Comparison of single injection and three monthly injections of intravitreal bevacizumab for macular edema associated with branch retinal vein occlusion.

PURPOSE: Our aim was to compare the 1 year efficacy and safety results of intravitreal bevacizumab (IVB) in two prospective, consecutive groups of patients with macular edema (ME) following branch retinal vein occlusion (BRVO). PATIENTS AND METHODS: Twenty-five eyes with ME after BRVO received one IVB injection (single-injection group) and 27 eyes received three monthly IVB injections (three-injection group). Both groups were followed monthly for 12 months. The best-corrected visual acuity (BCVA) and the central foveal thickness (CFT) on optical coherence tomography were evaluated before and after treatment. Patients were eligible to receive an IVB injection if the mean CFT increased 100 µm or more or the BCVA decreased 0.1 logarithm of the minimum angle of resolution (logMAR) unit or more compared with values measured on the last visit. RESULTS: The mean logMAR BCVA and CFT, respectively, improved from 0.56 to 0.33 and from 598 µm to 348 µm in the single-injection group (P<0.001) and from 0.55 to 0.26 and from 514 µm to 293 µm in the three-injection group (P<0.001). During the study period, the mean total number of injections was significantly smaller in the single-injection group than in the three-injection group (2.1 and 4.3, respectively, P<0.001). No serious complications related to the IVB injections developed in either group. CONCLUSION: The single-injection group achieved similar visual outcomes for ME secondary to BRVO with fewer injections compared with the three-injection group.

Aqueous vascular endothelial growth factor and ranibizumab concentrations after monthly and bimonthly intravitreal injections of ranibizumab for age-related macular degeneration.

PURPOSE: To evaluate vascular endothelial growth factor (VEGF) and ranibizumab concentrations in eyes with age-related macular degeneration (AMD) after monthly and bimonthly intravitreal ranibizumab (IVR) injections. METHODS: Aqueous humor samples were obtained from 26 eyes with AMD before and after IVR injections. Nine eyes received three monthly injections and 17 eyes received two bimonthly injections. The VEGF and ranibizumab concentrations were measured by enzyme-linked immunosorbent assay. RESULTS: The aqueous VEGF concentrations in the monthly injection group decreased below the lowest detectable limit in eight of nine eyes 1 month after the first injection and seven of nine eyes 1 month after the second injection (P < 0.001, mean baseline value, 94.7 pg/ml); the aqueous VEGF concentrations in the bimonthly injection group decreased below the lowest detectable limit in two of 17 eyes 2 months after the first injection (P < 0.001, mean baseline value, 152.4 pg/ml). The mean aqueous ranibizumab concentrations with monthly injections were 71.2 ng/ml 1 month after the first injection, and 96.3 ng/ml 1 month after the second injection. The mean aqueous ranibizumab concentrations in the bimonthly injection group were 2.5 ng/ml in 15 of 17 eyes, and below the lowest detectable limit in two of 17 eyes 2 months after the first injection. CONCLUSIONS: In this pilot study with limited follow-up, intravitreal injection of ranibizumab can suppress aqueous VEGF completely for 1 month in most cases. Its effect does not last for 2 months enough to suppress VEGF completely in most cases, although aqueous VEGF at 2 months after intravitreal injection of ranibizumab is less than that before injection in most cases.

Correlation between vascular endothelial growth factor and nonperfused areas in macular edema secondary to branch retinal vein occlusion.

PURPOSE: To determine the role of vascular endothelial growth factor (VEGF) in macular edema secondary to branch retinal vein occlusion (BRVO). PATIENTS AND METHODS: Aqueous humor samples were collected from 52 eyes with macular edema secondary to BRVO before intravitreal drug injections and from 62 control eyes with cataract. VEGF was measured using an enzyme-linked immunosorbent assay. Fluorescein angiography showed capillary nonperfused areas (NPAs). Macular edema was evaluated by optical coherence tomography as the central retinal thickness. RESULTS: The mean aqueous VEGF levels in eyes with BRVO and control eyes with cataract were, respectively, 290.5 pg/mL ± 294.9 pg/mL (range 81.9 pg/mL-1567.3 pg/mL) and 118.0 pg/mL ± 50.1 pg/mL (range 24.6 pg/mL-241.1 pg/mL), which differed significantly (P < 0.0001). The mean VEGF level in eyes with BRVO without apparent NPA was 171.4 pg/mL ± 52.5 pg/mL (range 90.9 pg/mL-299.9 pg/mL), which was significantly higher than controls (P = 0.001). VEGF levels were correlated positively with the size of NPA (P = 0.0002) but not with the central retinal thickness. CONCLUSION: The aqueous VEGF concentration in patients with macular edema secondary to BRVO increased significantly and was correlated significantly with the size of NPA. Aqueous VEGF increased even in eyes without apparent NPA.

Comparison of pneumatic displacement for submacular hemorrhages with gas alone and gas plus tissue plasminogen activator.

PURPOSE: To retrospectively evaluate efficacy, safety, and visual outcomes of pneumatic displacement for submacular hemorrhages (SMHs) with or without tissue plasminogen activator (tPA). METHODS: Sixty-eight eyes with fresh SMHs underwent pneumatic displacement. Thirty eyes received intravitreal injection of pure C3F8 gas alone and 38 eyes received gas with tPA (25 µg). The visual analog scale was used to evaluate displacement. The main outcome measures were the visual analog scale score and best-corrected visual acuity 1 month after treatment. The efficacy and safety of tPA were evaluated. RESULTS: The visual analog scale score was 4.9 ± 2.5 in the gas group and 5.9 ± 2.9 in the gas plus tPA group. Sixteen eyes (53.3%) in the gas group and 15 eyes (39.5%) in the gas plus tPA group had best-corrected visual acuity improvements. In the gas group, complications included retinal detachment (n = 1, 3.3%), vitreous opacity (n = 7, 23.3%), and rebleeding (n = 1, 3.3%). In the gas plus tPA group, vitreous opacity (n = 6, 15.8%) was the only complication. Overall, both groups had similar displacement of SMH, visual improvement, and complication rates at 1 month. CONCLUSION: Intravitreal injection of pure C3F8 gas displaced SMHs and improved best-corrected visual acuity in eyes with SMHs. No adjuvant effect or adverse reactions of tPA were found.

Comparison between one injection and three monthly injections of intravitreal bevacizumab for myopic choroidal neovascularization.

AIM: To compare the effects of one intravitreal bevacizumab (IVB) injection with three monthly injections for myopic choroidal neovascularization. METHODS: Group A included 13 patients treated with one IVB injection; group B included 19 patients treated with three monthly 1.25-mg IVB injections. All patients were followed monthly for 12 months with additional injections performed as needed. The best-corrected visual acuity (BCVA) and the central foveal thickness (CFT) on optical coherence tomography were evaluated before and after treatment. RESULTS: The mean logMAR BCVA improved from 0.59 to 0.49 at 12 months in group A (p = 0.21) and from 0.65 to 0.29 in group B (p < 0.001); the improved logMAR BCVA differed significantly between the groups (p < 0.05). The mean CFT decreased from 231 µm at baseline to 150 µm at 12 months in group A (p < 0.05) and from 279 to 156 µm in group B (p < 0.001). During the follow-up, 6 of 13 eyes in group A and 5 of 19 eyes in group B received additional injections. CONCLUSIONS: Treatment starting with three monthly IVB injections may achieve better functional outcomes with fewer retreatments compared with treatment starting with one IVB injection.

Negative correlation between aqueous vascular endothelial growth factor levels and axial length.

PURPOSE: The aim of this study was to evaluate the relationship between the concentrations of vascular endothelial growth factor (VEGF) in the aqueous humor and axial length. METHODS: Aqueous humor samples were obtained from 60 eyes of 60 patients without ocular diseases other than cataracts. No patients with diabetes mellitus were included. The VEGF concentration in the aqueous humor was measured using an enzyme-linked immunosorbent assay. RESULTS: The VEGF concentrations in the aqueous humor samples ranged from 25 to 241 pg/ml [mean ± standard deviation (SD), 116.6 ± 46.7 pg/ml]. The axial lengths ranged from 20.98 to 31.95 mm (mean ± SD, 24.09 ± 2.06 mm). The VEGF concentrations in the aqueous humor samples were correlated with axial length (Pearson product moment correlation test, ρ = -0.373; P = 0.003). CONCLUSIONS: The concentration of VEGF in the aqueous humor is negatively correlated with axial length.

Aqueous vascular endothelial growth factor after intravitreal injection of pegaptanib or ranibizumab in patients with age-related macular degeneration.

PURPOSE: The purpose of this study was to evaluate vascular endothelial growth factor (VEGF) concentrations in the aqueous humor of eyes after intravitreal injections of pegaptanib or ranibizumab in patients with age-related macular degeneration. METHODS: Aqueous humor samples were obtained from 16 eyes with choroidal neo-vascularization secondary to age-related macular degeneration before and after intravitreal injections of pegaptanib (0.3 mg; 5 eyes) and ranibizumab (0.5 mg; 11 eyes). The VEGF concentration was measured using an enzyme-linked immunosorbent assay using a primary antibody against VEGF121 and VEGF165. RESULTS: The VEGF concentrations in the aqueous humor of eyes with age-related macular degeneration ranged from 35.3 pg/mL to 142.4 pg/mL (mean +/- standard deviation, 90.9 pg/mL +/- 40.0 pg/mL) before the injection of pegaptanib and increased significantly, ranging from 298.2 pg/mL to 571.3 pg/mL (mean +/- standard deviation, 452.0 pg/mL +/- 106.4 pg/mL) 6 weeks after the injection (P = 0.005). The VEGF concentrations ranged from 47.2 pg/mL to 307.4 pg/mL (mean +/- standard deviation, 125.9 pg/mL +/- 77.2 pg/mL) before injection of ranibizumab and decreased to <31 pg/mL, the lower limit of detection, 4 weeks after injection. CONCLUSION: The VEGF concentrations in the aqueous humor of eyes with age-related macular degeneration decreased after injections of ranibizumab and increased after injections of pegaptanib.

Pharmacokinetics of bevacizumab and its effect on vascular endothelial growth factor after intravitreal injection of bevacizumab in macaque eyes.

PURPOSE: To evaluate the pharmacokinetics of intravitreally injected bevacizumab in the systemic circulation and the aqueous humor and its effect on vascular endothelial growth factor (VEGF) in the aqueous humor. METHODS: Bevacizumab (1.25 mg/50 microL) was injected into the vitreous cavity of the right eyes of three cynomolgus macaques. Aqueous humor and serum were obtained from the macaques just before injection and on days 1, 3, and 7 and weeks 2, 4, 6, and 8 after injection. The bevacizumab and VEGF concentrations were measured using enzyme-linked immunosorbent assay. RESULTS: Aqueous VEGF concentrations ranged from 63.2 to 106 pg/mL (mean, 80.0 +/- 22.6 pg/mL) before injection; decreased to <31.2 pg/mL, the lower limit of detection, in all eyes between 1 and 28 days after injection; and returned to the preinjection concentration at 42 days. Aqueous VEGF concentrations in the fellow eyes did not change throughout the experiment. Aqueous bevacizumab concentrations in the treated eyes reached a mean peak concentration of 49,500 +/- 10,900 ng/mL the day after injection and gradually declined, whereas those in the untreated eyes peaked at 3 days, with a mean concentration of 18.5 +/- 25.5 ng/mL, and declined to below 0.156 ng/mL, the limit of detection at 2 weeks. A maximum mean bevacizumab concentration of 1430 +/- 186 ng/mL was achieved in the serum 1 week after injection. CONCLUSIONS: Intravitreal injection of bevacizumab decreased the VEGF concentration in the treated eyes for at least 4 weeks and had no or a minimal effect on the untreated fellow eyes.

Subcutaneous inoculation of a whole virus particle vaccine prepared from a non-pathogenic virus library induces protective immunity against H7N7 highly pathogenic avian influenza virus in cynomolgus macaques.

Development of H7N7 highly pathogenic avian influenza virus (HPAIV) vaccines is an urgent issue since human cases of infection with this subtype virus have been reported and most humans have no immunity against H7N7 viruses. We made an H7N7 vaccine combining components from an influenza virus library of non-pathogenic type A influenza viruses. Antibody and T cell recall responses specific against the vaccine strain were elicited by subcutaneous inoculation with the whole virus particle vaccine with or without alum as an adjuvant in cynomolgus macaques. No significant difference was observed in magnitude of antibody responses between vaccination with alum and vaccination without alum, though vaccination with alum induced longer recall responses of CD8(+) T cells than did vaccination without alum. After challenge with a subtype of H7N7 HPAIV, the virus was detected in nasal swabs of unvaccinated macaques for 8 days but only for 1 day in the animals vaccinated either with or without alum, although the macaques vaccinated with alum showed elevated body temperature more briefly after infection. These findings demonstrated that this H7N7 HPAIV strain is pathogenic to macaques and that the vaccine conferred protective immunity to macaques against H7N7 HPAIV infection.

Amelioration of pneumonia with Streptococcus pneumoniae infection by inoculation with a vaccine against highly pathogenic avian influenza virus in a non-human primate mixed infection model.

BACKGROUND: Highly pathogenic avian influenza virus (HPAIV) infection has a high mortality rate in humans. Secondary bacterial pneumonia with HPAIV infection has not been reported in human patients, whereas seasonal influenza viruses sometimes enhance bacterial pneumonia, resulting in substantial morbidity and mortality. Therefore, if HPAIV infection were accompanied by bacterial infection, an increase in mortality would be expected. We examined whether a vaccine against HPAIV prevents severe morbidity caused by mixed infection with HPAIV and bacteria. METHODS: H7N7 subtype of HPAIV and Streptococcus pneumoniae were inoculated into cynomolgus macaques with or without vaccination of inactivated whole virus particles. RESULTS: Vaccination against H7N7 HPAIV decreased morbidity caused by HPAIV and pneumonia caused by S. pneumoniae. Bacterial replication in lungs was decreased by vaccination against HPAIV, although the reduction in bacterial colonies was not significant. CONCLUSIONS: Vaccination against HPAIV reduces pneumonia caused by bacterial superinfection and may improve prognosis of HPAIV-infected patients.

Intranasal administration of a live non-pathogenic avian H5N1 influenza virus from a virus library confers protective immunity against H5N1 highly pathogenic avian influenza virus infection in mice: comparison of formulations and administration routes of vaccines.

Outbreaks of highly pathogenic avian influenza viruses (HPAIVs) would cause disasters worldwide. Various strategies against HPAIVs are required to control damage. It is thought that the use of non-pathogenic avian influenza viruses as live vaccines will be effective in an emergency, even though there might be some adverse effects, because small amounts of live vaccines will confer immunity to protect against HPAIV infection. Therefore, live vaccines have the advantage of being able to be distributed worldwide soon after an outbreak. In the present study, we found that intranasal administration of a live H5N1 subtype non-pathogenic virus induced antibody and cytotoxic T lymphocyte responses and protected mice against H5N1 HPAIV infection. In addition, it was found that a small amount (100 PFU) of the live vaccine was as effective as 100 microg (approximately 10(10-11) PFU of virus particles) of the inactivated whole particle vaccine in mice. Consequently, the use of live virus vaccines might be one strategy for preventing pandemics of HPAIVs in an emergency.

Quantitative evaluation of ocular motility in blow-out fractures for selection of nonsurgically managed cases.

PURPOSE: To clarify in which cases of blow-out fractures ocular motility will naturally recover. DESIGN: A retrospective review of observational cases. METHODS: Involved ocular motility ranges were measured by the Hess screen test at 15 or 30 degrees in 23 nonsurgical blow-out fracture patients without muscle entrapment or strong mechanical ocular restriction and in eight surgical patients with the above. RESULTS: In nonsurgical patients, the eyes moved more than 10 or 20 degrees respectively on a 15- or 30-degree Hess screen test in the early period, whereas in the surgical patients, the eyes did not. No nonsurgical patients had serious ocular motility disturbances; however, natural ocular motility recovery in many patients took more than 4 weeks. CONCLUSIONS: When an involved eye without muscle entrapment or strong mechanical restrictions moves more than 10 or 20 degrees on each Hess chart, natural recovery can be expected.