Diabetic macular edema (DME) is a common ocular complication of diabetes patients. It mainly involve macular which is closely related with visual function, thus DME is one of the major reasons causing visual impairment or blindness for diabetes patients. How to reduce the visual damage of DME is always a big challenge in the ophthalmic practice. In the past three decades, there are tremendous developments in DME treatments, from laser photocoagulation, antiinflammation drugs to antivascular endothelial growth factor therapy. However, the mechanism of DME development is not yet completely clear; every existing treatment has its own advantages and weaknesses. Therefore DME treatment still challenges us to explore further to reduce the DME damages.
Objective To observe the effects of dual targets intervention on the expression of vascular endothelial growth factor (VEGF) and connective tissue growth factor (CTGF) in diabetic rat retina. Methods Forty-eight Sprague -Dawley rats were randomly divided into control group (CON1 group) and diabetes mellitus group (DM group). The rats of DM group were induced with streptozotocin injection creating a diabetic model. Retinas were obtained at eight, 10, 12 weeks after DM induction from both groups. CTGF and VEGF mRNA levels were examined by realtime reverse transcriptionpolymerase chain reaction (RT-PCR). Based on the results of above experiments, 60 rats with same conditions were selected. Fifty rats were induced with streptozotocin injection creating a diabetic model, and 10 rats comprised the control group (CON2 group). Then the 50 diabetic rats were randomly divided into ranibizumab and CTGF shRNA dual targets intervention group, ranibizumab singletarget intervention group, CTGF shRNA singletarget intervention group and nonintervention group. Retinas were obtained at one week after intervention from all the groups. CTGF and VEGF mRNA levels were examined by RT-PCR. Results The levels of CTGF mRNA were significantly higher in DM group than that in CON1 group at the 8th weeks after DM induction, and this upregulation was maintained through the 12th week (t=-2.49, -2.67, -2.42;P＜0.05). There was no difference on VEGF mRNA levels between DM group and CON1 group at the 8th weeks after DM induction(t=-0.443,P=0.669). VEGF mRNA levels of DM group started to be significantly elevated over those in the CON1 group at the 10th week, and remained to be higher at the 12th week (t=-2.35, -2.57;P＜0.05). The VEGF mRNA of ranibizumab single-target intervention group was significantly lower than that in non-intervention group (t=-3.44,P=0.014), which was similar to CON2 group (t=-1.37,P＞0.05); however, the CTGF mRNA level was significantly increased as compared to the nonintervention group (t=2.48,P＜0.05). In the CTGF shRNA single-target intervention group, the levels of CTGF and VEGF mRNA were decreased as compared to the non-intervention group (t=0.23, -2.92;P＜0.05). In the ranibizumab and CTGF shRNA dual targets intervention group, the levels of CTGF and VEGF mRNA were decreased as compared to the non-intervention group (t=-6.09, -5.11;P＜0.001), which was similar to CON2 group (t=-1.16, 1.139; P＞0.05). Conclusions Both CTGF and VEGF gene expression are up-regulated in early diabetic rat retina, and the level of CTGF increased earlier than VEGF. Ranibizumab combined with CTGF shRNA could simultaneously reduce the level of CTGF and VEGF mRNA in diabetic rat retina.
Objective To investigate the effect of photodynamic therapy (PDT) combined with intravitreal bevacizumab on wet age-related macular degeneration (AMD). Methods In this retrospective study, 34 eyes (28 cases) diagnosed with wet AMD received PDT combined intravitreal injection of bevacizumab, including 25 eyes with classic CNV and 9 eyes with minimally classic CNV by fluorescein angiography; On optical coherence tomography (OCT), 23 eyes showed intraretinal fluid (IRF) and 11 eyes presented subretinal fluid (SRF). After signing informed consent, all patients underwent initial standard PDT followed by intravitreal bevacizumab (1.25 mg) within succeeding 3 to 7 days. Best corrected visual acuity (BCVA) and OCT with routine eye examinations were evaluated monthly. Additional bevacizumab (1.25 mg) was injected intravitreally if new or increasing fluid appreciated on OCT, or BCVA lowered more than 5 letters even with stabilized fluid. Injection was discontinued if no fluid was showed on OCT (quot;dry macularquot;), or BCVA was stabilized even with fluid after two consecutive injections. BCVA and central retinal thickness (CRT) were analyzed and compared between baseline and 6 month follow-up. The correlation between parameters such as baseline BCVA, greatest linear dimension (GLD), type of CNV, SRF or IRF and posttreatment BCVA will be analyzed. The injection number of bevacizumab and complications were recorded. Results Compared to baseline, BCVA improved (9.4plusmn;10.2) letters and reach 44.9plusmn;21.3 letters (t=5.438，P＜0.01) and CRT decreased (184.6plusmn;214.6) mu;m (t=4.810，P＜0.01) at 6 month visit. The average of injection number was 1.9plusmn;0.9 (including initial injection of combination therapy). With multiple lineal regression analysis, only baseline BCVA correlated to posttreatment BCVA at 6 month visit (r=0.802.P＜0.01). The type of CNV, GLD, SRF or IRF on OCT and CRT at baseline were not associated to post-treatment BCVA (r=0.053, -0.183, 0.139 and 0.053, respectively.P＞0.05). BCVA of eyes with SRF (14.7 letters) increased more than eyes with IRF (6.9 letters) on OCT (t=-2.207，P=0.035). The change of BCVA after treatment (t=-0.076), change of CRT (t=-1.028) and number of injections (Z=-1.505) were not different between classic CNV and minimally classic CNV (P＞0.05). The change of CRT (t=-0.020) and number of injections (Z=-0.237) did not present difference between SRF and IRF (P＞0.05). The change of BCVA (t=1.159) and number of injections (Z=-1.194) were not correlated to whether residual fluid or not at 6 month visit (P＞0.05). No severe complications were noticed during follow-up.Conclusion For wet AMD patients, PDT combined intravitreal bevacizumab could improve visual acuity, reduce retinal thickness and control CNV progress in a short-term.
Objective To compare the clinic therapeutic effect of intravitreal ranibizumab injection versus photodynamic therapy (PDT) combined with intravitreal ranibizumab injection for idiopathic choroidal neovascularizatio (ICNV), and to investigate the clinical effect and safety of treatment. Methods A randomized controlled clinical prospective study was performed for 27 patients (27 eyes) diagnosed as ICNV. Fourteen patients were assigned to receive PDT and intravitreal ranibizumab injection (combination roup.n=14); the control group was treated with only intravitreal ranibizumab injection (single group, n=13).The combination group was treated with an intravitreal injection of ranibizumab (0.5 mg/0.05 ml) 1 week after PDT. The bestcorrected visual acuity (BCVA) (logMAR), examination of the ocular fundus, fluorescence fundus angiography (FFA), indocyanine green angiography (ICGA) and optical coherence tomography (OCT) were performed respectively at 1, 2, 3, 6 and 12 months after treatment. If choroidal neovascularization (CNV) was only partially regressed or the leakage went on during follow-up, those patients were re-injected with ranibizumab. Results After 12 months, the average vision is 0.22plusmn;0.11 in single group, and 0.21plusmn;0.12 in combination group, and the differences were not significant (t=0.187, P=0.853). In single group FFA and ICGA showed completely closed CNV in 10 eyes (77.92%), and almost closed CNV in 3 eyes (23.08%) with obvious reduction of fluorescence leakage. In combination group FFA and ICGA showed completely closed CNV in 12 eyes (85.71%), and almost closed CNV in 2 eyes (14.29%) with obvious reduction of fluorescence leakage; OCT showed the subretinal fluid absorption and reduction of CNV. The average macular retinal thickness (MRT) in single groups is （167.96plusmn;10.69） m, and in combination groups is （171.64plusmn;11.30）m. In single and combination groups MRT decreased significantly at the final follow-up, but no significant differences in both groups (t=-0.887.P=0.389). The average number of intravitreal injection was （1.5plusmn;0.7） in combination group and （2.4plusmn;1.0） in single group (t=2.821，P=0.009). There were no ocular or systemic adverse events observed except for one patient with subconjunctival hemorrhage in the single group.Conclusions Intravitreal ranibizumab injection and PDT combined with intravitreal bevacizumab injection are both effective and safe for the patients with ICNV. The combined therapy can induce CNV regression, fundus hemorrhage and exudation absorption more effectively, and have less recurred CNV and side effects.
Objective To evaluate the clinical efficacy of intravitreal injections of antivascular endothelial growth factor monoclonal antibody ranibizumab in choroidal neovascularization (CNV) secondary to pathologic myopia (PM). Methods This is a prospective, uncontrolled, open-label study. 34 eyes of 34 patients with CNV secondary to PM were included in the study. All affected eye were treated with intravitreal ranibizumab 0.05 ml (10 mg/ml). Before the injection, bestcorrected visual acuity of early treatment of diabetic retinopathy study (ETDRS), noncontact tonometer, ophthalmoscope, fundus photography, fundus fluorescein angiograph (FFA) and optical coherence tomography (OCT) examination were necessary. The initial average letters of ETDRS acuity were 33.85plusmn;14.67, range from 0 to 69. The initial average central macular thickness (CMT) was（293.41plusmn;79.45） m, range from 210 m to 543 m. The patients were followed up for 3 to 12 months. Best-corrected visual acuity, OCT and ophthalmoscope examination were assessed monthly. If necessary, FFA was used. The letters of ETDRS acuity and CMT were compared before and after treatment. Results All eyes received an average of 1.68 injections, the final vision of follow-up increased （13.50plusmn;9.94） letters than before （t=7.92，P=0.00）, CMT decreased （71.14plusmn;72.26） m (t=4.62，P=0.00). There were no systemic or ocular serious side effects during the follow up. Conclusion Intravitreal ranibizumab for pathologic myopia choroidal neovascularization showed visual acuity improvement, retinal thickness reduction and safety.
Objective To investigate the influence of vascular endothelial growth factor (VEGF) antagonist bevacizumab on the growth of human choroidal melanoma (CM) OCM-1 cell xenografts in nude mice, and to explore the probable mechanism.Methods OCM-1 cells were subcutaneously implanted on 18 nude mice to establish ectopic model of human CM. The nude mice with the tumor of 5 mm in diameter were randomly divided into three groups: untreated group (group A), normal saline （NS） group (group B), drug treated group (group C). Bevacizumab was intraperitoneally injected for 14 consecutive days in group C, and the same volume of NS was used at a same way in group B. The volume and weight of implanted tumor as well as inhibitory rates of drug on tumor were calculated, ki67 and survivin proteins were measured with immunohistochemistry, and the mRNA expression of VEGF and survivin were assessed by RT-PCR.Results The volume and weight of tumor was (598.86plusmn;321.81) mm3, (0.66plusmn;0.15) g; (1 715.15plusmn;278.16) mm3, (1.54plusmn;0.39) g and (1 750.23plusmn;206.36) mm3, (1.54plusmn;0.31) g in groups C, A and B, respectively. There were significant differences between group C and A (F=34.53, P=0.00) and group C and group B (F=8.69, P=0.01). The inhibitory rate of these three groups were 57.14%, 5.31%, 6.25%, respectively, and the proliferation index (PI) of ki67 in these three groups were (51.85plusmn;1.32)%, (46.30plusmn;1.39)%, (27.90plusmn;0.90)%, respectively, there were significant differences in ki67 PI between C group and A or B group (H=15.17, P=0.00). The expression of survivin mRNA was (0.49plusmn;0.02), (0.82plusmn;0.05) and (0.61plusmn;0.05) in groupss C, A and B, respectively, there were significant differences between C group and A or B group (F=15.17, P＜0.05) . The expression of VEGF mRNA was (0.32plusmn;0.08), (0.73plusmn;0.07), (0.80plusmn;0.04) in groups C, A and B, significant difference was found between group C and A or B group (F=12.05，P＜0.05). Conclusion Bevacizumab can inhibit the growth of human CM in nude mice probably by inhibiting the activity of VEGF and downregulating survivin expression of the tumor as well as inhibiting the growth of the tumor.
Objective To observe the clinical efficacy of intravitreal Ranibizumab on exudative agerelated macular degeneration (AMD).Methods The clinical data of 46 patients（52 eyes）with exudative AMD were analyzed retrospectively. All patients were diagnosed by examination of early treatment of diabetic retinopathy study (ETDRS) charts, color fundus photograph，fluorescein angiography（FFA）or indocyanine green angiography（ICGA）and optical coherence tomography（OCT）.They received intravitreal injection of 0.05 ml (10 mg/ml) Ranibizumab, once per month for 3 months. Further injection may be required if the monthly followup indicated. A total of 52 eyes received 214 times of injections, each eye received 2-6 injections (mean 4.12). The Followup duration was 12 months. Vision acuity, fovea thickness and CNV leakage before and after treatment were analyzed.Results At the 12th month after treatment, the mean letter of ETDRS charts was 37.80 (11.40 letters more that pretreatment index,Plt;0.01). FFA and (or) ICGA showed complete closures choroidal neovascularization (CNV) in 11 eyes（21.20%），partial closures in 34 eyes (65.40%)，no change in four eyes (7.70%)，lesion growth in two eyes（3.80%）and new lesion in one eye (1.90%).OCT indicated the average of fovea thickness was 187.50 mu;m (122.80 mu;m less than the pretreatment index, Plt;0.01).Conclusion Intravitreal injection of Ranibizumab for exudative AMD according to this therapeutic schedule was well tolerated，with an improvement in visual acuity，FFA or ICGA and OCT.
The introduction of anti-vascular endothelial growth factor (VEGF) therapy represents a landmark in the management of wet age-related macular degeneration (AMD). However, as a new therapy, several problems such as durability of the therapeutic effects, medication side effects, and medication selection have emerged. We should make appoint of improving the therapeutic effect and safety by realizing the limitation of the therapy, monitoring the clinical potential adverse reactions of anti-VEGF agents, and recommending individualized treatment.
Anti-vascular dndothelial growth factor (VEGF) drugs have open up a new treatment channel for ocular neovascular diseases. A lots of clinical data has proved that anti-VEGF drugs are effective and safe. But we should also notice that long-term and excessive usage of anti-VEGF drugs brings some new problems and complications, and even affect the normal ocular physiological process of the angiogenesis and retinal blood flow. So, it is necessary to pay attention to the problems and potential risks of excessive usage of anti-VEGF therapies for ocular neovascular disease.
Up-regulation of vascular endothelial growth factor (VEGF) is demonstrated to be a key role in formation process of intraocular neovascularization. Anti-VEGF treatment is the breakthrough of intraocular neovascular diseases therapy. Intrav itreal injection of antineovascularization drug looks to be an effective method on ocular neovascular diseases which with the advantages of good biocompatibility, low prices and longer intravitreal half-time etc. However, at present, it lack of multi-center study; the long-term efficacy and the systematic safety needs the further clinical verification. Various types of CNV showed the different therapeutic reactions to either PDT or Anti-VEGF agent, the treatment methods for exudative AMD include laser, PDT, and drug like Triamcinolone Acetonide，several anti-VEGF preparations. Therefore, understanding the pathogenesis of neovascular AMD and choosing a reasonable therapeutic methods are necessary. We should try to explore a safe, effective, economic, new approach. （Chin J Ocul Fundus Dis，2008，24：157-159）