JOURNAL OF OCULAR PHARMACOLOGY AND THERAPEUTICS
`Volume 26, Number 3, 2010
`ª Mary Ann Liebert, Inc.
`DOI: 10.1089/jop.2009.0134
`
`Ocular Surface Tolerability of Prostaglandin Analogs
`in Patients with Glaucoma or Ocular Hypertension
`
`Jess T. Whitson,1 William B. Trattler,2 Cynthia Matossian,3 Julia Williams,4 and David A. Hollander 4
`
`Abstract
`
`Purpose: To compare the ocular surface tolerability of latanoprost 0.005% preserved with 0.02% benzalkonium
`chloride (BAK), bimatoprost 0.03% preserved with 0.005% BAK, and travoprost 0.004% preserved with the
`proprietary preservative system sofZia in patients previously treated with latanoprost.
`Methods: This randomized, multicenter, investigator-masked, parallel-group study enrolled patients with open-
`angle glaucoma or ocular hypertension who had been on latanoprost monotherapy for at least 4 weeks. At
`baseline, patients were randomized to receive once-daily bimatoprost (n¼ 35), latanoprost (n¼ 38), or travoprost
`(n¼ 33) monotherapy for 3 months. Follow-up visits were at week 1, month 1, and month 3. The primary
`outcome measure was physician-graded conjunctival hyperemia at month 3. Secondary outcome measures
`included corneal staining with fluorescein and tear breakup time (TBUT).
`Results: There were no significant differences among the treatment groups in conjunctival hyperemia scores,
`corneal staining, or TBUT at the latanoprost-treated baseline or at any follow-up visit. Baseline mean (standard
`error of the mean) values were as follows—conjunctival hyperemia: bimatoprost 0.74 (0.10), latanoprost 0.74
`(0.11), travoprost 0.86 (0.12), P¼ 0.692; corneal staining: bimatoprost 0.59 (0.12), latanoprost 0.70 (0.13), travo-
`prost 0.48 (0.11), P¼ 0.423; TBUT (in seconds): bimatoprost 9.1 (1.0), latanoprost 8.6 (0.8), travoprost 7.9 (0.8),
`P¼ 0.578. Month 3 values were as follows—conjunctival hyperemia: bimatoprost 0.80 (0.12), latanoprost 0.74
`(0.10), travoprost 0.98 (0.13), P¼ 0.340; corneal staining: bimatoprost 0.71 (0.78), latanoprost 0.47 (0.64), travo-
`prost 0.36 (0.62), P¼ 0.110; TBUT (in seconds): bimatoprost 9.7 (5.3), latanoprost 9.2 (5.3), travoprost 9.7 (6.3),
`P¼ 0.909.
`Conclusions: There were no significant differences among bimatoprost (preserved with 0.005% BAK), latano-
`prost (preserved with 0.02% BAK), and travoprost (preserved with sofZia) in objective clinical measures of
`ocular tolerability, including physician-graded hyperemia, corneal staining, and TBUT after 3 months of treat-
`ment. Longer-term studies are needed to further evaluate the ocular surface tolerability of these prostaglandin
`analogs.
`
`Introduction
`
`The prostaglandin analogs (PGAs) latanoprost, bi-
`
`matoprost, and travoprost are commonly used as first-
`line therapy for lowering intraocular pressure (IOP)
`in
`glaucoma and ocular hypertension (OHT). In addition to
`effectively lowering IOP, these medications have a favorable
`safety and tolerability profile and are conveniently dosed
`once daily.1 The most common side effect of topical PGAs is
`conjunctival hyperemia, which is noninflammatory, typically
`transient, and not associated with sequelae.2–4
`
`Each of the PGAs is administered from a multidose bottle
`that contains a preservative to ensure sterility, but the type of
`preservative and its concentration differ among the PGAs.
`Latanoprost 0.005% (Xalatan; Pfizer Inc., New York, NY) and
`bimatoprost 0.03% (Lumigan; Allergan, Inc., Irvine, CA) are
`each preserved with benzalkonium chloride (BAK) at con-
`centrations of 0.02% and 0.005%, respectively, while travoprost
`0.004%, which was introduced in a formulation (Travatan)
`preserved with 0.015% BAK, is now available in a formulation
`(Travatan Z) preserved with the proprietary preservative sys-
`tem sofZia (Alcon Laboratories, Inc., Fort Worth, TX).
`
`1UT Southwestern Medical Center, Dallas, Texas.
`2Center for Excellence in Eye Care, Miami, Florida.
`3Matossian Eye Associates, Ewing, New Jersey.
`4Allergan, Inc., Irvine, California.
`
`287
`
`Exhibit 1091
`ARGENTUM
`IPR2017-01053
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`288
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`WHITSON ET AL.
`
`BAK remains the most commonly used preservative
`in ophthalmic medications because of its broad-spectrum
`bactericidal and bacteriostatic activity, compatibility with
`other formulation components, and activity at physio-
`logical pH.5–7 While corneal
`toxicity secondary to BAK
`has been demonstrated in prior studies in vitro8,9 as well as
`in some rabbit models,7,10–14 these studies may not accurately
`replicate the ocular surface conditions in patients undergoing
`standard treatment. In rabbits, BAK is absorbed into the
`conjunctiva where it may remain for 14 days,15 yet there is no
`evidence for accumulation of BAK in human conjunctiva.
`Although some rabbit models have used once-daily dosing to
`mimic the clinical dosing regimen,13,14 the models do not
`necessarily account for differences in blink rate and ocular
`surface clearance of topical preservatives in human eyes. Si-
`milar deleterious surface effects have not been seen in dogs,16
`and further study is needed to determine the effects of pre-
`servatives in ophthalmic solutions in human eyes.14
`The aim of this study was to compare the ocular surface
`tolerability of latanoprost 0.005% preserved with 0.02% BAK,
`bimatoprost 0.03% preserved with 0.005% BAK, and travo-
`prost 0.004% preserved with sofZia in patients with glau-
`coma or OHT.
`
`Methods
`
`investigator-masked,
`This was a randomized, 3-month,
`parallel-group comparison study carried out at 9 sites. The
`study was approved by an institutional review board at each
`site and adhered to Health Insurance Portability and Ac-
`countability Act regulations and Good Clinical Practice
`guidelines as outlined in the Declaration of Helsinki. All pa-
`tients provided written informed consent. The study was reg-
`istered with the identifier NCT00539526 at www.clinicaltrials
`.gov.
`Patients at least 18 years old with a diagnosis of open-
`angle glaucoma or OHT who had been on bilateral latano-
`prost monotherapy for at least 4 weeks were eligible for the
`study. Patients on latanoprost and 1 adjunctive medication at
`screening were also eligible, but were required to undergo a
`4-week washout of the adjunctive medication before the
`baseline visit. Primary exclusion criteria included uncon-
`trolled systemic disease, use of bimatoprost or travoprost
`within the previous 6 months, required use of ocular medi-
`cations other than the study medications during the study
`(intermittent use of BAK-free artificial tears was permitted),
`corneal scarring, history of refractive surgery, use of contact
`lenses, and punctal plug use. With the intention that the
`study population reflect glaucoma and OHT patients typi-
`cally seen in clinical practice, there was no selection for pa-
`tients with dry eye disease, but patients with dry eye were
`not excluded from the study.
`At the baseline visit, patients were randomized in a 1:1:1
`ratio to monotherapy with bimatoprost 0.03% (Lumigan;
`Allergan, Inc.), latanoprost 0.005% (Xalatan; Pfizer Inc.), or
`travoprost 0.004% with sofZia (Travatan Z; Alcon Labora-
`tories, Inc.) for 3 months. To maintain efficacy and achieve
`investigator masking, patients were provided with identi-
`cally appearing sealed cartons,
`labeled with the patient
`randomization number, which contained marketed bottles of
`the study medications, and patients were instructed not to
`disclose their study medication to the investigator or office
`personnel. Patients were instructed to instill 1 drop of study
`
`medication in each eye once daily in the evening between 7
`and 9 PM.
`The study protocol called for visits at baseline, week 1,
`month 1, and month 3 between 11 AM and 1 PM. The pri-
`mary outcome measure was conjunctival hyperemia at
`month 3. Hyperemia was evaluated by gross visual inspec-
`tion and graded by the investigator by comparison with
`color photographic standards on the Allergan bulbar hy-
`peremia grading guide using a scale of 0¼ none (normal),
`0.5¼ trace (trace flush, reddish pink), 1¼ mild (mild flush,
`reddish color), 2¼ moderate (bright red color), and 3¼ severe
`(deep, bright diffuse redness). Secondary outcome measures
`included corneal staining with fluorescein, tear breakup time
`(TBUT), and IOP. Corneal staining of superficial punctate
`keratopathy was graded on a scale of 0¼ none (no findings),
`0.5¼ trace (1–5 puncta), 1¼ mild (6–20 puncta), 2¼ moderate
`(>20 puncta), and 3¼ severe (too many puncta to count) at
`each visit. TBUT (in seconds) and IOP (2 consecutive mea-
`surements for each eye) were measured at each visit. IOP was
`measured to ensure patient safety and was collected at only a
`single timepoint at each visit.
`The analyses of outcomes were based on observed values
`in the per-protocol (PP) patient population of all patients
`with no major protocol violations. Among-group differences
`in outcome measures were analyzed using analysis of vari-
`ance. Average values from both eyes were used in each
`analysis. Categorical variables were analyzed using the
`chi-square test or the Fisher exact test. All statistical tests
`were 2-tailed with the alpha level for statistical significance
`set at 0.05.
`
`Results
`
`The study enrolled 106 patients who were on topical la-
`tanoprost monotherapy for at least 4 weeks at the baseline
`visit. There were no significant differences among the treat-
`ment groups in age, sex, race, iris color, or ocular diagnosis at
`baseline (Table 1). Most of the patients were women (58%),
`Caucasian (60%), and found to have open-angle glaucoma
`(86%). There was also no significant difference among
`treatment groups in patient history of exposure to topical
`IOP-lowering medications. Most of the patients had been on
`IOP-lowering medication for at least 1 year before the base-
`line visit (Table 1).
`After randomization to bimatoprost, latanoprost, or travo-
`prost monotherapy, 99 patients (93.4%) completed the 3-month
`study without any significant protocol violations and were
`included in the PP patient population used for analyses. Seven
`patients (3 in the bimatoprost group, 2 in the latanoprost group,
`and 2 in the travoprost group) discontinued from the study.
`Reasons for patient discontinuations were adverse events
`(swollen eyelids, n¼ 1 and headache, n¼ 1) and personal rea-
`sons (n¼ 1) in the bimatoprost group, adverse events (red/
`dry/gritty eyes, n¼ 1) and loss to follow-up (n¼ 1) in the la-
`tanoprost group, and adverse events (redness, n¼ 1) and
`missed visits (n¼ 1) in the travoprost group.
`The investigators graded conjunctival hyperemia, corneal
`staining with fluorescein, and TBUT at each study visit. At
`latanoprost-treated baseline, the mean [standard error of the
`mean (SEM)] conjunctival hyperemia score was 0.74 (0.10) in
`the bimatoprost group, 0.74 (0.11) in the latanoprost group,
`and 0.86 (0.12) in the travoprost group (P¼ 0.692). There
`were no significant differences among the treatment groups
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`OCULAR SURFACE TOLERABILITY OF PGAS
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`
`Table 1. Baseline Characteristics of Enrolled Patients
`Bimatoprost (N¼ 35) Latanoprost (N ¼ 38) Travoprost with sofZia (N¼ 33) Among-group P value
`
`Mean age (SD) in years
`Sex, n (%)
`Male
`Female
`Race, n (%)
`Caucasian
`Black
`Hispanic
`Iris color, n (%)
`Brown
`Blue
`Hazel
`Green
`Not available
`Diagnosis, n (%)
`Open-angle glaucoma
`Ocular hypertension
`Treatment historya, n (%)
`<1 year
`1–3 years
`>3–5 years
`>5 years
`Not available
`
`69.3 (12)
`
`67.3 (10)
`
`65.4 (12.6)
`
`13 (37.1)
`22 (62.9)
`
`23 (65.7)
`6 (17.1)
`6 (17.1)
`
`20 (57.1)
`11 (31.4)
`1 (2.9)
`3 (8.6)
`—
`
`28 (80.0)
`7 (20.0)
`
`3 (8.6)
`9 (25.7)
`5 (14.3)
`12 (34.3)
`6 (17.1)
`
`19 (50.0)
`19 (50.0)
`
`23 (60.5)
`7 (18.4)
`8 (21.1)
`
`23 (60.5)
`10 (26.3)
`2 (5.3)
`1 (2.6)
`2 (5.3)
`
`35 (92.1)
`3 (7.9)
`
`6 (15.8)
`8 (21.1)
`6 (15.8)
`13 (34.2)
`5 (13.2)
`
`13 (39.4)
`20 (60.6)
`
`18 (54.5)
`9 (27.3)
`6 (18.2)
`
`18 (54.5)
`5 (15.2)
`6 (18.2)
`2 (6.1)
`2 (6.1)
`
`28 (84.8)
`5 (15.2)
`
`7 (21.2)
`10 (30.3)
`6 (18.2)
`7 (21.2)
`3 (9.1)
`
`aDuration of exposure to 1 or more IOP-lowering medications before baseline.
`Abbreviations: IOP, intraocular pressure; SD, standard deviation.
`
`0.398
`
`0.493
`
`0.468
`
`0.877
`
`0.327
`
`0.790
`
`in mean conjunctival hyperemia scores at latanoprost-treated
`baseline or at any follow-up visit (P 0.340, Fig. 1). At month 3,
`the mean (SEM) score was 0.80 (0.12) in the bimatoprost
`group, 0.74 (0.10) in the latanoprost group, and 0.98 (0.13) in
`the travoprost group (P¼ 0.340). There were also no signifi-
`cant differences among the treatment groups in the change
`
`FIG. 1. Mean conjunctival hyperemia scores at each visit.
`There were no significant among-group differences in the
`mean hyperemia scores or in the mean change from baseline
`hyperemia scores at any visit (P 0.586). Error bars represent
`standard error of the mean.
`
`from baseline conjunctival hyperemia scores at week 1,
`month 1, and month 3 (P 0.586). At month 3, the mean
`(SEM) change from baseline conjunctival hyperemia scores
`was 0.05 (0.10) in the bimatoprost group, 0.06 (0.10) in the
`latanoprost group, and 0.07 (0.13) in the travoprost group
`(P¼ 0.994).
`The baseline mean (SEM) corneal staining score was 0.59
`(0.12) in the bimatoprost group, 0.70 (0.13) in the latanoprost
`group, and 0.48 (0.11) in the travoprost group (P¼ 0.423).
`There were no significant differences among the treatment
`groups in the baseline mean corneal staining score or the
`mean corneal staining score during follow-up (P 0.110,
`Fig. 2). The mean change from baseline corneal staining scores
`was also similar among the treatment groups at week 1,
`month 1, and month 3 (P 0.083). At month 3, the mean
`(SEM) change from baseline corneal staining scores was 0.15
`(0.15) in the bimatoprost group, 0.18 (0.11) in the latanoprost
`group, and 0.07 (0.12) in the travoprost group (P¼ 0.175).
`The baseline mean (SEM) TBUT was 9.1 (1.0) s in the bi-
`matoprost group, 8.6 (0.8) s in the latanoprost group, and 7.9
`(0.8) s in the travoprost group (P¼ 0.578). There were no
`significant differences among the treatment groups in the
`baseline mean TBUT or the mean TBUT at any follow-up
`visit (P 0.276, Fig. 3). Similarly, there were no significant
`among-group differences in the mean change from baseline
`TBUT at week 1, month 1, or month 3 (P 0.546). At month
`3, the mean (SEM) change from baseline TBUT was 0.5 (0.9) s
`in the bimatoprost group, 0.4 (1.0) s in the latanoprost group,
`and 1.7 (0.8) s in the travoprost group (P¼ 0.546).
`In this study, IOP measurements were taken at each visit
`as a safety precaution to ensure that IOP control was ade-
`quate. At latanoprost-treated baseline, the mean (SEM) IOP
`was 17.4 (0.5) mm Hg in the bimatoprost group, 17.1 (0.5)
`mm Hg in the latanoprost group, and 18.1 (0.8) mm Hg in
`the travoprost group (P¼ 0.449). There was no significant
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`WHITSON ET AL.
`
`FIG. 2. Mean scores of corneal staining with fluorescein at
`each visit. There were no significant among-group differ-
`ences in the mean corneal staining scores or in the mean
`change from baseline corneal staining scores at any visit
`(P 0.083). Error bars represent standard error of the mean.
`
`FIG. 4. Mean intraocular pressure (IOP) at each visit. The
`among-group differences in the mean change in IOP from
`baseline were statistically significant at week 1, month 1, and
`month 3 (P 0.015). Error bars represent standard error of
`the mean.
`
`difference among the treatment groups in the mean IOP at
`baseline or at any follow-up visit (P 0.207, Fig. 4). At month
`3, the mean (SEM) IOP was 15.6 (0.7) mm Hg in bimatoprost
`group, 16.9 (0.5) mm Hg in latanoprost group, and 16.3 (0.4)
`mm Hg in travoprost group (P¼ 0.207). However, at each
`follow-up visit (week 1, month 1, and month 3), there was a
`
`FIG. 3. Mean tear breakup time (TBUT) at each visit. There
`were no significant among-group differences in the mean
`TBUT or in the mean change from baseline TBUT at any visit
`(P 0.276). Error bars represent standard error of the mean.
`
`significant among-group difference in the mean change in
`IOP from baseline (P 0.015). At month 3, the mean (SEM)
`change from latanoprost-treated baseline IOP was 1.8 (0.6)
`mm Hg in the bimatoprost group, þ0.2 (0.5) in the latano-
`prost group, and 1.7 (0.6) mm Hg in the travoprost group.
`There were no serious adverse events during the study.
`Ocular adverse events were reported in 4 patients in each
`group (swollen eyelids, scratchiness, redness/scratchiness,
`and subconjunctival hemorrhage in the bimatoprost group;
`redness, flashes/floaters, photophobia, and dimmed vision
`in the latanoprost group; and redness/dryness/grittiness,
`scratchiness, dryness/scratchiness, and itchiness in the tra-
`voprost group).
`
`Discussion
`
`In this study, patients treated with latanoprost were ran-
`domized to topical treatment with bimatoprost, travoprost,
`or continuation on their existing therapy. The study treat-
`ments differed not only in the active drug but also in the type
`and concentration of preservative used. At 3 months, no
`significant differences among the PGAs were evident in ob-
`jective clinical measures of ocular surface toxicity including
`conjunctival hyperemia, corneal staining, or TBUT despite
`differences in BAK concentration or in the preservative.
`Although bimatoprost and travoprost are associated with an
`increased incidence of conjunctival hyperemia compared with
`latanoprost in treatment-naı¨ve patients and in those patients
`treated after washout of previous medication,17–19 no difference
`in mean conjunctival hyperemia scores was seen among the
`treatment groups in the present study. This finding may be
`explained by the study design in which patients were switched
`directly from latanoprost treatment to study treatment. A low
`rate of conjunctival hyperemia associated with PGA treatment
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`has been seen in a previous study in which patients replaced
`latanoprost with bimatoprost or travoprost.20
`Previous studies have suggested that chronic treatment
`with topical ocular hypotensive medications may cause
`changes in the tear film and the conjunctival and corneal
`epithelium.21,22 The clinical significance of these findings and
`the extent to which the active drug, rather than the preser-
`vative, may produce these effects have not been deter-
`mined.22,23 Studies in rabbits have shown deleterious effects
`of BAK on the ocular surface,7,10–14 but findings in this
`animal model may not reflect the clinical situation. The ac-
`cumulation of BAK in the conjunctiva that has been dem-
`onstrated in rabbits15 has not been demonstrated in human
`eyes. Rabbit eyes differ from human eyes in key character-
`istics that are likely to affect the exposure of the ocular sur-
`face to preservative, such as a much slower blink rate (4–5
`times/h vs. 6–15 times/min) and the presence of a nictitating
`membrane that could serve as a drug reservoir.24 The in-
`flammatory infiltration observed in the conjunctival epithe-
`lium of rabbit eyes exposed to BAK or BAK-containing
`medication12 is not seen in human eyes treated with bima-
`toprost 0.03% containing 0.005% BAK.2 Further, although
`changes in corneal epithelial cell morphology have been
`observed with latanoprost (0.02% BAK) in rabbits after only
`3 min of exposure,11 the long-term clinical use of latanoprost
`has been associated with a favorable profile in terms of both
`safety and ocular surface health.25,26
`There have been few reports of the effects of BAK in human
`eyes. Corneal epithelium exposure to BAK was shown to be
`transient after instillation of BAK-containing drops, with BAK
`concentrations below the level of detection in the tear film at
`5 min postinstillation in subjects who received a total of 5
`drops of medication (BAK concentrations after chronic dosing
`could differ).27 A single drop of a BAK-preserved b-blocker
`has been shown to decrease tear film stability in human
`subjects.28 While a recent cross-sectional study of 101 patients
`demonstrated an increase in lissamine green staining with
`each additional BAK-containing medication, no relationship
`was identified between the number of BAK-containing med-
`ications and TBUT or Schirmer testing.29 Although use of
`multidose bottles of ophthalmic medications is invariably
`associated with exposure to preservative, the potential effects
`of preservatives other than BAK, in particular sofZia, on the
`tear film and dry eye have not been well studied.
`Studies in rabbits have suggested that travoprost with
`sofZia causes less corneal epithelial damage, conjunctival
`inflammation, and loss of conjunctival goblet cells compared
`with latanoprost preserved with BAK,13,14 yet controlled
`clinical comparison studies to date have provided no evi-
`dence that travoprost preserved with sofZia is any better
`tolerated than travoprost preserved with BAK.30,31 In the
`phase 3 clinical trial, no statistical differences were observed
`in either ocular hyperemia or discontinuations due to treat-
`ment-related adverse events between travoprost preserved
`with BAK and travoprost preserved with sofZia.31 These
`results suggest that use of the preservative sofZia does not
`confer any advantage in short-term ocular tolerability over
`use of BAK. In a recent case series, patients who were using
`latanoprost and had symptoms of dry eye experienced sig-
`nificant improvement in TBUT and corneal staining after
`being switched to travoprost preserved with sofZia.32 The
`study was not controlled, and it is possible that the im-
`provement in ocular tolerability resulted from the 1-way
`
`switch study design and regression to the mean, or by use of
`travoprost rather than latanoprost. However, it is also pos-
`sible that preservative effects on ocular tolerability differ in
`patients with dry eye. Our study did not select for patients
`with dry eye symptoms, but patients with dry eye were not
`excluded, and no significant differences in tolerability were
`seen among the PGAs preserved with sofZia or varying
`concentrations of BAK over 3 months.
`IOP was measured in this study to ensure that patients
`had adequate IOP control. A substantial mean decrease in
`IOP from latanoprost-treated baseline to month 3 was seen in
`both the bimatoprost and travoprost groups but not in the
`latanoprost group. In this study, however, IOP was consid-
`ered a safety measure and was assessed at only 1 time of day
`at each visit.
`In this study there was no advantage in ocular surface
`effects of travoprost preserved with sofZia over either lata-
`noprost or bimatoprost, 2 PGAs preserved with BAK. The
`limitations of this study include its relatively short duration
`of 3 months and the lack of an a priori power calculation to
`determine sample sizes. Also, patients were not masked to
`treatment, and patients’ history of exposure to latanoprost,
`specifically, and to other BAK-containing medications was
`not evaluated. If ocular surface effects of preservative are
`reversible, but 4 weeks of washout is inadequate to allow for
`ocular surface recovery, differences among the treatment
`groups in use of adjunctive medication containing BAK be-
`fore washout could have affected the results. This seems
`unlikely, however, because there were no significant differ-
`ences among the treatment groups in clinical characteristics
`of the study eyes at baseline, or in history of exposure to
`topical IOP-lowering medications. Although the study treat-
`ments had no significant effect on tear film stability or ocular
`surface damage over 3 months, their long-term effects, as
`well as their effects in patients taking multiple topical med-
`ications and in patients with severe ocular surface disease,
`require further investigation.
`
`Acknowledgments
`
`This study was sponsored by Allergan, Inc. Melissa Earl,
`M.P.H. (IMEDS, Inc., Riverside, CA), performed the statisti-
`cal analyses. A freelance medical writer, Kate Ivins, Ph.D.,
`assisted in the development of the article.
`Principal investigators and sites: Stacey Ackerman, M.D.
`(Philadelphia, PA); Louis B. Cantor, M.D. (Indianapolis, IN);
`Ronald L. Gross, M.D. (Houston, TX); Barry Katzman, M.D.
`(San Diego, CA); Cynthia Matossian, M.D. (Doylestown, PA);
`Jody R. Piltz-Seymour, M.D. (Philadelphia, PA); Douglas
`Ripkin, M.D. (Streetsboro, OH); William B. Trattler, M.D.
`(Miami, FL); Jess T. Whitson, M.D. (Dallas, TX).
`
`Author Disclosure Statement
`
`Jess T. Whitson, William B. Trattler, and Cynthia Ma-
`tossian declare no proprietary interests in the study. Jess T.
`Whitson is a consultant of Alcon and is on the speaker’s
`bureau of Alcon, Allergan, and Pfizer. William B. Trattler, a
`consultant of Alcon, Allergan, and Aton, has received re-
`search support from Allergan, and is on the speaker’s bureau
`of Allergan. Cynthia Matossian is a consultant of AMO and
`has received lecture fees from Alcon, Allergan, and Ista. Julia
`Williams and David A. Hollander are employees of Allergan,
`Inc., the sponsor of the study.
`
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`References
`
`1. Ishida, N., Odani-Kawabata, N., Shimazaki, A., and Hara,
`H. Prostanoids in the therapy of glaucoma. Cardiovasc. Drug
`Rev. 24:1–10, 2006.
`2. Leal, B.C., Medeiros, F.A., Medeiros, F.W., Santo, R.M., and
`Susanna Jr., R. Conjunctival hyperemia associated with bi-
`matoprost use: a histopathologic study. Am. J. Ophthalmol.
`138:310–313, 2004.
`3. Abelson, M.B., Mroz, M., Rosner, S.A., Dirks, M.S., and Hir-
`abayashi, D. Multicenter, open-label evaluation of hyperemia
`associated with use of bimatoprost in adults with open-angle
`glaucoma or ocular hypertension. Adv. Ther. 20:1–13, 2003.
`4. Hollo´ , G. The side effects of the prostaglandin analogues.
`Expert Opin. Drug Saf. 6:45–52, 2007.
`5. Charnock, C. Are multidose over-the-counter artificial tears
`adequately preserved? Cornea 25:432–437, 2006.
`6. Furrer, P., Mayer, J.M., and Gurny, R. Ocular tolerance of
`preservatives and alternatives. Eur.
`J. Pharm. Biopharm.
`53:263–280, 2002.
`7. Noecker, R. Effects of common ophthalmic preservatives on
`ocular health. Adv. Ther. 18:205–215, 2001.
`8. Pisella, P.J., Debbasch, C., Hamard, P., et al. Conjunctival
`proinflammatory and proapoptotic effects of latanoprost
`and preserved and unpreserved timolol: an ex vivo and
`in vitro study. Invest. Ophthalmol. Vis. Sci. 45:1360–1368, 2004.
`9. Guenoun, J.M., Baudouin, C., Rat, P., Pauly, A., Warnet,
`J.M., and Brignole-Baudouin, F. In vitro study of inflamma-
`tory potential and toxicity profile of latanoprost, travoprost,
`and bimatoprost in conjunctiva-derived epithelial cells. In-
`vest. Ophthalmol. Vis. Sci. 46:2444–2450, 2005.
`10. Russ, H.H., Costa, V.P., Ferreira, F.M., et al. Conjunctival
`changes induced by prostaglandin analogues and timolol
`maleate: a histomorphometric study. Arq. Bras. Oftalmol.
`70:910–916, 2007.
`11. Whitson, J.T., Cavanagh, H.D., Lakshman, N., and Petroll,
`W.M. Assessment of corneal epithelial integrity after acute
`exposure to ocular hypotensive agents preserved with and
`without benzalkonium chloride. Adv. Ther. 23:663–671, 2006.
`12. Liang, H., Baudouin, C., Pauly, A., and Brignole-Baudouin,
`F. Conjunctival and corneal reactions in rabbits following
`short- and repeated exposure to preservative-free tafluprost,
`commercially available latanoprost and 0.02% benzalk-
`onium chloride. Br. J. Ophthalmol. 92:1275–1282, 2008.
`13. Kahook, M.Y., and Noecker, R. Quantitative analysis of
`conjunctival goblet cells after chronic application of topical
`drops. Adv. Ther. 25:743–751, 2008.
`14. Kahook, M.Y., and Noecker, R.J. Comparison of corneal and
`conjunctival changes after dosing of travoprost preserved
`with sofZia, latanoprost with 0.02% benzalkonium chloride,
`and preservative-free artificial tears. Cornea 27:339–343, 2008.
`15. Champeau, E.J., and Edelhauser, H.F. Effect of ophthalmic
`preservatives on the ocular surface: conjunctival and corneal
`uptake and distribution of benzalkonium chloride and
`chlorhexidine digluconate. In: Holly, F.J., ed. The Preocular
`Tear Film in Health, Disease and Contact Lens Wear. Lubbock,
`TX: Dry Eye Institute, Inc.; 292–302, 1986.
`16. Durand-Cavagna, G., Delort, P., Duprat, P., et al. Corneal
`toxicity studies in rabbits and dogs with hydroxyethyl cel-
`lulose and benzalkonium chloride. Fundam. Appl. Toxicol.
`13:500–508, 1989.
`17. Noecker, R.S., Dirks, M.S., Choplin, N.T., et al.; Bimatoprost/
`Latanoprost Study Group. A six-month randomized clinical
`trial comparing the intraocular pressure-lowering efficacy of
`bimatoprost and latanoprost in patients with ocular hyper-
`tension or glaucoma. Am. J. Ophthalmol. 135:55–63, 2003.
`
`WHITSON ET AL.
`
`18. Netland, P.A., Landry, T., Sullivan, E.K., et al.; Travoprost
`Study Group. Travoprost compared with latanoprost and
`timolol in patients with open-angle glaucoma or ocular hy-
`pertension. Am. J. Ophthalmol. 132:472–484, 2001.
`19. Parrish, R.K., Palmberg, P., Sheu, W.P.; XLT Study Group. A
`comparison of latanoprost, bimatoprost, and travoprost in
`patients with elevated intraocular pressure: a 12-week, ran-
`domized, masked-evaluator multicenter study. Am. J. Oph-
`thalmol. 135:688–703, 2003.
`20. Kammer, J., Katzman, B., Ackerman, S., and Hollander, D.
`Efficacy and tolerability of bimatoprost versus travoprost in
`patients previously on latanoprost: a 3-month, randomized,
`masked-evaluator, multicenter Study. Br. J. Ophthalmol. 94:
`74–79, 2010.
`21. Herreras, J.M., Pastor, J.C., Calonge, M., and Asensio, V.M.
`Ocular surface alteration after long-term treatment with an
`antiglaucomatous drug. Ophthalmology 99:1082–1088, 1992.
`22. Nuzzi, R., Finazzo, C., and Cerruti, A. Adverse effects of
`topical antiglaucomatous medications on the conjunctiva
`and the lachrymal response. Int. Ophthalmol. 22:31–35, 1998.
`23. Thygesen, J., Aaen, K., Theodorsen, F., Kessing, S.V., and
`Prause, J.U. Short-term effect of latanoprost and timolol eye
`drops on tear fluid and the ocular surface in patients with
`primary open-angle glaucoma and ocular hypertension. Acta
`Ophthalmol. Scand. 78:37–44, 2000.
`24. Chastain, J.E. General considerations in ocular drug deliv-
`ery. In: Mitra, A.K., ed. Ophthalmic Drug Delivery Systems,
`2nd ed. New York: Marcel Dekker, Inc.; 2003; pp. 59–108.
`25. Camras, C.B., Alm, A., Watson, P., Stjernschantz, J.; Latano-
`prost Study Groups. Latanoprost, a prostaglandin analog, for
`glaucoma therapy. Efficacy and safety after 1 year of treat-
`ment in 198 patients. Ophthalmology 103:1916–1924, 1996.
`26. Goldberg, I., Li, X.Y., Selaru, P., and Paggiarino, D. A 5-year,
`randomized, open-label safety study of latanoprost and
`usual care in patients with open-angle glaucoma or ocular
`hypertension. Eur. J. Ophthalmol. 18:408–416, 2008.
`27. Friedlaender, M.H., Breshears, D., Amoozgar, B., Sheardown,
`H., and Senchyna, M. The dilution of benzalkonium chloride
`(BAK) in the tear film. Adv. Ther. 23:835–841, 2006.
`28. Ishibashi, T., Yokoi, N., and Kinoshita, S. Comparison of the
`short-term effects on the human corneal surface of topical
`timolol maleate with and without benzalkonium chloride.
`J. Glaucoma 12:486–490, 2003.
`29. Leung, E.W., Medeiros, F.A., and Weinreb, R.N. Prevalence
`of ocular surface disease in glaucoma patients. J. Glaucoma
`17:350–355, 2008.
`30. Gross, R.L., Peace, J.H., Smith, S.E., et al. Duration of IOP
`reduction with travoprost BAK-free solution. J. Glaucoma
`17:217–222, 2008.
`31. Lewis, R.A., Katz, G.J., Weiss, M.J., et al.; Travoprost BAC-
`free Study Group. Travoprost 0.004% with and without
`benzalkonium chloride: a comparison of safety and efficacy.
`J. Glaucoma 16:98–103, 2007.
`32. Horsley, M.B., and Kahook, M.Y. Effects of prostaglandin
`analog therapy on the ocular surface of glaucoma patients.
`Clin. Ophthalmol. 3:291–295, 2009.
`
`Received: November 26, 2009
`Accepted: March 16, 2010
`
`Address correspondence to:
`Dr. Jess T. Whitson
`UT Southwestern Medical Center
`5303 Harry Hines Blvd., Suite 102
`Dallas, TX 75390-8866
`
`E-mail: jess.whitson@utsouthwestern.edu
`
`Downloaded by UNIVERSITY OF TORONTO from online.liebertpub.com at 01/07/18. For personal use only.
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