Comparison of subconjunctivally injected bevacizumab, ranibizumab, and pegaptanib for inhibition of corneal neovascularization in a rat model

AIM:To compare the efficacies of subconjunctival bevacizumab, ranibizumab, and pegaptanib sodium injections for the inhibition of corneal neovascularization in an experimental rat model. METHODS:Sixteen corneas of 16 rats were chemically cauterized and randomized into four groups:bevacizumab group that treated with 0.05mL/1.25mg bevacizumab, ranibizumab group that treated with 0.05mL/0.5mg ranibizumab, pegaptanib group that treated with 0.05mL/0.15mg pegaptanib sodium, and control group that treated with 0.05mL saline solution. Digital photographs of the corneas were taken and analyzed using an image analysis software program. All corneas were excised and examined histologically on the 15^th day. RESULTS: Each treatment group had significantly less neovascularized corneal areas and fewer blood vessels than the control group (all P<0.05). In addition, bevacizumab group had significantly less neovascularized corneal areas and fewer blood vessels than ranibizumab and pegaptanib groups (both P<0.05). However, there was no significant difference between the ranibizumab and pegaptanib groups regarding percentage of neovascularized corneal areas and number of blood vessels (both P>0.05). CONCLUSION:Subconjunctival bevacizumab, ranibizumab, and pegaptanib sodium were effective with no corneal epitheliopathy for inhibiting corneal neovascularization after corneal burn in rats. Bevacizumab was more effective than ranibizumab and pegaptanib sodium.     

Bevacizumab inhibits corneal neovascularization in an alkali burn induced model of corneal angiogenesis

BACKGROUND: New and uncontrolled blood vessel development in the cornea is a pivotal process in the pathogenesis of several corneal diseases. These corneal diseases may finally cause blindness and managing them therapeutically is problematic. The data supporting a causal role for vascular endothelial growth factor in corneal neovascularization are extensive. This study aimed to evaluate the effect of subconjunctival bevacizumab (Avastin) on experimental corneal neovascularization in rabbits. METHODS: Chemical cauterization of the cornea was performed by touching central cornea with a 5-mm-diameter NaOH-soaked cotton applicator for 10 s in 20 eyes of 20 White New Zealand rabbits. The rabbits were then divided randomly into two equal groups. Bevacizumab (2.5 mg) was administered to 10 eyes (group 1) by a subconjunctival injection immediately after chemical cauterization of corneal surface. As a control, 10 eyes (group 2) received an injection of distilled water. Rabbits were examined daily for detection of the first signs of neovascularization. Three weeks later, the extent of corneal neovascularization was evaluated by direct examination and photograph analyses. Total corneal neovascularization area, degree of circumference involved and longest neovascular pedicle length were assessed. RESULTS: Bevacizumab significantly decreased the total neovascularization area (P < 0.009), the circumference involved (P < 0.011) and the longest neovascular pedicle length (P < 0.023). CONCLUSION: Local injection of bevacizumab has a significant effect on inhibition of alkali burn-induced corneal neovascularization. This shows the potential value of bevacizumab in the treatment of corneal neovascularization.     

Ranibizumab Injection for Corneal Neovascularization Refractory to Bevacizumab Treatment

Vascular endothelial growth factor inhibitor is an emerging therapeutic modality for various ocular diseases with neovascularization (NV). However, for corneal NV, controversy remains regarding whether bevacizumab or ranibizumab is superior. A 32-year-old female diagnosed with herpetic keratoconjunctivitis with refractory corneal NV despite two previous subconjunctival and intrastromal bevacizumab injections, received two subconjunctival and intrastromal ranibizumab injections. Six months postoperatively, there was significant regression of the neovascular area and vessel caliber. Here, the authors report a case of improvement in corneal NV with subconjunctival and intrastromal ranibizumab injections, which was previously refractory to bevacizumab injection. The findings may suggest a new prospect in treating corneal NV.     

Measurement of central corneal thickness and pre-corneal tear film thickness of rabbits using the Scheimpflug system

AIM:To measure central corneal thickness (CCT) and pre-corneal tear film thickness using the Galilei dual-Scheimpflug analyzer (GSA) in New Zealand white rabbits.METHODS:Ten normal New Zealand white rabbits (20 eyes) were included in this study. With the assistance of 0.1% fluorescein, the pre-corneal tear film can be well visualized. Both eyes of each rabbit were scanned once with the GSA pre- and post-instillation of 1μL 0.1% fluorescein. The difference between the two measurements of CCT (4-mm diameter) was recorded as the pachymetric values of the central tear film.RESULTS:The CCT of pre- and post-instillation was 388.8±9.5μm and 407.0±10.5μm, respectively. After a paired t-test analysis, the central pre-corneal tear film thickness of 4mm diameter was 18.2±5.31μm with a 95% confidence interval of (15.7, 20.6)μm (P<0.001).CONCLUSION:GSA can be used to measure CCT and analyze central tear film thickness of rabbits with the help of fluorescein.     

Inhibition of corneal neovascularization by subconjunctival bevacizumab in an animal model

PURPOSE: To evaluate the effect of subconjunctival injection of bevacizumab on experimentally induced corneal neovascularization. DESIGN: Experimental animal study. METHODS: Twelve New Zealand white rabbits were involved, divided equally into four groups. Only one eye per rabbit was used. Topical instillation of 10 microl 5% NaOH solution was used, under general anesthesia, to induce corneal neovascularization secondary to corneal alkali burn in groups 2, 3, and 4. A single dose of 3.75 mg (25 mg/ml) bevacizumab was injected subconjunctivally. Group 1 (control group 1) was neither cauterized nor treated. Group 2 (control group 2) received a sham injection of balanced salt solution on day 14. Group 3 was treated on day 14 (after corneal neovascularization had been established). Group 4 was treated on day 1. Digital photographs were obtained and analyzed during the entire 28-day procedure. The area of neovascularization and scarring were measured in terms of the percentage of corneal surface affected. RESULTS: On day 28, the difference of neovascularization between groups 2, 3, and 4 was found to be statistically significant at the .05 level (one-way analysis of variance [ANOVA]): group 4 (4.7%+/-3.1%).1, one-way ANOVA). No side effects were noted. CONCLUSIONS: Subconjunctival administration of bevacizumab inhibits corneal neovascularization effectively in the rabbit experimental model, especially if administered early.     

Inhibition of corneal neovascularization after alkali burn: comparison of different doses of bevacizumab in monotherapy or associated with dexamethasone

Background: To compare the effects of different doses of bevacizumab with both saline and dexamethasone on inflammatory angiogenesis in the rat cornea induced by small chemical lesions. Methods: Corneal chemical cauterization was performed on 24 rats. Animals were divided randomly into six groups and received a daily subconjunctival injection for 7 days of: balanced salt solution 0.1 mL or dexamethasone phosphate 4 mg/day or bevacizumab 2.5 mg/day, 3.75 mg/day, 5.0 mg/day or bevacizumab 5.0 mg/day + dexamethasone phosphate 4 mg/day. Clinical examination under slit lamp was performed daily for 7 days to evaluate corneal opacity and vessel size evolution. Computer‐assisted quantitative image analysis was used to measure the total corneal area covered by neovascularization. Results: At final examination, the dexamethasone, bevacizumab 5.0 mg/day and dexamethasone + bevacizumab groups showed a significant lowering in corneal opacity score as compared with control (P = 0.024, P = 0.006 and P = 0.013, respectively). Also, a significant reduction on new vessels size score was observed. Surface of corneal neovascularization was significantly reduced in dexamethasone, bevacizumab 5.0 mg/day and dexamethasone + bevacizumab groups compared with control (P = 0.045, P = 0.047 and P = 0.044, respectively). Conclusion: Our study demonstrates the ability of a 5.0 mg/day bevacizumab subconjunctival injection, in monotherapy or associated with dexamethasone, to cause a short‐term involution of corneal neovascularization after corneal alkali burn. Combination of both of these treatments may have advantages to monotherapy approaches.     

Topical and subconjunctival bevacizumab for corneal neovascularization in an experimental rat model

Aims: To evaluate and compare the inhibitory effects of topical and subconjunctival bevacizumab on corneal neovascularization in a rat model. Methods: Twenty corneas of 20 rats were chemically cauterized with silver nitrate sticks. Animals were randomized into four groups: a control group that received only topical artificial tear drops twice daily, a subconjunctival injection group that received 1.25 mg (0.05 ml) of bevacizumab on the 1st, 4th, and 7th day, and two topical bevacizumab groups that received instillation of 4 or 12.5 mg/ml bevacizumab twice daily. Digital photographs of the cornea were taken and analyzed using an image analysis software program. On the 10th day, corneas were excised and examined histologically. Results: The mean percentage of the vascularized corneal area (%) in the control group was 63.32 ± 13.10 (mean ± SD), compared with 30.22 ± 15.73 in the subconjunctival injection group, 26.76 ± 10.23 in the 4-mg/ml topical group, and 25.52 ± 12.45 in the 12.5-mg/ml group. The differences between the control and each treatment group were significant (all p < 0.01). Further, histological examination revealed that each treatment group had fewer vessels than the control group (all p < 0.01). Conclusions: Both subconjunctival injection and topical use of bevacizumab are effective and safe in controlling corneal neovascularization.     

Comparison of the inhibitory effect of different doses of subconjunctival bevacizumab application in an experimental model of corneal neovascularization

AIM: To evaluate the inhibitory effect of subconjunctival bevacizumab as single- and multiple-dose application, and compare their effects on corneal neovascularization in a rat model. METHODS: Thirty adult Sprague-Dawley rats were used in this experimental study. The central cornea of the rats was cauterized chemically. The rats were randomly enrolled into three groups. All groups received subconjunctival injections. In Group 1 (control group, n=10), 0.05 mL 0.9% NaCl solution was injected on the first day. In Group 2 (single-dose group, n=10), 0.05 mL bevacizumab (1.25 mg) was injected on the first day. In Group 3 (multiple-dose group, n=10), four doses of 0.05 mL bevacizumab (1.25 mg) were injected on the first, third, fifth and seventh day. Slit-lamp examination of all rats was performed at the third and ninth day. Digital images of the corneas were taken and analyzed using image analysis software to calculate corneal neovascularization area. All rats were sacrificed on the tenth day. In corneal sections, the number of blood vessels, state of inflammation and collagen formation was evaluated histopathologically. RESULTS: In Group 3, corneal edema grades were significantly lower than Group 1 and Group 2 (P=0.02, and P=0.035, respectively). The mean percentage of neovascularized corneal area in Group 3 was significantly lower than Group 2 (P=0.005). On histopathological examination, Group 2 and Group 3 showed significantly less number of blood vessels than Group 1 (P=0.005, and P=0.001, respectively). Additionally, Group 3 showed significantly less number of blood vessels compared to Group 2 (P=0.019). Inflammation and edema grades were significantly lower in Group 3 compared to Group 1 (P=0.001). CONCLUSION: Subconjunctival bevacizumab injection is effective in inhibition of newly formed corneal neovascularization. The multiple-dose bevacizumab treatment seems to be more effective compared to single-dose treatment.     

Effect of subconjunctival bevacizumab (Avastin) on experimental corneal neovascularization in guinea pigs

PURPOSE: To evaluate the effect of subconjunctival bevacizumab (Avastin) on experimental corneal neovascularization in guinea pigs. METHODS: Forty eyes of 40 guinea pigs were chemically cauterized with 75% silver nitrate and 25% potassium nitrate sticks. Fifteen eyes (group 1) received 2 subconjunctival injections of bevacizumab (0.1 mL, 1.25 mg) simultaneously with cauterization and 3 days later. Fifteen eyes (group 2) received 2 subconjunctival injections of bevacizumab (0.1 mL, 1.25 mg) 3 and 5 days after cauterization. Ten eyes (group 3, control group) received 2 subconjunctival injections of 0.1 mL of balanced salt solution 3 and 5 days after cauterization. After we determined the burn and neovascularization scores for all groups, the animals were killed on the 10th day. The percentages of neovascularization on the surface of the cornea were measured in terms of pixels on digital photographs. The average number of vessels at maximally vascularized areas was determined for each specimen. RESULTS: Neovascularization score was 1.1 +/- 0.3 in group 1, 2.46 +/- 1.3 in group 2, and 3.5 +/- 0.5 in the control group. The difference was statistically significant (P < 0.001). The area of neovascularization at the cornea surface was 15.6% +/- 10.1% in group 1, 19.74% +/- 11.2% in group 2, and 23.5% +/- 7.4% in the control group (P = 0.194). The average number of neovascular vessels at group 1 was significantly reduced in comparison with group 2 and the control group (P < 0.001). CONCLUSIONS: Subconjunctival injection of bevacizumab decreases the extent of chemically induced corneal neovascularization in guinea pigs. The antineovascular effect of bevacizumab is higher if the injection is performed simultaneously with the chemical cauterization.     

Short- and long-term safety profile and efficacy of topical bevacizumab (Avastin®) eye drops against corneal neovascularization

Purpose

To evaluate the short- and long-term in vivo safety and efficacy of topical bevacizumab (Avastin) application for treatment of corneal neovascularization secondary to a variety of corneal diseases.

Methods

Thirty eyes of 27 patients with progressive corneal neovascularisation (not responding to conventional anti-inflammatory treatment) due to different underlying corneal diseases received topical bevacizumab (Avastin) eye drops (5 mg/ml Bevacizumab) for 0.5–12 months (five times/day on average). At each visit, a routine Snellen visual acuity assessment was performed, followed by ophthalmic examination including fluorescein staining. Changes of corneal neovascularization and vessel diameter were assessed using morphometry of standardized digital corneal photographs.

Results

Five patients (five eyes) developed new corneal epithelial defects during topical bevacizumab treatment. In 22 patients, no new epithelial defects were observed. None of the 27 patients complained about any drug-related ocular or systemic adverse events during follow-up. No allergic reactions were observed. Corneal photographs of 21 eyes (19 patients) could be assessed. The mean reduction in vascularized area during treatment was 61%. The mean reduction in vessel diameter under topical Avastin therapy was 24%.

Conclusions

Off-label topical bevacizumab therapy against corneal neovascularization secondary to different corneal diseases was generally well-tolerated for up to 12 months. Bevacizumab (Avastin) eye drops inhibit corneal neovascularization, and lead to a reduction of the vessel diameter. Our results suggest that off-label use of Bevacizumab eye drops is a relatively safe and well-tolerated option for the treatment of corneal neovascularization. Care should be taken in patients with epithelial defects and neurotrophic keratopathy.     

The inhibitory effect of different concentrations of topical bevacizumab on corneal neovascularization

Acta Ophthalmol. 2010: 88: 862–867

Abstract.

Purpose: This study aimed to evaluate the effects of different concentrations of topically administered bevacizumab (Avastin) on experimental corneal neovascularization (NV) in rats. Methods: Corneal NV was induced by chemical cauterization with silver nitrate sticks applied to the centre of the corneas of 37 Wistar rats. The rats were then randomized to four topical treatment groups: group 1 (n = 10) received 4 mg/ml bevacizumab; group 2 (n = 9) received 2 mg/ml bevacizumab; group 3 (n = 10) received 1 mg/ml bevacizumab, and group 4 (n = 8) represented a control group and received saline. All drops were initiated immediately after cauterization and applied twice per day for 7 days. Corneal NV was assessed 8 days after cauterization in a masked fashion, both qualitatively by clinical evaluation and quantitatively by blood vessel count in photographs of histological sections. Results: On clinical evaluation, groups 1 and 2 showed significantly less NV compared with the saline‐treated control group (p = 0.006 and p = 0.024, respectively). Histopathological evaluation showed that only group 1 differed significantly from controls (5% significance level) and normal corneal epithelium was seen in all groups. Conclusions: Topically administered bevacizumab at a concentration of 4 mg/ml significantly reduces corneal NV according to both clinical and histopathological evaluations; lower concentrations were less effective on both parameters. No corneal epitheliopathy was found using these concentrations.     

Subconjunctival bevacizumab injection for corneal neovascularization

PURPOSE: To report on the clinical use of subconjunctival bevacizumab in patients with corneal neovascularization. METHODS: The charts of 10 consecutive patients with corneal neovascularization who received subconjunctival injections of bevacizumab (2.5 mg/0.1 mL) were reviewed. Digital photographs of the cornea were graded by 2 masked observers for density, extent, and centricity of corneal vascularization. Image analysis was used to determine the area of cornea covered by neovascularization as a percentage of the total corneal area. RESULTS: No significant ocular or systemic adverse events were observed during 3.5 +/- 1.1 months of follow-up. Seven patients showed partial regression of vessels. The extent decreased from 6.0 +/- 1.2 (SD) clock hours before the injection to 4.6 +/- 1.0 clock hours after bevacizumab injection (P = 0.008). Density decreased from 2.7 +/- 0.2 to 1.9 +/- 0.3, respectively. (P = 0.007). No change was noticed in the centricity of corneal vessels. Corneal neovascularization covered, on average, 14.8% +/- 2.5% (SD) of the corneal surface before the injections, compared with 10.5% +/- 2.8% (P = 0.36, t test) after bevacizumab injection. Therefore, bevacizumab decreased corneal neovascularization by 29%. CONCLUSIONS: Short-term results suggest that subconjunctival bevacizumab is well tolerated and associated with a partial regression of corneal neovascularization.     

Safety,penetration and efficacy of topically applied bevacizumab: evaluation of eyedrops in corneal neovascularization after chemical burn

Purpose: That vascular endothelial growth factor (VEGF) plays a major role in inflammatory angiogenesis has been well established. This pilot study was designed to evaluate experimental treatment with bevacizumab eyedrops in corneal neovascularization induced by alkali burn. The feasibility of topical administration, corneal cell viability and corneal penetration were investigated in an animal model. Methods: Eighteen chinchilla bastard rabbit corneas injured with 1 m NaOH were divided into three groups: untreated, early and late treatment groups. Eyedrops of bevacizumab solution (25 mg/ml) were administered five times daily. Clinical examination under stereoscopic microscope was performed to evaluate corneal opacity, neovascularization, vessel size and oedema. Histopathology was analysed for vessel density and apoptotic reaction. Additionally, intracameral bevacizumab concentration was measured with enzyme‐linked immunosorbent assay (ELISA) after repeated topical applications. Results: A fast increase in aqueous bevacizumab concentration was achieved when the solution was instilled every minute onto a healthy eye surface. As well as clear anti‐angiogenic effects, anti‐fibrotic effects were also seen after corneal burn, maintaining corneal transparency. Early treatment of actively growing vessels showed a significantly better outcome, although apoptosis of pre‐existing vessels could also be induced by the late treatment. No specific toxicity was seen regarding epithelium, keratocytes or endothelium. Conclusions: The data from this pilot study suggest that bevacizumab eyedrops can sufficiently penetrate the corneal stroma and anterior chamber. When administered soon after alkali burn, bevacizumab seems to significantly reduce corneal damage. Combinations of established treatment regimens with topical bevacizumab might be considered in severe injuries with otherwise devastating prognoses.     

Subconjunctival bevacizumab injection for corneal neovascularization in recurrent pterygium

PURPOSE: We report on the use of subconjunctival bevacizumab on corneal vessel density in recurrent pterygia. METHODS: The charts of 5 patients with recurrent pterygium, who received subconjunctival injections of bevacizumab (2.5 mg/0.1 ml) were retrospectively reviewed. Ophthalmic evaluation included Snellen visual acuity (VA), tonometry and complete examination before the injection and at 1 week and 1 and 3 months thereafter. Digital photographs of the eyes were analyzed by image analysis software to determine the area of cornea covered by new vessels as a percentage of the total corneal area. RESULTS: No ocular or systemic adverse events were observed. No change in visual acuity was noted in any patient following the injection. The mean change in corneal vascularization after one bevacizumab injection was 0.03%+/-0.45, while after two injections the change was 0.025%+/-0.19 (both not statistically different than zero, t-test). CONCLUSIONS: Short-term results suggest that subconjunctival bevacizumab is well tolerated but does not cause regression of corneal vessels in recurrent pterygium.     

Inhibition of experimental corneal neovascularization by using subconjunctival injection of bevacizumab (Avastin)

PURPOSE: To evaluate the effect of subconjunctival bevacizumab (Avastin) administration on corneal neovascularization (NV) in rabbits. METHODS: NV was induced by placing a suture at the corneal periphery of the right eye of 20 rabbits. Immediately after suturing and again 1 week later, rabbits were divided into 2 groups and administered a subconjunctival injection of normal saline (control) or bevacizumab (Avastin; 5 mg/0.2 mL), respectively. On day 14, digital photographs of the cornea were taken and analyzed to determine the area of the cornea covered by NV. In addition, immunohistochemical analysis was used to determine CD31 and vascular endothelial growth factor (VEGF) expression in corneal tissue. RESULTS: Analysis of digital photographs showed that there was less corneal NV in bevacizumab-treated eyes than in controls (P < 0.001, Mann-Whitney U test). In addition, there was less staining for VEGF and CD31 in corneas from bevacizumab-treated eyes than in control eyes. Subconjunctival bevacizumab injections were not associated with any complications during observation. CONCLUSIONS: Subconjunctival bevacizumab administration decreased suture-induced corneal neovascularization in rabbits.     

结膜下注射Avastin抑制角膜新生血管的实验研究

目的:观察结膜下注射Avastin对实验性兔眼角膜新生血管(neovascularization,NV)的抑制作用,初步探讨作用机制。方法:应用5mm直径的加样器(末端附有棉片)吸入1mol/LNaOH接触新西兰兔右眼(20眼)中央角膜区烧灼30s,制作碱烧伤兔眼角膜NV模型。将实验兔随机分成2组,10眼(A组)碱烧伤后立即结膜下注射Avastin 2.5mg;其余10眼为对照组(B组),结膜下注射等量生理盐水。烧灼后次日每天裂隙灯观察角膜NV、角膜水肿情况,分别于3,7,14,21,28d裂隙灯照相并计算NV面积及NV抑制率。伤后7,28d各组随即处死5只实验兔,取角膜组织做石蜡切片行组织病理学检查及VEGF免疫组织化学检测。结果:两组兔眼伤后第1d角膜缘血管网明显扩张充血,3d时血管开始侵入角膜,7～14d时NV达到高峰,14～21d后NV稳定并逐渐回退。两组角膜NV长度、NV面积及角膜水肿程度存在差异(P<0.05);A组各时间点角膜NV抑制率为44.2%～55%。A组角膜上皮及实质层水肿较轻,NV较少,后弹力层基本完整,VEGF表达明显弱于B组。结论:结膜下注射Avastin对碱烧伤诱导的兔眼角膜NV形成及生长具有明显的抑制作用,可能通过下调VEGF表达发挥作用。     

贝伐单抗抑制角膜移植术后新生血管及免疫排斥反应的作用

目的 探讨贝伐单抗对同种异体角膜移植术后免疫排斥反应的影响,评价其对角膜植片存活的疗效及作用机制。设计 实验研究。研究对象 近交系F344大鼠15只为供体,近交系Lewis大鼠30只为受体。方法 受体大鼠右眼行穿透性角膜移植术后随机数字法分为3组：对照组（A组）、贝伐单抗组（B组）、地塞米松组（C组）,每组10只。B、C组分别于术后0、3、6、9天结膜下注射40 μl贝伐单抗注射液及20 μl地塞米松磷酸钠注射液;A组不做处理。术后裂隙灯下观察14天,记录排斥指数（RI,为植片水肿、混浊、新生血管长入评分合计）和新生血管侵袭面积（IA）。术后14天,采用免疫荧光法检测角膜植片中CD4+、CD8+免疫细胞的表达。主要指标 角膜新生血管面积,免疫排斥时间,免疫细胞的数量。结果 术后7天IA分别为：A组（22.50±3.67）mm2,B组（14.21±2.79）mm2,C组（15.38±0.84）mm2;A组明显多于B组及C组（P=0.00和0.01）,B组与C组无显著差异（P=0.059）。术后14天IA分别为：A组（27.96±0.50）mm2,B组（18.76±2.73）mm2,C组（23.74±2.14）mm2。A组及C组多于B组（P=0.000）。免疫排斥时间A组8天,B组11天,C组13天。B组及C组角膜植片存活时间均长于A组（P均=0.000）。免疫细胞： CD4+阳性细胞数：A组（13.2±2.94）个,B组（6.14±1.07）个,C组（3.5±1.78）个;CD8+阳性细胞数：A组（14.4±2.44）个,B组（4.5±1.51）个,C组（3.38±1.68）个。术后14天,B组、C组角膜植片中CD4+、CD8+细胞亦明显少于A组（P均=0.000）。结论 结膜下注射贝伐单抗可有效抑制大鼠同种异体穿透性角膜移植术后新生血管的生长,并可能通过此作用延缓移植排斥反应,延长角膜植片存活时间。但贝伐单抗抗移植排斥反应疗效略逊于地塞米松。（眼科,2017, 26： 101-105）     

结膜下注射贝伐单抗对兔角膜新生血管的抑制作用

目的 观察碱烧伤后不同时间结膜下注射贝伐单抗（Bevacizumab）角膜新生血管（CNV）的形成与转归.方法 新西兰白兔54只,制成单眼碱烧伤模型,随机分为3组,每组18只眼,A组碱烧伤后结膜下立即注射贝伐单抗2.5 mg（0.1 ml）,B组碱烧伤后3d结膜下注射贝伐单抗2.5 mg（0.1 ml）,C组结膜下注射生理盐水0.1ml,为对照组.共观察28 d.裂隙灯显微镜下观察角膜新生血管生长情况,行眼前段照相并计算其面积,伤后7、14、28 d各组随机取6例角膜行共焦显微镜检查,观察角膜组织炎性细胞浸润情况及角膜新生血管形态学变化.结果 A、B及C组角膜新生血管开始出现的时间分别为（5.9＋0.8）d、（3.5＋0.6）d及（3.4＋1.1）d,其中A组明显较C组延长（P＜0.05）,B组与C组差异无统计学意义（P =0.068）.伤后各时间点A、B组角膜新生血管的生长面积均明显较C组减少（P＜0.05）,A组与B组角膜新生血管面积比较,差异有统计学意义（P＜0.05）.共焦显微镜检查可见C组烧伤区大量炎性细胞浸润及新生血管形成,而A组角膜炎性细胞较少,烧伤区无新生血管形成,B组见少量新生血管侵入烧伤区.3组基质层均可见纤维及瘢痕组织增生,其中治疗组纤维增生程度与瘢痕组织均较对照组轻.结论 结膜下注射贝伐单抗可抑制角膜炎性细胞形成,改善损伤角膜基质,促进角膜愈合,从而减少碱烧伤引起的角膜新生血管的生长,在早期注射能取得更好的疗效.     

Bevacizumab(Avastin)抑制角膜新生血管的应用新进展

诱发角膜新生血管的因素涉及各种生长因子。研究表明:在角膜新生血管中广泛存在的血管内皮生长因子(vascular endothelial growth factor,VEGF)起着主要作用。一种可行的治疗角膜新生血管策略是:通过特异性的中和抗VEGF抗体竞争性的结合VEGF,从而抑制VEGF活性。近年来,利用抗VEGF治疗策略,抑制脉络膜新生血管获得了很好的效果。靶向VEGF治疗药物的疗效和安全性已经证明。因此我们设想,局部应用新的抗VEGF药物,如贝伐单抗、兰尼单抗等可以有效地抑制角膜新生血管,恢复角膜透明和视力。     

The Effect of Bevacizumab versus Ranibizumab in the Treatment of Corneal Neovascularization: A Preliminary Study

Purpose

To compare the short term effects of bevacizumab and ranibizumab injections on the regression of corneal neovascularization (NV).

Methods

Sixteen eyes of 16 patients with corneal NV were randomly assigned for an injection with 2.5 mg of bevacizumab (group 1, n = 8) or 1 mg of ranibizumab (group 2, n = 8) through subconjunctival and intrastromal routes. The patients were prospectively followed-up for one month after the injections. Corneal NV areas, as shown on corneal slit-lamp photographs stored in JPEG format, were calculated using Image J software before the injection, one week after the injection, and one month after the injection. The corneal NV areas were compared before and after the injections.

Results

Seven women and nine men, with an average age of 51 years, presented with corneal NV secondary to herpetic keratitis (7 cases), graft rejection (6), chemical burn (1), pemphigoid (1), and recurrent ulcer (1). In group I, the preoperative corneal NV area (8.75 ± 4.33%) was significantly decreased to 5.62 ± 3.86% one week after the injection and to 6.35 ± 3.02% one month after the injection (p = 0.012, 0.012, respectively). The corneal NV area in group 2 also exhibited a significant change, from 7.37 ± 4.33% to 6.72 ± 4.16% one week after the injection (p = 0.012). However, no significant change was observed one month after the injection. The mean decrease in corneal NV area one month after injection in group 1 (28.4 ± 9.01%) was significantly higher than in group 2 (4.51 ± 11.64%, p = 0.001).

Conclusions

Bevacizumab injection resulted in a more effective and stable regression of corneal NV compared to the ranibizumab injection. The potency and dose of these two drugs for the regression of corneal NV require further investigation.