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Enhanced Disruption of the Blood-Aqueous Barrier and the Incidence of Angiographic Cystoid Macular Edema by Topical Timolol and Its Preservative in Early Postoperative Pseudophakia
Kensaku Miyake, MD;
Ichiro Ota, MD;
Nobuhiro Ibaraki, MD, PhD;
Junsuke Akura, MD;
Satomi Ichihashi, MD;
Yuko Shibuya, MD;
Kumiko Maekubo, MD;
Sampei Miyake, MD
Arch Ophthalmol. 2001;119:387-394.
ABSTRACT
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Objective To investigate the effects of timolol maleate with preservative and
its preserved (PV) and nonpreserved vehicles (NPV) (benzalkonium chloride)
on the blood-aqueous barrier and angiographic cystoid macular edema (CME)
in early postoperative pseudophakia.
Patients and Methods Patients with ocular hypertension, normal tension glaucoma, and primary
open-angle glaucoma who underwent surgery for cataracts. The study included
a double-masked trial for timolol, PV, and NPV and a single-masked trial on
the effect of diclofenac sodium and fluorometholone acetate on all three.
The patients were divided into 6 groups, each of which were simultaneously
administered the following different combinations of compounds: timolol and
diclofenac (group A), timolol and fluorometholone (group B), PV and diclofenac
(group C), PV and fluorometholone (group D), NPV and diclofenac (group E),
and NPV and fluorometholone (group F). The 6 groups were then compared using
a laser flare cell meter to determine the degree of disruption of the blood-aqueous
barrier and fluorescein angiography to investigate angiographic CME. The differences
in mean daily fluctuations in intraocular pressure were compared on the preoperative
baseline day and for 5 weeks postoperatively. Twice daily administration of
0.5% timolol maleate or the vehicles was started 2 days before surgery, and
continued until 5 weeks after surgery. Diclofenac or fluorometholone drops
were instilled in the eyes 4 times preoperatively, on the day of surgery,
and 3 times daily for 5 weeks postoperatively.
Results The flare amount was higher on the third and seventh days in group B
than in group D, but was the same after the seventh day. The incidence of
angiographic CME was the same between both groups. These 2 factors were significantly
lower in group F. These 2 factors were also significantly lower in the 3 groups
that received diclofenac instead of fluorometholone, with no difference among
these groups. The intraocular pressure decline was significant in groups that
received timolol compared with groups that received PV or NPV.
Conclusions Timolol and its preservative, benzalkonium chloride, cause disruption
of the blood-aqueous barrier in early postoperative pseudophakia and increased
incidence of angiographic CME. The concurrent administration of nonsteroidal
anti-inflammatory drug such as diclofenac prevents these adverse effects without
interfering with the drop in intraocular pressure caused by timolol. The addition
of benzalkonium chloride to timolol contributes considerably to these adverse
effects.
Clinical Relevance The present results suggest the cause of similar complications produced
by other antiglaucoma eyedrops containing similar preservatives.
INTRODUCTION
THE REPORTS have indicated that, especially with their long-term administration,
topical antiglaucoma drugs cause inflammatory changes in the ocular surface,
ie, conjunctiva or Tenon capsule,1-5
and that their intraocular adverse effects, mainly in aphakias, include angiographic
cystoid macular edema (CME) or inflammatory disruption of the blood-aqueous
barrier.6-12
The recently developed drug latanoprost also has been reported to have these
intraocular adverse effects in pseudophakia.9-12
It remains unclear whether the cause is the main constituents of the drugs
or the preservative.
The most frequently used antiglaucoma drug thus far is timolol maleate,
use of which has shown a vast improvement of the ocular and systemic adverse
effects seen with the initial use of  -blockers.13-15
Timolol is a superior drug that does not affect pupil diameter or accommodation,
as did earlier antiglaucoma drugs,16 and it
has almost no adverse effects, such as burning or conjunctival hyperemia,
with short-term use. However, there have been a few reports of ocular toxic
effects attributed to long-term continuous use of timolol. These include ocular
cicatricial pemphigoid,17-18 conjunctival
hyperemia and burning accompanying superficial punctate keratitis, decreased
corneal sensation, and damage to the tear-film mucus layer.19-24
All antiglaucoma drugs contain preservatives. Timolol contains benzalkonium
chloride, the preservative most widely used in eyedrops. It is not known whether
the adverse effects of timolol are due to the agent, the preservative, or
both. Benzalkonium chloride has toxic effects on the cornea and conjunctiva
surface,25-26 and the main focus
of in vivo and in vitro research has been on the cytotoxic effects to the
corneal tissues.27-30
Little research has been performed to compare the effects of timolol with
and without added preservatives. The results of the few experimental studies
that have been performed suggest that the preservative contributes more to
the toxic effects or inflammatory changes than does the timolol,5, 31
but this theory has not been investigated in humans.
Other antiglaucoma drugs also contain preservatives, and inflammatory
changes, including the disruption of the blood-aqueous barrier and onset of
CME, have been reported.6-12
The cause of the complications with such drugs, however, remains unknown,
in particular whether they are due to the drug or the preservative.
To investigate the effect of timolol and its preservative on the disruption
of the blood-aqueous barrier as well as on the incidence of angiographic CME
after removal of cataracts and implantation of intraocular lenses, timolol
eyedrops, the vehicle containing benzalkonium chloride (PV), and vehicle not
containing benzalkonium chloride (NPV) were administered as therapy for early
postoperative pseudophakia after cataract surgery. The effects of concurrently
administered steroidal and nonsteroidal eyedrops were also investigated. The
blood-aqueous barrier function and angiographic CME were selected because
they are the most sensitive clinical variables for detecting intraocular inflammatory
changes.
PATIENTS AND METHODS
Patients with ocular hypertension, normal tension glaucoma, and primary
open-angle glaucoma participated in this study to investigate the effects
of (preserved) timolol, PV, and NPV on the disruption of the blood-aqueous
barrier and angiographic CME. The following 3 solutions were used in the study
in a double-masked control trial: 0.5% timolol eyedrops (Timoptol; Banyu Pharmaceutical
Co, Ltd, Osaka, Japan), PV containing benzalkonium chloride (0.1 mg) in 1
mL of sterile phosphate-buffered solution, and the same solution without benzalkonium
chloride (NPV). The 2 vehicles are otherwise identical in regard to pH and
osmolality. The eyedrops of the 2 vehicles used as controls were prepared
specially in our hospital pharmacy. The effects of simultaneously administered
0.5% diclofenac sodium nonsteroidal anti-inflammatory eyedrops (Diclode; Wakamoto
Pharmaceutical Co, Ltd, Tokyo, Japan) and 0.1% fluorometholone acetate steroidal
anti-inflammatory eyedrops (Flumetholone; Santen Pharmaceutical Co, Ltd, Osaka)
were also investigated. The preservative for diclofenac is chlorobutanol,
and that for fluorometholone is benzalkonium chloride (both at dilutions of
0.1 mg/1 mL). Due to the nature of the present study, it would have been better
to use the same preservative for both anti-inflammatory agents. Chlorobutanol,
however, is also not used as a preservative for steroidal eyedrops such as
betamethasone sodium phosphate and dexamethasone sodium phosphate. Moreover,
diclofenac is the most effective nonsteroidal anti-inflammatory eyedrop in
Japan for preventing inflammation after implant surgery. For these reasons,
anti-inflammatory agents with different preservatives were used, and due consideration
must be given to the above when interpreting the results of the present study.
Although the relative strength of fluorometholone is controversial, fluorometholone
has the same anti-inflammatory effect as betamethasone and dexamethasone,32-35 and
was chosen because it does not easily produce steroidal glaucoma. However,
because fluorometholone is a milky white substance, a double-masked trial
was impossble in this part of the study, and we therefore settled on a single-masked
trial.
In all eyes, locally administered antibiotics were injection of gentamicin
sulfate (Gentacin; Schering Plough Pharmaceutical Co, Ltd, Osaka) below the
Tenon capsule and ofloxacin eyedrops (Tarivid, Santen Pharmaceutical Co, Ltd),
which were not preserved. Systemically given antibiotics were also the same
in all eyes, which included intramuscular injection of isepamicin sulfate
(Isepacin; Schering Plough Pharmaceutical Co, Ltd) and oral capsule of cefdimir
(Cefzon; Fujizawa Pharmaceutical Co, Ltd, Osaka).
A total of 180 eyes (180 patients) initially were used in the study,
with 30 each randomly assigned to the following 6 groups: timolol and diclofenac
(group A), timolol and fluorometholone (group B), PV and diclofenac (group
C), PV and fluorometholone (group D), NPV and diclofenac (group E), and NPV
and fluorometholone (group F). The inclusion criteria for these 180 eyes were
that the patient be 40 years or older and have cataract and ocular hypertension,
normal tension glaucoma, or primary open-angle glaucoma. In the 5-week follow-up,
only 1 eye per patient was considered in the study. In addition, only eyes
in which disease had not advanced or eyes without progressive field loss during
preoperative examination are included in the study. The following patients
were excluded: those whose pupillary diameter was less than 4 mm when mydriasis
occurred due to the cataract surgery; those hypersensitive to diclofenac,
fluorometholone, timolol, or fluorescein sodium; those who had undergone previous
eye surgeries; and those with ocular diseases other than glaucoma or cataracts
or any systemic diseases and medications.
This study was approved by the institutional review board at Miyake
Eye Hospital, Nagoya, Japan, and conducted in accordance with the Helsinki
Declaration. Informed consent was obtained in writing from patients participating
in the study after they were given full explanations of the nature of the
study and the fluorescein fundus angiography used.
The surgery in all cases was performed through a 3-mm clear corneal
incision, with no sutures or, when necessary, 1 stitch. Following continuous
curvilinear capsulorrhexis and phacoemulsification, a foldable acrylic intraocular
lens (Acrylsof; Alcon Laboratory, Fort Worth, Tex) was implanted into the
lens capsule. All surgeries were performed by two of us (K.M. or I.O.). Preoperative
glaucoma treatment was discontinued 3 weeks before the start of the study
to wash out the effects of the antiglaucoma medications used. Timolol or vehicle
was given 2 days before the surgery, and administration was continued twice
daily for 5 weeks postoperatively. In addition, fluorometholone acetate or
diclofenac sodium was given 4 times on the day of surgery (7, 3, and 2 hours
and 30 minutes before surgery), and then 3 times per day for 5 weeks after
surgery. Concurrent drugs included systemically or locally administered antibiotics.
Intramuscular injection of isepamicin was performed once on the day
of surgery and continued for 5 days postoperatively. Three oral capsules of
cefdimir were given on the day of surgery and for 4 days postoperatively.
Injection of gentamicin below the Tenon capsule was performed just after the
operation. Ofloxacin eyedrops were given twice a day for 2 days preoperatively
and 3 times a day for 30 days postoperatively.
Clinical examinations were performed and observations were made concerning
patients' background, surgical procedures, visual acuity, intraocular pressure,
amount of anterior chamber flare measured by a laser flare cell meter, and
presence of CME measured by means of fluorescein angiography.
Visual acuity was measured at 1 to 3 days before surgery and on postoperative
days 1, 3, 7, 14, and 35. Baseline intraocular pressure was measured 3 days
before surgery 4 times, at 8 AM, noon, and 4 and 8 PM. The mean fluctuations
in intraocular pressure throughout the day were used for evaluation and compared
with the mean values obtained in the same way at 5 weeks postoperatively.
The degree of disruption of the blood-aqueous barrier was measured using a
laser flare cell meter (FC1000; Kowa Co, Ltd, Tokyo) 4 and 6 days before surgery
and 1 and 3 days and 1, 2, and 5 weeks after surgery.
After measurement of intraocular pressure, fluorescein angiography was
performed to measure angiographic CME formation at 5 weeks postoperatively.
The late phase (15 minutes after intravenous injection of 10% fluorescein
sodium) of fluorescein angiograms was graded by one of us (S.M.) using the
method previously mentioned36 in a double-masked
manner. Briefly, 0° means there is no sign of fluorescein leakage; I°,
slight fluorescein leakage into the cystic space but not sufficient enough
to enclose the entire fovea centralis; II°, complete circular accumulation
of the fluorescein in the cystic space but with a diameter of less than 2.0
mm; and III°, circular accumulation of the fluorescein larger than 2.0
mm in diameter. Figure 1 shows a
representative example of each grade.
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A representative example of each of grades at the late phase (15
minutes after intravenous injection of 10% fluorescein sodium) of fluorescein
angiograms. Rating of fluorescein angiography is explained in the "Patients
and Methods" section. Reproduced with permission from Miyake et al.11
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The age, surgical data, visual acuity, amount of aqueous flare, and
intraocular pressure of the patients in the 6 groups were analyzed using a
1-way analysis of variance. When differences were found among any of these
variables, we used the Tukey test for multiple comparison to determine the
site of difference. The degree of the drop in intraocular pressure in each
group was analyzed using a paired t test. Sex, type
of glaucoma, antiglaucoma medications, and family history of glaucoma were
analyzed using the  2 method. The incidence of angiographic
CME was analyzed using the Fisher exact test. In all tests, the level of significance
was taken to be P<.05. The data are recorded as
mean ± SD, unless otherwise indicated.
RESULTS
There was a posterior capsule rupture in 1 patient in group A, and a
failure of the continuous curvilinear capsulorrhexis in 1 patient in group
E. Several patients were not available for follow-up examinations of the fluorescein
fundus angiography because of health or commitments. Analysis was conducted
with the remaining total of 168 eyes, 28 in group A, 29 in group B, 29 in
group C, 28 in group D, 27 in group E, and 27 in group F. Among these patients
were some who could not be present for all laser flare cell meter and visual
acuity tests because of health or commitments. There was no significant difference
in the incidence of patients being lost to follow-up or dropped from the study
among the 6 groups.
There were no significant differences between patients in the 6 groups
in age, sex, type of glaucoma, medication history, or family history (Table 1). No differences were found among
groups in operation time, nuclear hardness (evaluated by a method described
previously37), ultrasound time, or amount of
intraocular irrigating solution (Table 2). No difference in the change in postoperative visual acuity was
seen (Table 3).
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Table 1. Demographic and Clinical Characteristics*
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Table 3. Corrected Visual Acuity*
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Before surgery, no significant difference was seen in intraocular pressure
among the 6 groups. In a comparison between the baseline of preoperative diurnal
intraocular pressure and intraocular pressure at 5 weeks, there was a significant
drop at 5 weeks in patients of all 6 groups (P<.001
in groups A and B; P<.01 in groups C-F). Moreover,
at 5 weeks there was a significantly larger decrease in intraocular pressure
in groups A and B, which were administered timolol, compared with groups C,
D, E, and F, in which both types of vehicle were used (P<.05). However, at 5 weeks, there were no significant differences
in intraocular pressure between groups A and B or between groups C, D, E,
and F (Table 4).
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Table 4. Reduction of Intraocular Pressure*
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The incidence of angiographic CME 5 weeks after surgery in the groups
that received fluorometholone eyedrops (groups B, D, and F), was significantly
higher (P<.01) than in the groups that received
diclofenac (groups A, C, and E) (Table 5). The incidence was also significantly higher (P<.01) in groups B and D than in group F. However, no significant
differences were noted between groups A, C, and E, all receiving diclofenac.
There was also no significant difference in incidence between groups B and
D.
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Table 5. Incidence of Angiographic Cystoid Macular Edema (CME)*
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No differences in aqueous flare were found among any of the 6 groups
before surgery or 1 day after surgery (Table 6). Group B had a significantly higher amount of aqueous flare
than group A on postoperative day 3 and at postoperative weeks 1, 2, and 5.
Similarly, groups D and F had significantly greater amounts of aqueous flare
on postoperative day 3 and postoperative weeks 1 and 2 than groups C and E
(P<.05 in all cases). Throughout the study period,
there was no significant difference in amount of aqueous flare between group
A and groups receiving vehicle with diclofenac (groups C and E). However,
among groups receiving fluorometholone, the amount of flare was significantly
higher in group B than in group D on postoperative day 3 and 1 week (P<.05). Similarly, group B had a significantly higher
amount of flare than group F on postoperative day 3 and weeks 1 and 2 (P<.05).
Finally, in comparing groups receiving vehicle and fluorometholone,
group D had a significantly higher flare value than group F at postoperative
weeks 1 and 2 (P<.05).
In summary, the results showed that the incidence of CME was the same
in the eyes treated with benzalkonium chloride–preserved timolol and
fluorometholone and in the eyes treated with preserved fluorometholone and
PV. Flare was higher on the third and seventh days in the former groups, but
afterward was the same between both groups. These values for NPV and preserved
fluorometholone were significantly lower. If preserved timolol, PV, NPV, and
chlorobutanol-preserved diclofenac are used in place of preserved fluorometholone,
there is no significant difference among the 3 groups in CME and flare. There
was a greater incidence of CME and more flare in the 3 groups receiving fluorometholone
than in any of the other 3 groups receiving diclofenac.
COMMENT
In the present study, we found that benzalkonium chloride–preserved
timolol eyedrops increase disruption of the blood-aqueous barrier in early
postoperative pseudophakia and incidence of CME. The PV of timolol had the
same actions. The difference in the effects of timolol and its PV was that
the latter caused somewhat less disruption to the blood-aqueous barrier, although
their effects on CME incidence were the same. These findings suggest that
the adverse effects of timolol are due, at least in considerable part, to
the preservative used. We also found that the concurrent administration of
nonsteroidal anti-inflammatory eyedrops (diclofenac) can prevent these effects
without adversely affecting the drop in intraocular pressure caused by timolol.
To our knowledge, our present findings are the first to suggest that
benzalkonium chloride might affect the blood-aqueous barrier and onset of
CME in early postoperative pseudophakic eyes. To the best of our knowledge,
there has been no previous report describing preservatives other than benzalkonium
chloride or antiglaucoma medications with such preservatives that produce
these kinds of complications.
The following 2 points are new knowledge and of considerable significance.
First, although numerous reports have described the adverse effects induced
by timolol, including inflammatory changes on the ocular surface such as in
the cornea, conjunctiva, and tear film,1-5,17-24
there are very few studies on intraocular lesions due to timolol; to our knowledge
only a single report5 describes the chronic
inflammatory changes of trabeculae induced by the long-term (mean, 5 years)
administration of antiglaucoma eyedrops, including timolol. This is the first
report on the acute effect. Second, although experimental evidence suggests
that the preservative of timolol participates in these adverse effects,5, 31 this is the first report of a clinical
investigation in humans. We found that although the incidence of CME is the
same with administration of preserved timolol and PV, there is a slight difference
in disruption to the blood-aqueous barrier. It has been suggested from animal
experiments as well that the adverse effects of timolol are rather small.5 Baudouin and associates5
reported no difference in the subconjunctiva infiltration of inflammatory
cells in rats between preserved timolol and PV. Furthermore, using a tissue
culture of human Tenon capsule fibroblasts, Williams and associates31 suggested that, rather than the direct stimulation
of cell proliferation by -blockers, other glaucoma medications and their
preservatives cause cell proliferation due to chronic inflammation. If preservatives
play a major role in the onset of early postoperative inflammatory complications
in pseudophakic eyes, the mechanism for this effect needs to be established.
Recent in vivo and in vitro studies have shown that various chemical
mediators are biosynthesized during the process of proliferation and pseudometaplasia
of lens epithelial cells that have been damaged in surgery.38-39
This process is closely linked to the natural course of early postoperative
inflammatory reactions such as pupillary fibrin formation.40-41
The synthesis of chemical mediators by lens epithelial cells also explains
the significant elevation in the amount of aqueous flare 1 to 2 weeks after
surgery compared with immediately afterward.38-40
In the present study, it was found that the amount of aqueous flare was the
same on postoperative day 1 in all 6 groups receiving different drugs. However,
an increase was seen on postoperative day 3 and at 1 and 2 weeks in the groups
given timolol, PV, or NPV with fluorometholone (groups B, D, and F). Such
an elevation of aqueous flare is enhanced by timolol and its PV.
Long-term administration of timolol eyedrops in humans reportedly induces
the invasion of inflammatory cells below the conjunctiva and Tenon capsule,
as well as inflammatory lesions that can be detected immunohistochemically.5 Any of these effects may be present in healthy experimental
animals or humans, and they take a considerable time.5
However, because the subjects in the present study already had postoperative
inflammation, one might argue that the adverse effects and inflammatory response
would appear sooner. It therefore appears that biosynthesis of inflammatory
mediators is accelerated as a result of the encouragement of lens epithelial
cell proliferation and pseudometaplasia by timolol and its PV, and thus the
disruption of the blood-aqueous barrier is intensified 1 or 2 weeks after
surgery. In other words, timolol and its PV are not direct inflammatory mediators.
If these substances contributed directly to the disruption of the blood-aqueous
barrier, the breakdown should have been greater in the eyes administered timolol
or PV 1 day after surgery. Moreover, concurrent administration of a nonsteroidal
anti-inflammatory agent with timolol or its PV suppressed disruption of the
blood-aqueous barrier to the same extent as administration of a nonsteroidal
anti-inflammatory agent with the NPV. This suggests that prostaglandin E or
other substances synthesized during the process of proliferation and pseudometaplasia
of lens epithelial cells, which is accelerated by timolol or its PV, act as
a direct mediator. This corresponds well to the hypothesis that the appearance
of postoperative inflammation and CME is related to prostaglandin E2 and cytokines biosynthesized due to surgical stimulation.36, 38-44
Administration of glaucoma drugs such as epinephrine bitartrate or latanoprost
into postoperative aphakic or pseudophakic eyes is known to cause disruption
to the blood-aqueous barrier and CME.6-9,11-12
The present findings have suggested a mechanism for these phenomena, ie, the
same preservative, benzalkonium chloride, is used in epinephrine and latanoprost.
It therefore seems plausible that, similar to the present findings, the preservative
rather than the agent in these medications is the main factor triggering the
complications. Miyake and associates11 have
found recently, in a study comparing latanoprost and its NPV, that the use
of latanoprost increases the incidence of CME and the disruption of the blood-aqueous
barrier in early postoperative pseudophakic eyes. Benzalkonium chloride is
also used as a preservative in latanoprost, indicating the possibility that
the contribution of the preservative is larger than that of a substituted
analogue of prostaglandin F2 in the onset of complications.
It has been reported recently that latanoprost increases the recurrence and
severity of uveitis and herpetic keratitis.10, 45
If the present findings indeed show that the preservatives in antiglaucoma
drugs are responsible in large part for the onset of inflammation, then the
suitability of timolol and other antiglaucoma drugs for patients with uveitis
and herpetic keratitis will have to be reconsidered seriously.
It was found that the inflammatory complications that appear with administration
of timolol in patients with early postoperative pseudophakia can be suppressed
with the concurrent administration of a nonsteroidal anti-inflammatory agent.
This has also been shown by Miyake and associates11
to be true with latanoprost. Although this is clinically significant, the
level of postoperative concurrent administration and the critical period for
administration require further investigation. In the 6 groups compared in
this study, no significant difference was found in the changes in postoperative
visual acuity, even when there was angiographic CME. This would suggest that,
clinically, the CME that appeared was not severe enough to affect visual acuity.
The present results, however, indicate that the long-term administration of
timolol in pseudophakic eyes should be undertaken cautiously with patients
who seem to be predisposed to blood-retinal barrier breakdown. In cases in
which timolol must be given, the concurrent administration of nonsteroidal
anti-inflammatory agent is recommended.
Since preservatives added to the agents and the vehicle in the present
study were different, care must be exercised in interpretation. Benzalkonium
chloride at 0.1 mg/1 mL was used for timolol, fluorometholone, and PV. A comparison
of the incidence of CME and the amount of anterior chamber flare in the 3
groups receiving preserved fluorometholone (groups B, D, and F), revealed
a higher value in groups B and D than in group F, but little difference between
groups B and D. These findings suggest that incidence of CME and the amount
of anterior chamber flare increases with the amount of benzalkonium chloride
used, and that the effect of timolol is relatively mild.
In the present study, we have also indicated that the nonsteroidal anti-inflammatory
agent diclofenac suppressed CME and flare in all groups, but the results are
difficult to interpret because chlorobutanol is used as the preservative for
diclofenac, whereas benzalkonium chloride is used for fluorometholone. The
toxic effects of benzalkonium chloride and chlorobutanol against corneal epithelial
cells have been studied in animal experiments, and it has been reported that
the toxic effects of benzalkonium chloride are stronger.46-49
Studies have been performed on the inflammatory effects of benzalkonium chloride,5 but no comparisons have been made between it and chlorobutanol.
The present results can thus be interpreted in 2 ways. One is that diclofenac
has a stronger anti-inflammatory effect than fluorometholone; the other is
that, of the 2 preservatives used, the inflammatory effect of chlorobutanol
was smaller than that of benzalkonium chloride. This defect in the design
of the present study means that, in the future, it will be necessary to compare
anti-inflammatory agents to which the same preservative has been added.
AUTHOR INFORMATION
Accepted for publication August 22, 2000.
Corresponding author and reprints: Kensaku Miyake, MD, Shohzankai
Medical Foundation, Miyake Eye Hospital, 1070-Kami 5, Higashiozone-cho, Kita-ku,
Nagoya, 462-0823, Japan (e-mail: miyake{at}spice.or.jp).
From the Shohzankai Medical Foundation, Miyake Eye Hospital, Nagoya
(Drs Miyake, Ota, Ichihashi, Shibuya, Maekubo, and Miyake), the Department
of Ophthalmology, Chiba Hokuso Hospital, Nippon Medical School, Chiba (Dr
Ibaraki), and Kushimoto Rehabilitation Center, Wakayama (Dr Akura), Japan.
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