The effect and safety of intravitreal injection of ranibizumab and bevacizumab on the corneal endothelium in the treatment of diabetic macular edema

Objective: To investigate the effect and safety of intravitreal injection (IVI) of bevacizumab and ranibizumab on corneal endothelial cell count and morphology in patients with diabetic macular edema.

Materials and methods: A total of 60 eyes from 60 consecutive patients who received 0.5?mg/0.05?ml IVIs of bevacizumab (n?=?30, IVB group) or 1.25?mg/0.05?ml ranibizumab (n?=?30, IVR group) for three consecutive months were investigated prospectively. Specular microscopy was performed to evaluate endothelial cell count, the percentage of hexagonal cells (pleomorphism), and the coefficient of variation of the cell size (polymegathism); optical biometry was performed to evaluate central corneal thickness. Results before injection and 1 month after the first and third injections were compared.

Results: The groups were matched for age (p?=?0.11) and gender (p?=?0.32). There was no significant difference in endothelial cell count (IVB group, p?=?0.66; IVR group, p?=?0.74), pleomorphism (IVB group, p?=?0.44; IVR group, p?=?0.88) and polymegathism (IVB group, p?=?0.21; IVR group, p?=?0.24) before injection or 1 month after the first and third injections. There was also no difference in central corneal thickness (IVB group, p?=?0.15; IVR group, p?=?0.58) before injection or 1 month after the first and third injections.

Conclusion: Monthly 1.25?mg/0.05?ml IVIs of bevacizumab or 0.5?mg/0.05?ml of ranibizumab for three consecutive months in the treatment of diabetic macular edema does not affect corneal morphology and has no harmful effects on the endothelium.     

Intravitreal anti-VEGF treatment for retinopathy of prematurity in infants with active adenoviral keratoconjunctivitis

Purpose: To evaluate the results of intravitreal anti-vascular endothelial growth factor (anti-VEGF) treatment for retinopathy of prematurity (ROP) in infants with active adenoviral keratoconjunctivitis (AKC).

Material and methods: A retrospective analysis was performed using the medical records of all infants treated with intravitreal injections of anti-VEGF agents during an AKC outbreak previously reported in the literature at a tertiary center for treatment of ROP. The infants were divided into two groups. Group 1 included nine infants (18 eyes) with AKC, while Group 2 included 13 infants (26 eyes) without AKC.

Results: During the AKC outbreak, 22 infants were treated with anti-VEGF agents for treatment-requiring ROP. In all patients in both groups, the ROP and plus disease displayed a significant regression within 2 days after the intravitreal injections. Moreover, no serious complications such as endophthalmitis, retinal detachment, cataract or intravitreal hemorrhage were observed after the treatment and there were no statistically significant differences between the groups in terms of postoperative complications.

Conclusion: Immediate and appropriate intervention is very important in cases of treatment-requiring ROP otherwise it can result in blindness. However, laser treatment for ROP is technically difficult in infants with active AKC. The results of this study showed that favorable outcomes without serious ocular complications could be obtained via intravitreal injections of anti-VEGF agents in infants with active AKC.     

Endophthalmitis after intravitreal injections

Endophthalmitis following intravitreal injection is an infrequent but serious clinical problem. Infectious endophthalmitis must be differentiated from noninfectious inflammation. Depending on the series, the risk of endophthalmitis is very low. The use of a standardized injection protocol can reduce the risk of infection.     

Long-term intraocular pressure changes after intravitreal injection of bevacizumab

Purpose: To assess the long-term intraocular pressure (IOP) changes after the intravitreal injection of bevacizumab (Avastin; Genentech, Inc., South San Francisco, CA) for treatment of age-related macular degeneration (AMD) and diabetic macular edema (DME) patients and evaluate the correlation factors.

Material and methods: Patients with neovascular AMD or DME underwent treat-and-extended anti-VEGF regimen in one eye and followed more than 12 months were enrolled in this study. We set three criteria of IOP elevation: (1) the IOP of the treated eye increased above the contralateral eye for at least two consecutive visits; (2) the IOP of the treated eye increased above the pre-injection IOP for at least two consecutive visits; (3) and the IOP of the treated eye increased more than 5?mmHg above the baseline IOP for at least two consecutive visits. We used mixed model univariate and multivariate analysis to assess the association between IOP elevation and independent parameters including age, sex, lens status, the number of injections, and underlying disease.

Results: In total 152 patients, 83 patients with AMD and 69 patients with DME, were included in this study. Mean follow-up time was 18.7 months, with a maximum of 50 months. In IOP elevation, 54 eyes (35.6%) showed an IOP increase above that of the contralateral eye (criteria 1), 50 eyes (33.4%) showed an IOP increase above the baseline IOP (criteria 2), and an IOP increase greater than 5?mmHg above the baseline IOP observed in nine eyes (5.9%) (criteria 3). In the univariate analysis, lens status and total number of injections were statistically significant for criteria 2 and 3 (all ps?<?0.05). However, in the multivariable analysis, only the number of intravitreal injections was statistically correlated with sustained IOP elevation for criteria 2 and 3 (p?<?0.001 and p?=?0.039, respectively).

Conclusions: Our results suggest that under long-term monitoring, with a treat-and-extended regimen, intravitreal bevacizumab injections were associated with sustained IOP elevation. In particular, multiple intravitreal injections could be associated with sustained IOP elevation.     

Impact of intravitreal triamcinolone acetonide versus intravitreal bevacizumab on retrobulbar hemodynamic in patients with diabetic macular edema

Purpose: To evaluate and compare retrobulbar hemodynamic changes measured with color Doppler imaging (CDI) in diabetic patients receiving intravitreal triamcinolone acetonide (IVTA) versus bevacizumab.

Methods: Patients with diffuse diabetic macular edema were assessed prospectively by CDI following intravitreal injection of triamcinolone acetonide (group I, 12 eyes) versus bevacizumab (group II, 14 eyes). CDI was used to measure the peak systolic velocity (PSV), end diastolic velocity (EDV) and the resistive index (RI) of the central retinal artery (CRA), ophthalmic artery (OA) and posterior ciliary arteries (PCA) one day preoperatively and one week postoperatively.

Results: In group I, EDV of OA and CRA decreased significantly (p?=?0.007 and 0.018, respectively). The PSV and RI of PCA decreased significantly (p?=?0.035 and 0.002, respectively). In group II, both the PSV and EDV of the CRA decreased significantly (p?=?0.000). Comparing the percentage of change in both groups, PSV of the CRA decreased significantly in group II (p?=?0.034), while IVTA has more significant effect on the ophthalmic artery hemodynamic parameters as EDV decreased and RI increased significantly (p?=?0.045 and 0.043, respectively)

Conclusion: Intravitreal injections of triamcinolone acetonide and bevacizumab have a significant effect on the ocular hemodynamic. The effect of bevacizumab is statistically significant on the PSV of CRA compared to IVTA.     

玻璃体腔注射左氧氟沙星眼内药动学

目的研究眼玻璃体腔注射左氧氟沙星在眼内药动学过程和特点.方法兔眼玻璃体腔注射0.5 mg左氧氟沙星液后0.25,0.67,2,6,12,24,48,72 h,各取4只兔眼玻璃体和房水样本,采用高效液相内标法检测左氧氟沙星浓度,并应用药动学软件计算相关药动学参数.结果在玻璃体腔注射左氧氟沙星液后48 h为所测得玻璃体和房水最低血药浓度,分别为(0.58±0.17)mg·L-1和(0.25±0.06)mg·L-1.玻璃体和房水血药浓度高于目前眼内炎常见致病菌50%和90%最小抑菌浓度MIC50(16mg·L-1)/MIC90(64 mg·L-1),时间分别达6～12 h和2～6 h以上,消除半衰期各为4.276 h和3.979 h.结论左氧氟沙星0.5 mg玻璃体腔注射能在玻璃体和房水中获得一定时间的药物治疗浓度,一般需每日注射一次.     

Intravitreal bevacizumab effects on VEGF levels in distant organs: an experimental study

Purpose: The aim of this study was to determine the effects of single-dose intravitreal bevacizumab on the levels of vascular endothelial growth factor (VEGF) in serum and distant organs.

Methods: Adult New Zealand albino rabbits (n?=?40) were divided into experimental and control groups. Experimental rabbits received a single 0.05?ml intravitreal injection of 1.25?mg bevacizumab (Avastin) into the right eye, and control rabbits (n?=?8) received no injection. Following injection, group 1 rabbits (n?=?8) were sacrificed on day 1, group 2 rabbits (n?=?8) on day 7, group 3 rabbits (n?=?8) on day 14, and group 4 rabbits (n?=?8) on day 28; control rabbits were sacrificed on day 28. After sacrifice, samples of brain, heart, liver, kidney and blood were collected. Levels of VEGF in serum and tissue were measured using enzyme-linked immunosorbent assay. The presence of bevacizumab was evaluated by immunofluorescence staining in tissues.

Results: Positive bevacizumab immunoreactivity was observed in brain, heart and kidney. Serum VEGF levels significantly decreased in groups 3 and 4 compared with controls (p?p?Conclusions: Intravitreal bevacizumab not only may escape from the blood-retinal barrier and enter the general circulation, but also may be disseminated to distant organs. Our study demonstrates that a single dose of intravitreally injected bevacizumab decreases VEGF levels in serum and liver.     

Bowel perforation in non-small cell lung cancer after bevacizumab therapy

Summary   Background: Bevacizumab is increasingly used in combination with chemotherapy for treatment of unresectable non-small cell lung cancer. The aim of this report is to underline possible risks associated with this otherwise well-tolerated drug. Patient: A 69-year-old patient with metastatic non-small cell lung cancer was started on a palliative chemotherapy regimen containing carboplatin, paclitaxel, and bevacizumab. Results: After the second cycle of chemotherapy, the patient developed abdominal pain. On emergency laparotomy, there was diffuse perforation of the colonic wall, so the patient underwent a Hartmann's procedure with subtotal colectomy. Histopathological examination confirmed the diagnosis of ischemic colitis. Conclusion: Gastrointestinal perforation is a known adverse event of bevacizumab therapy which so far has occurred only in patients with predisposing risk factors. Our patient illustrates that there must always remain a high index of suspicion regarding bowel perforation in patients developing acute abdominal pain under bevacizumab therapy, even if they have no apparent risk factors.     

渗出性老年黄斑变性患者玻璃体腔注射康柏西普前后房水中血管内皮生长因子、色素上皮细胞衍生因子浓度的变化

目的 探讨玻璃体腔注射康柏西普治疗对渗出性老年黄斑变性（eAMD）患者的临床疗效及房水中血管内皮生长因子（VEGF）、色素上皮细胞衍生因子（PEDF）水平的变化。方法 选取2013年5月—2017年4月在西电集团医院眼科治疗的eAMD患者75例（75眼）作为研究对象,随机分为治疗组和对照组,分别有38、37例。治疗组患者玻璃体腔注入0.05 mL康柏西普注射液,对照组患者注入0.5 mL曲安奈德注射液,比较两组患者治疗前后最佳矫正视力（BCVA）、黄斑中心凹视网膜厚度（CRT）以及房水中VEGF、PEDF浓度,并观察术后并发症的发生情况。结果 治疗前,两组BCVA、CRT、房水中VEGF、PEDF浓度均无显著差异;术后1、3、6个月治疗组BCVA、CRT均显著高于治疗前,同组治疗前后比较差异有统计学意义（P<0.05）,而对照组无显著变化。治疗后治疗组VEGF显著降低、PEDF显著升高,同组治疗前后比较差异有统计学意义（P<0.05）,而对照组无显著变化。两组治疗期间不良反应的发生情况比较无显著差异。结论 玻璃体腔注射康柏西普可以显著降低eAMD患者房水中VEGF浓度,提高PEDF水平,改善视力,疗效显著,且无严重的并发症,值得临床应用和推广。     

贝伐单抗在中晚期宫颈癌中的应用

宫颈癌是女性常见的恶性肿瘤。早期宫颈癌可通过手术根治,但中晚期宫颈癌患者5年生存率较低,且生活质量不甚理想。靶向治疗是继传统治疗方法以外的一种有效的新型治疗方法。贝伐单抗是以抑制血管内皮生长因子为作用机制的分子靶向治疗药物。该文综述了有关贝伐单抗在宫颈癌中的临床应用及研究进展。     

Drug delivery techniques for treating age-related macular degeneration

Introduction: Currently, the standard therapy for neovascular age-related macular degeneration involves the use of anti-vascular endothelial growth factor (VEGF) drugs, which are delivered by repeated office-based intravitreal injections. This treatment is generally very effective in stabilizing or improving vision, although repeated injections create a burden for patients, family members and physicians. In addition, the cumulative risks of endophthalmitis and other complications increase with the number of injections.

Areas covered: In the clinic, much attention is focused on the relative efficacies of the three major anti-VEGF medications (bevacizumab, ranibizumab and aflibercept) as well as the most popular re-injection regimens (monthly, as-needed and treat-and-extend). In theory, intravitreal anti-VEGF drug delivery with sustained-release devices would offer similar visual results with fewer required re-injections. Various approaches have been studied, including noninvasive techniques, intraocular implants and colloidal carriers, such as liposomes, microparticles and nanoparticles.

Expert opinion: Despite its theoretical appeal, sustained-release drug delivery will not replace current techniques unless it offers one or more advantages in efficacy, safety, convenience or cost. Currently, many patients maintain stable vision with intravitreal injections at intervals of 2 months or longer, so sustained-release techniques will have to lengthen these intervals substantially to become widely accepted. As we continue to collect data from clinical trials, the role of sustained-release techniques will become better defined.     

Multivesicular liposomes for sustained release of bevacizumab in treating laser-induced choroidal neovascularization

Bevacizumab is an anti-vascular endothelial growth factor drug that can be used to treat choroidal neovascularization (CNV). Bevacizumab-loaded multivesicular liposomes (Bev-MVLs) have been designed and developed to increase the intravitreal retention time of bevacizumab and reduce the number of injection times. In this study, Bev-MVLs with high encapsulation efficiency were prepared by double emulsification technique, and antibody activity was determined. The results revealed that 10% of human serum albumin (HSA) could preserve the activity of bevacizumab. In vitro release of Bev-MVLs appeared to be in a more sustained manner, the underlying mechanisms of Bev-MVLs indicated that bevacizumab was released from MVLs through diffusion and erosion. Results of sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) demonstrated that bevacizumab could retain its structural integrity after being released from MVLs in vitro. In vivo imaging was used to evaluate the retention time of antibody in rat eyes, while pharmacokinetic analysis was performed on rabbit eyes. These results indicated that Bev-MVLs exhibited sustained release effects as compared to bevacizumab solution (Bev-S). Bev-MVLs could effectively inhibit the thickness of CNV lesion as compared to Bev-S at 28?days after treatment. Furthermore, these data suggest that Bev-MVLs are biologically feasible to increase the retention time of bevacizumab in vitreous humor. This novel Bev-MVLs may therefore serve as a promising sustained release drug delivery system for the treatment of CNV.     

Results of intravitreal ranibizumab treatment for retinopathy of prematurity in infants

Purpose: To assess the results of intravitreal ranibizumab treatment for retinopathy of prematurity (ROP) in infants.

Methods: A single-institution, retrospective consecutive case series.

Results: Thirty-one patients who received ranibizumab treatment for ROP were evaluated in this study. The mean follow-up time was 14?±?1.37?months. Vascularization of the peripheral retina had completed with delay in the majority of cases and also avascular areas were present in the peripheral retinas of five infants at one year of age. Although recurrence of ROP developed in 14 infants after single-dose ranibizumab treatment, only four infants received additional treatment due to recurrence of ROP requiring treatment. No serious ocular complications were reported, but, two infants died in this series.

Conclusion: Even so ranibizumab treatment is an effective therapy for ROP in early period, close monitoring after injection is necessary due to the high incidence of recurrence. In addition, questions remain regarding the systemic safety of ranibizumab. Further studies are needed to study the systemic and ocular side effects of ranibizumab.     

不同剂量的重组人血管内皮抑素腹腔给药对腹水瘤小鼠的疗效观察

目的 观察不同剂量重组人血管内皮抑素(恩度)对腹水瘤小鼠腹水疗效的差异.方法 建立腹水瘤小鼠模型.将160只小鼠随机分成5组,每组32只,依次给予相同体积的生理盐水(Control组)、12.5 mg·kg-1恩度、25 mg·kg-恩度、50 mg·kg-恩度、100 mg·kg-1恩度,隔天给药.记录各组小鼠的体质量、腹围及生存期,观察腹水的性状,检测腹膜通透性.结果 (1)第7天各组随机解剖13只小鼠检测腹膜通透性,观察到小鼠腹水发生率为80％;(2)体质量方面,仅100 mg·kg-1剂量组与Control组的差异有统计学意义(P＜0.05),余剂量组比较均差异无统计学意义(P＞0.05);(3)腹围方面,对比Control组,50 mg·kg-1和100 mg·kg-1剂量组比较差异有统计学意义(P＜0.05),余剂量组比较均差异无统计学意义(P＞0.05);(4)随着恩度剂量增加,血性积液程度整体上呈减少趋势;(5)与Control组相比,各恩度剂量组的生存期、540 nm波长处Evan蓝的吸光度(OD540)值的比较均差异无统计学意义(P＞0.05).结论 恩度对血性积液的效果与剂量相关.50、100 mg·kg-1剂量组相对其余剂量组腹水抑制作用明显,为恩度腔内治疗的有效剂量.     

贝伐单抗对肝癌细胞株HepG2增殖的抑制作用

目的通过体外实验探讨贝伐单抗(bevacizumab)对人肝癌细胞HepG2增殖的抑制作用及可能的分子机制。方法MTT法检测贝伐单抗对肝癌细胞增殖的抑制作用;流式细胞仪检测细胞凋亡;RT-PCR分析肝癌细胞株VEGF、Flt-1、KDR mRNA表达量的变化。结果不同质量浓度的贝伐单抗对肝癌细胞株HepG2的增殖有抑制作用;贝伐单抗可诱导肝癌细胞株HepG2的凋亡;贝伐单抗作用于肝癌细胞株HepG2后,其VEGF、KDR mRNA表达量均减少。结论贝伐单抗可能通过阻断VEGF的促增殖作用而抑制HepG2细胞增殖。     

Vascular biology support for the use of bevacizumab in colorectal cancer

In colorectal cancer, increased expression of the angiogenesis promoter vascular endothelial growth factor correlates with invasiveness, vascular density, metastases, recurrence and prognosis. Bevacizumab is a recombinant humanised monoclonal antibody to vascular endothelial growth factor. In recent clinical trials, bevacizumab has been shown to prolong the time to disease progression and the survival of patients with colorectal cancer. In six patients with adenocarcinoma of the rectum, bevacizumab decreased tumour blood perfusion and volume, interstitial fluid pressure, the number of circulating endothelial cells and fluorodeoxyglucose uptake. Surgical specimens showed a marked response in all six patients with only microscopic disease in five of the patients. These effects of bevacizumab on the vascular biology of tumours probably underlie the progression and survival benefits observed in clinical trials of colorectal cancer.     

Determination of the toxicity of intravitreal minocycline in rabbit eyes

Purpose: To evaluate the retinal toxicity of intravitreal minocycline in rabbit eyes.

Methods: Intravitreal injection of minocycline with concentrations of 1000, 500, 250, 125 and 62.5?μg in 0.1?ml was performed in 10 New Zealand albino rabbits. Each concentration was injected into two rabbit eyes. For each dose, normal saline was injected in one contralateral eye and the other fellow eye remained non-injected. Electrophysiologic testing was performed before and 4 weeks after injections. The eyes were enucleated 4 weeks after injections and examined using light microscopy.

Results: The clinical examination was unremarkable after injections. Electroretinography recordings were significantly affected at all doses in at least one of the a- or b-waves of photopic or scotopic responses. Histopathologic examination revealed marked atrophy and loss of integrity in all retinal layers in all minocycline injected eyes. Contralateral eyes were normal.

Conclusion: In our study, intravitreal minocycline was toxic to the retina in albino rabbits even at a concentration of 62.5?µg/0.1?ml.     

The Pharmacology Study of a New Recombinant Human VEGF Receptor-Fc Fusion Protein on Experimental Choroidal Neovascularization

PURPOSE: KH902, a recombinant fusion protein, is designed for treatment of neovascular age-related macular degeneration. The study is to investigate the prevention efficacy of KH902 on experimental choroidal neovascularization (CNV) in a monkey model. MATERIALS AND METHODS: Binding assay and endothelial cell proliferation assay were used to evaluate activity and bioactivity of KH902 in vitro while an initial comparison of bioactivity was made between KH902 and Ranizumab (Lucentis). Ocular and systemic levels of KH902 were analyzed by enzyme-linked immunosorbent assay (ELISA) method after single intravitreal administration to evaluate its availability to ocular fundus. In vivo pharmacological study, CNV was induced by laser in monkeys and KH902 prevention efficacy on CNV was evaluated by incidence of CNV and several ophthalmic examinations. RESULTS: KH902 is a unique fusion protein with high affinity to VEGF and good availability to target tissue, beneficial to good bioactivity in vivo. In vivo pharmacological study, the incidence of CNV formation was largely reduced in KH902 treatment groups. Furthermore, the leakage of CNV in control group which crossed over to KH902 treatment 40 days after laser was much less than that before KH902 treatment. CONCLUSION: KH902 was effective to prevent the formation of experimental CNV and also to treat pre-existed CNV without evidence of toxicity. This study suggests that KH902 has promise as a local anti-angiogenic treatment of CNV-related diseases.     

Safety and efficacy of various concentrations of topical lidocaine gel for intravitreal injection

Introduction: Intravitreal injection (IVT) is one of the most common vitreoretinal procedures, a large majority are performed with local anesthesia. The purpose of this study was to investigate the safety to the cornea and anesthetic efficacy of five concentrations of lidocaine gel.

Methods: A prospective clinical trial was conducted testing lidocaine gel in five preparations: 2, 3.5, 5, 8 and 12%. Patients with macular degeneration, diabetic edema or retina vein occlusion were scheduled for intravitreal treatment received topical anesthesia with lidocaine gel 5 and 10 min before the procedure. Patients answered the visual analog scale for pain during the procedure. Corneal and conjunctival was evaluated using the Oxford scale.

Results: In total, 260 patients were randomized into five groups. The mean pain scores (± standard deviation) were 2.63 (± 1.68) in the 2% group, 2.08 (± 1.35) in the 3.5%; 2.00 (± 1.65) in the 5%, 1.93 (± 1.40) in the 8% and 1.83 (± 1.35) in the 12% group. Mean pain score among all groups was similar (p = 0.077). There was no significant difference between groups in regard to keratitis mean score (p = 0.897).

Conclusions: Lidocaine gel at concentrations from 2 to 12% induced similar anesthetic effect for IVTs, without adverse effects on cornea and conjunctiva.