RESUMO
PURPOSE: To analyze the urinary metabolomic profile of central serous chorioretinopathy cases. METHODS: In a cross-sectional study, 80 participants with central serous chorioretinopathy were compared with 80 age-matched and sex-matched controls. Urinary metabolites were measured using Metabolon's Discovery HD4 platform. RESULTS: Of 1,031 metabolites total that were measured in urine samples, 53 were upregulated and 27 downregulated in central serous chorioretinopathy participants compared with controls. After exclusion of potentially confounding xenobiotics and bile compounds that could represent digestive processes, 14 metabolites were significantly higher and 12 metabolites were significantly lower in cases compared with controls. One upregulated metabolite (tetrahydrocortisol sulfate) is involved in the corticosteroid subpathway. The downregulated metabolites are unrelated to the identified corticosteroid subpathway. CONCLUSION: The upregulation of urinary tetrahydrocortisol sulfate in central serous chorioretinopathy cases provides a precise molecular basis to further study the role of corticosteroids in producing choroidal venous congestion.
Assuntos
Coriorretinopatia Serosa Central , Humanos , Tetra-Hidrocortisol , Estudos Transversais , Corioide , Corticosteroides , Angiofluoresceinografia , Tomografia de Coerência ÓpticaRESUMO
PURPOSE: To assess changes in retinal nonperfusion (RNP) in patients with retinal vein occlusion (RVO) treated with ranibizumab. DESIGN: Secondary outcome measure in randomized double-masked controlled clinical trial. PARTICIPANTS: Thirty-nine patients with central RVO (CRVO) and 42 with branch RVO (BRVO). METHODS: Subjects were randomized to 0.5 or 2.0 mg ranibizumab every month for 6 months and then were re-randomized to pro re nata (PRN) groups receiving either ranibizumab plus scatter laser photocoagulation or ranibizumab alone for an additional 30 months. MAIN OUTCOME MEASURES: Comparison of percentage of patients with increased or decreased area of RNP in patients with RVO treated with 0.5 versus 2.0 mg ranibizumab, during monthly injections versus ranibizumab PRN, and in patients treated with ranibizumab PRN versus ranibizumab PRN plus laser. RESULTS: In RVO patients given monthly injections of 0.5 or 2.0 mg ranibizumab for 6 months, there was no significant difference in the percentage who showed reduction or increase in the area of RNP. However, regardless of dose, during the 6-month period of monthly injections, a higher percentage of patients showed a reduction in area of RNP and a lower percentage showed an increase in area of RNP compared with subsequent periods of ranibizumab PRN treatment. After the 6-month period of monthly injections, BRVO patients, but not CRVO patients, randomized to ranibizumab PRN plus laser showed significantly less progression of RNP compared with patients treated with ranibizumab PRN. CONCLUSIONS: Regardless of dose (0.5 or 2.0 mg), monthly ranibizumab injections promote improvement and reduce progression of RNP compared with PRN injections. The addition of scatter photocoagulation to ranibizumab PRN may reduce progression of RNP in patients with BRVO, but a statistically significant reduction was not seen in patients with CRVO.
Assuntos
Inibidores da Angiogênese/uso terapêutico , Ranibizumab/uso terapêutico , Oclusão da Veia Retiniana/tratamento farmacológico , Veia Retiniana/fisiologia , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Idoso , Terapia Combinada , Progressão da Doença , Método Duplo-Cego , Feminino , Angiofluoresceinografia , Seguimentos , Humanos , Injeções Intravítreas , Fotocoagulação a Laser , Masculino , Pessoa de Meia-Idade , Fluxo Sanguíneo Regional/efeitos dos fármacos , Fluxo Sanguíneo Regional/fisiologia , Oclusão da Veia Retiniana/fisiopatologia , Tomografia de Coerência Óptica , Acuidade Visual/fisiologiaRESUMO
PURPOSE: To determine whether scatter and grid laser photocoagulation (laser) adds benefit to ranibizumab injections in patients with macular edema from retinal vein occlusion (RVO) and to compare 0.5-mg with 2.0-mg ranibizumab. DESIGN: Randomized, double-masked, controlled clinical trial. PARTICIPANTS: Thirty-nine patients with central RVO (CRVO) and 42 with branch RVO (BRVO). METHODS: Subjects were randomized to 0.5 mg or 2.0 mg ranibizumab every 4 weeks for 24 weeks and re-randomized to pro re nata ranibizumab plus laser or ranibizumab alone. MAIN OUTCOME MEASURES: Mean change from baseline best-corrected visual acuity (BCVA) at week 24 for BCVA at weeks 48, 96, and 144 for second randomization. RESULTS: Mean improvement from baseline BCVA at week 24 was 15.5 and 15.8 letters in the 0.5-mg and 2.0-mg CRVO groups, and 12.1 and 14.6 letters in the 0.5-mg and 2.0-mg BRVO groups. For CRVO, but not BRVO, there was significantly greater reduction from baseline mean central subfield thickness (CST) in the 2.0-mg versus 0.5-mg group (396.1 vs. 253.5 µm; P = 0.03). For the second randomization in CRVO patients, there was no significant difference from week 24 BCVA in the ranibizumab plus laser versus the ranibizumab only groups at week 48 (-3.3 vs. 0.0 letters), week 96 (+0.69 vs. -1.6 letters), or week 144 (+0.4 vs. -6.7 letters), and a significant increase from week 24 mean CST at week 48 (+94.7 vs. +15.2 µm; P = 0.05) but not weeks 96 or 144. For BRVO, there was a significant reduction from week 24 mean BCVA in ranibizumab plus laser versus ranibizumab at week 48 (-7.5 vs. +2.8; P < 0.01) and week 96 (-2.0 vs. +4.8; P < 0.03), but not week 144, and there were no differences in mean CST change from week 24 at weeks 48, 96, or 144. Laser failed to increase edema resolution or to reduce the ranibizumab injections between weeks 24 and 144. CONCLUSIONS: In patients with macular edema resulting from RVO, there was no short-term clinically significant benefit from monthly injections of 2.0-mg versus 0.5-mg ranibizumab injections and no long-term benefit in BCVA, resolution of edema, or number of ranibizumab injections obtained by addition of laser treatment to ranibizumab.
Assuntos
Inibidores da Angiogênese/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Fotocoagulação a Laser , Edema Macular/terapia , Oclusão da Veia Retiniana/terapia , Idoso , Terapia Combinada , Método Duplo-Cego , Feminino , Humanos , Injeções Intravítreas , Edema Macular/diagnóstico , Edema Macular/tratamento farmacológico , Edema Macular/cirurgia , Masculino , Pessoa de Meia-Idade , Ranibizumab , Oclusão da Veia Retiniana/diagnóstico , Oclusão da Veia Retiniana/tratamento farmacológico , Oclusão da Veia Retiniana/cirurgia , Tomografia de Coerência Óptica , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Acuidade Visual/fisiologiaRESUMO
Interleukin-18 (IL-18) is increased along with IL-1ß by activation of the inflammasome and has been implicated in inflammatory and autoimmune diseases, but its role in the eye is uncertain. In patients with macular edema due to retinal vein occlusion, intraocular IL-18 levels increased significantly (P < 0.001) after treatment with ranibizumab particularly in patients with high baseline IL-18 which correlated with good visual outcome (P < 0.05). In mice with ischemic retinopathy, suppression of VEGF caused an increase in IL18 mRNA due to an increase in IL-18-positive myeloid cells. VEGF significantly and specifically inhibited IL-18 production by myeloid cells stimulated with lipopolysaccharide (P < 0.001). Intraocular injection of IL-18 reduced VEGF-induced leakage and neovascularization, and reversed VEGF-induced suppression of Claudin5 expression and Claudin 5 labeling of vascular tight junctions. Injection of IL-18 also increased expression of Thrombospondin 1 and reduced ischemia-induced retinal neovascularization relevant to diabetic retinopathy and subretinal neovascularization relevant to neovascular age-related macular degeneration. Thus, VEGF and IL-18 suppress each other's production and effects on the vasculature suggesting that IL-18 may provide benefit in multiple retinal/choroidal vascular diseases.
Assuntos
Olho/irrigação sanguínea , Olho/metabolismo , Interleucina-18/metabolismo , Neovascularização Patológica/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Animais , Anticorpos Monoclonais Humanizados/farmacologia , Claudina-5/genética , Claudina-5/metabolismo , Citocinas/genética , Citocinas/metabolismo , Regulação da Expressão Gênica/fisiologia , Interleucina-18/genética , Camundongos , Neovascularização Patológica/genética , Permeabilidade , Ranibizumab , Vasos Retinianos/fisiologia , Junções Íntimas/fisiologia , Fator A de Crescimento do Endotélio Vascular/genéticaRESUMO
PURPOSE: To compare aqueous levels of fluocinolone acetonide (FAc) after administration of FAc inserts or FAc implants (Retisert; Bausch & Lomb, Rochester, NY). DESIGN: Comparison of pharmacokinetics from 2 prospective, interventional, clinical trials. PARTICIPANTS: Thirty-seven patients with diabetic macular edema (DME) (Fluocinolone Acetonide in Human Aqueous [FAMOUS] Study, C-01-06-002) and 7 patients with uveitis (NA-00019318). METHODS: Aqueous FAc was measured after administration of FAc implants or 0.2 µg/day (low dose, ILUVIEN; Alimera Sciences Inc., Alpharetta, GA) or 0.5 µg/day (high dose) FAc inserts. MAIN OUTCOME MEASURES: The primary end point was aqueous levels of FAc. RESULTS: At 1 month after administration for subjects who received 1 treatment, mean aqueous FAc levels were 2.17 (low dose) and 3.03 ng/ml (high dose) for FAc inserts and 6.12 ng/ml for FAc implants with maximum levels of 3.83, 6.66, and 13.50 ng/ml, respectively. At 3 months, mean FAc levels were 1.76, 2.15, and 6.12 ng/ml, respectively. Between 6 and 36 months after low-dose inserts, aqueous levels of FAc were remarkably stable, ranging from 1.18 to 0.45 ng/ml. After high-dose inserts, mean FAc levels were stable between 6 and 24 months, ranging from 1.50 to 0.84 ng/ml and then decreasing to 0.35 ng/ml at 30 months and 0.15 ng/ml at 36 months. In implant-containing eyes, mean FAc levels remained >6 ng/ml through 15 months, the last time point with measurements from at least 6 eyes. CONCLUSIONS: Low- and high-dose FAc inserts both provide stable long-term release of FAc with comparable peak levels in the aqueous: slightly >2 ng/ml for approximately 3 months followed by steady-state levels between 1.0 and 0.5 ng/ml through 36 months for low-dose inserts versus levels between 1.5 and 1.1 ng/ml through 24 months for high-dose inserts. Steady-state aqueous levels after FAc implants were >6 ng/ml. These results provide new insights that aid in the interpretation of efficacy trials and indicate that there is a dose effect for steroid-induced ocular hypertension. In susceptible patients, prolonged aqueous levels of FAc >1 ng/ml moderately increased the risk of glaucoma and levels >6 ng/ml posed a markedly increase risk.
Assuntos
Humor Aquoso/metabolismo , Implantes de Medicamento , Fluocinolona Acetonida/farmacocinética , Glucocorticoides/farmacocinética , Cromatografia Líquida de Alta Pressão , Retinopatia Diabética/metabolismo , Fluocinolona Acetonida/administração & dosagem , Glucocorticoides/administração & dosagem , Humanos , Edema Macular/metabolismo , Espectrometria de Massas , Estudos Prospectivos , Uveíte/metabolismoRESUMO
PURPOSE: To identify characteristics of loci associated with locus-level sensitivity loss or improvement during treatment with N-acetylcysteine (NAC) in retinitis pigmentosa (RP). DESIGN: Retrospective analysis of prospectively collected data in the FIGHT RP clinical trial. METHODS: Patients (n = 30) were treated with 600, 1,200, or 1,800 mg of NAC twice daily for 3 months and then 3 times/day for 3 months. Microperimetry locus-level changes between baseline and month 6 were correlated with baseline characteristics of loci using regression models. The main outcome measurement was locus-level sensitivity change ≥6 dB. RESULTS: Baseline mean sensitivity (3,468 loci; 51 evaluable eyes) was 7.7 dB and for foveal, parafoveal, and perifoveal loci were 20.2, 11.8, and 5.8 dB. During treatment, 287 loci (8.28%) increased ≥6 dB, and 119 of 1,613 loci with baseline sensitivity ≥6 dB decreased ≥6 dB (7.38%). A higher dose of NAC was associated with lower likelihood of sensitivity loss ≥6 dB (P = .033). Loci with low baseline sensitivity were more likely to decrease ≥6 dB (P = .034) but also more likely to increase ≥6 dB (P < .001). Foveal versus perifoveal loci (P < .001) and superior versus inferior loci (P = .005) were more likely to increase ≥6 dB. CONCLUSIONS: Higher doses of NAC reduced risk of macular loci sensitivity loss in RP. Greater sensitivity depression reversibility in the fovea during treatment suggests that high foveal cone density protects cones from irreversible loss of function in RP making them more likely to show improved function during NAC treatment.
Assuntos
Acetilcisteína/administração & dosagem , Sequestradores de Radicais Livres/administração & dosagem , Macula Lutea/fisiologia , Retinose Pigmentar/tratamento farmacológico , Acetilcisteína/farmacocinética , Administração Oral , Adulto , Idoso , Feminino , Sequestradores de Radicais Livres/farmacocinética , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Retinose Pigmentar/fisiopatologia , Estudos Retrospectivos , Sensibilidade e Especificidade , Acuidade Visual , Testes de Campo Visual , Campos Visuais/fisiologia , Adulto JovemRESUMO
PURPOSE: To compare Iluvien intravitreal inserts that release 0.2 or 0.5 microg/day of fluocinolone acetonide (FA) in patients with diabetic macular edema (DME). DESIGN: Prospective, randomized, interventional, multicenter clinical trial. PARTICIPANTS: We included 37 patients with DME. METHODS: Subjects with persistent DME despite > or = 1 focal/grid laser therapy were randomized 1:1 to receive an intravitreal insertion of a 0.2- or a 0.5-microg/day insert. MAIN OUTCOME MEASURES: The primary end point was aqueous levels of FA throughout the study with an important secondary outcome of the change from baseline in best-corrected visual acuity (BCVA) at month 12. RESULTS: The mean aqueous level of FA peaked at 3.8 ng/ml at 1 week and 1 month after administration of a 0.5-microg/day insert and was 3.4 and 2.7 ng/ml 1 week and 1 month after administration of a 0.2-microg/day insert. For both inserts, FA levels decreased slowly thereafter and were approximately 1.5 ng/ml for each at month 12. The mean change from baseline in BCVA was 7.5, 6.9, and 5.7 letters at months 3, 6, and 12, respectively, after administration of a 0.5 microg/day-insert and was 5.1, 2.7, and 1.3 letters at months 3, 6, and 12, respectively, after administration of a 0.2-microg/day insert. There was a mild increase in mean intraocular pressure after administration of 0.5-microg/day inserts, but not after administration of 0.2-microg/day inserts. CONCLUSIONS: The FA intravitreal inserts provide excellent sustained intraocular release of FA for > or = 1 year. Although the number of patients in this trial was small, the data suggest that the inserts provide reduction of edema and improvement in BCVA in patients with DME with mild effects on intraocular pressure over the span of 1 year. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.
Assuntos
Retinopatia Diabética/tratamento farmacológico , Sistemas de Liberação de Medicamentos , Fluocinolona Acetonida/administração & dosagem , Glucocorticoides/administração & dosagem , Edema Macular/tratamento farmacológico , Humor Aquoso/metabolismo , Disponibilidade Biológica , Cromatografia Líquida de Alta Pressão , Retinopatia Diabética/metabolismo , Implantes de Medicamento , Fluocinolona Acetonida/farmacocinética , Angiofluoresceinografia , Glucocorticoides/farmacocinética , Humanos , Pressão Intraocular/efeitos dos fármacos , Edema Macular/metabolismo , Estudos Prospectivos , Retina/efeitos dos fármacos , Espectrometria de Massas em Tandem , Tomografia de Coerência Óptica , Acuidade Visual/efeitos dos fármacos , Corpo VítreoRESUMO
PURPOSE: To determine the long-term effects of intraocular antagonism of vascular endothelial growth factor (VEGF) in patients with macular edema caused by retinal vein occlusions (RVOs). DESIGN: Prospective randomized trial. PARTICIPANTS: Twenty patients with macular edema caused by branch RVOs (BRVOs) and 20 patients with central RVOs (CRVOs). METHODS: After the month 3 primary end point, patients were seen every 2 months and received injections of an anti-VEGF agent as needed for recurrent edema. MAIN OUTCOME MEASURES: Mean change from baseline best-corrected visual acuity (BCVA) at month 24 with assessment of other parameters of visual function and center subfield thickness (foveal thickness [FTH]). RESULTS: For 17 patients with BRVO who completed 2 years of follow-up, the mean improvement from baseline in BCVA at month 24 was 17.8 letters compared with 15.6 letters at month 3. Improvement by at least 6, 3, or 2 lines occurred in 18%, 59%, and 76% of patients, respectively. The Snellen equivalent BCVA at month 24 was 20/40 or better in 10 patients. With an average of 2 injections of ranibizumab during year 2, the mean FTH at month 24 was 245.8 µm compared with 217.1 µm at month 3 and 481.5 µm at baseline. For 14 patients with CRVO who completed 2 years of follow-up, the mean improvement in BCVA at month 24 was 8.5 letters compared with 12.0 letters at month 3. Improvement by at least 6, 3, or 2 lines occurred in 14%, 21%, and 43% of patients, respectively. The Snellen equivalent BCVA at month 24 was 20/40 or better in 4 patients. With an average of 3.5 injections of ranibizumab in year 2, mean FTH at month 24 was 338 µm compared with 278 µm at month 3 and 533 µm at baseline. Duration of RVO >1 year at study entry and nonperfusion of perifoveal capillaries for 360 degrees correlated with reduced visual outcomes. CONCLUSIONS: Antagonism of VEGF provides substantial long-term benefit to patients with macular edema caused by RVO, but frequent injections are required in some patients with BRVO and most patients with CRVO.
Assuntos
Inibidores da Angiogênese/administração & dosagem , Anticorpos Monoclonais/administração & dosagem , Edema Macular/tratamento farmacológico , Oclusão da Veia Retiniana/tratamento farmacológico , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Anticorpos Monoclonais Humanizados , Angiofluoresceinografia , Seguimentos , Humanos , Injeções Intravítreas , Edema Macular/etiologia , Edema Macular/fisiopatologia , Estudos Prospectivos , Ranibizumab , Recidiva , Oclusão da Veia Retiniana/complicações , Oclusão da Veia Retiniana/fisiopatologia , Retratamento , Tomografia de Coerência Óptica , Resultado do Tratamento , Acuidade Visual/fisiologiaRESUMO
PURPOSE: The purpose of this study was to evaluate the safety and efficacy of octreotide, a somatostatin analog, for treatment of postsurgical cystoid macular edema. METHODS: Twenty-one patients with chronic, refractory postsurgical cystoid macular edema and Early Treatment Diabetic Retinopathy Study best-corrected visual acuity of 20/25 to 20/400 were randomized 2:1 to 30 mg monthly intramuscular octreotide or placebo. Outcome measures were visual acuity (primary) and macular thickness and fluorescein angiographic leakage (secondary). RESULTS: Fourteen eyes received octreotide and seven eyes received placebo. Mean duration of cystoid macular edema was 2.65 and 1.99 years for Sandostatin long-acting release and placebo groups, respectively. Visual acuity at 6 months improved > or =2 lines in 7 of 14 eyes (50%) in the treatment group and 0 of 7 eyes in the placebo group (P = 0.046). Improvement in retinal thickening and angiographic leakage occurred in 3 of 13 eyes (23.1%) and 3 of 14 eyes (21.4%) of the treatment group, respectively, and in 1 of 7 eyes (14.3%) (P = 1.0 compared with the treatment group) and 0 of 7 eyes in the placebo group (P = 0.52 compared with the treatment group). The three eyes that improved in all parameters were treated with octreotide. CONCLUSION: Although there were no statistically significant differences between both groups in retinal thickening or angiographic leakage, octreotide-treated patients were more likely to experience a > or =2-line improvement in visual acuity. However, this observation cannot be generalized because of the small sample size.
Assuntos
Antineoplásicos Hormonais/administração & dosagem , Edema Macular/tratamento farmacológico , Octreotida/administração & dosagem , Complicações Pós-Operatórias , Adulto , Idoso , Idoso de 80 Anos ou mais , Doença Crônica , Preparações de Ação Retardada , Método Duplo-Cego , Feminino , Angiofluoresceinografia , Humanos , Injeções Intramusculares , Edema Macular/etiologia , Edema Macular/fisiopatologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Retina/patologia , Resultado do Tratamento , Acuidade Visual/fisiologiaRESUMO
BACKGROUNDIn retinitis pigmentosa (RP), rod photoreceptors degenerate from 1 of many mutations, after which cones are compromised by oxidative stress. N-acetylcysteine (NAC) reduces oxidative damage and increases cone function/survival in RP models. We tested the safety, tolerability, and visual function effects of oral NAC in RP patients.METHODSSubjects (n = 10 per cohort) received 600 mg (cohort 1), 1200 mg (cohort 2), or 1800 mg (cohort 3) NAC bid for 12 weeks and then tid for 12 weeks. Best-corrected visual acuity (BCVA), macular sensitivity, ellipsoid zone (EZ) width, and aqueous NAC were measured. Linear mixed-effects models were used to estimate the rates of changes during the treatment period.RESULTSThere were 9 drug-related gastrointestinal adverse events that resolved spontaneously or with dose reduction (maximum tolerated dose 1800 mg bid). During the 24-week treatment period, mean BCVA significantly improved at 0.4 (95% CI: 0.2-0.6, P < 0.001), 0.5 (95% CI: 0.3-0.7, P < 0.001), and 0.2 (95% CI: 0.02-0.4, P = 0.03) letters/month in cohorts 1, 2, and 3, respectively. There was no significant improvement in mean sensitivity over time in cohorts 1 and 2, but there was in cohort 3 (0.15 dB/month, 95% CI: 0.04-0.26). There was no significant change in mean EZ width in any cohort.CONCLUSIONOral NAC is safe and well tolerated in patients with moderately advanced RP and may improve suboptimally functioning macular cones. A randomized, placebo-controlled trial is needed to determine if oral NAC can provide long-term stabilization and/or improvement in visual function in patients with RP.TRIAL REGISTRATIONNCT03063021.FUNDINGMr. and Mrs. Robert Wallace, Mr. and Mrs. Jonathan Wallace, Rami and Eitan Armon, Marc Sumerlin, Cassandra Hanley, and Nacuity Pharmaceuticals, Inc.
Assuntos
Acetilcisteína/administração & dosagem , Células Fotorreceptoras Retinianas Cones/metabolismo , Retinose Pigmentar/tratamento farmacológico , Acuidade Visual/efeitos dos fármacos , Acetilcisteína/efeitos adversos , Administração Oral , Adulto , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Retinose Pigmentar/metabolismo , Retinose Pigmentar/patologia , Retinose Pigmentar/fisiopatologiaRESUMO
OBJECTIVE: To assess the value of sampling aqueous humor for measurement of potential molecular targets and for pharmacokinetic analysis. DESIGN: Substudy within the context of clinical trials. PARTICIPANTS: Forty patients with macular edema caused by central retinal vein occlusion (CRVO) or branch retinal vein occlusion (BRVO), 11 patients with diabetic macular edema (DME), and 8 patients with neovascular age-related macular degeneration (NVAMD). METHODS: Assays for potential molecular targets were performed on aqueous samples from patients participating in drug studies (CRVO, BRVO, and DME) or patients receiving standard care (NVAMD). Ranibizumab levels were measured in patients with CRVO or BRVO after the first and second injections of ranibizumab. MAIN OUTCOME MEASURES: Aqueous levels of vascular endothelial growth factor (VEGF), interleukin (IL)-6, IL-1beta, tumor necrosis factor (TNF)-alpha, and ranibizumab. RESULTS: Aqueous levels of VEGF were significantly higher in patients with DME than in patients with CRVO, which were significantly higher than those in patients with BRVO. Patients with NVAMD had aqueous VEGF levels in an intermediate range, significantly higher than those in patients with BRVO. One month after the second injection of ranibizumab, 27 of 39 patients with vein occlusions had no residual edema; mean aqueous levels of IL-6, IL-1beta, and TNF-alpha were not greater in patients with residual edema; this provides a blueprint for definitive studies with larger cohorts. There was no significant difference in aqueous ranibizumab levels 1 month after the first injection of 0.5 mg versus injection of 0.3 mg, but 1 month after the second injection ranibizumab levels were significantly higher in eyes injected with 0.5 mg. There were substantial differences in levels among patients, but levels in the same patient at months 1 and 2 were highly correlated. No significant difference in aqueous ranibizumab levels was detected between phakic and pseudophakic patients who received the same dose. CONCLUSIONS: These data suggest that aqueous samples are useful for investigating potential involvement of molecular targets in various disease processes and for pharmacokinetic or pharmacodynamic studies.
Assuntos
Anticorpos Monoclonais/administração & dosagem , Humor Aquoso/metabolismo , Biomarcadores/metabolismo , Retinopatia Diabética/tratamento farmacológico , Monitoramento de Medicamentos , Degeneração Macular/tratamento farmacológico , Edema Macular/tratamento farmacológico , Anticorpos Monoclonais/farmacocinética , Anticorpos Monoclonais Humanizados , Ensaios Clínicos como Assunto , Retinopatia Diabética/metabolismo , Ensaio de Imunoadsorção Enzimática , Humanos , Injeções , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Degeneração Macular/metabolismo , Edema Macular/metabolismo , Ranibizumab , Oclusão da Veia Retiniana/tratamento farmacológico , Oclusão da Veia Retiniana/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Corpo VítreoRESUMO
Macular edema is a major cause of vision loss in patients with central retinal vein occlusion (CRVO) or branch retinal vein occlusion (BRVO). It is not clear how much of the edema is due to hydrodynamic changes from the obstruction and how much is due to chemical mediators. Patients with macular edema due to CRVO (n = 20) or BRVO (n = 20) were randomized to receive three monthly injections of 0.3 or 0.5 mg of ranibizumab. At the primary endpoint, month 3, the median improvement in letters read at 4 m was 17 in the 0.3-mg group and 14 in the 0.5-mg group for CRVO, and 10 and 18, respectively for the BRVO group. Optical coherence tomography (OCT) showed that compared to injections of 0.3 mg, injections of 0.5 mg of ranibizumab tended to cause more rapid reductions of central retinal thickening that lasted longer between injections, but in 3 months, excess central retinal thickening which is a quantitative assessment of the macular edema, was reduced by approximately 90% in all four treatment groups. There was no correlation between the amount of improvement and duration of disease or patient age at baseline, but there was some correlation between the aqueous vascular endothelial growth factor (VEGF) level at baseline and amount of improvement. These data indicate that excess production of VEGF in the retinas of patients with CRVO or BRVO is a major contributor to macular edema and suggest that additional studies investigating the efficacy of intraocular injections of ranibizumab are needed.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Edema Macular/tratamento farmacológico , Oclusão da Veia Retiniana/tratamento farmacológico , Fator A de Crescimento do Endotélio Vascular/biossíntese , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais Humanizados , Humor Aquoso/metabolismo , Fóvea Central/efeitos dos fármacos , Fóvea Central/patologia , Humanos , Edema Macular/etiologia , Edema Macular/metabolismo , Pessoa de Meia-Idade , Ranibizumab , Oclusão da Veia Retiniana/complicações , Oclusão da Veia Retiniana/metabolismoRESUMO
PURPOSE: To evaluate long-term visual and anatomic outcomes in patients with retinal vein occlusion (RVO) treated with anti-vascular endothelial growth factor (VEGF) agents. DESIGN: Prospective, interventional case series. PARTICIPANTS: Patients with central RVO (CRVO) or branch RVO (BRVO). METHODS: Number of anti-VEGF injections and improvement from baseline best-corrected visual acuity (BCVA) and central subfield thickness (CST) were prospectively recorded in 40 eyes of 39 CRVO patients and 50 eyes of 47 BRVO patients. RESULTS: Mean follow-up was 58 months for BRVO and 78 months for CRVO. Within 6 months of last follow-up, 58% of BRVO patients and 75% of CRVO patients required anti-VEGF injections to control edema. Analysis of the course of each patient over time showed that for BRVO patients, BCVA letter score increased by a mean of 24, from baseline of 52 (20/100) to peak of 76 (20/32), and subsequently decreased by 13, to 63 (20/50), at final visit; and for CRVO patients, BCVA letter score increased by a mean of 26, from baseline of 48 (20/100) to peak of 74 (20/32), and subsequently decreased by 18, to 56 (20/80), at last follow-up. Loss from peak BCVA occurred primarily owing to persistent/recurrent edema and related foveal damage. CONCLUSIONS: Patients with RVO showed large improvements in BCVA after initiation of anti-VEGF injections, but in many patients some visual gains were lost over time owing to bouts of recurrent edema. Sustained suppression of VEGF may help to provide optimal outcomes in RVO and reduce treatment burden.
Assuntos
Edema Macular/tratamento farmacológico , Ranibizumab/administração & dosagem , Oclusão da Veia Retiniana/complicações , Acuidade Visual , Inibidores da Angiogênese/administração & dosagem , Progressão da Doença , Seguimentos , Injeções Intravítreas , Edema Macular/etiologia , Edema Macular/fisiopatologia , Projetos Piloto , Estudos Prospectivos , Oclusão da Veia Retiniana/fisiopatologia , Fatores de Tempo , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidoresRESUMO
PURPOSE: To investigate the safety, tolerability, and bioactivity of intravenous infusions of bevacizumab in patients with choroidal neovascularization (CNV) attributable to causes other than age-related macular degeneration. DESIGN: Nonrandomized clinical trial. METHODS: Ten patients with CNV received infusions of 5 mg/kg of bevacizumab. The primary efficacy outcome measure was change in visual acuity (VA; Early Treatment Diabetic Retinopathy Study letters read at 4 meters) at 24 weeks and secondary measures were changes from baseline in excess foveal thickness (center subfield thickness), area of fluorescein leakage, and area of CNV. RESULTS: Infusions were well tolerated and there were no ocular or systemic adverse events. At baseline, median VA was 25.5 letters read at 4 meters (20/80) and median foveal thickness was 346 mum. At the primary endpoint (24 weeks), median VA was 48.5 letters (20/32), representing four lines of improvement from baseline (P = .005), median foveal thickness was 248 mum representing a 72% reduction in excess foveal thickness (P = .007). Four of nine patients had complete elimination of fluorescein leakage, three had near complete elimination (reductions of 91%, 88%, and 87%), two had modest reductions, and one had no reduction. All patients except one showed a reduction in area of CNV with a median reduction of 43%. CONCLUSIONS: Despite the small number of patients studied, the marked improvement in VA accompanied by prominent reductions in foveal thickness, fluorescein leakage, and area of CNV suggest a beneficial effect. It may be worthwhile to consider further evaluation of systemic bevacizumab in young patients with CNV.
Assuntos
Inibidores da Angiogênese/administração & dosagem , Anticorpos Monoclonais/administração & dosagem , Neovascularização de Coroide/tratamento farmacológico , Miopia Degenerativa/complicações , Doenças Retinianas/complicações , Adulto , Inibidores da Angiogênese/efeitos adversos , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Bevacizumab , Permeabilidade Capilar , Neovascularização de Coroide/etiologia , Feminino , Angiofluoresceinografia , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Tomografia de Coerência Óptica , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Acuidade Visual/efeitos dos fármacosRESUMO
PURPOSE: To compare standard and frequent topical steroids for postsurgical macular edema (ME). DESIGN: Randomized clinical trial. METHODS: Subjects with postsurgical ME stratified into post-cataract surgery ME (PCSME) and post-other surgery ME (POSME) were randomized to ketorolac 4 times a day (qid) + 1% prednisolone acetate (PA) every hour while awake (q1hWA, Group 1) or qid (Group 2). Mean change from baseline best-corrected visual acuity (BCVA) was determined at week 12, after which group 2 subjects with persistent edema were crossed over to PA q1hWA. RESULTS: Twenty-two subjects (13 PCSME and 9 POSME) were randomized to Group 1 and 20 (12 PCSME and 8 POSME) to Group 2. At week 12, change from baseline BCVA (ETDRS letters) in Group 1 vs 2 was +11.6 vs +8.5 (P = .32) and for subgroups was +10.6 vs +7.8 (P = .23) for PCSME and +13.1 vs +9.4 (P = .47) for POSME. Mean change from baseline central subfield thickness (CST, µm) at week 12 in Group 1 vs 2 was -100.8 vs -63.9 (P = .30). Mean change from baseline intraocular pressure was +2.6 vs +1.7 mm Hg (P = .52). Eight subjects in Group 2 with residual ME at week 12 were switched to PA q1hWA and at week 24, the mean changes from week 12 BCVA and CST were +7.0 letters (P = .01) and -108.25 µm (P = .04). CONCLUSIONS: Our data suggest that patients with postsurgical ME should initially be treated with ketorolac and PA qid, but if edema does not resolve after 12 weeks, a switch to ketorolac qid and PA q1hWA may provide benefit.
Assuntos
Extração de Catarata/efeitos adversos , Glucocorticoides/administração & dosagem , Edema Macular/tratamento farmacológico , Complicações Pós-Operatórias , Prednisolona/análogos & derivados , Acuidade Visual , Administração Tópica , Idoso , Anti-Inflamatórios não Esteroides/administração & dosagem , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Seguimentos , Humanos , Cetorolaco/administração & dosagem , Macula Lutea/patologia , Edema Macular/diagnóstico , Edema Macular/etiologia , Masculino , Pessoa de Meia-Idade , Prednisolona/administração & dosagem , Pró-Fármacos , Tomografia de Coerência Óptica , Resultado do TratamentoRESUMO
OBJECTIVES: To assess the safety, pharmacokinetics, and biological activity of IV administration of vascular endothelial growth factor trap (VEGF Trap), a recombinant protein containing the binding domains of VEGF receptors 1 and 2, in patients with neovascular age-related macular degeneration (AMD). DESIGN: Randomized, multicenter, placebo-controlled clinical trial. PARTICIPANTS: Twenty-five patients were enrolled (11 male, 14 female); 19 received VEGF Trap (0.3 [n = 7], 1.0 [n = 7], or 3.0 mg/kg [n = 5]), and 6 received a placebo. METHODS: Patients were randomized to receive a placebo or 0.3-, 1.0-, or 3.0-mg/kg VEGF Trap--a single IV dose followed by a 4-week observation period and then 3 doses 2 weeks apart. MAIN OUTCOME MEASURES: Safety and biological activity, including change in excess retinal thickness and volume assessed by optical coherence tomography and visual acuity (VA) measured by the Early Treatment Diabetic Retinopathy Study protocol. RESULTS: The majority of adverse events attributable to VEGF Trap were mild to moderate in severity, but 2 of 5 patients treated with 3.0 mg/kg experienced dose-limiting toxicity (1 with grade 4 hypertension and 1 with grade 2 proteinuria); therefore, all patients in the 3.0 mg/kg-dose group were withdrawn from the study. The mean percent changes in excess retinal thickness were -12%, -10%, -66%, and -60%, respectively, for the placebo and 0.3-, 1.0-, and 3.0-mg/kg groups at day 15 (P<0.02 by analysis of covariance [ANCOVA]) and -5.6%, +47.1%, and -63.3% for the placebo and 0.3- and 1.0-mg/kg groups at day 71 (P<0.02, ANCOVA). A significant change in VA was not noted in this small study. CONCLUSIONS: The maximum tolerated dose of IV VEGF Trap in this study population was 1.0 mg/kg. This dose resulted in elimination of about 60% of excess retinal thickness after either single or multiple administrations. Alternative routes of delivery to increase the therapeutic window are being explored.
Assuntos
Neovascularização de Coroide/tratamento farmacológico , Degeneração Macular/tratamento farmacológico , Receptores de Fatores de Crescimento do Endotélio Vascular/administração & dosagem , Proteínas Recombinantes de Fusão/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Neovascularização de Coroide/etiologia , Neovascularização de Coroide/metabolismo , Relação Dose-Resposta a Droga , Feminino , Angiofluoresceinografia , Humanos , Infusões Intravenosas , Degeneração Macular/complicações , Degeneração Macular/metabolismo , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Proteínas Recombinantes de Fusão/efeitos adversos , Proteínas Recombinantes de Fusão/farmacocinética , Retina/patologia , Tomografia de Coerência Óptica , Acuidade VisualRESUMO
PURPOSE: The Diabetic Macular Edema Treated with Ozurdex (DMEO) Trial measured aqueous pro-permeability factors (PPFs) in diabetic macular edema (DME) patients before and after injection of dexamethasone implant or vascular endothelial growth factor (VEGF)-neutralizing protein and correlated changes in levels with changes in excess foveal thickness (EFT) to identify potential PPFs contributing to DME. DESIGN: Prospective, randomized crossover clinical trial. METHODS: Twenty DME patients randomized to dexamethasone implant or VEGF-neutralizing protein had aqueous taps and spectral-domain optical coherence tomography (SDOCT) at baseline and every 4 weeks for 28 weeks. Aqueous levels of 55 vasoactive proteins were measured with protein array. Crossover at week 16 provided changes in protein levels after each intervention in all 20 patients. RESULTS: After dexamethasone implant there was significant correlation between changes in levels of 13 vasoactive proteins with changes in EFT, including 3 known PPFs: angiopoietin-2 (r = 0.40, P = .001), hepatocyte growth factor (HGF; r = 0.31, P = .02), and endocrine gland-VEGF (EG-VEGF, r = 0.43, P < .001). Reduction of prolactin, insulin-like growth factor binding protein-3, and matrix metalloproteinase-9 correlated with edema reduction after injection of a VEGF-neutralizing protein as well as dexamethasone implant, suggesting their modulation is likely secondary to changes in edema rather than causative. CONCLUSIONS: Correlation of edema reduction with reduction in the PPFs angiopoietin-2, HGF, and EG-VEGF provides potential insight into the multifactorial molecular mechanism by which dexamethasone implants reduce edema and suggest that additional study is needed to investigate the contributions of these 3 factors to chronic DME.
Assuntos
Dexametasona/uso terapêutico , Retinopatia Diabética/tratamento farmacológico , Proteínas do Olho/metabolismo , Glucocorticoides/uso terapêutico , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Edema Macular/tratamento farmacológico , Edema Macular/metabolismo , Idoso , Inibidores da Angiogênese/uso terapêutico , Humor Aquoso/metabolismo , Bevacizumab , Estudos Cross-Over , Preparações de Ação Retardada/uso terapêutico , Retinopatia Diabética/metabolismo , Retinopatia Diabética/patologia , Implantes de Medicamento , Feminino , Humanos , Edema Macular/patologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Acuidade VisualRESUMO
OBJECTIVES: To report the prevalence of visually significant cataract and cataract surgery and to determine demographic and socioeconomic factors that influence use of cataract surgery in a US Hispanic population. METHODS: Proyecto VER is a population-based study of Hispanic individuals, 40 years or older, living in southern Arizona. Visual acuity was measured monocularly, and a dilated ophthalmic examination was performed to determine lens opacities. Visually significant cataract was defined as severe levels of opacity and acuity worse than 20/40. Risk factors were compared between those who obtained cataract surgery in the past and those having visually significant cataract. RESULTS: A majority of the 4774 participants in this study were of Mexican descent; 2.8% had visually significant cataract and 5.1% had undergone bilateral cataract surgery. Among those currently or previously needing surgery, having medical insurance (odds ratio, 2.88; P<.001) and speaking English (odds ratio, 1.80; P = .04) were significantly associated with having obtained surgery in the past. CONCLUSIONS: Visually significant cataract appears to be high among US Hispanic individuals of Mexican descent, as evidenced by rates of cataract and cataract surgery. Language and financial barriers in this population impede access to surgery. Further work to remove these barriers and provide sight restoration is warranted among Hispanic individuals of Mexican descent living in the United States.
Assuntos
Extração de Catarata/estatística & dados numéricos , Catarata/etnologia , Acessibilidade aos Serviços de Saúde , Americanos Mexicanos , Adulto , Distribuição por Idade , Idoso , Idoso de 80 Anos ou mais , Arizona/epidemiologia , Atitude Frente a Saúde , Barreiras de Comunicação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pobreza , Prevalência , Atenção Primária à Saúde/estatística & dados numéricos , Distribuição por Sexo , Fatores SocioeconômicosRESUMO
Retinitis pigmentosa (RP) is a group of diseases in which a mutation in one of the large variety of genes causes death of rod photoreceptors. After rods die, cone photoreceptors gradually die resulting in constriction of visual fields and eventual blindness in many patients. Studies in animal models of RP have demonstrated that oxidative damage is a major contributor to cone cell death. In this study, we extended those findings to patients with RP, because compared to control patients, those with RP showed significant reduction in the reduced to oxidized glutathione (GSH/GSSG) ratio in aqueous humor and a significant increase in aqueous protein carbonyl content. In contrast, there was no significant decrease in the serum GSH/GSSG ratio or increase in carbonyl content of serum proteins. These data indicate that patients with RP have ocular oxidative stress and damage in the absence of manifestations of systemic oxidative stress and/or damage indicating that demonstrations of oxidative damage-induced cone cell death in animal models of RP may translate to human RP. These observations lead to the hypothesis that potent antioxidants will promote cone survival and function in patients with RP and that the aqueous GSH/GSSG ratio and carbonyl content on proteins may provide useful biomarkers. Antioxid. Redox Signal. 23, 643-648.