Pharmacokinetics and distributions of bevacizumab by intravitreal injection of bevacizumab-PLGA microspheres in rabbits

· AIM: To investigate the pharmacokinetics and distributions of bevacizumab by intravitreal injection of prepared bevacizumab-poly(L-lactic-co-glycolic acid)(PLGA) microspheres in rabbits, to provide evidence for clinical application of this kind of bevacizumab sustained release dosage form.·METHODS: Bevacizumab was encapsulated into PLGA microsphere via the solid- in- oil- in- hydrophilic oil(S/O/h O) method. Fifteen healthy New Zealand albino-rabbits were used in experiments. The eyes of each rabbit received an intravitreal injection. The left eyes were injected with prepared bevacizumab-PLGA microspheres and the right eyes were injected with bevacizumab solution. After intravitreal injection, rabbits were randomly selected at day 3, 7, 14, 28 and 42 respectively, three animals each day. Then we used immunofluorescence staining to observe the distribution and duration of bevacizumab in rabbit eye tissues, and used the sandwich ELISA to quantify the concentration of free bevacizumab from the rabbit aqueous humor and vitreous after intravitreal injection.·RESULTS: The results show that the concentration of bevacizumab in vitreous and aqueous humor after administration of PLGA formulation was higher than thatof bevacizumab solution. The T1/2of intravitreal injection of bevacizumab-PLGA microspheres is 9.6d in vitreous and 10.2d in aqueous humor, and the T1/2of intravitreal injection of soluble bevacizumab is 3.91 d in vitreous and4.1d in aqueous humor. There were statistical significant difference for comparison the results of the bevacizumab in vitreous and aqueous humor between the left and right eyes(P 【0.05). The AUC0-tof the sustained release dosage form was 1-fold higher than that of the soluble form. The relative bioavailability was raised significantly.The immunofluorescence staining of PLGA-encapsulated bevacizumab(b-PLGA) in rabbit eye tissues was still observed up to 42 d. It was longer than that of the soluble form.· CONCLUSION: The result of this study shows the beneficial effects of PLGA in prolonging the residency of bevacizumab in the vitreous. And the drug delivery system may have potential as a treatment modality for related disease.

Effect of intravitreal injection of bevacizumab-chitosan nanoparticles on retina of diabetic rats

AIM:To investigate the effects of intravitreal injection of bevacizumab-chitosan nanoparticles on pathological morphology of retina and the expression of vascular endothelial growth factor(VEGF)protein and VEGF mRNA in the retina of diabetic rats.·METHODS:Seventy-two 3-month aged diabetic rats were randomly divided into 3 groups,each containing 24animals and 48 eyes.Both eyes of the rats in group A were injected into the vitreous at the pars plana with 3μL of physiological saline,while in groups B and C were injected with 3μL(75μg)of bevacizumab and 3μL of bevacizumab-chitosan nanoparticles(containing 75μg of bevacizumab),respectively.Immunohistochemistry was used to assess retinal angiogenesis,real-time PCR assay was used to analyze the expression of VEGF mRNA,and light microscopy was used to evaluate the morphology of retinal capillaries.·RESULTS:Real-time PCR assay revealed that the VEGF mRNA expression in the retina before injection was similar to 1 week after injection in group A(P】0.05),while the VEGF mRNA expression before injection significantly differed from those 4 and 8 weeks after injection(P【0.05).Retinal expression of VEGF protein and VEGF mRNA was inhibited 1 week and 4 weeks after injection(P【0.05)in group B,and the expression of VEGF protein and VEGF mRNA was obviously inhibited until 8 weeks after injection(P【0.05)in group C.Using multiple comparisons among group A,group B,and group C,the VEGF expression before injection was higher than at 1,4 and 8 weeks after injection(P【0.05).The amount of VEGF expression was higher 8 weeks after injection than 1 week or 4 weeks after injection,andalso higher 1 week after injection compared with 4 weeks after injection(P【0.05).No toxic effect on SD rats was observed with bevacizumab-chitosan nanoparticles injection alone.·CONCLUSION:The results offer a new approach for inhibiting angiogenesis of diabetic retinopathy and indicate that the intravitreal injection of bevacizumab inhibits VEGF expression in retina,and bevacizumabchitosan nanoparticles have a longer duration of action.

Intravitreal injection practice patterns among Chinese ophthalmologists

AIM:To describe the practice patterns of intravitreal injections(IVIs)among ophthalmologists in China.METHODS:This was a cross-sectional online survey.Ophthalmologists who had performed accumulated more than 100 injections were contacted by the Brightness Center,a hospital-based national network,to complete an anonymous,24-question,internet-based survey.They were surveyed on practices in injection techniques,pre-,and post-injections procedures.RESULTS:A total of 333 ophthalmologists from 28 provinces/municipalities/autonomous regions responded to the survey(50.68%response rate).The 91.29%of the respondents evaluated systemic risk factors by medical history,electrocardiogram(ECG)and blood test.All the respondents used pre-injection prophylactic antibiotics.Most checked intraocular pressure(IOP,99.1%)and blood pressure(96.1%)before injections.A majority of the respondents performed injections in the operating room(98.8%),wore masks(99.7%),gloves(99.4%)and sterile surgical clothing(96.1%),performed topical anesthetics(97.9%),and applied povidone-iodine(95.8%)pre-injection.The 61.26%of the respondents dilated pupil.About half of the respondents(51.05%)performed bilateral injections in the same setting.Superior temporal quadrant(40.54%)was the most frequent site of injection.Around three quarters used 30-gauge needles.Most respondents(97.9%)measured the site of injection from limbus.More than half(53.45%)performed conjunctiva displacement prior to injection.The 32.43%of the respondents checked IOP post-injection and 87.99%physicians checked hand motion(HM)or counting fingers(CF)after injection,while 36.94%observed optic nerve perfusion.All participants used topical antibiotics post-injections.Most physicians(91.89%)reviewed patients on the following day.CONCLUSION:This study provides a description of the real-world practice patterns in IVIs in China and offers critical information regarding education and training of ophthalmologists and amendment of local society guidelines.

Intravitreal bevacizumab and Ahmed glaucoma valve implantation in patients with neovascular glaucoma

AIM:To explore the efficacy of preoperative intravitreal bevacizumab(IVB) injection combined with Ahmed glaucoma valve(AGV) implantation in the treatment of neovascular glaucoma(NVG).METHODS:This retrospective study included 35 eyes from 35 patients who underwent preoperative IVB and AGV implantation for treatment of NVG. Findings such as intraocular pressure(IOP) number of anti-glaucoma medications, visual acuity(VA), surgical success rates,and complications were recorded.RESULTS:AfterAGVimplantation,IOPwas18.2±4.0mmHg,15.5±3.3 mm Hg and 9.8±2.6 mm Hg at 6, 12 and 36 mo,significantly decreased compared with pre-IOP(P 【0.01).The number of anti-glaucoma medications was 0.9 ±0.5,0.8 ±0.9 and 0.8 ±0.6 at 6, 12 and 36 mo, significantly decreased compared to pre-treatment(P 【0.01). At last visit, there were 19 eyes with stable VA, 4 with VA improvement, 12 with diminished VA and 3 with complete loss light perception. There were 7 cases that failed during 3-year fellow up period. Cumulative probabilities of valve survival by Kaplan-Meier analysis were 82.9%,74.1% and 71.0% at 12, 24 and 36 mo, respectively. Cox stepwise regression analysis found that the survival time was significant associated with the pre-visual acuity 【2/400(P 【0.05). Post-operative complications occurred in 8eyes, of which hyphema presented in 2 eyes, choroidal effusion in 2 eyes.CONCLUSION:The procedure of preoperative IVB andAGV implantation should be one of treatments for NVG because of its safety and effectiveness.

Effects of two different doses of intravitreal bevacizumab on subfoveal choroidal thickness and retinal vessel diameter in branch retinal vein occlusion

AIM： To investigate the effects of two different doses of intravitreal bevacizumab on subfoveal choroidal thickness （SFChT） and retinal vessel diameter in patients with branch retinal vein occlusion. METHODS： An interventional, restrospective study of 41 eyes of 41 patients who had completed 12mo of follow-up, divided into group 1 （1.25 mg of bevacizumab, 21 eyes of 21 patients） and group 2 （2.5 mg of bevacizumab, 20 eyes of 21 patients）. Complete ophthalmic examination, fluorescein angiography, enhanced depth imaging optical coherence tomography and measurement of retinal vessel diameter with IVAN software were performed at baseline and follow-up. RESULTS： The SFChT changed from 279.1 （165-431） μm at baseline to 277.0 （149-413） μm at 12mo in group 1 （P= 0.086）, and from 301.4 （212-483） μm to 300.3 （199-514） μm in group 2 （P=0.076）. The central retinal arteriolar equivalent （CRAE） changed from 128.8 ±11.2 μm at baseline to 134.5±8.4 μm at 12mo in group 1, and from 134.6±9.0 μm to 131.4±12.7 μm in group 2 （P =0.767）. The central retinal venular equivalent （CRVE） changed from 204.1±24.4 μm at baseline to 196.3±28.2 μm at 12mo in group 1, and from 205.8±16.3 μm to 194.8±18.2 μm in group 2 （P=0.019）. The mean central macular thickness （P〈0.05） and average best-corrected visual acuity （BCVA; P〈0.05） improved in both groups CONCLUSION： Changes in the SFChT are not statistically significant and not different according to the doses of bevacizumab. The CRAE did not show significant change, however, the CRVE showed significant decrease regardless of the dose.

Comparison of intravitreal bevacizumab with macular photocoagulation for treatment of diabetic macular edema: a systemic review and Meta-analysis

AIM: To further evaluate the efficacy and safety of intravitreal bevacizumab(IVB) versus macular photocoagulation(MPC) in treatment of diabetic macular edema(DME) by Meta-analysis. METHODS: Pertinent publications were identified through systemic searches of Pub Med, Medline,EMBASE, and the Cochrane Controlled Trials Register up to 30 November, 2013. Changes in central macular thickness(CMT) in μm and best-corrected visual acuity(BCVA) in log MAR equivalents were extracted at 1, 3, 6,12 and 24 mo after initial treatment, and a Meta-analysis was carried out to compare results between groups receiving IVB and MPC.RESULTS: Five randomized controlled trial(RCTs) and one high-quality comparative study were identified and included. Our Meta-analysis revealed that both IVB and MPC resulted in the improvements of CMT and BCVA in eyes with DME at 1mo after initial treatment, with IVB being significantly superior to MPC(P =0.01 and 0.02,respectively). The improvements of both measure outcomes at 3, 6, 12 and 24 mo after treatment did not vary significantly between the IVB groups and MPC groups(CMT at 3mo, P =0.85; at 6mo, P =0.29; at 12 mo,P =0.56; at 24 mo, P =0.71; BCVA at 3mo, P =0.31; at 6mo,P =0.30; at 12 mo, P =0.23; at 24 mo, P =0.52). However,the number of observed adverse events was low in all studies.CONCLUSION: Current evidence shows IVB treatment trends to be more effective in improvements of macular edema and vision in eyes with DME at an earlier follow up(1mo) compared with MPC. At other time, both interventions have comparable efficacy without statistical significances.

Predictors of short-term outcomes related to central subfield foveal thickness after intravitreal bevacizumab for macular edema due to central retinal vein occlusion

AIM：To investigate the predictive factors for shortterm effects of intravitreal bevacizumab injections on central subfield foveal thickness（CSFT）in patients with macular edema（ME）secondary to central retinal vein occlusion（CRVO）.·METHODS：This was a retrospective study in 60 eyes treated with intravitreal bevacizumab injections for ME due to CRVO.Follow-up was three months.The Early Treatment Diabetic Retinopathy Study（ETDRS）score and CSFT measured by spectral-domain optical coherence tomography（SD-OCT）were used to observe the changes in best-corrected visual acuity（BCVA）.Baseline BCVA,CSFT,age,CRVO duration and the presence of cystoid macular edema（CME）or subretinal fluid（SRF）were analyzed as potential predictive factors of the effects of intravitreal bevacizumab injections.·R ESULTS：BCVA improved from 0.9 log MAR at baseline to 0.6 log MAR at 3mo,which was associated with a significant reduction in CSFT from 721μm to 392μm 3mo after injection.About 50%of CME cases and more than90%of SRF cases responded to treatment with a complete resolution at 3mo.Age（=0.036）and low baseline CSFT（=0.037）were associated with a good 3-month prognosis.Patients〉60 years old achieved better CME resolution（=0.031）and lower CSFT at 3mo（305μm 474μm,=0.003）.·CONCLUSION：Intravitreal bevacizumab significantly improved visual acuity and CSFT in patients with CRVO after 3mo.Older age and lower baseline CSFT were good predictors of short-term CSFT outcomes.The retinal thickness response to bevacizumab might depend on the resolution of CME rather than SRF.

Improvement of visual acuity based on optical coherence tomography patterns following intravitreal bevacizumab treatment in patients with diabetic macular edema

AIMTo report the visual outcome based on various patterns of optical coherence tomography (OCT) morphology in diabetic macular edema (DME), following treatment with anti-VEGF intravitreal bevacizumab (IVB) injection.

Panretinal photocoagulation versus panretinal photocoagulation plus intravitreal bevacizumab for high-risk proliferative diabetic retinopathy

AIM： To evaluate the effects of panretinal photocoagulation （PRP） compared with PRP plus intravitreal bevacizumab （IVB） in patients with high-risk proliferative diabetic retinopathy （PDR） according to the Early Treatment Diabetic Retinopathy Study criteria.METHODS： The data were collected retrospectively from the eyes of high-risk PDR patients, which were divided into two groups. After treated with standard PRP, the eyes were randomly assigned to receive only PRP （PRP group） or PRP plus intravitreal injection of 1.25 mg of bevacizumab （PRP-Plus group）. Patients underwent complete ophthalmic evaluation, including best corrected visual acuity （BCVA）, intraocular pressure （IOP）, and new vessel size in fluorescein angiography （FA） and optical coherence tomography for the assessment of central subfield macular thickness （CSMT） at baseline and at weeks 12 （±2）, 16 （±2）, 24 （±2） and 48 （±2）. Main outcome measures also included vitreous clear-up time and neovascularization on the disc （NVD） regression time. Adverse events associated with intravitreal injection were investigated.RESULTS： Thirty consecutive patients （n=36 eyes） completed the 48-week follow-up. There was no significant difference between the PRP and PRP-Plus groups with respect to age, gender, type or duration of diabetes, area of fluorescein leakage from active neovascularizations （NVs）, BCVA or CSMT at baseline. The mean vitreous clear-up time was 12.1±3.4wk after PRP and 8.4±3.5wk after PRP combined with IVB. The mean time interval from treatment to complete NVD regression on FA examination was 15.2±3.5wk in PRP group and 12.5±3.1wk in PRP-Plus group. No significant difference in CSMT was observed between the groups throughout the study period. However, the total area of actively leaking NVs was significantly reduced in the PRP-Plus group compared with the PRP group （P〈0.05）. Patients received an average of 1.3 injections （range： 1-2）. Ten eyes （27.8%） underwent 2 injections. Two eyes had ocular complication of PDR progression to dense vitreous hemorrhage （VH）. No major adverse events were identified.CONCLUSION： The adjunctive use of IVB with PRP is associated with a greater reduction in the area of active leaking NVs than PRP alone in patients with high-risk PDR. Short-term results suggest combined IVB and PRP achieved rapid clearance of VH and regression of retinal NV in the treatment of high-risk PDR. Further studies are needed to determine the effect of repeated intravitreal bevacizumab injections and the proper number of bevacizumab injections as an adjuvant.

Immediate intraocular pressure rise after intravitreal injection of ranibizumab and two doses of triamcinolone acetonide

AIM: To evaluate prospectively immediate intraocular pressure (IOP) changes after the intravitreal injection of ranibizumab, 2 and 4mg triamcinolone acetonide. METHODS: Patients who underwent intravitreal injection of 0.1mL (4mg) triamcinolone acetonide (TA, Group T4), 0.05mL (2mg) TA (Group T2) and 0.05mL (0.5mg) ranibizumab (Group R) comprised the study population. Overall, 229 eyes of 205 patients were injected. Fifty-four eyes (23.6%) were in Group T4, 69 eyes (30.1%) in Group T2 and 106 eyes (46.3%) in Group R. If IOP was less than 26mmHg immediately after the injection no further measurement was performed. If IOP was ≥26mmHg, IOP was remeasured till the reading was below 26mmHg at 5, 15 and 30 minutes. RESULTS: Immediately after the injection, the IOP of 28 eyes (51.9%) in Group T4, 22 eyes (31.9%) in Group T2 and 51 eyes (48.1%) in Group R were over 25mmHg. At 30 minutes, IOP of one eye (1.9%) in group T4, two eyes (2.9%) in group T2 and two eyes (1.9 %) in Group R were over 25mmHg. Immediate post-injection IOP was significantly higher in Group T4 and Group R when compared to Group T2 (P <0.001 and P <0.001, respectively). IOP was significantly higher in eyes without vitreous reflux when compared to those with vitreous reflux in all groups (P <0.001). CONCLUSION: IOP may remarkably increase immediately after the intravitreal injection of 2 or 4mg triamcinolone acetonide, and 0.5mg ranibizumab. Absence of vitreous reflux is the most important predicting factor for immediate IOP rise after the injection.

Role of bevacizumab intraocular injection in the management of neovascular glaucoma

AIM:To assess the long-term effects of intraocular bevacizumab(Avastin)injections as an adjunctive drug to manage patients with neovascular glaucoma(NVG).METHODS:A retrospective study was conducted consisting of 34 eyes with secondary NVG caused by proliferative diabetic retinopathy(n=25),ischemic central retinal vein occlusion(n=8),and retinal ischemia resulting from persistent detachment(n=1)were managed by intraocular injections of bevacizumab(1.25 mg/0.05 m L),in addition to other treatments.The main outcome measure was the change in the degree of iris neovascularization.Secondary outcomes included intraocular pressure and the number of additional interventions or antiglaucoma medications administered after injection.RESULTS:All patients were followed-up for at least 12 mo.At the last follow-up,complete regression of rubeosis irides was detectable in 13(38.2%)eyes and incomplete regression in 21 eyes(61.8%).The mean intraocular pressure was 45.32±7.185 mm Hg at baseline and significantly decreased to 26.15±5.679 mm Hg at the last follow-up visit(P=0.000005).Patients received an average of 4.97 injections.As additional treatments,12 eyes(35%)received laser photocoagulation and 6 eyes(18%)underwent retinocryopexy.No further treatment was needed in 16 eyes(47.1%).CONCLUSION:Intravitreal bevacizumab injection can have a favorable effect in controlling intraocular pressure and pain control in patients with NVG because it decreases the angiogenesis and helps to augment the results of conventional procedures.The primary cause of retinal ischemia should be always targeted.

Intravitreal injection of resveratrol inhibits laser-induced murine choroidal neovascularization

AIM:To determine the effects of intravitreal resveratrol(RSV)on murine laser-induced choroidal neovascularization(CNV).METHODS:The toxicity of RSV to choroidal endothelial cell(CEC)was measured using thiazolyl blue tetrazolium bromide(M一)assay.Effects of RSV on choroidal endothelial cell(CEC)migration were evaluated with a modified Boyden chamber assay,while tube formation was evaluated in a 2-D gel assay.CNV was induced by laser photocoagulation in mice.The effects of intravitreal injection of RSV on CNV development were evaluated by fluorescein angiography(FA),confocal analysis of isolectin B4 labeled choroidal flat mounts,and histologic examination of CNV membranes.Immunostaining was used to analyze the expression and phosphorylation of vascular endothelial growth factor receptor 2(VEGFR2).RESULTS:No significant cell toxicity was observed in CEC if the concentration of RSV was less than 200 pmol/L(P>0.05).RSV inhibited vascular endothelial growth factor(VEGF)-induced CEC migration(P<0.05)and tube formation(P<0.05)invitro.Furthermore,intravitrealinjectionof RSV significantly inhibited laser induced CNV formation in mice.The FA leakage,CNV volume and CNV area analysis revealed that there were 41%,45%,and 58%reduction in RSV-treated eyes(1.691±0.1032,178163±78623μm^3 and 6508±619.0μm^2,respectively)compared with those in control(2.724±0.08447,379676±98382μm3and16576±2646μm^2,respectively;P<0.05).Phospho-VEGFR2expression was much weaker in the sections of CNV lesions in RSV injected mice compared with that in control(P<0.05).CONCLUSION:Intravitreal injection of RSV exerts an inhibitory effect on CNV,which may through suppressing endothelial cell migration,tube formation and VEGFR2 phosphorylation.

Effects of moxifloxacin exposure on the conjunctival flora and antibiotic resistance profile following repeated intravitreal injections

AIMTo evaluate the effects of moxifloxacin exposure on the conjunctival flora and antibiotic resistance profile following repeated intravitreal injections.

Study of the Influence of Angiostatin Intravitreal Injection on Vascular Leakage in Retina and Iris of the Experimental Diabetic Rats

Purpose: To examine the effect of an intravitreal injection of angiostatin on vascular leakage in retina and iris of the diabetes and study its possible mechanism. Methods: Experimental diabetes was induced in 24 rats by an intravenous injection of streptozotocin (STZ) during 48 adult rats. Three groups were randomization distributed of them. There were 8 of both normal and diabetic rats in each group. STZ-diabetic rats and age-matched normal rats received an intravitreal injection of 5 μl of sterile PBS (Phosphate Buffered Saline) into the right eye, and the left eye was non-injected in the group A; Angiostatin was injected into the vitreous of the right eye (7.5 μg / 5 μl / eye), and the left eye received the same volume of sterile PBS as the control in the group B and C. The vascular permeability of retina and iris was measured using the Evans blue method at 2 days following the injection in the group A and B. Expression of VEGF in retina was evaluated using western blot analysis 24 hours following the injection in the group C. Results: Diabetic rats showed significant increases of vascular permeability in the retina ( P < 0.01) and iris ( P < 0.05). Angiostatin-injected eyes showed significant decreases in vascular permeability in the retina ( P < 0.01) and iris ( P < 0.05) comparing with the PBS-injected eyes in STZ-diabetic rats. In contrast, intravitreal injection of the same dose of angiostatin into the age-matched normal rats did not result in any significant reduction in vascular permeability in the retina and iris, when compared with the contralateral eye with PBS injection ( P > 0.05). Angiostatin injection significantly reduced VEGF level in the retinas of STZ-diabetic rats but did not affect retinal VEGF level in normal rats. Conclusions: Angiostatin significantly reduce pathological vascular permeability in the retina and iris of STZ-diabetic rats but not in normal rats. Angiostatin down-regulates VEGF expression and thus, blocks the major cause of vascular leakage in the diabetic retina. Therefore, angiostatin may have a therapeutic potential in the treatment of diabetic macular edema, cystoid macular edema, uvietis and other diseases with vascular leakage.

Comparison of intra-pleural injection efficacy between Endostar and Bevacizumab combined with pemetrexed/cisplatin for the treatment of malignant pleural effusion in patients with epidermal growth factor receptor-/anaplastic lymphoma kinase-lung adenocarci

Objective To compare intra-pleural injection efficacy and safety between Endostar and bevacizumab combined with pemetrexed/cisplatin for the treatment of malignant pleural effusion in patients with epidermal growth factor receptor(EGFR)-/anaplastic lymphoma kinase(ALK)-lung adenocarcinoma. Methods Sixty-four pCVatients with EGFR-/ALK-lung adenocarcinoma with malignant pleural effusion(MPE) were admitted to the authors' hospital between January 2016 and June 2017. Patients were randomly divided into two groups: Endostar combined with pemetrexed/cisplatin(Endostar group); and bevacizumab plus pemetrexed/cisplatin(Bevacizumab group). They underwent thoracic puncture and catheterization, and MPE was drained as much as possible. Both groups were treated with pemetrexed 500 mg/m^2, intravenous drip(d1), cisplatin 37.5 mg/m^2 per time, intra-pleural injection(d1, d3). Patients in the Endostar group were treated with Endostar 30 mg per time, intra-pleural injection(d1, 3), and patients in the Bevacizumab group were treated with bevacizumab 5 mg/kg per time, intra-pleural injection(d1). Only one cycle of treatment was applied. MPE was extracted before treatment and on day 7 after treatment. The levels of vascular endothelial growth factor(VEGF) were determined using ELISA. Efficacy and side effects were evaluated according to the Response Evaluation Criteria in Solid Tumors(RECIST) version 1.1, and National Cancer Institute Common Terminology Criteria for Adverse Events(CTCAE) version 3.0 criteria. Results The objective response rates in the Endostar and Bevacizumab groups were 50.0% and 56.3%, respectively; there was no statistical difference between the groups(P > 0.05). After one cycle of treatment, the mean VEGF levels in MPE in both groups decreased significantly, and there was no significant difference in the degree of decline between the two groups(P > 0.05). In both groups, pre-treatment VEGF levels for patients achieving complete response were significantly higher than those for patients achieving stable disease + progressive disease(P < 0.05). No specific side effects were recorded. Conclusion Endostar and Bevacizumab demonstrated similar efficacy in controlling MPE in patients with EGFR-/ALK-lung adenocarcinoma through an anti-angiogenesis pathway, with tolerable side effects. The levels of VEGF in MPE could predict the efficacy of intra-pleural injection of anti-angiogenesis drugs.

Effects of perioperative managements on ocular surface microbiota in intravitreal injection patients

AIM:To investigate the effects of on ocular surface microbiota in patients who received intravitreal injections.METHODS:Samples of ocular surface microbiota were obtained from 41 eyes of 41 patients who visited the Department of Ophthalmology.Patients were separated for three groups.Group A did not receive perioperative managements or intravitreal injection.Group B1 received only once and B2 received more than twice.In operating room,the samples were collected on the ocular surface.Operating taxonomic units(OTUs) clustering and alpha/beta diversity analysis was performed.The microbial 16S rRNA from samples were analyzed using the Hi Seq 2500 platform.RESULTS:Alpha diversity did not differ in each group,and beta diversity differed in the B2 group.Beta diversity showed a significant difference between Group A and B2(P=0.048).With the perioperative managements before intravitreal injection,the composition and relative abundance were altered.Top 10 microbiota on phylum and genus level,and then microbiota notably changed at genus level were listed.Gram-negative bacteria were varied more.Furthermore,Proteus was not found in Groups A and B1,but it was appeared after the patients received perioperative management and intravitreal injections in Group B2.CONCLUSION:With the perioperative managements,the balance of microbiota on the ocular surface is destroyed,and relative composition and abundance of microbiota on the ocular surface is obviously altered.The clinical doctors should pay more attention on the consequence of perioperative managements before intravitreal injection.

The ocular toxicity and pharmacokinetics of simvastatin following intravitreal injection in mice

AIM：To investigate the retinal toxicity and pharmacokinetics of simvastatin intravitreally injected into mice.METHODS：Forty-eight 6-8-week-old C57BL/6J mice were used in this study.Simvastatin was intravitreally injected into the right eye of each mouse;the left eye was injected with vehicle and was used as a control.Bilateral dark-adapted electroretinography（ERG）was performed 1 and 7d following injection.Histology was examined using a combination of light,fluorescence and electron microscopy.Highperformance liquid chromatography（HPLC）was used to determine the decay in the retinal simvastatin concentration.RESULTS：ERG revealed no significant changes in the simvastatin-injected eyes compared to control.Histologic studies showed normal retinal morphology in eyes injected with simvastatin up to a final vitreal concentration of 200μmol/L.No significant changes in the number of photoreceptors,bipolar cells or ganglion cells were found.The retinal simvastatin concentration decayed exponentially,with a half-life of 1.92-2.41h.CONCLUSION：Intravitreal injection of up to 200μmol/L simvastatin produced no signs of adverse effects in the mouse retina.Simvastatin reaches the retina shortly after intravitreal injectionand has a short half-life.

Short-term outcomes after the loading phase of intravitreal bevacizumab and subthreshold macular laser in non-center involved diabetic macular edema

AIM： To compare the effectiveness of intravitreal bevacizumab and subthreshold macular photocoagulation （SMP）, for the treatment of non-center involved diabetic macular edema （non-CI DME）. METHODS： Prospective, randomized, controlled clinical study included patients with type 2 diabetes, non-CI DME and best-corrected visual acuity （BCVA） of 0.30 logMAR or better. Each eye was randomized into three groups： group 1, monthly intravitreal bevacizumab; group 2, single SMP; group 3, single SMP and monthly bevacizumab. Main outcome measures were BCVA, and macular thickness measured with optical coherence tomography as macular central subfield thickness （CST）, macular area of greater thickness （MAGT） and total macular volume （TMV）. Results were analyzed after 3mo. RESULTS： A total of 32 eyes were included. Group 3 improved in BCVA （0.19±0.16 to 0.12±0.14 logMAR; P=0.041） and in TMV （7.90±0.57 to 7.65±0.73 mm3; P=0.025）. Group 1 improved in MAGT （325±26.26 to 298.20±44.85 μm; P=0.022） and TMV （7.79±0.57 to 7.50±0.56 mm3, P=0.047）. Group 2 didn’t show significant improvement of any variable. CONCLUSION： The loading phase of bevacizumab as monotherapy or combined with SMP is superior to SMP as monotherapy in providing short-term visual and anatomical improvement in non-CI DME.

Ocular flora in patients undergoing intravitreal injections: antibiotic resistance patterns and susceptibility to antiseptic picloxydine

AIM: To study antibiotic resistance patterns and susceptibility to eye antiseptic picloxydine of conjunctival flora in patients undergoing intravitreal injections(IVIs).METHODS: Conjunctival swabs were taken in 4 groups of patients, 20 patients in each group(n=80): without IVIs and ophthalmic operations in history(group N1;control group);with the first IVI and antibiotic eye drops Tobrex applied 3 d before IVI and 5 d after it(group N2);with 20 or more IVIs and repeated courses of antibiotic eye drops(group N3);with the first IVI and antiseptic eye drops Vitabact(picloxydine) applied 3 d before IVI and 5 d after it(group N4). In groups N2 and N4 swabs were taken at baseline and after the treatment. Efficacy of picloxydine in inhibition of growth of conjunctival isolates susceptible and resistant to antibiotic was studied in vitro. Minimal inhibition concentrations(MIC) were determined with microdilution test.RESULTS: Two of the three patients who had to undergo the IVI procedure showed conjunctiva bacterial contamination. Along with few Staphylococcus aureus and Gram-negative isolates susceptible to most antibiotics, the majority(71%-77%) of causative agents were coagulase-negative Staphylococci(Co NS), 40%-50% of which were multidrug resistant(MDR). Eye disinfection in the operating room and peri-injection courses of Tobrex or Vitabact resulted in total elimination of isolates found at baseline. However, in 10% and 20% of patients, respectively, recolonization of the conjunctiva with differing strains occurred. In patients with repeated IVI and Tobrex/Maxitrol treatment, the conjunctival flora showed high resistance rates: 90% of Co NS were MDR. In the in vitro study, picloxydine showed bactericidal effect against Staphylococci isolates both antibiotic resistant and susceptible with MIC≥13.56 μg/m L. Incubation of bacteria for 15 min in Vitabact eye drops, commercially available form of picloxydine, 434 μg/m L, showed total loss of colony forming units of all tested isolates including Pseudomonas aeruginosa. CONCLUSION: The confirmed efficacy of eye antiseptic picloxydine against conjunctival bacterial isolates and the presence of its commercial form, 0.05% eye drops, convenient for use by patients before and after injection, make this eye antiseptic promising for prophylaxis of IVIassociated infectious complications.

Intravitreal Bevacizumab for the Treatment of Chronic or Recurrent Central Serous Chorioretinopathy

Background: We report the use of intravitreal bevacizumab as an option for the treatment of chronic or recurrent central serous chorioretinopathy (CSC). Methods: Eight eyes with chronic or recurrent CSC received intravitreal bevacizumab (1.25 mg/0.05 cc) and underwent best corrected visual acuity (VA), optical coherent tomography (OCT), fluorescein angiography (FA) and indocyanine green angiography (ICG) before, and one, three and six months after treatment. Results: All patients showed improvement in visual acuity, fluorescein angiographic leakage, choroidal hyperpermeability and reduced or resolved neurosensory detachment following treatment. Two patients require a second dose of intravitreal bevacizumab. Conclusions: Intravitreal injection of bevacizumab was associated with visual improvement and reduced neurosensory detachment without adverse events in patients with chronic or recurrent CSC. Although these results are promising, further investigations would be helpful to understand this therapy for patients with CSC.