J. Biomedical Science and Engineering, 2013, 6, 8-14 JBiSE
http://dx.doi.org/10.4236/jbise.2013.610A2002 Published Online October 2013 (http://www.scirp.org/journal/jbise/)
Dobesilate for dry age-related macular degeneration*
Pedro Cuevas1#, Luis A. Outeiriño2, Carlos Azanza2, Javier Angulo1, Guillermo Giménez-Gallego3
1Departamento de Investigación, IRYCIS, Hospital Universitario Ramón y Cajal, Madrid, Spain
2Departamento de Oftalmología, Hospital de Día Pío XII, Madrid, Spain
3Departamento de Estructura y Función de Proteínas, Centro de Investigaciones Biológicas, CSIC, Madrid, Spain
Received 24 March 2013; revised 29 August 2013; accepted 16 September 2013
Copyright © 2013 Pedro Cuevas et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
ABSTRACT
We have evaluated the effects of intravitreal dobesi-
late, a synthetic fibroblast growth factor inhibitor, in
patients with dry age-related macular degeneration,
an inflammatory-related retinal disease without
available treatment up to date. 36 eyes from 36 pa-
tients with dry age-related macular degeneration
were treated with a single intravitreal dobesilate in-
jection. The end points were the improvement from
baseline visual acuity and normalization of retinal
histology at one month. Intravitreal dobesilate injec-
tion resulted in a significant improvement in func-
tional and anatomical outcomes at one month after
injection. Our results suggest that intravitreal dobe-
silate may increase the chance of visual acuity gain in
dry age-related macular degeneration, even in cases
with initial low vision. This study supports the find-
ings of previously published case reports, regarding
the short-term improvement in visual acuity by in-
travitreal dobesilate injection in different degenera-
tive retinal diseases.
Keywords: Dry Age-Related Macular Degeneration;
Fibroblast Growth Factor Inhibition; Intravitreal
Dobesilate
1. INTRODUCTION
Age-related macular degeneration (AMD) is the primary
cause of blindness and visual disability in people aged
over 50 and its prevalence increases exponentially after
the age of 70 [1,2]. AMD is diagnosed as either wet (ne-
ovascular) or dry (atrophic). Wet AMD is characterized
by choroidal nevoascularization (CNV): the formation of
hyperpermeable new blood vessels beneath the retinas
that leak plasma and often bleed, leading to the forma-
tion of scar tissue which can severely and irreversibly
compromise visual acuity. Although it constitutes only
10% - 15% of all cases, wet AMD accounts for almost
80% of AMD-related blindness [3].
Dry AMD, in contrast, does not involve leaking ves-
sels from choroidal vasculature. Dry AMD is character-
ized by a well-defined constellation of clinical features,
including drusen, pigment abnormalities/focal hyper- or
hypo-pigmentation of the retinal pigment epithelium
(RPE), and geographic atrophy (GA) of the macula. GA
represents the atrophic late stage of dry AMD [1,2]. GA
is characterized by roughly oval areas of hypopigmenta-
tion and is usually the consequence of RPE cell loss.
Loss of RPE cells, responsible for the overlying photo-
receptors surviving, leads to the gradual degeneration of
nearly photoreceptors, resulting in thinning of the retina.
RPE degeneration leads to the death of photoreceptor
cells causing irreversible vision loss. Since the natural
evolution of dry AMD is toward a wet AMD condition,
the holy grail of therapy for AMD is to avoid the devel-
opment of CNV. Today, there are no approved treat-
ments for dry AMD.
Considering the significant medical, personal, social
and economic costs of AMD, the need for novel thera-
peutic and preventive strategies for AMD is pressing.
Innovation in AMD pharmacotherapy, in turn, depends
largely upon a thorough understanding of the molecular
mechanisms underlying AMD pathogenesis. There is
ample evidence that inflammation plays an important
role in both dry and wet AMD [4-9]. Several studies
have documented a significant association between in-
flammatory diseases and upregulation of fibroblast
growth factor (FGF) [10-16]. Recently, it has been pos-
ited the importance of FGF in neuroinflammatory dis-
eases such as AMD where inflammation is one of the
main components of disease progression and FGF and its
receptors (FGF/FGFR) are prominently expressed [17].
*Consent: obtained.
Competing interest: the authors report no conflicts of interest in this
work.
#Corresponding author.

P. Cuevas et al. / J. Biomedical Science and Engineering 6 (2013) 8-14 9
This study supports an important clinical interest for
searching safe and efficient inhibitors of FGF/FGFR axis
to treat retinal inflammatory diseases, including AMD.
The aim of this study was to analyze treatment with a
single dose of intravitreal dobesilate in patients who
were diagnosed with dry age-related macular degenera-
tion.
2. METHODS
2.1. Participants
In this consecutive study, more than 200 patients with
age-related macular degeneration who visited the Clínica
Oftalmológica Hospital Pío XII of Madrid (Spain) be-
tween January 2012 and October 2012, were screened,
and 36 eyes from 36 patients with dry age-related macu-
lar degeneration were included. Baseline data for all
study patients is shown in Table 1. The study was ap-
proved by the local institutional review board and in-
formed consent was obtained from every patient for the
intravitreal injection. The subjects were also provided
information about the off-label use of dobesilate.
2.2. Inclusion/Exclusion Criteria
Inclusion criteria were the presence of early, intermedi-
ate or late stages of dry AMD. Eyes that met any of the
following criteria were excluded from enrolment: 1) had
severe disease that was judged by the treating investiga-
tor as being unlikely to benefit from further therapy
(such as those with central ischemia or macular scarring);
2) had vision loss from other coexisting ocular disease
and 3) had undergone ocular surgical interventions
within 6 months prior to study entry.
2.3. Procedures
Examination at baseline included best corrected visual
Table 1. Baseline characteristics of the patients.
Sex
Male 16
Female 20
Age
Mean 70 ± 7
Intermediate phase of dry AMD
Male 14
Female 16
Late phase of dry AMD (geographic atrophy)
Male 2
Female 4
acuity (BCVA) with a Snellen chart at a distance of 20
feet, slit lamp biomicroscopy of the anterior segment and
fundus, and spectral domain optical coherence tomogra-
phy (SD-OCT). The data recorded included complains as
scotoma, blurred vision and metamorphopsia.
The intravitreal injection of dobesilate was performed
in accordance with the guidelines for intravitreal injec-
tions [18]. Before injection administration, the eye was
washed with povidone-iodine (5%) and the eyelashes and
lid region were then wiped, also with povidone-iodine
(5%). Then, each patient received 18.75 mg of dobesilate
in a single intravitreal injection of 150 μl of a solution of
diethylamonium 2,5-dihydroxybenzesulfonate (etamsy-
late; dycinone®, Sanofi-Aventis, Paris, France). Antibi-
otic eye drops were then applied. Patients returned to the
outpatient clinic for routine postinjection follow-up at
day one and day three after injection; a slit lamp exami-
nation and pressure measurements were performed to
rule out intraocular inflammation or elevated intraocular
pressure (IOP). BCVA, slit lamp biomicroscopy of the
anterior segment and fundus, and SDCOT were con-
ducted again at 1 month postinjection. The ocular symp-
toms, such as scotoma, metamorphopsia and blurred vi-
sion were examined by questioning each patient before
and after treatment. Scotoma and metamorphopsia on the
Amsler grid were scored according to Verma et al. [19].
Accordingly, scotoma and metamorphopsia were graded
numerically from 0 to IV, where a grade 0 indicates ab-
sence of scotoma and metamorhopsia, and a grade IV
indicates very severe scotoma and metamorphopsia.
Blurred vision was scored from 0 to 4, where a score of 0
indicates no vision disturbance and a score of 4 indicates
very severe blurred vision.
2.4. Endpoints
The primary endpoint was the improvement of visual
acuity at 1 month compared with baseline. The second
endpoint was the effect of treatment in the normalization
of retinal structure at the same time after treatment.
2.5. Statistics
The paired t-test was used to statistically evaluate
changes in visual acuity at baseline and one month after
treatment. A p value < 0.05 was considered to be statis-
tically significant. Graphic representation of the data is
expressed as mean ± standard error of the mean (SEM).
3. RESULTS
3.1. Visual Outcomes
In the current study, 36 eyes of 36 patients of both sexes
were enrolled. All patients tolerated well the injection.
The mean BCVA at baseline was 0.44 ± 0.03. At one

P. Cuevas et al. / J. Biomedical Science and Engineering 6 (2013) 8-14 10
month examination, 32 eyes (89%) showed visual acuity
improvement and only 4 eyes (11%) experienced visual
acuity worsening. Individual patient BCVA values be-
fore and after treatment are shown in Table 2. The mean
BCVA after treatment was 0.59 ± 0.03 (p < 0.001).
Changes in BCVA after intravitreal injection of dobesi-
late appear in Figure 1. As the Table 3 shows, scotoma,
metamorphopsia and blurred vision were consistently
reduced, inducing the improvement of quality of vision
in all 32 cases.
3.2. Anatomical Outcomes
The effect of intravitreal dobesilate in retinal structural
outcomes was assessed with SD-OCT. At baseline, inner
retinal layer was normal, whereas the outer retinal layers
showed structural alterations: 1) the integrity of photore-
ceptor inner segment and outer segment were not pre-
served; 2) retinal pigment epithelium (RPE) showed
rarefactions and thinning. In contrast, normalization of
outer retinal layers was achieved in 32 patients after do-
besilate treatment. As an example of effectiveness of
Table 2. Change of BCVA from baseline to last observation.
P Baseline Treatment P Baseline Treatment
One month One month
1 0.40 0.50 19 0.60 0.90
2 0.50 0.60 20 0.40 0.60
3 0.60 0.70 21 0.50 0.70
4 0.50 0.80 22 0.30 0.40
5 0.40 0.80 23 0.40 0.50
6 0.50 0.60 24 0.20 0.60
7 0.60 0.60 25 0.20 0.40
8 0.40 0.70 26 0.20 0.90
9 0.20 0.90 27 0.30 0.60
10 0.60 0.20 28 0.30 0.50
11 0.40 0.60 29 0.40 0.50
12 0.50 0.40 30 0.50 0.60
13 0.60 0.50 31 0.70 0.80
14 0.70 0.60 32 0.30 0.50
15 0.70 0.80 33 0.20 0.30
16 0.70 0.80 34 0.40 0.60
17 0.40 0.40 35 0.30 0.20
18 0.50 0.90 36 0.30 0.50
Intravitreal dobesilate injection improved BCVA in patients with dry age-
related macular degeneration. P: Patient number (n = 36).
n = 36
***
1.0
0.8
0.6
0.4
0.2
0.0
BCVA
b
aseline 1-month treated
Figure 1. Visual acuity 1 month after an intra-
vitreal injection of dobesilate showing statisti-
cally significant improvement.
dobesilate, we show a SD-OCT scan of a patient with
GA (Figure 2). GA is characterized by confluent areas
of cell death of photoreceptors and RPE, is bilateral in
more than half of patients, and is responsible for 10% of
cases of legal blindness from AMD [20]. To date no ef-
fective treatment for progressive vision loss is available
for GA.
3.3. Safety
There were no cases of treatment-associated complica-
tions such as retinal detachment, endophthalmitis or per-
sistent elevated IOP.
4. DISCUSSION
Clinically and histologically, AMD is generally classi-
fied into two major subtypes: dry or non-exudative AMD,
of which GA is a severe form, and wet or exudative
AMD. Wet AMD is very debilitating and often develops
after early dry AMD. The key feature of wet AMD is
choroidal neovascularization (CNV), the growth of new
hyperpermeable blood vessels from the choroids into the
region underlying the RPE or extending into the subreti-
nal space [21]. Dry AMD progresses more slowly and
manifests RPE and photoreceptor cell dysfunction and
degeneration [4]. Although the aetiology of AMD is not
completely understood, it is indisputable that inflamma-
tion has a critical role in both dry and wet AMD [4-9].
Consequently, conventional therapies based on inhibiting
choroidal neovascularization do not seem to be an ap-
propriate strategy for dry AMD management. However,
the aetiology of this disease suggests that the treatment
of inflammation could be a suitable alternative to treat
dry AMD.
Previously, we have reported the efficacy of dobesilate,
a synthetic inhibitor of FGF/FGFR axis [22] in patients
with retinal diseases [23-27]. FGF in spite of being an

P. Cuevas et al. / J. Biomedical Science and Engineering 6 (2013) 8-14 11
Table 3. Change in ocular symptoms score from baseline to
last observation.
P B T P B T P B T P BT
S 1 II I 10 II II 19 III 0 28 II 0
M II I I 0 II 0 III I
BV 1 0 1 1 1 0 31
S 2 III II 11 I III 20 II I 29 II I
M I I I II II I III 0
BV 1 0 1 2 2 1 20
S 3 I 0 12 I 0 21 I 0 30 II I
M I 0 II 0 I I I0
BV 0 0 1 0 1 0 10
S 4 0 0 13 I I 22 II I 31 00
M I 0 I III II 0 00
BV 1 0 0 1 1 0 10
S 5 I 0 14 II II 23 I 0 32 00
M 0 0 I 0 I I 00
BV 1 0 1 1 1 0 10
S 6 I 0 15 I II 24 II I 33 00
M 0 0 I II II I I0
BV 0 0 1 1 1 0 10
S 7 I 0 16 II I 25 III I 34 III II
M 0 0 I I II 0 III II
BV 0 0 0 1 3 0 22
S 8 II I 17 I 0 26 II 0 35 I0
M II 0 I 0 II 0 I0
BV 1 0 1 0 1 0 11
S 9 III 0 18 I I 27 III I 36 II III
M II 0 II II III I II II
BV 1 0 1 1 3 0 22
Dobesilate injection in the vitreous gel improved ocular symptoms associ-
ated to dry age-related macular degeneration. S: Scotoma; M: Metamor-
phopsia; BV: Blurred Vision; P: Patient number (n = 36); B: Baseline; T:
after one month of Treatment.
angiogenesis promoter [28] is involved also in inflam-
mation [10-16] and seems to play key roles in neurode-
generative diseases such as Alzheimer’s and Parkinson’s
diseases as well as in AMD [17].
Dobesilate features suggest that its intravitreal appli-
cation could be of potential clinical benefit in dry AMD
management. In this report, we describe the rapid nor-
malization of retinal structure, running parallel to a con-
(a)
(b)
N
→ T
(c)
Figure 2. Fundus photographs of the left eye of an enrolled
patient at baseline with peripheral areas of pigment accumula-
tion, autofluorescence deposits and patches of geographic at-
rophy of the retinal pigment epithelium (a). Optical coherence
tomography of the central macula before treatment with dobe-
silate (b), showing loss in some areas of both outer retinal lay-
ers and pigment epithelial cells, and one month after treatment
(c), with improvement of vision from 0.20 to 0.60. Note the
anatomical recovery of outer retinal layers and retinal pigment
epithelium after a single intravitreal injection of dobesilate.
siderable improvement of visual acuity in patients with
dry AMD after a single intravitreal administration of
dobesilate. This study adds some more valuable data to
the recently reported promising good results to the use of
dobesilate in both dry and wet AMD and also in other
retinal diseases [23-27].
It may result somehow surprising that an inhibitor of
FGF shows the good safety profile of dobesilate, given
the broad spectrum of physiological activities in which
FGF is involved [29-32]. In effect, FGF has been de-
tected in most adult tissues tightly bound to the sulphated
glycosaminoglycans (GAG) of the extracellular matrix

P. Cuevas et al. / J. Biomedical Science and Engineering 6 (2013) 8-14 12
(ECM), at times at very high levels [22]. Thus, under
normal physiological conditions, FGF does not act as a
signalling molecule in solution, but as a solid phase
growth factor. As far as FGF remains part of the ECM, it
cannot be inhibited by dobesilate, which has an affinity
constant for FGF approximately 3000 times lower than
that of the sulphated GAG of the ECM; furthermore, it
reaches extraordinarily high concentrations [22]. Never-
theless, the physiological FGF signalling system gets
sometimes subverted, causing very serious physiological
disturbances, when high concentrations of free FGF are
accumulated, either through uncontrolled synthesis or
mobilization by heparanases and other specialized pro-
teins which could be upregulated in inflammatory condi-
tions [33-35]. In contrast to ECM bounded FGF, dobesi-
late efficiently inhibits free FGF [22]. Consequently, it
inhibits mainly pathological FGF, leaving the relatively
untouched physiological FGF pool.
Several limitations are inherent in the current study.
First, the design was prospective, the sample size was
small and there was no control group. Second, this one
time follow-up of patients does not describe visual acuity
evolution over time and the results may be transient.
However, this study shows for the first time the efficacy
and safety of a new therapy for dry age-related macular
degeneration that has been considered as an orphan dis-
ease. Furthermore, treatment with dobesilate increased
visual acuity above the expected baseline decrease dur-
ing the natural evolution of untreated dry AMD. In sum,
dobesilate with a long history of use, and abundant pre-
clinical data supporting its biological effects and its po-
tential efficacy, is promising as a FGF targeted therapy
for AMD. A large population cohort study is needed to
establish the effectiveness of intravitreal dobesilate in
treating dry AMD patients.
5. AUTHOR CONTRIBUTIONS
Conceived and designed the study: PC, GGG, LO. Per-
formed the study LO, CA. Analyzed the data: LO, CA,
JA, GGG, and PC. PC, GGG, wrote the paper. All au-
thors read and approved the final manuscript.
6. ACKNOWLEDGEMENTS
We are indebted to the patients who participated in this study.
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P. Cuevas et al. / J. Biomedical Science and Engineering 6 (2013) 8-14 14
ABBREVIATIONS
BCVA: Best corrected visual acuity
SD-OCT: Spectral domain optical coherence tomography
FGF: Fibroblast growth factor
FGFR: Fibroblast growth factor receptors