197
AdPEDF.11 doses greater than 10(8) PU. This study
provides evidence that adenoviral vector-mediated ocular
gene transfer is a viable approach in the treatment of ocu-
lar disorders, suggesting that further studies of the efficacy
of AdPEDF.11 in the treatment of patients with neovas-
cular AMD, as well as promising combined treatments,
should be performed
(36)
.
5.4 Ranibizumab and Sorafenib
In two cases of recurrent exudative AMD in which intra-
vitreal ranibizumab was used in combination with oral
sorafenib, a tyrosine kinase inhibitor, improvements were
observed in optical coherence tomography
(37)
, indicating
this might also be a promising combination treatment.
5.5 Hydroxymethylglutaryl-coenzyme A reductase
inhibitors, ACE inhibitors, trimethazine and third-
generation beta-blockers
Statins have been referred as hypolipidemic, anti-inflam-
matory and antioxidant agents, improving endothelial
function by increasing nitric oxide synthesis and release.
Therefore, they might influence AMD pathogenesis.
In fact, some studies refer a favourable effect on AMD,
suggesting a role for these substances in combined treat-
ment
(38)
.
A recent article refers treatment with ACE-inhibitors and/
or AR blockers, combined with a statin, aspirin and third-
generation beta-adrenergic receptor blockers or trimetha-
zine can be used with some advantage in certain forms of
AMD
(39)
.
6. The future of combined treatment
Only time will tell, whether double and triple treatments,
will display similar efficacy results as the gold standard
treatment.
One-year results (May 2009) of a prospective, random-
ized study of triple treatment with PDT, bevacizumab and
triamcinolone in three patient groups were recently pub-
lished. Study results were not superior to those observed
for monotherapy with the antiangiogenic agent, although
the number of retreatment sessions needed to stabilize
vision after one year was smaller
(40)
.
It is known that some patients respond better to mono-
therapy, while others respond better to combined treat-
ment; this is very likely due to individual patient and dis-
ease characteristics.
In the near future, development of non-anti-VEGF treat-
ments with neuroprotective, antifibrotic and anti-inflam-
matory actions may contribute to the increased efficacy of
new combined treatments.
Subtenon injection of long acting cortisones (anecortave)
in combination with other procedures, namely anti-
VEGF agents, should be studied
(41)
. Despite having been
abandoned in monotherapy, these agents might prove use-
ful in the combined treatment of AMD
(42)
.
Intensive research is currently in course regarding alter-
native actions on crucial neovascularization cascade steps
and mechanisms that trigger this process (signalling), since
these have the potential to become alternative strategies
for the combined treatment of AMD. Emerging therapies
will be described in a separate chapter. It shall be referred
that the complexity of signalling pathways supports the
concept of combined therapy as a way of achieving more
adequate control of biological functions in general and
neovascularization in particular
(43, 44)
.
7. Practical aspects
Combined therapies have long been used in the treatment
of oncological and numerous other systemic diseases.
In neovascular AMD, the objective of combined treat-
ments acting upon different stages of the physiopatho-
logical process or the signalling pathway that triggers its
mechanisms of action is to achieve synergistic action;
therefore, an increased treatment effect and/or a decrease
in the number of retreatment sessions required to stabilize
vision are to be expected, as well as a more prolonged ef-
fect, smaller doses and increased drug tolerance
(1)
.
Treatment of this disease focuses on three main targets
(1)
.
1. Neovascularization.
2. The angiogenic process.
3. The inflammatory, cicatricial and exudative process.
In clinical practice, the following therapies are currently
used in combined treatment:
1 – Photodynamic therapy with verteporfin, with stand-
ard, low or very low fluence.
2 – Antiangiogenic agents ranibizumab 0.5mg (Lucentis
®
),
bevacizumab 1.25mg (Avastin
®
) and pegaptanib 0.3mg
(Macugen
®
) (and VEGF Trap – aflibercept – in a phase III
study).
3 – Anti-inflammatory treatment with intravitreal dex-
amethasone and triamcinolone, with or without core
vitrectomy to allow injection of a greater volume of
an anti-VEGF (0.5mg/0.5ml) and dexamethasone
(0.5mg/0.5ml) solution.
Combined Treatment
