular degeneration: an overview

Introduction: Anti-VEGF therapy improved the quality of life for millions of patients suffering from wet age-related macular degeneration (wet-AMD); unfortunately, this therapy involves multiple injections over many years. The administration of anti-VEGF can overcome the blood-retinal barrier with agents entering the systemic circulation and causing a significant decrease in VEGF serum concentration. Although circulating VEGF protects the integrity and patency of vessels, prolonged anti-VEGF treatment has the potential to increase the risk of thromboembolic events.

Areas covered: In this review, we discuss the safety data from recent trials involving available anti-VEGF drugs.

Expert opinion: During the 2 years of follow-up in the relevant clinical trials, the rates of serious adverse events such as stroke, heart attack and death were similar for patients treated with different anti-VEGF drugs. Moreover the arterial thrombotic risk appears sufficiently low when compared with the natural incidence of arterial thrombotic events in this category of elderly patients and acceptably balanced against the advantage of improved vision. Since the use of these drugs is likely to become increasingly widespread and prolonged, it is desirable that the scientific community improves the pharmacovigilance program on all anti-VEGF drugs, expanding knowledge with studies that compares head to head all four compounds belonging to anti-VEGF armamentarium.     

Inhibitory Effects of Anti-VEGF Antibody on the Growth and Angiogenesis of Estrogen-induced Pituitary Prolactinoma in Fischer 344 Rats: Animal Model of VEGF-targeted Therapy for Human Endocrine Tumors

Estrogen-induced pituitary prolactin-producing tumors (PRLoma) in F344 rats express a high level of vascular endothelial growth factor (VEGF) associated with marked angiogenesis and angiectasis. To investigate whether tumor development in E2-induced PRLoma is inhibited by anti-VEGF monoclonal antibody (G6-31), we evaluated tumor growth and observed the vascular structures. With simultaneous treatment with G6-31 for the latter three weeks of the 13-week period of E2 stimulation (E2+G6-31 group), the following inhibitory effects on the PRLoma were observed in the E2+G6-31 group as compared with the E2-only group. In the E2+G6-31 group, a tendency to reduction in pituitary weight was observed and significant differences were observed as (1) reductions in the Ki-67-positive anterior cells, (2) increases in TUNEL-positive anterior cells, and (3) repair of the microvessel count by CD34-immunohistochemistry. The characteristic “blood lakes” in PRLomas were improved and replaced by repaired microvascular structures on 3D observation using confocal laser scanning microscope. These inhibitory effects due to anti-VEGF antibody might be related to the autocrine/paracrine action of VEGF on the tumor cells, because VEGF and its receptor are co-expressed on the tumor cells. Thus, our results demonstrate that anti-VEGF antibody exerted inhibitory effects on pituitary tumorigenesis in well-established E2 induced PRLomas.