Download Regional ocular gentamicin levels after transcorneal and

Investigative Ophthalmology & Visual Science, Vol. 31, No. 5, May 1990
Copyright © Association for Research in Vision and Ophthalmology
Regional Ocular Gentamicin Levels after Transcorneal
and Transscleral Iontophoresis
Robyn E. Grossman, Douglas F. Chu, and David A. Lee
Transcorneal and transscleral iontophoresis were compared to subconjunctival injection (control) in
the delivery of gentamicin into rabbit eyes. Gentamicin levels in the cornea, aqueous, and vitreous were
measured by a fluorescence polarization assay at various time intervals after treatment. A mean peak
corneal concentration of 376.1 Mg/ml was achieved 2 hr after transcorneal iontophoresis. This was
significantly higher than the level obtained in control eyes (P = 0.016). A mean peak aqueous humor
concentration of 54.8 Mg/m' occurred 2 hr after transcorneal iontophoresis. This was significantly
higher than the peak level of 14.2 Mg/ml after subconjunctival injection (P = 0.003). Inhibitory levels
(approximately 5 Mg/ml) were maintained in both aqueous and cornea for 8 hr after transcorneal
iontophoresis. After transscleral iontophoresis, the mean peak vitreous humor concentration was 53.4
Mg/ml at 16 hr and remained inhibitory through 24 hr; the peak aqueous level was 23.2 Mg/ml and
remained inhibitory for 24 hr. Peak drug concentrations in the vitreous were significantly higher than
control (P = 0.026). Therapeutic vitreous humor levels were not achievable after transcorneal iontophoresis or subconjunctival injection. Potential corneal toxicity of transcorneal iontophoresis was
demonstrated by measuring corneal thickness and endothelial cell counts prior to and 3 days after
transcorneal iontophoresis of gentamicin and balanced saline solution (BSS) (control). No significant
differences existed between eyes treated with gentamicin compared to those treated with BSS or when
pre- versus postiontophoresis of gentamicin in the same eyes were compared. Transcorneal and
transscleral iontophoresis may be an effective noninvasive method of delivering inhibitory levels of
gentamicin to the cornea, aqueous humor, and vitreous for the treatment of intraocular infections.
Invest Ophthalmol Vis Sci 31:909-916,1990
Iontophoresis is a technique of introducing drugs
in the form of ions into tissues noninvasively, by the
means of an electric current.1 This technique has
been used in several areas of medicine—for example,
in the administration of local anesthesia for myringectomy,2 as a means of inducing localized sweating
with pilocarpine for diagnostic sweat testing in patients suspected of having cystic fibrosis,3 and in the
administration of vidarabine monophosphate to patients with herpes orolabialis.4 In dentistry, fluoride
has been iontophoresed in patients with hypersensitive dentin.5 Iontophoresis has several potential applications in ophthalmology, namely in achieving inhibitory levels of drugs in the eye for the treatment of
bacterial endophthalmitis and keratitis. To date, var-
ious researchers have used a myriad of methods to
achieve inhibitory levels of drugs in the cornea,
aqueous, and vitreous humor of the eye. Subconjunctival, retrobulbar, intravenous, and intramuscular injections along with topical application all have
been tried,6"10 but most do not achieve adequate drug
levels and involve other complications as well.
Iontophoresis has been studied as a noninvasive
method of solving some of these difficulties in achieving inhibitory levels of drugs in ocular tissues. Among
the drugs that deserve attention is the aminoglycoside
gentamicin, which has two positive charges per molecule at physiologic pH and a molecular weight of
approximately 430; is lipid insoluble; and is effective
against a wide variety of pathogenic gram-negative
and gram-positive bacteria.""13 Previous gentamicin
studies involving Pseudomonas have determined the
mean inhibitory concentration to be 3.13 /u,g/ml14;
another study showed that 94% of 1142 isolates were
sensitive to 10 Mg/ml or less.9 In addition, gentamicin
concentrations of 5 yug/ml or less inhibit over 90% of
strains of Proteus rettgeri, P. vulgaris, and P. marganii,i5 whereas 99% of Staphylococcus strains are
sensitive to 5 /xg/ml or less.16 Gentamicin is toxic at
levels above 285 /tg/ml.17 Because of gentamicin's
From the Jules Stein Eye Institute, Department of Ophthalmology, University of California—Los Angeles School of Medicine,
Los Angeles, California.
Supported by Karl Kirchgessner Foundation, Lucille Ellis Simon
Research Fund, Elsie B. Ballantyne Research Fund, Research to
Prevent Blindness, and National Eye Institute grant EY-07701.
Submitted for publication: January 5, 1989; accepted September
13, 1989.
Reprint requests: David A. Lee, MD, Jules Stein Eye Institute,
Room 2-118, 800 Westwood Plaza, Los Angeles, CA 90024-1771.
909
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910
INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE / May 1990
polar nature, small molecular weight, and lipid insolubility, it is well suited for use in iontophoresis.
Transcorneal and transscleral iontophoresis each
have potential uses in the treatment of disorders involving different areas of the eye. Investigators have
been able rapidly to achieve high levels of drug in the
cornea and aqueous humor after transcorneal iontophoresis.1418"20 Others have been able to achieve high
levels of drug in the aqueous and vitreous humor
after transscleral iontophoresis.21"26 The purpose of
the current study is to compare transcorneal and
transscleral iontophoresis to each other and to subconjunctival injection in achieving regional ocular
gentamicin concentrations at various time intervals
after treatment.
Materials and Methods
Gentamicin sulfate powder (Sigma, St. Louis, MO)
was combined with 2% agar to form a concentration
of 100 mg/ml as follows: 0.2 g agar (Sigma) was dissolved in 7.0 ml of distilled water heated to near-boiling. The mixture was allowed to cool to approximately 50°C, and 1.0 g gentamicin sulfate powder
was added. Enough distilled water was then added to
this mixture to make a total volume of 10.0 ml. The
caps were removed from 0.25 ml microcentrifuge
tubes (Fisher Scientific, Pittsburgh, PA), and these
tubes were filled with the mixture from the bottom to
within 0.25 inch from the top, with care to avoid air
bubbles. The tubes were then recapped, dated, and
refrigerated at 20°C.
When ready to use, the distal end of the microcentrifuge tube was cut off with a razor blade. A fresh
tube was used for each eye. The internal diameter of
the end of the tube was approximately 3 mm. The
agar was then extruded approximately 2 mm by inserting the tube firmly onto a tuberculin syringe. The
anode of the iontophoresis device was then inserted
through the syringe into the agar. The device was
grounded by attaching the other electrode by means
of an alligator clip to the shaven ear contralateral to
the eye receiving iontophoresis.
Healthy adult pigmented rabbits weighing 2-3 kg
were used in this study. The study conformed to the
ARVO Resolution on the Use of Animals in Research. Immediately before iontophoresis the animals
were anesthetized with intramuscular ketamine HC1
60 mg/kg (Parke Davis, Morris Plains, NJ) and intramuscular Xylazine 12 mg/kg (Mobay, Shawnee, KS).
The eyes were then proptosed with a lid speculum.
For transcorneal iontophoresis, the agar-gentamicin electrode was applied to the central cornea of one
eye with a current of 0.2 mA for 10 min. The iontophoresis device used was based on a design by Brubaker.27 At the end of this period of time, the eye was
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Vol. 31
irrigated with balanced salt solution (BSS; Alcon,
Fort Worth, TX) to remove any residual drug from
the ocular surface. The fellow eye received a 20-mg
subconjunctival injection of gentamicin sulfate (0.5
ml of 40 mg/ml; Elkin-Sinn, Cherry Hill, NJ). At 0.5,
1, 2, 4, 8, and 16 hr after transcorneal iontophoresis
and subconjunctival injection, aqueous humor, vitreous humor, and corneal samples were taken in respective order.
The aqueous humor was removed by paracentesis
using a 25-gauge needle attached to a 3-cc syringe.
The needle was inserted through the peripheral clear
cornea into the anterior chamber, with care to avoid
damaging the iris, lens, or cornea. Approximately 150
ix\ aqueous humor was aspirated. The vitreous humor
was removed by inserting an 18-gauge needle through
the pars plana 2-3 mm posterior to the limbus into
the center of the vitreous cavity, and 0.5-1.0 ml vitreous was aspirated. To further liquefy the vitreous
humor, it was expressed through a 25-gauge needle
into a microcentrifuge tube. The corneal samples
were obtained by trephining the cornea with an 8.5mm diameter trephine and then excising the central
cornea with scissors. Once removed, the cornea button was rinsed with 5 drops of BSS (0.33 ml) and
frozen on dry ice until prepared for assay. At that
time the corneas were thawed and placed individually
on a clean glass microscope slide. With a straightedged razor, the corneas were minced into very fine
pieces and put into preweighed microcentrifuge
tubes. The mincing and transfer process took approximately 30 sec per cornea. After reweighing the tubes
to determine the weight of the mass of the cornea
tissue, the tubes were agitated in a Vortex mixer for
10 sec. This ensured that no pieces of cornea were
adherent to the sides of the tubes. To each tube, 0.5
ml 0.01 M phosphate buffered saline was added. The
tubes were allowed to incubate for 18 hr in a water
bath heated to 37 °C and shaking at 100 oscillations/
min. The tubes were then centrifuged for 10 min at
2000 rpm. The supernatant was pipetted and placed
into separate microcentrifuge tubes. All samples were
stored on dry ice before assaying. The concentration
of gentamicin in the cornea was derived with the following formula:
(cone gentamicin in cornea)
_ (cornea wt + buffer vol)
(cornea wt)
X (cone gentamicin in buffer)
Drug concentrations are expressed in micrograms per
gram tissue or micrograms per milliliter buffer.
Buffer volume is expressed in milliliters, and cornea
weight in grams.28
IONTOPHORESIS OF GENTAMICIN / Grossman er al
No. 5
911
rabbits both before and 3 days after iontophoresis.
One eye of each rabbit had transcorneal iontophoresis of gentamicin as described above. The fellow eye
was used as a control and received transcorneal iontophoresis of BSS under the same conditions. As
measures of corneal toxicity, two variables were calculated: increase in corneal thickness and decrease in
endothelial cell count. A comparison was made for
the two variables between the eyes treated with BSS
and those treated with gentamicin; in addition, values
after iontophoresis were compared to the values before iontophoresis for both groups of eyes.
Data analysis included gentamicin levels in
aqueous, vitreous, and cornea in transcorneal iontophoresis compared to subconjunctival injection, and
in transscleral iontophoresis compared to subconjunctival injection. A Wilcoxon rank sum test was
used with the accepted level of significance at P
< 0.05. For the toxicity studies, the analysis of variance (ANOVA) test was used to determine if there
was a difference between the corneas treated with
gentamicin and those treated with BSS, as well as to
compare preiontophoresis versus postiontophoresis
values.
Transscleral iontophoresis was performed with a
new device which was similar to the device used for
transcorneal iontophoresis but which could deliver
higher adjustable current levels. Transscleral iontophoresis with this device was performed in a manner
similar to transcorneal iontophoresis, except that the
current was adjusted to deliver 2.0 mA (28.2
mA/cm2) for 10 min, and the electrode was placed
2-3 mm posterior to the limbus over the pars plana
area of the sclera. The fellow eye received a 20-mg
subconjunctival injection of gentamicin sulfate as
described above. At 0.5, 1, 2, 4, 8, 16, 24, and 36 hr
after transscleral iontophoresis and subconjunctival
injection, aqueous humor and vitreous humor samples were removed as described above.
All aqueous humor, vitreous humor, and cornea
samples were assayed for gentamicin levels by the
University of California—Los Angeles Toxicology
Laboratory using a fluorescence polarization assay
(TDx System Analyzer; Abbott Laboratories Diagnostic Division, Irving, TX). In addition, the gentamicin-agar mixture was assayed in order to ensure
that the drug had not been inactivated during the
heating process which incorporated gentamicin into
the liquid agar.
The potentially toxic effects of transcorneal iontophoresis on the cornea were monitored by measuring
corneal thickness and endothelial cell counts with a
Heyer Schulte specular microscope (Model HS-CEM
3; Coopervision, Irvine, CA), with Kodak Tri-X
black and white film (ASA-400). The endothelial cell
count for each eye was the average of at least three
separate counts in central corneal areas of 0.02 mm2.
These measurements were made in both eyes of six
Results
Table 1 summarizes the mean gentamicin levels in
the vitreous and aqueous after transscleral iontophoresis, and in the vitreous, aqueous and cornea
after both transcorneal iontophoresis and subconjunctival injection.
The peak gentamicin level in the cornea after
transcorneal iontophoresis was 376.1 jug/ml, achieved
2.0 hr after treatment. This was significantly higher
Table 1. Regional gentamicin concentrations after iontophoresis and subconjunctival injection
Hr
Region
Treatment
Aqueous subconj.
humor
injection
transcorneal
iontophoresis
transscleral
iontophoresis
Cornea
0.5
1
2
4
8
16
24
8.2 ± 5.3
(10)
32.0 ± 5.4*
(10)
20.8 ± 12.7*
12.4 ± 6.0
(15)
41.8 ± 10.3*
(12)
18.7 ± 8.8
14.2 + 4.5
(5)
54.8 + 21.7*
2.0 ± 0.9
0.2 ± 0.1
—
(10)
4.7 ± 1.4*
(5)
8.9 ± 4.6*
(6)
0.4 ± 0.2
—
23.2 ± 14.3
8.1 ± 4.5
(14)
21.9 ± 6.0*
(8)
7.9 ± 4.3
(8)
(8)
(7)
(6)
(5)
(4)
5.9 ± 3.3
(4)
—
—
0.0 ± 0.0
(4)
—
—
—
(9)
20.8 + 10.2 15.9 ± 7.2
subconj.
84.7 ±31.8
71.8 ± 63.5
injection
(4)
(4)
(4)
(3)
transcorneal
323.8 ± 84.3* 283.0 ± 185.6* 376.1 ± 206.7* 48.1 ± 10.7
iontophoresis
(6)
(9)
(4)
(6)
Vitreous subconj.
humor
injection
transcorneal
iontophoresis
transscleral
iontophoresis
2.6 ± 2.5
(6)
0.5 ± 0.5
(4)
6.8 ± 2.9*
(6)
2.2 ±
3.8
(6)
0.4 ±
0.2
(4)
8.3 ±
8.6*
0.8 +
0.3
(4)
0.3 +
0.2
(3)
12.7 +
(6)
All drug concentrations given in ng/m\; mean ± standard deviation. Number in parentheses is n.
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(6)
0.4 ± 0.6
(6)
0.4 ± 0.2
(4)
(2)
7.5 ± 4.9*
8.0 ± 4.5
(3)
11.6 ± 2.7
(4)
0.4 ± 0.3
(6)
0.2 ± 0.1
(3)
9.2* 25.3 ± 17.5* 37.5 ± 18.7* 53.4 ±35.4* 46.4 ±12.6*
(4)
(3)
(5)
(3)
* Iontophoresis drug level is significantly higher than control (subconjunctival) level, P < 0.05.
912
INVESTIGATIVE OPHTHALMOLOGY b VISUAL SCIENCE / May 1990
than the mean level of 20.8 Mg/ml, achieved in control eyes at 2.0 hr after a subconjunctival injection of
gentamicin (P = 0.016). Mean corneal concentrations after transcorneal iontophoresis were significantly higher (P < 0.05) at 0.5, 1, and 2 hr than those
in control eyes (Fig. 1). Gentamicin levels in the cornea remained inhibitory through 8 hr after both
transcorneal iontophoresis and subconjunctival injection.
The peak gentamicin concentration in the aqueous
humor was 54.8 ^g/ml 2 hr after transcorneal iontophoresis, which was almost four times higher than the
peak level of 14.2 /ig/ml achieved in control eyes.
Aqueous humor levels after transcorneal iontophoresis were significantly higher than levels in control eyes
for all time intervals measured except 16 hr (Fig. 2).
Significant differences between aqueous humor levels
after transscleral iontophoresis and control eyes existed only 0.5, 8 and 16 hr after treatment (P = 0.018,
P = 0.003, and P = 0.013, respectively). After transscleral iontophoresis, however, the aqueous humor
levels were still within inhibitory range at 24 hr.
Transscleral iontophoresis resulted in very high
concentrations of gentamicin in the vitreous humor,
Vol. 31
and inhibitory levels were achieved as early as 0.5 hr
after treatment (Fig. 3). The levels continued to rise
steadily, reaching a peak of 53.4 jig/ml at 16 hr, and
remained inhibitory through 24 hr. At 36 hr no drug
could be detected in the vitreous humor. Peak vitreous levels after transscleral iontophoresis were over
20 times higher than the peak level achieved by subconjunctival injection. Transscleral iontophoresis
was shown to achieve significantly higher values (P
< 0.05) than subconjunctival injection at all measured time intervals. (Gentamicin levels were assumed to be undetectable in the vitreous 24 hr after
subconjunctival injection.) Inhibitory vitreous
humor levels were never achieved after transcorneal
iontophoresis or subconjunctival injection, and there
was no significant difference between these two
methods at any time interval.
In assessing potential toxicity to the cornea, we
found that after iontophoresis the mean increase in
corneal thickness from pretreatment values (0.320.35 mm) was not significantly different from zero for
either the control eyes (-0.007 mm) or the gentamicin eyes (0.012 mm). The mean decrease in corneal
cell count after treatment was actually larger for the
400 -i
a
FOLLOWING TRANSCORNEAL IONTOPHORESIS
•—
FOLLOWING SUBCONJUNCTIVAL INJECTION
300 O
_
Fig. 1. Gentamicin concentration in cornea after
transcorneal iontophoresis
and subconjunctival injection.
200 -
100-
HOURS POST IONTOPHORESIS
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IONTOPHORESIS OF GENTAMICIN / Grossman er ol
No. 5
Q
FOLLOWING TRANSCORNEAL IONTOPHORESIS
•—
FOLLOWING SUBCONJUNCTIVAL INJECTION
---»--
oc
Fig. 2. Gentamicin concentration in aqueous after
transcorneal iontophoresis,
transscleral iontophoresis,
and subconjunctival injection.
LJJ
LJJ
(/)
s
FOLLOWING TRANSSCLERAL IONTOPHORESIS
2
H
o
z
o
u
_
o
913
•H
C
a
a>
E
• •*
E
o>
30
10
40
HOURS POST IONTOPHORESIS
o—
FOLLOWING TRANSSCLERAL IONTOPHORESIS
•—
FOLLOWING SUBCONJUNCTIVAL INJECTION
---m-—
Fig. 3. Gentamicin concentration in vitreous after
transcorneal iontophoresis,
transscleral iontophoresis,
and subconjunctival injection.
HOURS POST IONTOPHORESIS
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FOLLOWING TRANSCORNEAL IONTOPHORESIS
914
Vol. 31
INVESTIGATIVE OPHTHALMOLOGY 6 VISUAL SCIENCE / May 1990
control eyes (317.0 cells/mm2) than for the gentamicin eyes (281 cells/mm2). The decrease in cell count
was significantly different from zero for the control
group but not for the gentamicin group.
When analyzed to see if there was a difference between the eyes treated with gentamicin and those
treated with BSS, we found that neither the mean
increase in corneal thickness (P = 0.18) nor the decrease in corneal cell count (P = 0.81) were significantly different between the two groups.
Is!
Discussion
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These experiments show that transcorneal iontophoresis may be a safe and effective means of achieving inhibitory concentrations of gentamicin in the
aqueous humor and cornea. These results are consistent with a previous study in which inhibitory levels
of gentamicin were obtained in the cornea and
aqueous humor after transcorneal iontophoresis.14
The gentamicin concentrations in the cornea and
aqueous after transcorneal iontophoresis were also
strikingly higher than those reported by Insler et al
after topical and systemic administration.9 Corneal
concentrations at approximately 1 hr after administration can easily be compared as follows: 283.0
/zg/ml after transcorneal iontophoresis, 71.8 /xg/ml
after subconjunctival injection, 16.2 ^ig/g after topical
administration (3 drops of 13.6 mg/ml), and 6.1 ^g/g
after intramuscular injection (four injections of 1
mg/kg each).9 Aqueous humor concentrations, in respective order, are: 41.8 /ig/ml, 12.4 /xg/ml, 0.3
jug/ml, and 0.4 /ug/ml.9 Transcorneal iontophoresis is
not, however, an effective means of achieving therapeutic drug concentrations in the vitreous humor in
the phakic rabbits used in our study. It has been
shown that inhibitory drug levels can be obtained in
the vitreous humor after transcorneal iontophoresis
in aphakic rabbits because of the absence of the lensiris barrier.14
Transscleral iontophoresis was attempted with our
original device designed by Brubaker,27 but we were
unable to achieve inhibitory concentrations of drug
in the vitreous humor because the current (0.2 mA)
was insufficient. A review of previous research using
transscleral iontophoresis of gentamicin showed successful experiments using a current density of
63.7-765 mA/cm2 (Table 2). Table 2 summarizes the
known literature of iontophoresis of gentamicin and
compares the relationships between current level,
current density, duration of iontophoresis, and iontophoresis location to regional drug concentrations.
Our original device could deliver a maximum current
density of only 2.82 mA/cm2. To solve this problem,
we designed a new iontophoresis device in which
O
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73
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No. 5
915
IONTOPHORESIS OF GENTAMICIN / Grossman er al
current density could be increased to 28.2 mA/cm2.
The new device proved quite effective in delivering
sufficient drug concentrations for our study and was
later confirmed effective in studies by Choi and Lee25
and Grossman and Lee.26
Our modified iontophoresis device differed from
those used in previous studies21'24 in that we made use
of a probefilledwith the drug solution rather than an
eyecup. Previous authors made use of the eyecup held
under negative pressure in order to prevent a buildup of bubbles, to prevent leakage of the drug solution,
and to keep the iontophoresis solution firmly adhered
to the eye. The agar-gentamicin mixture proved to be
quite useful in preventing any of the solution from
dripping out of the microcentrifuge tube during the
iontophoresis, and also prevented bubble formation.
In addition, we believed that firmly holding the probe
against the eye would provide adequate contact. Further studies25'26 successfully made use of the modified
iontophoresis box using a nonagar-based drug solution, and thus found it to be effective with liquids as
well. Our technique may be easier to use and more
convenient than previous iontophoresis techniques.
From our studies on corneal toxicity of gentamicin
when delivered by iontophoresis, we found no significant difference between changes in corneal thickness
and endothelial cell counts in eyes treated with gentamicin and eyes treated with BSS. However, in four
of six corneas treated with gentamicin, there were
mild corneal opacities, which were not present in any
of the six eyes treated with BSS. This suggests that the
opacities were due to the gentamicin rather than to
the electric current. Other investigators who have extensively studied potential corneal damage by electric
current maintain that current densities of up to 20
mA/cm2 are safe in rabbits. The current used for
transcorneal iontophoresis in our study was 2.82
mA/cm2 and was therefore well below the toxic
level.18
We were not as concerned about damage caused to
the retina by the current in eyes receiving transscleral
iontophoresis because the electrode was applied over
the pars plana, an area which is not critical for vision.
In addition, it has been shown that the procedure is
well tolerated using a much higher current density.23
In conclusion, iontophoresis is an effective and
noninvasive means of delivering inhibitory concentrations of gentamicin to various portions of the eye.
High corneal and aqueous humor levels are achieved
rapidly after transcorneal iontophoresis, and this
technique may have useful applications in the treatment of bacterial keratitis. Therapeutic and sustained
vitreous humor levels are best achieved with transscleral iontophoresis. This technique shows promise
as either a primary treatment or as an adjunct to
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intravitreal injection for the treatment of bacterial
endophthalmitis.
Key words: gentamicin, iontophoresis, subconjunctival injection, transcorneal, transscleral
Acknowledgments
The authors wish to thank members of the University of
California—Los Angeles (UCLA) Toxicology Laboratory
for their help in performing assays. The authors also wish to
thank Noel Wheeler and Susan Ingalls of the UCLA Department of Biostatistics for their expertise in performing
statistical analysis.
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