Volume 8, Number 7 |
July 2012 |
WELCOME to Review
of Ophthalmology's Retina
Online e-newsletter. Each month, Medical Editor Philip Rosenfeld,
MD, PhD, and our editors provide you with this timely and easily
accessible report to keep you up to date on important information
affecting the care of patients with vitreoretinal disease.
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Treatment of Neovascular AMD for Two Years with Ranibizumab and Bevacizumab
The authors of the following multicenter, randomized clinical trial sought to describe the effects
of ranibizumab and bevacizumab when administered monthly or as needed for 2 years and to describe the
impact of switching to as-needed treatment after 1 year of monthly treatment.
Participants were patients (n=1,107) who were followed up during year 2 among 1,185 patients with
neovascular age-related macular degeneration (AMD) who were enrolled in the clinical trial. At enrollment, the
authors assigned patients to 4 treatment groups defined by drug (ranibizumab or bevacizumab) and dosing
regimen (monthly or as needed). At 1 year, they randomly reassigned patients initially assigned to monthly
treatment to monthly or as-needed treatment, without changing the drug assignment. The mean outcome measure was
mean change in visual acuity.
Among patients following the same regimen for 2 years, mean gain in visual acuity was similar for both
drugs (bevacizumab-ranibizumab difference, –1.4 letters; 95% confidence interval [CI], –3.7 to
0.8; p=0.21). According to the study authors, mean gain was greater for monthly than for as-needed
treatment (difference, –2.4 letters; 95% CI, –4.8 to –0.1; p=0.046). They noted that
the proportion without fluid ranged from 13.9% in the bevacizumab-as-needed group to 45.5% in the
ranibizumab monthly group (drug, p=0.0003; regimen, p<0.0001). They also found that switching
from monthly to as-needed treatment resulted in greater mean decrease in vision during year 2 (–2.2 letters;
p=0.03) and a lower proportion without fluid (–19%; p<0.0001). Rates of death
and arteriothrombotic events were similar for both drugs (p>0.60). The proportion of patients
with 1 or more systemic serious adverse events was higher with bevacizumab than ranibizumab (39.9% vs.
31.7%; adjusted risk ratio, 1.30; 95% CI, 1.07–1.57; p=0.009). Most of the excess events
have not been associated previously with systemic therapy targeting vascular endothelial growth factor (VEGF),
the authors reported.
They determined that ranibizumab and bevacizumab had similar effects on visual acuity over a 2-year period and
that treatment as needed resulted in less gain in visual acuity, whether instituted at enrollment or after 1 year
of monthly treatment. There were no differences between drugs in rates of death or arteriothrombotic events.
The interpretation of the persistence of higher rates of serious adverse events with bevacizumab is uncertain
because of the lack of specificity to conditions associated with inhibition of VEGF.
Source: Martin DF, Maguire MG, Fine SL, et al.; Comparison of Age-related Macular Degeneration
Treatment Trials (CATT) Research Group. Ranibizumab and bevacizumab for treatment of neovascular
age-related macular degeneration: two-year results. Ophthalmology. 2012;119(7):1388–1398.
Comparison of Ranibizumab and Bevacizumab for Neovascular AMD Treatment
To compare the efficacy and safety of ranibizumab and bevacizumab intravitreal injections to treat
neovascular age-related macular degeneration (AMD), researchers conducted a multicenter,
noninferiority factorial trial with equal allocation to groups. The noninferiority limit was 3.5 letters.
They randomized participants to 4 groups: ranibizumab or bevacizumab, given either every month (continuous) or
as needed (discontinuous), with monthly review. Participants included people >50 years of age with
untreated neovascular AMD in the study eye who read ≥25 letters on the Early Treatment Diabetic Retinopathy
Study chart. The primary outcome is at 2 years; this paper reports a pre-specified interim analysis at 1 year.
The primary efficacy and safety outcome measures are distance visual acuity and arteriothrombotic events or
heart failure. Other outcome measures are health-related quality of life, contrast sensitivity, near visual
acuity, reading index, lesion morphology, serum vascular endothelial growth factor (VEGF) levels, and costs.
Between March 27, 2008 and October 15, 2010, the researchers randomized and treated 610 participants. They noted
that 1 year after randomization, the comparison between bevacizumab and ranibizumab was inconclusive
(bevacizumab minus ranibizumab –1.99 letters, 95% confidence interval [CI], –4.04 to 0.06) and
that discontinuous treatment was equivalent to continuous treatment (discontinuous minus continuous
–0.35 letters; 95% CI, –2.40 to 1.70). They also found that foveal total thickness did not differ by drug, but was 9% less with continuous treatment (geometric mean ratio [GMR], 0.91; 95% CI, 0.86 to 0.97;
p=0.005). Additionally, fewer participants receiving bevacizumab had an arteriothrombotic event or
heart failure (odds ratio [OR], 0.23; 95% CI, 0.05 to 1.07; p=0.03) and there was no difference
between drugs in the proportion experiencing a serious systemic adverse event (OR, 1.35; 95% CI, 0.80 to 2.27;
p=0.25). The researchers reported that serum VEGF was lower with bevacizumab (GMR, 0.47; 95% CI, 0.41
to 0.54; p<0.0001) and higher with discontinuous treatment (GMR, 1.23; 95% CI, 1.07 to 1.42;
p=0.004) and that continuous and discontinuous treatment costs were £9,656 ($14,984)
and £6,398 ($9,930) per patient per year for ranibizumab and £1,654 ($2,567) and £1,509
($2,342) for bevacizumab; bevacizumab was less costly for both treatment regimens (p<0.0001).
The comparison of visual acuity at 1 year between bevacizumab and ranibizumab was inconclusive. Visual acuities
with continuous and discontinuous treatment were equivalent. Other outcomes are consistent with the drugs
and treatment regimens having similar efficacy and safety.
Source: Chakravarthy U, Harding SP, Rogers CA, et al.; the IVAN Study Investigators. Ranibizumab
versus bevacizumab to treat neovascular age-related macular degeneration: one-year findings from the
IVAN randomized trial. Ophthalmology. 2012;119(7):1399–1411.
A Look at Stroke Rates Following Introduction of VEGF Inhibitors
for Macular Degeneration
In the following population-based, time series analysis using encrypted, linked healthcare databases
in Ontario, Canada, scientists sought to assess whether stroke rates among patients with retinal disease
were influenced by the rapid and sequential uptakes of bevacizumab and ranibizumab for age-related
macular degeneration (AMD).
They included all patients aged 66 years or older with physician-diagnosed retinal disease in the previous
5 years between 2002 and 2010 (n=116,388). A secondary analysis evaluated patients who had undergone
photodynamic therapy (PDT) within the preceding year (n=10,059).
The study scientists used segmented regression analysis to evaluate changes in the rate of hospitalization
for ischemic stroke associated with the introduction of bevacizumab and ranibizumab. They compared stroke rate
across 3 mutually exclusive periods: the period before the availability of bevacizumab or ranibizumab, the period
of bevacizumab dominant AMD therapy, and the period of ranibizumab dominant AMD therapy. Hospitalizations for
ischemic stroke were the main outcome measures.
Among patients with retinal disease, neither the trend nor the level of the stroke time series changed with the
uptake of bevacizumab (trend change coefficient –0.0026 stroke hospitalizations/1000 subjects/month
[95% confidence interval {CI}, –0.0066 to 0.0014; p=0.20]; level change coefficient,
0.036 stroke hospitalizations/1000 subjects [95% CI, –0.070 to 0.14; p=0.51]), or ranibizumab
(trend change coefficient: –0.0011 stroke hospitalizations/1000 subjects/month [95% CI, –0.0087
to 0.0065; p=0.78]; level change coefficient: –0.017 stroke hospitalizations/1000 subjects
[95% CI, –0.14 to 0.11; p=0.79]). The scientists observed similar results in the analysis
restricted to patients with recent PDT and in analyses stratified on age, sex, history of stroke, and history
of diabetes.
They concluded that rapid uptake of vascular endothelial growth factor (VEGF) inhibitors for AMD was not
associated with a change in the rate of hospitalization for stroke among Ontario seniors with retinal
disease. Furthermore, stroke rates in the bevacizumab and ranibizumab periods were not different.
These population-level results complement the findings of a recently published trial comparing bevacizumab
and ranibizumab, and may assist clinicians and policy makers as they balance the comparative efficacy, safety,
and cost of these 2 closely related treatments.
Source: Campbell RJ, Bell CM, Paterson JM, et al. Stroke rates after introduction of vascular
endothelial growth factor inhibitors for macular degeneration: a time series analysis. Ophthalmology.
2012; June 20 [Epub ahead of print]. DOI: 10.1016/j.ophtha.2012.05.028.
Improvement of Photoreceptor Integrity and Associated Visual
Outcome in Neovascular AMD
In Korea, investigators evaluated the association between improvement of photoreceptor integrity and visual
acuity (VA) after anti-vascular endothelial growth factor (anti-VEGF) injections in neovascular age-related
macular degeneration (AMD) in the following retrospective, cross-sectional study.
They retrospectively reviewed 87 eyes of 84 patients who were newly diagnosed with neovascular AMD and treated
with anti-VEGF injections. Using spectral-domain optical coherence tomography (SD-OCT), they also graded the
status of the inner segment/outer segment photoreceptor junction (IS/OS) and classified this into 3 groups at
baseline and 1 and 2 months after 3 monthly injections. Finally, they analyzed the proportion of the improved
IS/OS line after treatment and correlated this with VA.
The investigators reported that the number of eyes in the IS/OS+ group, representing disrupted IS/OS line less
than 200 µm, was increased from 9 (10%) at baseline to 33 (38%) at 1 month. They found a
significant difference in the ratio of IS/OS+ group between baseline and 1 month (p<.001) and noted
that those in the IS/OS± group, showing focal disrupted IS/OS line between 200 and 800 µm, decreased
from 29 (33%) to 22 eyes (25%). The study investigators also observed improvement of the IS/OS line at
1 month compared to baseline in 43 eyes (49%) and this was correlated with better VA (p<.016).
They saw no increase of VA in 44 eyes without definite improvement and there was no significant correlation
between improvement of the IS/OS line and VA from 1 to 2 months.
In conclusion, assessing the change of the photoreceptor integrity before and after treatment would be a
useful indicator to predict initial response to treatment and visual prognosis in patients with neovascular AMD.
Source: Kim YM, Kim JH, Koh HJ. Improvement of photoreceptor integrity and associated visual outcome
in neovascular age-related macular degeneration. Am J Ophthalmol. 2012;154(1):164–173.e1.
Impact of Fellow Eye VA on VA of Study Eyes Receiving Ranibizumab for AMD
The following study investigated whether extremes in visual acuity (very good or very poor) of the fellow
eye (FE) influence visual acuity of the study eye in patients receiving intravitreal ranibizumab treatment
for neovascular age-related macular degeneration (AMD).
From 2 randomized, controlled, clinical trials (MARINA and ANCHOR), a retrospective analysis of
ranibizumab-treated patients who maintained stable FE visual acuity (±5 letters from baseline at each of
Months 1, 4, 6, and 12) was performed, comparing patients with untreated FE visual acuity that was either 20/32
or better (very good) or 20/200 or worse (very poor). Visual acuity of the treated study eyes, which received
monthly intravitreal ranibizumab (0.3 mg or 0.5 mg), was compared between the 2 FE cohorts and the Month 6 and
Month 12 visits.
A total of 145 patients were analyzed. In the cohort with very poor FE visual acuity (n=55), there were 35 patients
in MARINA and 20 patients in ANCHOR; in the cohort with very good FE visual acuity (n=90), there were 52 patients
in MARINA and 38 patients in ANCHOR. The mean (standard deviation) gain of the study eye visual acuity in the
very good FE cohort was 10.3 (13.3) and 10.8 (13.7) letters at Months 6 and 12, respectively, compared with a
lesser mean visual acuity gain of 4.6 (12.2) and 6.7 (11.7) letters at Months 6 and 12 in the very poor vision
FE cohort. There was no statistically significant difference (adjusted) in the study eye visual acuity change
between the 2 cohorts at either 6 months (p=0.11) or 12 months (p=0.26).
This retrospective analysis of the MARINA and ANCHOR study data did not support the hypothesis that FE visual
acuity plays a significant role in driving visual acuity of patients receiving monthly intravitreal
ranibizumab injections for neovascular AMD. Visual acuity of the FE by itself is, therefore, not a useful
parameter in predicting visual acuity in a majority of ranibizumab-treated patients.
Source: Zweifel SA, Saroj N, Shapiro H, Bailey Freund K. The effect of fellow eye visual acuity on
visual acuity of study eyes receiving ranibizumab for age-related macular degeneration.
Retina. 2012;32(7):1243–1249.
PCV Treated with Combined Reduced Fluence PDT and Intravitreal Ranibizumab
The following prospective noncomparative study was performed to report the results of reduced
fluence photodynamic therapy (PDT) combined with intravitreal ranibizumab in patients with polypoidal
choroidal vasculopathy (PCV) with active exudation and hemorrhage.
A total of 17 PCV eyes were treated, and follow-up for all patients was 12 months. PDT was administered with
reduced fluence (exposure time of 70”) and followed (48 hours later) by intravitreal ranibizumab (0.5 mg
in 50 µL). Intravitreal ranibizumab, with or without reduced fluence PDT, was repeated as indicated by
clinical and angiographic findings.
During the follow-up, the mean best-corrected visual acuity (BCVA) significantly improved from 0.45 ±
0.29 logarithm of the minimum angle of resolution (logMAR) at baseline to 0.29 ± 0.28 logMAR at 12 months.
The mean total macular volume (documented by optical coherence tomography retinal map examination) decreased
from 7.5 ± 1.18 mm³ to 6.7 ± 0.8 mm³. In 95% of the cases, BCVA remained stable or
improved.
It was concluded that reduced fluence PDT limits laser exposure, minimizing the risks of PDT-induced adverse
effects. Intravitreal injections of ranibizumab 0.5 mg reduced bleeding and leakage in PCV eyes and interfere
with rebound upregulation of vascular endothelial growth factor because of PDT-induced choroidal
hypoperfusion. Combined treatment may improve treatment outcomes in PCV while minimizing ocular and
systemic complications of treatment.
Source: Ricci F, Calabrese A, Regine F, e al. Combined reduced fluence photodynamic therapy
and intravitreal ranibizumab for polypoidal choroidal vasculopathy. Retina. 2012;32(7):1280–1288.
Intravitreal Ranibizumab Plus PDT for PCV
To clarify the efficacy of combined therapy with intravitreal ranibizumab injections and photodynamic therapy
(PDT) in patients with symptomatic polypoidal choroidal vasculopathy (PCV), investigators retrospectively reviewed
28 naive eyes of 28 patients (17 men, 11 women; mean age, 73.4 years; range, 55–85 years) with 20/40 or
less baseline visual acuity treated with 3 consecutive monthly intravitreal injections of ranibizumab
(0.5 mg/0.05 mL) and PDT and followed-up for at least 12 months. PDT was administered 1 day or 2 days after
the initial injection of ranibizumab.
The investigators found that mean best-corrected visual acuity (BCVA) levels significantly
(p<0.0001) improved from 0.33 at baseline to 0.61 at 12 months. They noted that the mean improvement
in BCVA 12 months from baseline was 2.65 lines and that the BCVA at 12 months improved in 15 eyes (53.6%)
by ≥3 lines and was stable (defined as a loss of <3 lines of vision) in 13 eyes (46.4%). They also noted
that the central retinal thickness significantly (p<0.0001) decreased from 366 µm to 151 µm
at 12 months. Furthermore, the mean numbers of PDT treatments and injections during 12 months including the
treatments during the initial regimen were 1.1 and 3.7, respectively. No complications developed.
Combined intravitreal ranibizumab and PDT for PCV maintained or improved visual acuity and reduced the
exudation without adverse events.
Source: Saito M, Iida T, Kano M. Combined intravitreal ranibizumab and photodynamic therapy
for polypoidal choroidal vasculopathy. Retina. 2012;32(7):1272–1279.
Outcomes of Three Monthly Ranibizumab Injections and
As-Needed Reinjections for PCV in Japanese Patients After 1 Year
The authors of the following Japanese prospective, consecutive case series
investigated the 1-year outcomes of monthly intravitreal injections of ranibizumab for 3 months followed by
an as-needed reinjection schedule to treat polypoidal choroidal vasculopathy (PCV) in Japanese patients.
A total of 85 eyes of 82 consecutive Japanese patients with naïve symptomatic PCV received monthly
intravitreal injections of ranibizumab for 3 months followed by an as-needed reinjection schedule. The authors
studied 81 eyes (95%) followed for 1 year.
They noted that a mean of 4.2 ± 1.3 (mean ± standard deviation) injections were administered over 1 year
and that 23 of 81 eyes (28%) did not require additional injections and 32 eyes (40%) required only 1
injection after the 3 monthly injections. They also found that mean (± standard error) logarithm of minimal
angle of resolution (logMAR) visual acuity (VA) at baseline was 0.59 ± 0.37 and improved to 0.37 ±
0.30 (p=.001). Thirty eyes (37%) and 5 eyes (6%), respectively, had improved and decreased VA of
0.3 or more logMAR unit, the authors observed. They also reported that indocyanine green angiography showed that
the polypoidal lesions resolved in 21 eyes (26%) and 32 eyes (40%) 3 months and 1 year after the
first injection, respectively. Abnormal choroidal vessels remained in all eyes.
To conclude, monthly injections of ranibizumab for 3 months to treat PCV improved the VA, and a reinjection
schedule based on need maintained the improved VA. The polypoidal lesions tended to improve over 1 year,
whereas abnormal choroidal vessels remained in all eyes. Further long-term follow-up is needed to determine
the efficacy of ranibizumab therapy for PCV.
Source: Hikichi T, Higuchi M, Matsushita T, et al. One-year results of three monthly
ranibizumab injections and as-needed reinjections for polypoidal choroidal vasculopathy in
Japanese patients. Am J Ophthlamol. 2012;154(1):117–124.e1.
Enlargement of Choroidal Atrophy Following Intravitreal Bevacizumab
for Myopic CNV
Investigators in Japan sought to determine the factors significantly associated with an enlargement of the area
of chorioretinal atrophy (ChRA) after intravitreal bevacizumab (IVB) to treat myopic choroidal
neovascularization (mCNV).
They reviewed the medical charts of 27 eyes with a mCNV that had received IVB. The ophthalmic examinations
included measurements of the best-corrected visual acuity, visual fields with the Humphrey 10-2 Field
Analyzer, fluorescein angiography, and indocyanine green angiography. The investigators measured the area
of the mCNV and the chorioretinal atrophy (ChRA) on the FA images.
According to the investigators, eyes with an enlargement of the ChRA had significantly larger mCNVs at the
baseline, a greater reduction in the size of the mCNV, a higher incidence of subretinal hemorrhage, longer duration
of follow-up, received more injections of IVB, and had a greater decrease of retinal sensitivity
(p≤0.041). They also noted that multiple regression analyses showed that the factors most
significantly associated with an enlargement of the ChRA were the CNV size at baseline, the number of IVB
injections, and the duration of the follow-up period (p<0.0001).
Their findings showed that eyes with a larger CNV at the baseline and longer follow-up period had a greater
risk of developing ChRA even if IVB treatment was performed for mCNV.
Source: Uemoto R, Nakasato-Sonn H, Kawagoe T, et al. Factors associated with enlargement of
choroidal atrophy after intravitreal bevacizumab for myopic choroidal neovascularization. Graefes Arch
Clin Exp Ophthalmol. 2012;250(7):989–997.
Use of Intravitreal Ranibizumab for the Treatment of
CNV Secondary to Angioid Streaks
To assess the medium to long-term efficacy and safety of intravitreal ranibizumab for the treatment of
choroidal neovascularization (CNV) secondary to angioid streaks (AS), 12 eyes of 9 patients treated
with intravitreal ranibizumab (0.5 mg in 0.05 ml) for CNV secondary to AS were retrospectively identified
in the following UK study.
Efficacy of treatment was determined by changes in best-corrected LogMAR visual acuity (BCVA) and optical
coherence tomography and changes with respect to baseline BCVA were defined as improved or reduced with a gain
or loss of more than 10 letters, respectively, or stable if remaining within 10 letters.
Over a mean follow-up of 21.75 months (range: 1–54), patients received mean 5.75 (range: 2–15)
intravitreal ranibizumab injections per affected eye. BCVA improved in three eyes (25%), stabilized in
eight eyes (66.67%), and deteriorated in one eye (8.33%). There was no significant change in central
retinal thickness (CRT) over the follow-up period (p=0.1072). Moreover, no drug-related systemic side
effects were recorded.
The long-term treatment of CNV secondary to AS with intravitreal ranibizumab showed a stabilization in CRT and
an improvement or stabilization of BCVA. The absence of systemic side effects was reassuring. Further
long-term prospective studies are required to validate these findings.
Source: Shah M, Amoaku WM. Intravitreal ranibizumab for the treatment of choroidal
neovascularisation secondary to angiod streaks. Eye. 2012; June 22. [Epub ahead of print].
DOI: 10.1038/eye.2012.116.
Combination Therapy with Bevacizumab and Dexamethasone
Intravitreal Implant in RVO
To determine whether dexamethasone intravitreal implant 0.7 mg (Ozurdex; Allergan, Inc.) with
bevacizumab (Avastin; Genentech, Inc.) therapy can be synergistic, providing further improvements in
visual acuity, sustainability, and macular thickness when compared with dexamethasone intravitreal
implant 0.7 mg alone the authors of the following prospective, interventional case series intended to
monitor changes in visual acuity and macular thickness in patients diagnosed with retinal vein occlusion
(RVO), after injection of bevacizumab followed by a scheduled dexamethasone intravitreal implant.
This study was designed to emulate patient care as received in the typical ophthalmology practice. The
authors included patients diagnosed with RVO, who were seen between September 2009 and July 2010, in this study
if they had received previous anti-vascular endothelial growth factor (anti-VEGF) therapy. They included patients
in the analysis if the previous anti-VEGF therapy had taken place at least 6 weeks before and optical
coherence tomography (OCT) was >300 µm on spectral-domain OCT. Exclusion criteria included history
of vitrectomy, and/or rubeotic or advanced glaucoma. All patients were evaluated with Snellen visual acuity
and measured for macular thickness (calculated by spectral-domain OCT) and intraocular pressure. At baseline,
all patients were injected with bevacizumab, followed by dexamethasone intravitreal implant injection 2 weeks
later. These patients were re-examined on a monthly basis and retreated when edema occurred.
The study authors reported that the primary outcome measure was the time to reinjection based on OCT and
vision criteria and that the secondary outcomes were increases in visual acuity and the reduction of OCT
thickness during that period. They identified 34 eyes of 33 patients, with a mean age of 72.8 years and
diagnosed 35% with central RVO and 65% with branch RVO. Of these patients, 97% gained vision
during the study. Mean visual acuity improved from initially 11 letters to a maximum of 25 letters during the
study period. In addition, vision improved by at least 15 letters in 29% of patients initially up to
64% during the study period. Macular thickness decreased with the combination treatment by OCT, and the
effect continued an average of 126 days from the initial bevacizumab treatment. Retreatment was unnecessary
in 18% of the population during the 6-month study period.
This study demonstrates efficacy and the duration of effect using a combination of bevacizumab and
dexamethasone versus dexamethasone alone. The combination is synergistic, increasing visual acuity and prolonging
the time between injections, compared with either of these medications alone. Therefore, the combination of a
VEGF inhibitor and a dexamethasone implant may be a valuable option for RVO treatment.
Source: Singer MA, Bell DJ, Woods P, et al. Effect of combination therapy with bevacizumab
and dexamethasone intravitreal implant in patients with retinal vein occlusion. Retina.
2012;32(7):1289–1294.
Effects of Bevacizumab and Ranibizumab on Microvascular
Retinal Endothelial Cells
Retinal endothelial cells are crucially involved in the genesis of diabetic retinopathy, which is treated
with vascular endothelial growth factor (VEGF) inhibitors. Of these, ranibizumab can completely
restore VEGF-induced effects on immortalized bovine retinal endothelial cells (iBREC). In most
experiments supporting diabetic retinopathy therapy with bevacizumab, only non-retinal EC or retinal
pigment epithelial cells have been used. Also, bevacizumab but not ranibizumab can accumulate in retinal
pigment epithelial cells. In Germany, researchers aimed to investigate the effects of bevacizumab on
VEGF-induced changes of iBREC properties and potential uptake and accumulation of both inhibitors.
They visualized uptake of VEGF inhibitors by iBREC with or without pretreatment with VEGF165
by immunofluorescence staining and western blot analyses. Measured transendothelial resistance (TER) of
iBREC (±VEGF165) showed effects on permeability, indicated also by the western blot-determined
tight junction protein claudin-1. The researchers also studied the influence of bevacizumab on proliferation
and migration of iBREC in the presence and absence of VEGF165.
They reported that bevacizumab strongly inhibited VEGF-stimulated and basal migration, but was less efficient
than ranibizumab in inhibiting VEGF-induced proliferation or restoring the VEGF-induced decrease of TER and
claudin-1. This ability was completely lost after storage of bevacizumab for 4 weeks at 4°C. Ranibizumab
and bevacizumab were detectable in whole cell extracts after treatment for at least 1 h; bevacizumab
accumulated during prolonged treatment. As noted by the researchers, ranibizumab was found in the
membrane/organelle fraction, whereas bevacizumab was associated with the cytoskeleton.
They concluded that both inhibitors had similar effects on retinal endothelial cells; however, some differences
were recognized. Although barrier properties were not affected by internalized bevacizumab in vitro, potential
adverse effects due to accumulation after repetitive intravitreal injections remain to be investigated.
Source: Deissler HL, Deissler H, Lang GE. Actions of bevacizumab and ranibizumab on microvascular
retinal endothelial cells: similarities and differences. Br J Ophthalmol. 2012;96(7):1023–1028.
Inhibition of Pathological Retinal Neovascularization
The goal of this study was to evaluate the in vitro and in vivo anti-angiogenic effects of ERΒ
selective agonist, Β-LGND2, using human retinal microvascular endothelial cell (HRMVEC) cultures
and a mouse model for oxygen-induced retinopathy (OIR).
Scientists determined the selectivity of Β-LGND2 using binding and transactivation assays. They evaluated
the effects of Β-LGND2 on pathological neovascularization in OIR mice by histology and retinal mounts
stained with isolectin B4 to quantify aberrant angiogenesis. They also evaluated gene expression and protein
levels using Q-PCR, angiogenesis protein array, and Western blotting. Additionally, the scientists used a cell
death detection ELISA kit to evaluate HRMVECs following hypoxic and hyperoxic conditions. They evaluated
in vitro angiogenesis by growth factor-induced proliferation, tube formation, and cell migration assays.
According to the study scientists, Β-LGND2-treated OIR mice had a reduced number of neovascular tufts
compared with vehicle-treated animals and a significant amount of normal blood vessel maturation similar to
normoxia controls. They noted that Β-LGND2 inhibited in vitro hypoxia- or hyperoxia-induced cell death and
the formation of endothelial tubular structures in an ERΒ-specific mechanism. However, Β-LGND2 did
not significantly inhibit growth factor-induced HRMVEC proliferation and migration. Gene and protein studies
revealed that OIR mice treated with Β-LGND2 had lower levels of pro-angiogenic factors like VEGF and HIF1α.
To conclude, Β-LGND2 inhibited in vitro and in vivo pathological neovascularization in the retina in an
ERΒ-specific mechanism. These results show that Β-LGND2, a nonsteroidal ERΒ selective agonist,
could be a useful therapeutic for ocular diseases involving aberrant angiogenesis like ROP, wet-AMD, and
diabetic retinopathy.
Source: Giddabasappa A, Eswaraka JR, Barrett CM, et al. Β-LGND2, an ERΒ selective
agonist inhibits pathological retinal neovascularization. Invest Ophthalmol Vis Sci. 2012; June 19.
[Epub ahead of print]. DOI: 10.1167/iovs.12-9627.
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