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Current Eye Research, 37(1), 55–61, 2012
Copyright © 2012 Informa Healthcare USA, Inc.
ISSN: 0271-3683 print/ 1460-2202 online
DOI: 10.3109/02713683.2011.593722
ORIGINAL ARTICLE
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Vitreous Pharmacokinetics and Retinal Safety of
Intravitreal Preserved Versus Non-preserved
Triamcinolone Acetonide in Rabbit Eyes
Rafael C. Oliveira1,8, André Messias1, Rubens C. Siqueira1, Marco A. Bonini-Filho1, Antônio
Haddad2, Francisco M. Damico3, Alfredo Maia-Filho4, Pedro TB Crispim5, Juliana B Saliba6,
Jefferson A. S. Ribeiro1, Ingrid U. Scott7, Armando S. Cunha-Jr6, and Rodrigo Jorge1
1
Department of Ophthalmology, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil,
Department of Cellular and Molecular Biology and Pathogenic Agents, School of Medicine of Ribeirão Preto, University
of São Paulo, Ribeirão Preto, Brazil, 3Department of Ophthalmology, University of São Paulo, São Paulo, Brazil,
4
Faculty of Veterinary Medicine, University of Rio Preto, São José do Rio Preto, Brazil, 5Department of Mathematics,
Federal University of Rondônia, Porto Velho, Brazil, 6Faculty of Pharmacy, Federal University of Minas Gerais, Belo
Horizonte, Brazil, 7Departments of Ophthalmology and Public Health Sciences, Penn State College of Medicine,
Hershey, PA, USA, and 8Department of Medicine, Federal University of Rondônia, Porto Velho, Brazil
2
ABSTRACT
Purpose: To compare the intravitreal pharmacokinetic profile of a triamcinolone acetonide formulation containing the preservative benzyl alcohol (TA-BA) versus a preservative-free triamcinolone acetonide formulation
(TA-PF), and evaluate potential signs of toxicity to the retina.
Methods: A total of 60 New Zealand male white rabbits, divided into two groups, were studied. In the TA-BA
group, 30 rabbits received an intravitreal injection of TA-BA (4 mg/0.1ml) into the right eye. In the TA-PF
group, 30 rabbits received an intravitreal injection of TA-PF (4 mg/0.1ml) into the right eye. The intravitreal
drug levels were determined in 25 animals from each group by high-performance liquid chromatography
(HPLC). The potential for toxicity associated with the intravitreal triamcinolone injections was evaluated in
five randomly selected animals from each group by electroretinography (ERG) and by light microscopy.
Results: Median intravitreal concentrations of TA-BA (µg/ml) were 1903.1, 1213.0, 857.8, 442.0, 248.6 at 3, 7, 14,
21 and 28 days after injection. Intravitreal concentrations of TA-PF (µg/ml) were 1032.9, 570.1, 516.6, 347.9, 102.8
at 3, 7, 14, 21 and 28 days after injection. The median intravitreal triamcinolone concentration was significantly
higher in the TA-BA compared to the TA-PF group at 7 days post-injection (p < 0.05). There was no significant
difference between the two groups in median triamcinolone concentration at the other time points evaluated.
There was no evidence of toxic effects on the retina in either group based on ERG or histological analyses.
Conclusions: Following a single intravitreal injection, the median concentration of triamcinolone acetonide is
significantly higher in the TA-BA compared to the TA-PF group at 7 days post-injection. No toxic reactions in
the retina were observed in either group.
Keywords: Triamcinolone, Preservative benzyl alcohol, Vitreous pharmacokinetics, Retina
INTRODUCTION
delivery has not been demonstrated to be effective due
to such factors as limited intraocular penetration and
multidrug resistance associated proteins.2 Systemic
administration may be effective but long-term use may
be associated with numerous side effects. Intravitreal
injections may deliver therapeutic levels of the drug
while minimizing the risk of systemic side effects.3
The treatment of posterior segment diseases such as
age-related macular degeneration (AMD) and macular
edema associated with various conditions is limited by
the challenges of delivering effective doses of drugs
to the vitreous, retina and choroid1. To date, topical
Received 29 July 2010; accepted 30 May 2011
Correspondence: Rafael C. Oliveira, Departamento de Oftalmologia, Faculdade de Medicina de Ribeirão Preto, Avenida Bandeirantes,
3900, Ribeirão Preto− São Paulo, 14049-900, Brazil. Tel: +55 69 3229 2929. Fax: +55 69 3229 1820. E-mail: [email protected]
55
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56 R.C. Oliveira et al.
Intravitreal administration of triamcinolone acetonide has been widely used for the treatment of posterior segment diseases including diabetic retinopathy,4
retinal vein occlusion,5 Irvine-Gass syndrome,6 uveitis,7
choroidal neovascularization associated with AMD8,
and proliferative vitreoretinopathy.9 Unfortunately,
there have been reports of sterile endophthalmitis10,11
and vision loss thought to be related to the preservative
and/or dispersion agent.12
In the present study, the intravitreal pharmacokinetic
profile of a triamcinolone acetonide formulation containing the preservative benzyl alcohol (TA-BA) was
compared with that of a preservative-free triamcinolone
acetonide formulation (TA-PF), and potential signs of
retinal toxicity were also investigated.
MATERIALS AND METHODS
Sixty male New Zealand white rabbits, each weighing
approximately 2.0 to 2.5 kg, were included. Throughout
the observation period, the animals were maintained
at the animal facility of the Faculty of Veterinary
Medicine of the University of Rio Preto, São José do
Rio Preto, São Paulo, Brazil. They were kept in a quiet
and climatically controlled environment, with free
access to standard rabbit chow and water.
Experiments were carried out in accordance with
the guidelines set forth by the Association for Research
in Vision and Ophthalmology (ARVO) statement for
the use of animals in ophthalmic and vision research.
The study was approved by the Ethics Committee for
Animal Experimentation of the School of Medicine of
Ribeirão Preto, University of São Paulo.
Surgical Procedures
The animals were divided into two groups. In the
TA-BA group, 4 mg of a triamcinolone acetonide formulation (40 mg/ml) containing the preservative
benzyl alcohol (Kenalog® Bristol-Myers, EUA) were
injected into the vitreous of the right eye of 30 rabbits.
In the TA-PF group, 30 rabbits received an intravitreal
injection of 4 mg of a preservative-free triamcinolone
acetonide formulation (40 mg/ml) (Ophthalmos® São
Paulo, Brazil).
The rabbits were anesthetized with an intramuscular injection of 30 mg/kg ketamine hydrochloride
(Ketamin®, Cristália, Brazil− 50 mg/ml) and 4 mg/kg
xylazine hydrochloride (Coopazine®, Schering-Plough
Coopers, Brazil− 20 mg/ml). The ocular surface was then
anesthetized by topical instillation of 1% proparacaine
ophthalmic drops (Anestésico®, Allergan). The pupils
were dilated with 1 drop each of 2.5% phenylephrine
hydrochloride and 0.5% tropicamide. At baseline, clinical penlight eye examination and intraocular pressure
(IOP) measurement (TonoPen® (Mentor, US) were
performed, and after adequate anesthesia and akinesia
were achieved, the right eye was injected 1.5 mm behind
the surgical limbus in the superotemporal quadrant
with 0.1 ml of either TA-BA or TA-PF. Anterior chamber paracentesis was performed to reduce the IOP in
all rabbits.
All animals were euthanized with an overdose
of intravenous thiopental (Thiopentax®, Cristália,
Brazil) 100 mg/kg. Five rabbits in each group were
euthanized at 3, 7, 14, 21 and 28 days following injection and their right eyes were enucleated immediately
and processed for determination of intravitreal drug
levels by high-performance liquid chromatography
(HPLC). The vitreous of all 25 rabbits in each group
was removed and frozen at −18°C until the triamcinolone concentrations were determined. The potential
for toxicity associated with the intravitreal triamcinolone injections was evaluated in five animals of
each group by histopathologic analyses and in three
of these five animals of each group by ERG at 28 days
after intravitreal injection.
Drug Level Analysis
The intravitreal drug levels were determined by highperformance liquid chromatography (HPLC) using the
method described by Robinson et al. (2006). The equipment used was Waters, pump 515, automatic injector
717 plus, UV detector 2487-dual lambda absorbance,
software Millenium® v.2.15.01 (Nova-Pak®, Waters,
USA). A C-18 column (5μm; 3.9 × 150 mm) was also
used for separation. The flow rate used was 1.0 ml/
min with a mobile phase of 60% of acetonitrile and
40% of water by volume. The experiments were performed at 20°C after the sample filtration (Durapore,
0.2 µm, Millipore). Under these experimental conditions, the retention time was 7.0 min and detection
limit was 10 ng/ml. The amount of triamcinolone was
expressed as triamcinolone equivalent concentration
(μg/ml).
TA-BA and TA-PF Distribution of Particle Size
The distribution of particles by size within both formulations was determined with a laser particle analyzer
(Hydro 2000S(A), Malvern Instruments Ltd., Malvern,
UK).
Clinical Examination
Clinical evaluation included ocular inspection and binocular indirect ophthalmoscopy preoperatively and at
3, 7, 14, 21, and 28 days after injection. In all rabbits,
the clinical evaluation was performed by two masked
observers. The IOP of experimental eyes was measured
Current Eye Research
Preserved and Non-preserved Intravitreal TA 57
in five animals of each group at baseline and at 1 minute
and 3, 14 and 28 days post-injection using a TonoPen®
(Mentor, US).
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Electroretinography (ERG)
Electrophysiological measurements were performed at
28 days after intravitreal injection in three animals of
each group.
The ERG protocol is based on the international standard for electroretinography (ISCEV). Six rabbits were
kept in a dark room for at least 3 h for dark adaptation
before anesthesia, which was performed by intramuscular injection of 1–2 mg/kg body weight xylazine and
10 mg/kg body weight ketamine. Pupillary dilatation
was performed with 1 drop of tropicamide 15 minutes
before ERG started.
ERG responses were recorded in both eyes simultaneously by means of JET contact electrodes on the
corneas (Microcomponents SA). Subcutaneous needles
in the skin near the lateral canthus of both eyes were
used as references; a ground electrode was placed on
the back. Electrode impedance was checked before and
after each measurement and was less than 5 kΩ at 25 Hz.
Eyes were stimulated using a Ganzfeld LED stimulator
(ColorDome; Diagnosys LLC, Littleton, MA). Flashes of
white light (6,500 K) with a duration of 4 ms were delivered in 5 steps of increasing luminance (0.0001, 0.0003,
0.001, 0.003, and 0.01, and 10 cd.s/m2) with 30 s inter
stimulus interval (ISI) in the dark adapted stage.
A hyperbolic saturation model13 was fitted for the
interrelation between b-wave amplitude and luminance
(I) for derivation of 2 parameters: Vmax: saturated b-wave
amplitude; and k: luminance necessary for b-wave to
reach ½ of Vmax (semisaturation point).
Oscillatory potentials (OP) were obtained from the
response elicited by the flash of 3 cd.s/m2 by means of
a fast Fourier transform (FFT) implemented as a band
pass frequency filter (from 60 to 300 Hz). The absolute
value of the area under the curve for all OP wavelets was
determined between a- and b-wave implicit times.
After 10 min of light adaptation with a background
light of 30 cd/m2, light adapted ERG recordings were
performed with luminance flashes 3 cd.s/m2 (ISI = 2 s)
followed by a 30 Hz white flicker stimulus of 3 cd.s/m2.
Responses were amplified (band pass filter: 0.3–300
Hz) and stored for off-line analysis using the Espion
(Diagnosys LLC, Littleton, MA) after averaging of 6 up
to 40 individual measurements at each step depending
on the signal/noise ratio.
Histopathologic Study
Five rabbits from each group, six of which were also
used for ERG analysis, were euthanized at 28 days for
histopathologic analysis. These animals were not used
© 2012 Informa Healthcare USA, Inc.
for dosing of intravitreal concentration of triamcinolone. The experimental eyes were enucleated and then
prepared for light and electron microscopy.
The eyes were hemisected at the equator and their
posterior segments were fixed in 2% formaldehyde plus
2% glutaraldehyde in a 0.1 M phosphate buffer, pH 7.2,
for 4 h, at 4°C. After washing in buffer, small pieces were
fixed in 1% osmium tetroxide in 0.1 M phosphate buffer
for 2 h, at 4°C. They were then dehydrated in graded
ethanol, cleared in propylene oxide and embedded
in Epon 812 resin. Semi thin sections (0.5 μm) were
stained with Toluidine blue for examination by light
microscopy (Carl Zeiss®, Germany). If any abnormality
was detected at light microscopy, electron microscopy
(Philips®, EM 208, EUA) would then be performed.
Statistical Analysis
The Mann-Whitney non-parametric test was used to
compare outcomes in both groups. For all tests, the level
of significance was set at α = 0.05, two tailed.
RESULTS
In Vivo Release Study
The TA concentration in the vitreous throughout 28
days of evaluation is presented in Figure 1. Median
intravitreal concentrations (µg/ml) for TA-BA x TA-PF
groups were 1903.1 × 1032.9 (p = 0.4647); 1213.0 × 570.1
(p = 0.0283); 857.8 × 516.6 (p = 0.0510); 442.0 × 347.9
(p = 0.2506); and 248.6 × 102.8 (p = 0.1745); at 3, 7, 14,
21 and 28 days after injection, respectively. Median
intravitreal TA concentration was significantly higher
in the TA-BA compared to the TA-PF group at 7 days
post-injection (p < 0.05), and at day 14 there was a
trend toward significance (p = 0.0510). At the other time
points investigated, there was no significant difference
between the two groups in intravitreal TA concentration (Figure 1A).
Clinical Examination and IOP Analysis
Mild hyperemia was noted by penlight inspection
immediately after injection in all rabbits. At the day 3
examination, no inflammatory signs were evident by
direct visual inspection in any rabbit from both groups.
Indirect ophthalmoscopy did not demonstrate evidence
of drug toxicity in any rabbit from both groups during
the 28-day study period. No endophthalmitis, retinal
detachment or cataract developed during the study
period.
There was a significant increase in IOP at 1 min and
at 3 days after the procedure in both groups (p < 0.05).
There was no significant difference between the two
58 R.C. Oliveira et al.
groups in IOP at any of the study evaluation time points
(Figure 1B).
TA-BA and TA-PF Distribution of Particle Size
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Analysis of the mean distribution of TA particle size
demonstrates that the TA-PF particles were significantly
smaller compared to the TA-BA particles (Figure 2).
ERG
There were no significant differences in ERG responses
when results from treated and non-treated eyes were
compared.
The parameters from the hyperbolic function (NakaRushton) Vmax, and k are represented in Tables 1 and 2 for
all animals, and an example is shown in Figures 3 and 4.
Similar results were observed in the two groups for the
a- and b-wave amplitude and implicit time measured on
the high intensity flash ERG response (Table 2).
There were also no significant differences between
treated and non-treated eyes with respect to light
adapted responses.
Histopathologic Study
Histopathologic examination demonstrated no signs
of retinal toxicity or inflammatory cell infiltration. No
structural abnormalities were noted at day 28 by light
microscopy and the normal anatomy of the retina was
preserved in both groups (Figure 5).
Figure 1 In vivo profile of TA-BA (solid line) and TA-PF group
(dashed line) concentrations after intravitreal injections (mean ±
standard deviation) (A) and intra-ocular pressure in each group
(mean ± SD) (B).
Figure 2 (A) TA-BA, and (B) TA-PF particle size distribution.
Table 1 Parameters Vmax and k from the relationship between ROD b-wave amplitude and luminance in all animals.
Rabbit
R1 (BA)
R2 (BA)
R3 (BA)
R1 (PF)
R2 (PF)
R3 (PF)
Vmax µV
Treated eye
211.9
234.1
281.2
246.8
253.7
258.9
Non-treated eye
271.5
260.9
292.6
249.0
321.0
284.9
k log cd.s/m2
Treated eye
−3.03
−2.91
−3.26
−2.82
−3.09
−3.19
Non-treated eye
−2.99
−2.96
−3.37
−2.96
−3.23
−3.28
Current Eye Research
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Preserved and Non-preserved Intravitreal TA 59
Figure 4 Examples of high intensity from the treated and
non-treated eyes of one rabbit of each group.
Figure 3 Examples of scotopic ROD ERG responses and the
relationship between b-wave amplitude and stimuli luminance
from the treated and non-treated eyes of one rabbit of each group.
Parameters Vmax and k are illustrated on the first example.
DISCUSSION
The present study suggests a trend of higher intravitreal TA concentrations through 14 days post-injection if
TA was associated with the benzyl alcohol preservative
© 2012 Informa Healthcare USA, Inc.
(TA-BA). Due to the variability in TA concentration
measurements, a larger number of rabbits would be
needed to determine whether there is a difference
between the formulations with respect to intravitreal
TA concentration. One may hypothesize that the faster
initial clearance of triamcinolone in the TA-PF group
is related to the smaller triamcinolone particles in this
group compared to the TA-BA group,14 although a
previous study using a different TA-PF formulation
reported no significant difference in vitreous levels of
TA-BA compared to TA-PF.15 In fact, this subject is controversial. According to Oishi et al. (2008),16 TA preparations with smaller and well dispersed intravitreal
particles may have a shorter elimination half-life, and
the suspension medium in which they are prepared
may contribute to a quick dispersion without agglutination in the vitreous body. Accordingly, Moshfeghi
et al. (2009)17 found that larger particles and greater
aggregation may have less migration of particles
throughout the vitreous cavity and longer duration of
degradation. However, Missel et al. (2010)18 suggest
the dissolution rates of TA preparations with different
particle sizes cease to increase at particle diameters
much larger than the particle size for either Kenalog®
(14–21 μM) or Triesence™ (5–6 μM), and the dissolution rates for these two products would be comparable
under conditions in which they form well-defined
depots within the vitreous.
Intravitreal triamcinolone levels from both the
TA-BA and the TA-PF formulations show variability
within each group and study period at each of the
time points investigated. This variation has been
60 R.C. Oliveira et al.
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Table 2 a- and b-wave amplitude and implicit time, and oscillatory potentials (OP) area under the curve (AUC) from the scotopic
high intensity flash ERG (10.cd.s/m2) in all animals.
a-wave amplitude (µV) a-wave implicit time (ms) b-wave amplitude (µV) b-wave implicit time (ms)
OP (µV.ms)
Rabbit Treated Non-treated Treated Non-treated
Treated Non-treated Treated
Non-treated Treated Non-treated
R1 (BA)
148.6
194.3
8
8
314.1
385.8
47
47
427.5
478.9
R2 (BA)
166.0
176.9
8
7
346.0
406.9
51
65
483.8
532.9
R3 (BA)
211.9
200.5
7
7
411.7
399.5
62
63
472.1
402.4
R1 (PF)
206.6
204.7
8
8
357.4
373.3
60
61
516.5
509.8
R2 (PF)
205.7
222.3
8
8
340.2
477.6
57
58
437.7
452.9
R3 (PF)
200.6
217.9
7
7
402.6
448.2
60
61
471.9
479.5
Figure 5 Semi-thin retina sections of a rabbit from the TA-BA group 28 days after injection (A = TA-BA; right eye; B = control; left eye)
and a rabbit from the TA-PF group also 28 days after injection (C = TA-PF; right eye; D = control; left eye). No histological changes were
verified in all retinal layers from TA-BA and TA-PF rabbits, as well as in controls.
reported previously and is related to drug shaking
and aspiration variation intrinsic to the intravitreal
injection procedure.19 This may also explain the
3-day triamcinolone dosage of less than 2 mg in both
groups, when compared to the approximately 3.5 mg
reported by Kim et al. for both formulations at the
same study period (estimated data according to elimination rate constant).15 As a consequence, extrapolated
TA half-lives from both formulations in the current
study (TA-PF: 7.995 ± 2.793 days; TA-BA: 8.166 ± 1.287
days) are also lower than the ones reported by Kim
(TA-PF: 24 days; TA-BA: 23 days). However, since the
procedures in both groups were performed by the
same experienced retinal surgeon, using an adequate
number of animals,15,20 bias regarding the intravitreal
injection was reduced, supporting the comparative
analysis.
There was no significant difference in IOP between
the two groups throughout the 28-day study period.
However, a significant increase in IOP occurred in
both groups at 1 min and at 3 days post-injection when
compared to pre-injection IOP. The initial IOP increase
after injection was relieved by anterior chamber
paracentesis; however, median IOP remained above
pre-injection levels in both groups at 3 days after TA
injection. Similar corticosteroid-related IOP increase
in rabbits was also reported by Kai et al.21 In addition
to ocular hypertension, cataract is also an important
complication of intraocular steroids21 and was not
observed in the present study, probably due to the
short follow-up period.
The potential for triamcinolone acetonide-related
retinal toxicity remains a controversial issue. Yu et al.22
observed destruction of photoreceptor outer segments
and migration of macrophage-like cells in the subretinal
space after intravitreal injection of 4 and 8 mg of TA-BA in
rabbits eyes. On the other hand, and consistent with the
results of the current study, Kim et al.15 observed no histopathologic or ERG evidence of retinal toxicity following
intravitreal injection of TA-BA or TA-PF in rabbit eyes.
In summary, TA-BA and TA-PF show similar vitreous pharmacokinetics in normal rabbit eyes, except for
a faster initial clearance of triamcinolone in the TA-PF
group. Both TA-BA and TA-PF were well tolerated and
Current Eye Research
Preserved and Non-preserved Intravitreal TA 61
no associated retinal toxicity was evident in this shortterm study. The observed retinal safety profile of both
intravitreal TA-PF and TA-BA, at a 4 mg dose, reinforces
that these drugs may be effective alternative therapeutic
strategies in human eyes.
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Declaration of interest: The authors report no conflicts
of interest. The authors alone are responsible for the
content and writing of the paper.
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