418
`
`CLINICAL SCIENCE
`Prevalence of ocular symptoms and signs with preserved
`and preservative free glaucoma medication
`P J Pisella, P Pouliquen, C Baudouin
`. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`
`BrJOphthalmol 2002;86:418–423
`
`See end of article for
`authors’ affiliations
`. . . . . . . . . . . . . . . . . . . . . . .
`
`Correspondence to:
`C Baudouin; APHP
`Ambroise Paré Hospital,
`University Paris V,
`Ophthalmology
`Department, 9, avenue
`Charles de Gaulle, 92100
`Boulogne, France;
`baudouin@quinze-vingts.fr
`
`Accepted for publication
`21 November 2001
`. . . . . . . . . . . . . . . . . . . . . . .
`
`Aim: To determine the incidence of ocular toxicity of preservatives with glaucoma medications.
`Methods: A prospective epidemiological survey was carried out in 1999 by 249 ophthalmologists on
`4107 patients. Ocular symptoms, conjunctiva, cornea, and eyelids were assessed. A c 2 test was used
`for differences between preserved eye drops (P) and preservative free eye drops (PF).
`Results: 84% patients used P, 13% received PF, and 3% a combination of P and PF eye drops. All
`symptoms were more prevalent with P than with PF drops (p<0.001): discomfort upon instillation (43%
`versus 17%), and symptoms between instillations such as burning-stinging (40% versus 22%), foreign
`body sensation (31% versus 14%), dry eye sensation (23% versus 14%), tearing (21% versus 14%),
`and eyelid itching (18% versus 10%). An increased incidence (>2 times) of ocular signs was seen with
`P eye drops. The prevalence of signs and symptoms was dose dependent, increasing with the number
`of P drops. A reduction in the symptoms and signs was observed when patients changed from P to PF
`eye drops (p<0.001).
`Conclusions: Symptoms and signs are less prevalent when PF drops are used. Moreover, most of the
`adverse reactions induced by P glaucoma medication are reversible after removing preservatives.
`
`Medical treatment is considered an effective way of con-
`
`trolling glaucoma in its initial stage.1 For treatment to
`be effective, side effects need to be minimised to pro-
`mote compliance and allow continuation of therapy. Further-
`more, topical medication should not inhibit the future success
`of surgical treatment of glaucoma.
`The benefits of reducing microbial contamination through
`use of preservatives are offset by the known ocular side effects
`of preservatives.2 The toxic action of preservatives on the ocu-
`lar surface has been widely demonstrated in vitro as well as in
`vivo, in both humans and animals.3–5 Studies have shown that
`preservative free timolol and carteolol eye drops are less toxic
`for the ocular surface,6–8 suggesting that the side effects of b
`blocker eye drops are mainly the result of the presence of pre-
`servatives.
`Preservatives decrease the stability of the precorneal tear
`film.5 9–12 They have a detergent effect on the lipid layer,13
`resulting in increased evaporation. Preservatives also destabi-
`lise the tear film indirectly by decreasing the density of goblet
`cells in the conjunctival epithelium.11 14 15 Any destabilisation
`compromises the ability of the tear film to provide protection
`and trophic factors to the cornea. Understandably, worsening
`of pre-existing dry eye is a common complication associated
`with
`the
`use
`of
`eye
`drop
`solutions
`containing
`preservatives.16–18
`Subtle signs of ocular toxicity, such as superficial punctate
`keratitis, indicate chronic cell injury that can well have long
`term consequences. In the cornea, application of preservatives
`induces reduction in cell proliferation and viability. Hence,
`corneal healing is impaired19 and the epithelial barrier
`compromised.6
`Histopathological and impression cytology studies of the
`conjunctiva have demonstrated inflammation, squamous
`metaplasia, and subconjunctival fibrosis in the conjunctiva
`and Tenon’s capsule associated with the use of topical
`preservatives.7 20–26 These side effects are dose dependent and
`increase with frequency of instillation.27
`Benzalkonium chloride inhibits proliferation of trabecular
`cells at a concentration of 0.00002% in in vitro models.28 In
`humans, this cytotoxicity constitutes a potential risk but has
`
`investigated systematically.
`neither been reported nor
`Nevertheless, inflammatory reactions may be seen in the
`trabeculum, particularly in glaucoma patients undergoing
`topical multidrug treatment or long term topical treatment.
`These disorders, similar to those seen in the conjunctiva, may
`be due at least in part to the presence of preservatives. They
`could therefore directly affect trabecular filtration, and thus
`the course of the glaucoma itself.27
`It has been shown that failure of surgical treatment is
`mainly linked to the duration and the extent of previous
`medical treatment.29–32 The failure of surgical treatment seems
`to be associated with inflammation of the ocular surface
`structures,25 a feature more frequent in patients treated over
`it is
`the long term with glaucoma eye drops.25 26 Hence,
`suspected that the toxicity of the preservatives contained in
`glaucoma eye drops has a role in the failure of surgical
`treatment.33
`Preservatives induce, according to their nature, an allergic
`reaction but more frequently a cytotoxic reaction (90%).34 The
`degree and type of allergy incurred depends upon patient fac-
`tors and the type of preservative. Benzalkonium salts, which
`are considered moderately sensitising,35 36 usually result in
`contact allergies and delayed hypersensitivity reactions.
`Further, long term use of these agents may result in a form of
`conjunctival scarring known as drug induced pemphigoid,37 38
`in which chronic allergic reaction leads to a marked and self
`sustaining inflammatory process.
`While the ocular toxicity of preservatives has been demon-
`strated both in animals and in humans in numerous studies,
`few epidemiological data are available with regard to the
`nature and the frequency of these complications in glaucoma
`patients.
`This study examined a large population being treated for
`chronic open angle glaucoma in ophthalmological practice. Its
`aim was to investigate the nature of the side effects of topical
`b blockers of varying dose, both preserved and preservative
`free in terms of symptoms and ocular signs of irritation. The
`study design was developed following a pilot study of 919
`patients.39
`
`www.bjophthalmol.com
`
`Page 1 of 6
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`SENJU EXHIBIT 2080
`LUPIN v. SENJU
`IPR2015-01100
`
`

`
`Prevalence of ocular symptoms and signs with preserved and preservative tree glaucoma medication
`
`4l9
`
`Table I Glaucoma medications available in France at the time of the study in
`preserved and preservative free loan
`
`B Blockers
`Tirnolol
`Behxolol
`Carteolol
`"2 A9°ni5B
`Apraclonidine
`Brimonidine
`' etr
`".';*'°"'°'“,,......."" °
`Miotics
`Pilooarpine
`Carbonic an
`Dorzolam'
`Prostnglandin analogues
`latunoprost
`
`ruse inhibitors
`
`Praservedeyodropstxt
`
`0. I , 0.25, 0.50
`0.I, 0.25, 0.3, 0.5, 0.6
`0.5, I, 2
`
`Preservative free
`us)
`
`(I
`'5" W
`
`0. I , 0.25, 0.50
`0.25, 0.5
`—
`
`0.5
`0.2
`
`0.5, I, 2
`
`2
`
`50 pg/ml
`
`I
`—
`-
`
`I, 2
`
`—
`
`—
`
`Combination lonntdations (preserved form only): dorzolamide/tirnolol, pilotarpine/timolol,
`pilooarpine/carteolol.
`
`MATERIALS AND METHODS
`This study was a practice based prospective epidemiological
`study examining a population currently treated by topical
`glaucoma medication. Ophthalmologists in private practice
`enrolled patients under their management, presenting with
`ocular hypertension and/or chronic open angle glaucoma, and
`receiving medical treatment. Enrolment was based on routine
`attendance for glaucoma management. The investigators
`received case report forms and a leaflet with instructions. The
`observations required were clinical evaluations commonly
`employed in routine ophthalmic examination.
`the
`survey,
`During this cross
`sectional observational
`patients attended for one visit. The ophthalmologist in case of
`necessity (in particular,
`treatment change) could plan a
`second visit. At
`the first visit, demographic data and
`information on treatment history were collected: age, sex, and
`duration of the treatment. At each visit, a questionnaire was
`completed about the number of preserved and preservative
`free eye drops used, and ocular symptoms: discomfort or pain
`upon instillation, and symptoms between instillations (for-
`eign body sensation, stinging or burning sensation, dry eye
`sensation, tearing, eyelid itching). Clinical examination of the
`palpebral and bulbar conjunctiva, cornea and eyelids was
`undertaken. Superficial punctate keratitis was evaluated as
`"absent,” "mild" (a few points), "severe” (more than 25% of
`the corneal surface).
`No change in the therapeutic practices by the ophthalmolo-
`gist was requested but the patient’s treatment could be modi-
`fied depending on their clinical status. Any change to the pre-
`scription was at the discretion of the ophthalmologist. If
`marked signs or symptoms of ocular toxicity were observed,
`preservative free eye drops could be considered. In France, at
`
`the time of the study, a number of medications were available
`in preservative free form (Bible 1). These were either available
`as unit dose solutions or multidose bottles with a membrane
`
`system preventing contamination of preservative free formu-
`lations for up to 1 month after opening. More formulations
`were available in preserved formulations, primarily providing
`smaller increments in the available dosages. Carbonic anhy-
`drase inhibitors, syrnpathomirnetics, prostaglandins, and
`combination drops were only available in preserved formula-
`tions.
`
`Data were described by mean, standard deviation and range
`for quantitative variables, and by proportion for qualitative
`variables. At the first visit, a x’ test was used to test for differ-
`ences in prevalence of signs and symptoms between preserved
`(P) and preservative free (PF) eye drops. At the second visit,
`depending upon the change in treatment, patients were sepa-
`rated into subgroups and the results obtained at visits 1 and 2
`were compared in order to assess the effect of these changes
`on ocular tolerance.
`
`RESULTS
`
`A total of 4107 patients were enrolled in 1999 by 249 ophthal-
`mologists. Of this number, only 1181 patients needed to make
`a second visit.
`
`At the first visit, patients were mainly women (58%) with a
`mean age of 66 years (SD 12, range 10-96). About 80% of
`patients were between the age of 50 and 80 years. The patients
`had been treated with eye drops for a median of 3.9 years
`(0-46). The majority of prescribed medications were pre-
`served: 3469 (84%) patients used preserved (P) glaucoma eye
`drops, 552 (13%)
`received one preservative free (PF)
`medication, the remaining patients (3%) were treated with a
`
`Table 2 Frequency of symptoms reported by patients treated with preserved and
`preservative Free eye drops at the first visit
`Preservedeyedrops
`(n=3469)
`
`Preservutivefraeeyedrops
`(n=552)
`
`Disootnlort upon instilation
`Foreign body sensation
`Stinging or burning sensation
`Dry eye sensation
`Tearing
`Eyelid ihlfltg
`Presenoeotsymptomsotirritationbetween
`instillations
`
`43%
`3 I %
`40%
`23%
`2 I ‘X
`I 8%
`6I%
`
`I7%‘'
`I4%"
`22%‘
`I4%'
`I 4%‘
`I0%'
`36%‘
`
`'Preservative Iree versus preserved comparison: p<0.00I Ix’ test).
`
`
`
`Page 2 of 6
`
`www.biophthalmol.oom
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`

`
`420
`
`Pisella, Pouliquen, Baudouin
`
`Table 3 Frequency of ocular signs in patients treated with preserved and
`preservative free eye drops at the first visit
`Preserved eye drops
`(n=3469)
`
`Preservative free eye drops
`(n=552)
`
`Presence of coniundival signs
`Canjunctival redness
`Coniunctival follicles
`Fluorescein staining in the nasal lsulbar
`conjunctiva
`Presence of an SPK
`Superficial punctate lteratitis
`Mild
`Se-were
`Presence of at least one palpebral sign
`Anterior blepharitis
`Posterior blepharitis (meibomiitis)
`Eczema
`
`49%
`41%
`22%
`l3%
`
`l9%
`
`l7%
`2%
`22%
`16%
`7%
`6%
`
`‘Preservative free versus preserved comparison: p<0.00l Ix’ test).
`
`26%‘
`20%’
`l l%"
`5%‘
`
`9%‘
`
`8.9%‘
`0.6%‘
`9%‘
`7%‘
`3%‘
`l%'
`
`
`
`70
`
`60
`__ 50
`§. 40
`4'5’
`% 30
`“-
`
`20
`'0
`0
`
`Coni_unctivu|
`
`Palpebral
`
`
`
`SPK
`
`Comparison at the first visit between P and PF eye drops
`showed that all symptoms occurred more frequently in
`patients treated with P eye drops than in those receiving PF
`eye drops (Table 2, p<0.00l ). Discomfort upon instillation was
`up to 2.5 times more prevalent ir1 those using P eye drops: 43%
`versus 17% (p<0.00l, x’ test). A difference ir1 incidence of
`symptoms favouring PF drops (p<0.00l, 1‘ test) was found for
`every symptom (Table 2).
`Signs of ocular surface damage were also reported more
`frequently in patients treated with P eye drops than in patients
`using PF eye drops (‘Bible 3, p<0.00l ). The presence of at least
`one conjunctival sign was reported in close to half of the
`patients treated with preserved eye drops but only a quarter of
`those treated with PF eye drops. For the cornea, the prevalence
`either of mild or severe superficial punctate keratitis was sig-
`nificantly higher in patients treated with preserved eye drops.
`The frequency of blepharitis and eczema was also significantly
`higher in patients treated with P eye drops. In particular, the
`frequency of eczema of the eyelids while remaining low was
`'
`'
`markedly increased (3.6—fold) in patients treated with P eye
`drops.
`Frequencies of the symptoms and objective signs (conjunc-
`tival, corneal, or palpebral signs) increased as a function of the
`number of P eye drops used by the patient (Fig 1).
`Of the patients enrolled, 118] patients needed to make a
`second visit
`for a medical reason. They had the same
`demographic and pathological characteristics as the entire
`initial population. The mean interval between the two visits
`was 4 months.
`
`The precise number of eye drops used was recorded in 956
`patients. These patients could be classified and analysed in
`four main subgroups according to the change of their
`treatment after the first visit (Fig 2).
`
`Figure 2 Treatment modification
`after the first visit (n=956).
`
`Wed
`
`d
`
`D N
`D I
`I 2 p,e5e,,,ed eye amp pmdud,
`I 3 preserved eye drop products
`
`md d
`
`Fi9""'° I P'°"°l°“°° °l ‘i9"‘ °"d ‘Y"‘P'°""—“"'“b°' °l P'°‘°“'°d
`eye drops used at the first visit.
`
`combination of P and PF treatments. The majority of
`practitioners used both P and PF medications (79.1%) from
`time to time.
`
`Of the 4107 patients surveyed at the first visit, 57% reported
`at least one symptom some time after instillation. Discomfort
`on instillation (40%) was the most commonly reported symp-
`tom followed by symptoms between instillations—burning
`and stinging (37%), foreign body sensation (28%), dry eye
`sensation (22%), tearing (20%), and eyelid itching (17%).
`There were also objective signs of ocular irritation such as
`conjunctiva] hyperaemia (38%), conjunctival follicles (20%),
`and superficial punctate keratitis (18%).
`
`
`preserved eye drops
` Preserved eye drops
`
`
`Preservative free eye drops
`(n = I76)
`
`Preservative free eye drops
`
`PF.PF group
`(n = I76)
`
`Page 3 of 6
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`

`
`Prevalence of ocular symptoms and signs with preserved and preservative free glaucoma medication
`
`42l
`
`Table 4 Frequency of symptoms and signs at visits 1 and 2 in P-PF group
`
`Visit I (preserved)
`
`No‘
`
`(35)
`
`Patient symptoms
`Discomfort upon instillation
`Patients presenting with at least one symptom between instillations
`Ocular signs found at the clinical examination
`presenting with at least one)
`Palpehral sign
`Conjunctivul sign
`Superhero‘' lpunctate keratin‘'s
`
`196/340
`283/342
`
`l 22/342
`233/338
`85/334
`
`‘Number of patients lot which the variable had been recorded.
`
`Table 5 Frequency of symptoms and signs at visit l and visit 2 in P-DP group
`
`Visit ‘I (preserved)
`
`V'it 2
`(preservative free)
`
`No‘
`
`(as)
`
`No‘
`
`(as)
`
`Patiatt sympbms
`Discomfort upon instillation
`Patients presenting with at least one sympbm bdween instilations
`Ocular signs found at the clinical examination
`presenting with at least one)
`Pabebralsi ns
`Conjunctiva signs
`SuperlIc'ial punctate lteratitis
`
`28/57
`48/57
`
`25/57
`44/56
`13/57
`
`'Numl:erolpatientslorwlIiclt Itevariable had been recorded.
`
`8/56
`31/57
`
`7/57
`25/57
`5/55
`
`l4.3%
`54.4%
`
`12.3%
`43.9%
`8.9%
`
`For 349 patients, treatment was changed from one or more
`P eye drops to exclusively PF eye drops at the end of visit 1 as
`hi this group signs and symptoms of ocular irritation were
`high at visit 1 (group P-PF). For these patients, the frequencies
`of all signs and symptoms were markedly decreased at visit 2
`(‘table 4). The prevalence of all symptoms decreased 2.7-fold to
`5.2-fold. The most frequently observed sign, conjunctiva]
`hyperaemia, decreased from 61% to 16%. All these changes
`were statistically significant (p<0.00l ).
`For 57 patients treated with preserved eye drops before the
`first visit, the number of preserved eye drop products was
`reduced but at least one preserved eye drop product continued
`to be used (group P-DP). In this group, the frequency of the
`signs and symptoms of ocular irritation was high at visit 1. At
`visit 2,
`the proportion of patients reporting symptoms
`decreased as did objective signs between the two visits (']able
`5, p<0.00l ).
`In the two groups of patients (PF-PF and P-P), whose treat-
`ment was not modified, there was no change in the frequency
`of symptoms and objective signs of eye irritation at the second
`visit (p>0.05 for all criteria).
`
`DISCUSSION
`
`Results of this survey show a high prevalence of ocular surface
`impairment in glaucomatous patients in daily ophthalmologi-
`cal practice. ‘lb the best of our knowledge, no other survey on
`both symptoms experienced and ocular changes with topical
`medication in glaucomatous patients is available for compari-
`son with these results.
`
`Van Beck et aI“' conducted a prospective observational study
`examining the side effects of [3 blockers used in glaucoma
`therapy in general ophthalmological practice. They recorded a
`small number of ocular side effects (34 defined cases, 1.5]
`cases per l0()O patient years). Interestingly, the nature of these
`reactions was similar
`to those reported in our study-
`periorbital dermatitis or blepharitis, conjunctivitis, conjuncti-
`val hyperaemia, and punctate keratitis. It is important to note
`that van Beck et al sought only cases where the ophthalrnolo-
`gist altered the medication because of side effects. It is likely
`
`Page 4 of 6
`
`that ocular irritation and subtle signs of ocular damage were
`not detected by this method. Our findings would cast doubt on
`the observation that topical B blocker therapy is associated
`with few clinically important side effects.” This survey shows
`that ocular surface impairment is not a marginal phenomenon
`in glaucoma patients but rather occurs in a large number of
`patients and therefore constitutes a real healthcare concern.
`One of the merits of this study is that it covered a large
`population examined by close to 250 ophthalmologists in
`France. In general, the majority of medications for glaucoma
`therapy were preserved. However, most practitioners used
`both preserved and preservative free medications, limiting the
`bias of individual ophthalmologists. There were, however,
`some limitations inherent to this observational study. It is
`possible that patients will not show interest in participating in
`the clinical trial if they have no concerns about their medica-
`tions, thereby biasing the sample to problematic patients.
`However, this effect would be minimal as participating in the
`study would not constitute significant
`inconvenience or
`impact their treatment. Also, unlike prospective clinical trials,
`the drug types used and the dosages are not controlled. Treat-
`ment regimens could be classified into groups of sufficient
`sample size to allow meaningful statistical comparison.
`Unavoidably, the patients and the investigators were not
`masked as to the type of drop they were using (preserved or
`preservative free). Those who were aware of changing to a
`preservative free medication may have felt encouraged to
`report improved symptoms. However, the positive response to
`a change to preservative free medication was supported by the
`observations at the first visit where medication had not been
`
`altered. In both instances patients who used preservative free
`medications had fewer symptoms and this was corroborated
`by less frequent signs of ocular surface irritation.
`The demographic characteristics of the glaucomatous
`patients are similar to those found in other surveys in
`France." Moreover, the fact that almost half the patients
`included reported symptoms between instillations is in agree-
`ment with the study conducted by De Jong et al, in which 10
`out of 21 patients treated with preserved eye drops presented
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`

`
`422
`
`Pisella, Pouliquen, Baudouin
`
`some signs of ocular irritation.6 In addition, the presence of
`symptoms and of objective signs of irritation was correlated.
`This epidemiological study has demonstrated that ocular
`irritation is a very common condition in glaucomatous
`patients treated with eye drops. Even if no data are available
`on the ocular state of control patients of the same age without
`treatment,
`the striking difference in the frequency of
`symptoms between patients treated with preserved eye drops
`and preservative free eye drops is greatly in favour of the
`hypothesis that this is not a common natural feature in
`patients of that age.
`The frequency of both symptoms and objective signs of
`ocular surface irritation was higher in patients treated with
`preserved eye drops compared to preservative free eye drops. A
`comparable conclusion was drawn by Höh.42 In a study by
`Zimmerman (cited by Höh42), the frequency of eye irritation
`after a few weeks of treatment was higher with preserved
`(29%) than with preservative free (10%) eye drops. The results
`of this survey show that use of preserved eye drops greatly
`increases the frequency of ocular irritation in glaucoma
`patients. Moreover, the frequency of signs and symptoms is
`correlated with the number of preserved eye drops used. This
`is in agreement with reports in the literature, which showed
`increased ocular damage with higher doses.23 It is acknowl-
`edged that while information about patient compliance with a
`prescribed medication regimen was not collected, non-
`compliance was likely to be distributed evenly throughout the
`patients assessed.
`In this survey, a change from a preserved to preservative
`free glaucoma eye drop, or even a reduction in the number of
`preserved eye drops used is associated with a significant
`decrease in the frequency of signs and symptoms of ocular
`irritation. This also shows that preservative adverse reactions
`are reversible and that removing preservatives is of benefit to
`glaucoma patients. Similar findings are reported in the
`literature.6 40 De Jong et al’s study included 21 glaucomatous
`patients treated with eye drops containing benzalkonium
`the preservative led to partial
`chloride.6 Withdrawal of
`normalisation of the permeability of the corneal epithelium
`and to decrease or disappearance of the symptoms in eight of
`the 10 patients complaining of a sensation of burning or dry
`eye. Moreover, Gordon observed the disappearance of corneal
`signs after discontinuation of a treatment by eye drops in 22 of
`65 patients (34%) presenting with superficial punctate kerati-
`tis of unknown origin.43 An improvement in symptoms after
`withdrawal of the preservative was also observed in the man-
`agement of dry eye syndrome,44–46 a pathology frequently
`found in glaucomatous patients.47
`The toxic effect of preservatives is very rapid in vitro: 0.007%
`benzalkonium chloride induces the lysis of 50% of cultured
`epithelial cells in less than 2 minutes.48 The damage to the
`ocular surface observed during the treatment with preserved
`antiglaucoma eye drops probably reflects an imbalance
`between mucosal regeneration and daily low grade cytotoxic-
`ity of the preservative. This intolerance and repeated toxic
`impairment of the ocular surface may further result in chronic
`inflammation and conjunctival infiltration by inflammatory
`cells.27 The conjunctival epithelium is a very reactive tissue on
`which apoptotic (that is, drug induced) and immune (that is,
`cytokine mediated) phenomena are closely correlated.49–51
`Hence, the disappearance of the signs of superficial irritation
`within a few weeks following preservative withdrawal is logi-
`cal and could explain the results of this epidemiological
`survey.
`Therapeutic habits in glaucoma treatment have changed
`and ophthalmologists prescribe preservative free b blockers
`more frequently. In this survey preservative free glaucoma
`medication were in use in 15% of patients and an additional
`18% were changed to PF drops at a follow up visit.
`In the present study, nearly half the patients experienced
`symptoms of ocular irritation with their glaucoma medication
`
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`
`corroborated by observation of objective signs of ocular
`surface irritation. A large proportion of these symptoms could
`be ascribed to preservatives as demonstrated by previous
`studies, and strongly supported by this survey. The phenom-
`enon was frequent and not limited to a small category of
`allergic patients. It is probably due to a direct toxic effect on
`eye structures, as widely demonstrated in animals and in vitro
`experiments. Moreover, the toxicity of preserved eye drops is
`strongly suspected to impair the efficacy of subsequent
`surgery for the glaucoma, which constitutes a real healthcare
`concern.
`The exclusive use of preservative free eye drops or even a
`reduction of the number of preserved eye drops used clearly
`reduces the signs of ocular surface irritation in glaucoma
`patients. Overall, preservative free eye drop products have a
`significant medical advantage.
`
`ACKNOWLEDGEMENTS
`We would like to thank Mrs Agnès Lanoue and Mr Sylvain Bouton for
`their help during this investigation.
`
`. . . . . . . . . . . . . . . . . . . . .
`Authors’ affiliations
`P J Pisella, C Baudouin, APHP Ambroise Paré Hospital, University Paris
`V, Ophthalmology Department, 9, avenue Charles de Gaulle, 92100
`Boulogne, France
`P J Pisella, Bretonneau University Hospital, Ophthalmology Department,
`2, boulevard Tonnellé, 37044 Tours Cedex 1, France
`P Pouliquen, Théa Laboratories, 12, rue Louis-Blériot, - ZI du Brézet,
`63017 Clermont-Ferrand, Cedex 2, France
`C Baudouin, XV-XX National Hospital, University Paris V, 28, rue de
`Charenton, 75012 Paris, France
`
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