 |
|
Transscleral Diffusion of Carboplatin
An In Vitro and In Vivo Study
Amanda E. Simpson, BS;
Jake A. Gilbert, BS;
David E. Rudnick, MS;
Dayle H. Geroski, PhD;
Thomas M. Aaberg, Jr, MD;
Henry F. Edelhauser, PhD
Arch Ophthalmol. 2002;120:1069-1074.
ABSTRACT
| |
Objectives To compare the in vitro scleral permeability of carboplatin using either
a fibrin sealant or a balanced salt solution (BSS) vehicle and to measure
in vivo ocular tissue levels following subconjunctival injection of carboplatin
in fibrin sealant or BSS.
Methods The permeability of carboplatin in fibrin sealant or BSS through human
eye bank sclera was tested using an in vitro perfusion apparatus. Levels of
carboplatin permeating the sclera were measured every hour for 24 hours using
atomic absorption spectrometry. In vivo studies were performed in Dutch Belted
rabbits injected subconjunctivally with carboplatin in either fibrin sealant
or BSS; eyes were enucleated at 1 hours, 48 hours, and 2 weeks after
injection, and levels of carboplatin were measured in various tissues.
Results In vitro carboplatin in fibrin sealant had a peak permeability constant
of 13.7 ± 2.3 x 10-6 cm/s; carboplatin in BSS,
27.0 ± 1.7 x 10-6 cm/s. After 24 hours, 33.2%
± 1.8% of the carboplatin was retained in the fibrin sealant, while
5.5% ± 1.0% was retained in the BSS. In vivo subconjunctival injection
of carboplatin in fibrin sealant vehicle achieved 11.83 ± 5.16 µg/mL
in the vitreous at 1 hours and 0.03 ± 0.06 µg/mL in the
vitreous at 2 weeks. The fibrin sealant also attained 396.59 ± 177.84
µg/mg in the choroid and retina at 1 hours and 3.38 ±
1.97 µg/mg in the choroid and retina at 2 weeks. (Data are given as
mean ± SEM.)
Conclusion Fibrin sealant provided a more controlled and localized release of carboplatin
and delivered carboplatin to the ocular tissues for up to 2 weeks.
Clinical Relevance This study reports the use of fibrin sealant as a subconjunctival delivery
vehicle for carboplatin, and quantifies ocular drug levels achieved in an
animal model.
INTRODUCTION
RETINOBLASTOMA IS the most common primary intraocular malignancy of
childhood, with approximately 200 new cases each year in the United States.1-2 Focal treatments, such as cryotherapy,
laser photocoagulation, and thermotherapy, have evolved as excellent treatment
options, but are limited to small or single tumors.3
Large tumors or vitreous seeds have necessitated enucleation or external beam
radiation.4-5 External beam radiation
effectively controls some tumors when used alone, but not without significant
morbidity, including an increased rate of vitreous hemorrhage, cataract formation,
midface hypoplasia, vision loss, and second tumor formation in the field of
radiation.6-8 Because
of these factors, chemotherapy (systemically and locally) is the treatment
of choice for eyes with significant tumors.
Retinoblastoma has been shown to respond to newer drug regimens and
carboplatin has become a cornerstone in the treatment of this disease. However,
when given systemically, the physician must be alert to potential adverse
effects, including leukemogenic effects, immune incompetence, and death. Localized
periocular delivery of carboplatin is an option that could maintain treatment
benefits while avoiding these serious adverse effects. Several in vitro studies9-10 have confirmed that isolated sclera
is permeable to various compounds, such as dexamethasone, methotrexate, and
dextran 10, 40, and 70 polymers. Murray et al11
were also able to show that intraocular tumor growth could be inhibited in
transgenic murine retinoblastoma using subconjunctival delivery of carboplatin.
In addition, serial subconjunctival injections of carboplatin are somewhat
effective in the treatment of human intraocular retinoblastoma.12
For local cancer treatment, an increased concentration and a longer
duration of drug exposure are ideal. This might be achieved by incorporating
chemotherapeutic drugs into a sustained-release vehicle. One such medium that
might aid in the local delivery of carboplatin is a human-derived fibrin protein
sealant, which, on polymerization, provides a semisolid medium for drug delivery.
MacPhee et al13 showed that human fibrin can
serve to deliver fluorouracil concentrations sufficient to kill renal tumor
cells. When the anhydrous form of the chemotherapeutic agent was used, delivery
was extended up to 120 hours. Typically, the amount of carboplatin available
at the injection site is limited by its volume and concentration. However,
because the anhydrous form of a drug can be incorporated as a slurry directly
into the fibrin sealant, at a concentration above its solubility limit, more
drug can be delivered from a smaller volume of vehicle. Approved by the Food
and Drug Administration, fibrin sealant is also advantageous as a delivery
vehicle because it is formulated to contain human proteins, which minimizes
immunogenicity and foreign body reactions and eliminates the need for physical
removal of the clot, which is naturally degraded by the body.
It is postulated that retinoblastoma may be better treated by delivery
of carboplatin in fibrin sealant. Therefore, one arm of this study involved
a series of in vitro experiments intended to evaluate the transscleral permeability
of carboplatin from a fibrin sealant vehicle and the commonly used balanced
salt solution (BSS) vehicle. The design of the in vitro scleral perfusion
chambers used in these experiments simulated a static depot of drug adjacent
to the sclera. This controlled setup eliminated variable factors, such as
drug dispersion, tear fluid turnover, and blood flow. This allowed for a more
direct comparison of the drug diffusion kinetics from each medium and for
the determination of whether using a sustained-release vehicle might provide
a benefit in delivering carboplatin locally to the eye. The goal in the other
portion of this study was to determine carboplatin concentrations in various
ocular tissues after subconjunctival administration to the rabbit eye. The
aim was to achieve a maximum release of carboplatin by "overloading" the fibrin
sealant with significantly more drug than can be ordinarily dissolved in the
usual BSS vehicle.
MATERIALS AND METHODS
PREPARATION OF CARBOPLATIN IN FIBRIN SEALANT
Fibrin sealant (HEMASEEL APR 4-mL kit; Haemacure Corp, Sarasota, Fla)
was prepared according to insert instructions with slight modification. The
fibrin sealant was supplied as a 2-part kit composed of blood-clotting factors
that worked similar to an epoxy glue. One part was a human sealer protein
concentrate that was reconstituted with 2 mL of bovine fibrinolysis inhibitor
solution, and the other part was human thrombin, 1000 IU, that was reconstituted
with 2 mL of calcium chloride solution, 80 µmol. To prepare the sealant,
all parts were heated to 37°C and reconstituted with their respective
solutions. The protein concentrate was stirred for 10 minutes. The 2 solutions
were then loaded into a syringe unit (Duploject; Immuno-US, Rockville, Md),
which consisted of a clip for 2 identical syringes and a common plunger that
ensured that equal volumes of the 2 components were forced through a common
joining piece before being mixed in the application needle. On injection,
the 2 solutions polymerized to form a clot at the injection site. For the
in vitro experiments, 50 mg of carboplatin (Paraplatin; Bristol-Myers Squibb
Co, Princeton, NJ) was incorporated into the fibrin sealant where the thrombin
and protein concentrate were reconstituted. For the in vivo experiments, 150
mg of carboplatin was added. This yielded a calculated initial concentration
of 12.5 and 37.5 mg/mL for the in vitro and in vivo experiments, respectively.
IN VITRO SCLERAL PERMEABILITY
Scleral tissue was obtained from 10 human donor eyes (Georgia Eye Bank,
Atlanta) that had been stored in moist chambers for no longer than 8 days.
Scleral preparation and in vitro diffusion setup were performed according
to Rudnick et al.9 The perfusion apparatus
clamped the sclera between a donor chamber on the episcleral side and a receiver
chamber on the choroidal side. Approximately 300 µL of carboplatin in
either fibrin sealant or BSS (Alcon Laboratories, Inc, Ft Worth, Tex) was
applied to the episcleral surface. The choroidal side was perfused continuously
with BSS. The perfusate was collected in a fraction collector every hour for
24 hours and analyzed by atomic absorption spectroscopy to determine the concentration
of carboplatin that had diffused through the sclera. Based on these data,
2 time-dependent diffusion curves were created. One depicted the absolute
amount of carboplatin that diffused across the sclera, and one showed the
diffusion of carboplatin as a percentage of the peak. The diffusion constant, Ktrans (measured in centimeters per second),
was measured at the point of peak flux for carboplatin in each delivery vehicle
and was calculated as follows:
Ktrans = [Rtotal/(A x t)] x [1/D],
where Rtotal equals the total moles
through sclera in time t; A,
the surface area of the sclera (measured in centimeters squared); t, time (measured in seconds); and D, concentration
of original solution in the donor chamber (measured in moles per milliliter).
IN VIVO SUBCONJUNCTIVAL INJECTIONS
Dutch Belted rabbits (N = 44; weight, 1.5-2.4 kg) were used to determine
ocular tissue levels of carboplatin following subconjunctival injection using
either a fibrin sealant or a BSS delivery vehicle. The animals were anesthetized
with intramuscular injections of 0.6-mL xylazine hydrochloride, 20 mg/mL,
and 0.6-mL ketamine hydrochloride, 100 mg/mL, before injection procedures.
One group received 300 µL of fibrin sealant containing carboplatin (approximately
37.5-mg/mL calculated concentration) injected subconjunctivally in the left
eye. The injection was made in the superior temporal region, carefully avoiding
extraocular muscles. Samples of fibrin sealant from the injection syringes
were saved and analyzed to verify the initial carboplatin concentration. The
right eye served as a control and remained untouched. Formation of the fibrin
sealant clot adherent to the sclera was evaluated immediately after injection
by visual and tactile inspection. A second group of rabbits received 300 µL
of BSS containing carboplatin (approximately 10-mg/mL calculated concentration)
in the subconjunctival space of the left eye. A slitlamp examination was performed
and photographs were taken immediately after injection and 2 weeks thereafter.
Rabbits were anesthetized as previously described and killed with an overdose
of pentobarbital sodium (Euthanasia-5 solution; Henry Schein, Inc, Port Washington,
NY), 324 mg/mL, at 1 hours, 48 hours, and 2 weeks after injection.
All animals were handled according to the Association for Research in Vision
and Ophthalmology statement for the use of animals in ophthalmology and visual
research.
TISSUE SAMPLING
Blood samples were obtained via direct cardiac tap. After enucleation,
the aqueous humor was removed from each eye with a 25-gauge needle inserted
into the anterior chamber. Eyes were immediately frozen in an acetone and
dry-ice bath and stored at -70°C until dissection. The frozen eye
was divided with a scalpel into the portion of the sclera directly exposed
to the fibrin sealant injection (exposed sclera) and the portion that was
not exposed. The remaining fibrin clot was removed from the sclera to which
it was adherent. Next, choroid and retina together were peeled away from the
attached sclera. The frozen vitreous was then divided in 2, one closest to
the fibrin sealant (exposed vitreous) and one further from the fibrin sealant
(unexposed vitreous). Blood samples were placed in a heparinized tube and
spun down at 1000g for 10 minutes, and 0.5 mL of
plasma was removed. All samples were weighed and then dissolved in nitric
acid.
CARBOPLATIN MEASUREMENT
Carboplatin concentrations were measured by flameless atomic absorption
spectroscopy, using a graphite furnace (model HGA-600; PerkinElmer Inc, Shelton,
Conn), with the use of a graphite tube atomizer and an automatic sample dispenser,
as described by Madden et al,14 with minor
modifications. A standard curve covering the range of 0 to 1080 µg/L
was run at the start and end of each group of samples and after each change
to a new graphite tube. Samples were diluted to achieve concentrations within
the standard curve. Sample concentrations were determined by comparison of
the peak area of the signal with that of the external standards.
STATISTICAL ANALYSES
All average values are reported as mean ± SEM. The t test was used to determine the significance between mean values. P<.05 was considered significant.
RESULTS
IN VITRO SCLERAL PERMEABILITY
Analysis of presamples from the episcleral side (donor chamber) of the
in vitro scleral permeability experiments showed that the carboplatin concentrations
were 8.0 ± 0.3 and 6.9 ± 0.2 mg/mL for fibrin sealant and BSS,
respectively. Figure 1, A, shows
the diffusion of carboplatin across the sclera from each vehicle as a function
of time. Figure 1, B, uses the same
values to illustrate the amount that diffused across the sclera as a percentage
of the peak. At the end of 24 hours, 33.2% ± 1.8% of the initial carboplatin
remained in the fibrin sealant and 5.5% ± 1.0% remained in the BSS
(Table 1). The peak Ktrans of carboplatin from BSS was 27.0 ± 1.7 x
10-6 cm/s, while the peak Ktrans of carboplatin from fibrin sealant was 13.7 ± 2.3 x
10-6 cm/s (Table 1).
|
|
|
|
A, Amount of carboplatin that diffused through the sclera from balanced
salt solution (BSS) (n = 5) or fibrin sealant (n = 5) using in vitro perfusion
chambers. B, Percentage of the peak carboplatin that diffused through the
sclera in vitro. The curve is extrapolated to estimate the percentage at 48
hours.
|
|
|
|
|
|
|
Table 1. Ktrans and Percentage
of Carboplatin Remaining in FS or BSS Vehicle*
|
|
|
IN VIVO SUBCONJUNCTIVAL INJECTIONS
The average initial concentration of carboplatin in fibrin sealant was
24.5 ± 0.7 mg/mL, vs 8.1 ± 0.1 mg/mL in BSS. Table 2 shows concentrations of carboplatin delivered by either
fibrin sealant or BSS to the ocular tissues of the treated eyes and found
in the blood plasma at 1 hours, 48 hours, and 2 weeks.
|
|
|
|
Table 2. In Vivo Carboplatin Concentrations in Ocular Tissue*
|
|
|
Because injection concentrations were different for BSS and fibrin sealant,
carboplatin levels in each tissue were also shown standardized to an initial
injection concentration of 10 mg/mL. These corrected drug levels for the treated
and untreated eyes are shown in Table 3. Carboplatin as delivered by fibrin sealant was significantly higher
in the exposed sclera at 48 hours (P<.01) and
in the plasma at 1 hours (P = .02). Carboplatin
levels were higher from the BSS in the unexposed sclera (P = .01) and in the plasma (P = .03) at 48
hours. Also, carboplatin levels from BSS in the untreated eye were significantly
higher in the aqueous humor at 1 (P<.01)
and 48 hours (P = .01), the choroid and retina at
48 hours (P = .01) and 2 weeks (P = .01), the sclera at 48 hours (P = .04)
and 2 weeks (P = .03), and the vitreous at 1
(P = .03) and 48 hours (P
= .01). After enucleation, at all time points, a fibrin sealant bleb could
still be noted in the superior-temporal region of the eye. However, with treatments
of BSS, this was not observed given that the vehicle disseminated promptly
on injection.
|
|
|
|
Table 3. In Vivo Carboplatin Concentrations Normalized to the Same
Initial Injection Concentration*
|
|
|
COMMENT
The in vitro portion of this study was a preliminary analysis that demonstrated
that fibrin sealant could indeed provide a transscleral release of carboplatin.
The perfusion chambers used in these experiments held an isolated piece of
sclera that kept the carboplatin/vehicle solution static on one side of the
tissue. Factors such as drug dispersion, tear fluid turnover, and blood flow
were not taken into account and, therefore, these experiments were not designed
to be a quantitative predictor of carboplatin levels that could be achieved
in vivo. However, they assessed the value of the sealant as a local drug delivery
vehicle for carboplatin. To gain an accurate understanding of the levels that
could be achieved in vivo, a series of rabbits were given subconjunctival
injections of carboplatin in fibrin sealant.
The in vitro diffusion profiles in Figure 1, A, show that the amount of carboplatin that diffused through
the sclera from the BSS vehicle was initially higher than the amount that
diffused from the fibrin sealant. However, those amounts eventually decreased
below the carboplatin levels being released from the sealant. Figure 1, B, depicts how quickly each vehicle was depleted of carboplatin
by expressing the values from Figure 1,
A, as a percentage of the peak. The curves from Figure 1, B, which were extrapolated to 48 hours, show that the
levels of carboplatin were exhausted more rapidly from BSS than from fibrin
sealant, illustrating how the sealant was providing a more stabilized drug
release. For the in vitro studies, the concentration of drug in each vehicle
was chosen to establish a diffusion curve over 24 hours, rather than to maximize
drug release. Figure 1, B, shows
that, at the current concentration and volume of injection, the projected
release of BSS would be 0.2% of the peak, while the fibrin sealant would be
at a 22-fold higher level, 4.4%. However, one benefit of the sealant over
BSS is that it can be loaded with drug above its solubility limit, to provide
higher levels of drug for extended periods. Rather than simple diffusion out
of an aqueous drug delivery vehicle, the fibrin sealant becomes a durable
reservoir of undissolved drug available for delivery.
The Ktrans for each drug delivery
system was also an indicator that fibrin sealant provided a more controlled
release of carboplatin (Table 1).
The Ktrans of BSS was significantly higher
than that of fibrin sealant, indicating that the carboplatin diffused out
of the BSS more quickly, while the lower Ktrans for fibrin sealant indicated that the carboplatin was diffusing out
more slowly. The drug was held in the fibrin sealant and available for an
extended release. This finding was confirmed by our results that showed that
a significantly higher amount of carboplatin remained in the fibrin sealant
at the end of the 24-hour experiments (Table 1). Not surprisingly, during the 24-hour in vitro experiments,
more total carboplatin diffused through the sclera from the BSS. However,
the remaining drug in the sealant would still be available for continued diffusion
beyond 24 hours. It is possible that, in vivo, with tear dilution, blood flow,
and an increased surface area of nonocular tissue to absorb drug, having the
carboplatin give a stabilized local release rather than an initial dump of
all the available drug could result in more total carboplatin being released
into the eye to treat retinoblastoma.
The in vivo portion of this study established quantitative data on the
levels of carboplatin reaching several ocular tissues after a subconjunctival
injection of each carboplatin delivery medium. To our knowledge, there were
no comprehensive data on concentrations of carboplatin established in the
rabbit eye through subconjunctival administration using either of these vehicles.
However, Mendelsohn et al15 studied intraocular
levels of carboplatin following intravenous vs peribulbar administration in
primates. To compare carboplatin levels in the rabbit eye achieved with local
administration of fibrin sealant with the levels previously detected in primates
achieved with local administration of BSS, a series of rabbits were given
subconjunctival injections of carboplatin in BSS at the typical concentration
of 10 mg/mL. Mendelsohn et al found that after peribulbar administration of
10 mg of carboplatin (1 mL of 10-mg/mL carboplatin in BSS), aqueous humor
levels peaked at 2.0 µg/mL, vitreous levels peaked at 2.38 µg/mL,
and plasma levels peaked at 0.89 µg/mL in a 2-hour period. In our rabbit
model, we injected approximately 2.4 mg of carboplatin in the BSS (300 µL
of 8.1 ± 0.1 mg/mL) using a similar protocol to that of Mendelsohn
et al. At 1 hours, the aqueous humor had a peak concentration of 18.74
± 5.83 µg/mL, and the vitreous levels in the portion exposed
and unexposed to the injection site were 1.84 ± 0.56 and 0.75 ±
0.14 µg/mL, respectively. The plasma level at 1 hours was 1.58
± 0.14 µg/mL. These levels are similar to those found in primates,
except for the level in the aqueous humor, which was most likely higher because
of a more anterior injection site. The data imply that carboplatin in BSS
is capable of diffusing into the eye in a similar fashion in rabbits and primates.
As previously discussed, the ability to overload drug into fibrin sealant
and its ability to provide a semisolid drug reservoir represent the major
advantages of this vehicle. Consequently, for the in vivo portion of this
study, rabbits given subconjunctival injections of fibrin sealant had an increased
load of carboplatin to maximize release to the eye. For the subconjunctival
injections of fibrin sealant, approximately 7.35 mg of carboplatin was used
(300 µL of 24.5 ± 0.7 mg/mL). With this concentration, the fibrin
sealant–injected rabbits had a carboplatin level of 11.83 ± 5.16
and 3.98 ± 1.99 µg/mL in the exposed and unexposed vitreous,
respectively, at 1 hours. Although intravenous carboplatin can deliver
drug to the vitreous, of major concern is the inadequacy of this route and
the recurrence of vitreous and subretinal seeds despite control of primary
retinal tumors. Abramson et al16 determined
the intraocular levels of carboplatin 1 to 2 hours following the intravenous
administration of carboplatin in children who were scheduled for enucleation.
They found that the mean concentration of carboplatin in the vitreous was
4.05 µg/mL. Given subsequent data showing an efficacy of 14 to 20 mg
of carboplatin delivered subconjunctivally, one might extrapolate that 4.05
µg/mL is capable of causing regression of vitreous seeds.10
With the injection of carboplatin in fibrin sealant, a vitreous level of 11.83
µg/mL was reached, more than twice the concentration detected by Abramson
et al. It is likely that this higher level in the vitreous would be capable
of effecting a more complete recession of vitreous seeds with a single injection.
The data in this article show that with the fibrin sealant, carboplatin can
be detected in the vitreous for up to 2 weeks. However, at this later time
point, the exposed and unexposed vitreous levels were near baseline and had
increased variability.
Because of where retinoblastoma arises, the choroid and retina sample
is clinically relevant. Our results showed that fibrin sealant delivered 396.59
± 177.84 µg/mg after 1 hours and 3.38 ± 1.97 µg/mg
after 2 weeks. Unfortunately, few studies have looked at levels of carboplatin
that can be reached in the choroid or retina with periorbital injection and,
therefore, we have no comparison. To our knowledge, this is the first study
in drug delivery that measures the target tissue level, a value that is perhaps
the most significant of all.
For the in vivo experiments, the injection concentration of carboplatin
was higher in fibrin sealant than in BSS. In an attempt to compare the effectiveness
of the 2 delivery vehicles, the drug levels in the eye were standardized to
a common initial concentration of 10 mg/mL. In this respect, the levels of
carboplatin in sclera unexposed to the injection site were higher from BSS
at 48 hours, while the fibrin sealant achieved a significantly higher level
in the exposed sclera at 48 hours (Table
3). This is likely because carboplatin injected in BSS is free to
disperse around the globe and diffuse into additional nonocular tissues. In
contrast, the fibrin sealant retains the drug in a semisolid medium, which
acts to reduce dispersion and allow drug diffusion through the sclera at the
original injection site. The higher levels of drug found in the untreated
eye are another indication that the BSS was allowing a greater dispersal of
carboplatin. Forster et al17 confirmed an arterial
connection between the 2 internal ophthalmic arteries of the rabbit, which
may have enhanced the transmission of available drug to the untreated eye.
Indeed, significantly higher levels of carboplatin from BSS were found in
every tissue of the contralateral eye for at least 2 of the 3 time points
(Table 3). This artery is absent
in humans, and one would expect less carboplatin to reach the contralateral
eye.
One potential drawback to using fibrin sealant as a local delivery vehicle
for carboplatin is the possibility of reaching levels beyond the toxicity
limit. In the previously mentioned systemic study by Abramson et al,16 higher intraocular concentrations were obtained in
human eyes affected with retinoblastoma than previous unaffected animal models
had predicted. This was attributed to possible disruption of the blood-vitreous
barrier. Because our study was performed using unaffected rabbits, the amount
of carboplatin in the vitreous may reach toxic levels if used to treat humans.
Previous data18 show carboplatin to have a
maximum nontoxic dose of 3 µg when given as an intravitreal injection.
Other data19 confirm retinal toxicity at 10
µg or higher when administered in a similar manner. In our study, using
transscleral delivery, a peak vitreous value of approximately 11.83 µg/mL
was achieved, which is slightly above the threshold shown to be toxic. Preliminary
toxicity data suggest that there is a temporary decline in retinal function
as seen by a transient decrease in electroretinographic amplitude at 2 days
posttreatment.20 More extensive electroretinographic
studies are under way to determine the long-term toxicity level for increasing
concentrations of carboplatin in a fibrin sealant vehicle.
Incorporating carboplatin into fibrin sealant gives a more controlled
drug release in addition to providing a stable medium for the drug to reside.
While the most favorable concentration of carboplatin to use within the sealant
has yet to be determined, the drug can be loaded into this vehicle above its
solubility limit, enabling higher amounts to be achieved in ocular tissues.
With this in mind, the fibrin sealant vehicle may be a superior mode of delivery
for periorbital injections of carboplatin in the treatment of retinoblastoma.
AUTHOR INFORMATION
Submitted for publication September 18, 2001; final revision received
April 1, 2002; accepted April 16, 2002.
This study was supported in part by core grant P30-EY06360 from the
National Institutes of Health, Bethesda, Md; the Knights Templar Eye Foundation,
Inc, Chicago, Ill; the Foundation Fighting Blindness, Owings Mills, Md; and
Research to Prevent Blindness Inc, New York, NY.
We thank Haemacure Corp for donating the fibrin sealant; Brian Sippy,
MD, PhD, for assisting with the histological determination and photography;
and Machelle Pardue, PhD, for performing the electroretinographic studies.
Corresponding author and reprints: Henry F. Edelhauser, PhD, Emory
Eye Center, 1365B Clifton Rd NE, Suite B2600, Atlanta, GA 30322 (e-mail: ophthfe{at}emory.edu).
From the Department of Ophthalmology, Duke University Medical Center,
Durham, NC (Ms Simpson); Emory Eye Center, Atlanta, Ga (Ms Simpson, Messrs
Gilbert and Rudnick, and Drs Geroski, Aaberg, and Edelhauser); and Associated
Retinal Consultants, Grand Rapids and Royal Oak, Mich (Dr Aaberg). The authors
have no proprietary interest in the products or companies described in this
article.
REFERENCES
| |
1. Parkin DM, Stiller CA, Draper GJ, et al. The international incidence of childhood cancer. Int J Cancer. 1988;42:511-520.
ISI
| PUBMED
2. Pendergrass TW, Davis S. Incidence of retinoblastoma in the United States. Arch Ophthalmol. 1980;98:1204-1210.
FREE FULL TEXT
3. Friedman DL, Himelstein B, Shields CL, et al. Chemoreduction and local ophthalmic therapy for intraocular retinoblastoma. J Clin Oncol. 2000;18:12-17.
FREE FULL TEXT
4. Shields CL, Shields JA, Kiratli H, et al. Treatment of retinoblastoma with indirect ophthalmoscope laser photocoagulation. J Pediatr Ophthalmol Strabismus. 1995;32:317-322.
ISI
| PUBMED
5. Shields CL, Shields JA, De Potter P, et al. Plaque radiotherapy in the management of retinoblastoma. Ophthalmology. 1993;100:216-224.
ISI
| PUBMED
6. Brooks HJL, Meyer D, Shields JA, Balas AG, Nelson LB, Fontanesi J. Removal of radiation-induced cataracts in patients treated for retinoblastoma. Arch Ophthalmol. 1990;108:1701-1708.
FREE FULL TEXT
7. Weiss AH, Karr DJ, Kalina RE, et al. Visual outcomes of macular retinoblastoma after external beam radiation
therapy. Ophthalmology. 1994;101:1244-1249.
ISI
| PUBMED
8. Roarty JD, McLean IW, Zimmerman LE. Incidence of second neoplasms in patients with retinoblastoma. Ophthalmology. 1988;95:1583-1587.
ISI
| PUBMED
9. Rudnick DE, Noonan JS, Geroski DH, Prausnitz MR, Edelhauser HF. The effect of intraocular pressure on human and rabbit scleral permeability. Invest Ophthalmol Vis Sci. 1999;40:3054-3058.
FREE FULL TEXT
10. Olsen TW, Edelhauser HF, Lim JI, Geroski DH. Human scleral permeability. Invest Ophthalmol Vis Sci. 1995;36:1893-1903.
FREE FULL TEXT
11. Murray TG, Cicciarelli N, O'Brien JM, et al. Subconjunctival carboplatin therapy and cryotherapy in the treatment
of transgenic murine retinoblastoma. Arch Ophthalmol. 1997;115:1286-1290.
FREE FULL TEXT
12. Abramson SH, Frank CM, Dunkel IJ. A phase I/II study of subconjunctival carboplatin for intraocular retinoblastoma. Ophthalmology. 1999;106:1947-1950.
FULL TEXT
|
ISI
| PUBMED
13. MacPhee MJ, Campagna A, Best A, Kidd R, Drohan W. Fibrin sealant as a delivery vehicle for sustained and controlled release
of chemotherapy agents. In: Sierra D, Saltz R, eds. Surgical Adhesives
and Sealants: Current Technology and Applications. Lancaster, Pa: Technomic
Publishing; 1996:145-153.
14. Madden T, Sunderland M, Santana VM. The pharmacokinetics of carboplatin in pediatric patients with cancer. Clin Pharmacol Ther. 1992;51:701-707.
ISI
| PUBMED
15. Mendelsohn ME, Abramson DH, Madden T, Tong W, Tran HT, Dunkel IJ. Intraocular concentrations of chemotherapeutic agents after systemic
or local administration. Arch Ophthalmol. 1998;116:1209-1212.
FREE FULL TEXT
16. Abramson DH, Frank CM, Chantada GL, et al. Intraocular carboplatin concentrations following intravenous administration
for human intraocular retinoblastoma. Ophthalmic Genet. 1999;20:31-36.
FULL TEXT
| PUBMED
17. Forster S, Mead A, Sears M. An interophthalmic communicating artery as explanation for consensual
irritative response of the rabbit eye. Invest Ophthalmol Vis Sci. 1979;18:161-165.
FREE FULL TEXT
18. Zlioba A, Peyman GA, Nikoleit J. Retinal toxicity study of intravitreal carboplatin and iproplatin. Ann Ophthalmol. 1988;20:71-72.
ISI
| PUBMED
19. Harbour JW, Murray TG, Hamasaki D, et al. Local carboplatin therapy in transgenic murine retinoblastoma. Invest Ophthalmol Vis Sci. 1996;37:1892-1898.
FREE FULL TEXT
20. Gilbert JA, Hejny C, Pardue MT, et al. Electroretinogram effects of sustained transscleral drug delivery of
carboplatin from fibrin sealant [ARVO abstract]. Available at: http://www.arvo.org. Accessibility verified
June 5, 2002.
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati  Twitter
What's this?
THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES
|
Human Transscleral Albumin Permeability and the Effect of Topographical Location and Donor Age
Anderson et al.
IOVS 2008;49:4041-4045.
ABSTRACT
| FULL TEXT
Subconjunctival Topotecan in Fibrin Sealant in the Treatment of Transgenic Murine Retinoblastoma
Tsui et al.
IOVS 2008;49:490-496.
ABSTRACT
| FULL TEXT
Topotecan Vitreous Levels after Periocular or Intravenous Delivery in Rabbits: An Alternative for Retinoblastoma Chemotherapy
Carcaboso et al.
IOVS 2007;48:3761-3767.
ABSTRACT
| FULL TEXT
Pharmacokinetics of Intraocular Drug Delivery by Periocular Injections Using Ocular Fluorophotometry
Ghate et al.
IOVS 2007;48:2230-2237.
ABSTRACT
| FULL TEXT
Bovine and Porcine Transscleral Solute Transport: Influence of Lipophilicity and the Choroid-Bruch's Layer.
Cheruvu and Kompella
IOVS 2006;47:4513-4522.
ABSTRACT
| FULL TEXT
Topotecan Combination Chemotherapy in Two New Rodent Models of Retinoblastoma
Laurie et al.
Clin. Cancer Res. 2005;11:7569-7578.
ABSTRACT
| FULL TEXT
CAI Is a Potent Inhibitor of Neovascularization and Imparts Neuroprotection in a Mouse Model of Ischemic Retinopathy
Franklin et al.
IOVS 2004;45:3756-3766.
ABSTRACT
| FULL TEXT
Subconjunctival Nano- and Microparticles Sustain Retinal Delivery of Budesonide, a Corticosteroid Capable of Inhibiting VEGF Expression
Kompella et al.
IOVS 2003;44:1192-1201.
ABSTRACT
| FULL TEXT
|
