Saudi Journal of Ophthalmology (2011) 25, 389–394
`
`King Saud University
`
`Saudi Journal of Ophthalmology
`
`www.saudiophthaljournal.com
`www.ksu.edu.sa
`www.sciencedirect.com
`
`GLAUCOMA UPDATE
`
`Antiglaucoma drugs: The role
`of preservative-free formulations
`
`Alessandro Bagnis, MD, PhD; Marina Papadia, MD, PhD; Riccardo Scotto, CO;
`Carlo E. Traverso, MD *
`
`Eye Clinic, Department of Neurosciences, Ophthalmology and Genetics, University of Genova, Genova, Italy
`
`Received 6 August 2011; revised 18 August 2011; accepted 24 August 2011
`Available online 28 August 2011
`
`KEYWORDS
`
`Glaucoma medications;
`Benzalkonium chloride;
`Preservative-free
`formulations;
`Ocular surface toxicity;
`Compliance
`
`Abstract Hypersensitive reactions to eyedrops are a common finding in clinical practice and rep-
`resent a frequent cause of discontinuation of the therapy. Moreover, experimental and clinical stud-
`ies show that long term use of topical drugs may induce ocular surface changes causing discomfort
`and potentially negatively affecting the compliance to the treatment as well as the success rate of
`filtering procedures. The exact mechanism involved and the roles of the active compound and
`the preservatives in inducing such detrimental effects of ophthalmic solutions are unclear. During
`the last years several antiglaucoma agents have been marketed as either preservative-free or ben-
`zalkonium chloride-free formulations in an attempt to reduce the adverse effects related to preser-
`vatives. This paper summarizes the body of evidence from existing studies about preservatives in
`antiglaucoma eyedrops, focusing on the latest compounds commercially available. A systematic
`review of the literature was performed.
`Current research is focusing not only on the efficacy of the drugs but also on their tolerability.
`Based on the existing data, there is a rationale to support the use of benzalkonium-free solutions
`whenever possible, especially in patients suffering from concomitant ocular surface diseases, expe-
`riencing local side effects and in those expected to need multiple and prolonged topical treatments.
`ª 2011 King Saud University. Production and hosting by Elsevier B.V. All rights reserved.
`
`* Corresponding author. Address: Clinica Oculistica, Universita` di
`Genova, Viale benedetto XV, 16132 Genova, Italy. Tel.: +39
`0103538469; fax: +39 0103538494.
`E-mail addresses: alebagnis@libero.it, mc8620@mclink.it
`Traverso).
`
`(C.E.
`
`1319-4534 ª 2011 King Saud University. Production and hosting by
`Elsevier B.V. All rights reserved.
`
`Peer review under responsibility of King Saud University.
`doi:10.1016/j.sjopt.2011.08.004
`
`Production and hosting by Elsevier
`
`Exhibit 1026
`ARGENTUM
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`000001
`
`

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`390
`
`Contents
`
`A. Bagnis et al.
`
`390
`Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`1.
`390
`2. Antiglaucoma drugs and therapeutic regimens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`391
`3. Antiglaucoma drugs and allergic reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`391
`4. Antiglaucoma drugs and ocular surface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`391
`5. Antiglaucoma drugs and preservatives. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`392
`6. Antiglaucoma drugs: how to reduce the exposure to preservatives? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`6.1. Reducing the number of drops. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 392
`6.2. Using of preserved formulation not containing BAK . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 392
`6.3.
`Preservative-free formulations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 393
`7. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`393
`References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`393
`
`1. Introduction
`
`Glaucoma is a group of ocular diseases with multifactorial
`aetiology characterized by a clinically characteristic optic neu-
`ropathy and associated visual field loss (Falkenberg and Bex,
`2007). The vast majority of glaucomatous patients are older
`than 60 years, and due to longer life expectancy, the prevalence
`of glaucoma is increasing worldwide (Coleman, 1999).
`The relative risk to develop glaucoma rises continuously
`with the level of the intra-ocular pressure (IOP); however,
`there is no evidence of a threshold IOP for the onset of the dis-
`ease (European Glaucoma Society, 2008a).
`Primary open-angle glaucoma (POAG), the most common
`form of the disease in the western world, can be categorized as
`either ‘‘high pressure’’ or ‘‘normal pressure’’, depending
`whether the IOP lies above or under the normally expected
`range, In both cases, there is a characteristic cupping of the
`optic disc along with possible visual field loss and loss of reti-
`nal ganglion cells. If the IOP is consistently more than two
`standard deviations above the normal mean, while all other
`ocular findings (visual field, optic disc appearance etc.) are
`within normal
`limits, the condition is classified as ocular
`hypertension (OH). Exfoliation syndrome and pigment disper-
`sion are risk factors for secondary open-angle glaucoma. Trau-
`ma, or conditions such as uveitis, may cause damage to the
`drainage pathways within the eye, and, therefore, be linked
`to the onset of secondary open-angle glaucoma (Yee, 2007).
`Angle-closure glaucoma (AGC), is caused by forces which
`either pull (e.g., neovascularization of the iris, inflammation)
`or push (pupillary block, posterior synechiae, uveitis) the iris
`forward or push the lens forward (e.g., mature cataract, small
`anterior segment) thereby narrowing the iridocorneal angle. In
`its primary form, angle closure is more frequent in Asian
`population.
`Although many molecules aimed to arrest or even reverse
`the apoptotic damage of the optic nerve and retinal ganglion
`cells (Ammar et al., 2011), elevated IOP is still considered
`the most important risk factor for glaucoma development.
`At present, the only effective treatment for glaucoma is to low-
`er the IOP and for this purpose a broad spectrum of medica-
`tions are available (Leske et al., 2008).
`IOP can be lowered either through a decrease of aqueous
`production (i.e., the amount of aqueous that is produced by
`the ciliary tissues), or by increasing outflow through the conven-
`tional trabecular pathway or the alternate uveoscleral pathway.
`
`Many of the currently available topical medications are
`associated with adverse effects, such as dry eye, burning, sting-
`ing sensations, tearing and allergic reactions (Jaenen et al.,
`2007). Discomfort due to instillation, or ocular adverse events
`caused by the drug itself, may have an impact on the patient’s
`quality of life, and are thought to be associated with poor
`compliance. This leads to poor IOP control, which in turn,
`may increase the need for eventual filtration surgery, which
`is associated with risks, the most common being an increase
`cataract formation (Baudouin, 2008).
`
`2. Antiglaucoma drugs and therapeutic regimens
`
`The goal of glaucoma treatment is to maintain the patient’s
`visual function and related quality of life (European Glaucoma
`Society, 2008b). Besides the functional loss and having the
`diagnosis of a potentially blinding disease, other factors alone
`or in combination may affect patients’ quality of life: inconve-
`nience of the treatment, side effects and therapy costs.
`Most patients with POAG are initially treated with topical
`medications. Ideally one should use the lowest dose of a partic-
`ular drug that will produce the greatest therapeutic response
`with the least number of side effects. Indeed, many of the
`currently available topical medications are associated with
`adverse effects, such as dry eye, burning, stinging sensations,
`tearing and allergic reactions (Jaenen et al., 2007). There is a
`general consensus to start glaucoma medical therapy with
`one topical intraocular pressure (IOP) lowering medication.
`If the first choice monotherapy alone is not effective to reduce
`IOP or is not tolerated, it is preferable to switch to another
`molecule that is initiated as monotherapy. Adjunctive therapy
`should be considered whenever a monotherapy does not reach
`target IOP or the target must be lowered as the disease is pro-
`gressing (South East Asia Glaucoma Interest Group, 2008;
`European Glaucoma Society, 2008c). Antiglaucoma drugs
`can be combined with each other in order to reach the target
`IOP. As a general rule, in most patients it is not recommended
`to use more than two drugs in two separate bottles or to add
`more than one single drug to a fixed-combination since compli-
`ance is likely to suffer. However, multiple topical treatments
`are often required to reduce the IOP to the desirable target.
`Glaucomatous patients have been shown to suffer from
`symptoms related to ocular surface disease (i.e., burning, itch-
`ing, red eye, tearing, blurred vision) in a higher prevalence than
`normal population (Stewart et al., 2011). Although the cause is
`
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`Antiglaucoma drugs: The role of preservative-free formulations
`
`391
`
`thought to be multi-factorial, the chronic use of topical medi-
`cations seems to play a major role and the prevalence appears
`to increase with the greater the number of antiglaucoma drops
`prescribed (Stewart et al., 2011). Long-term use of topical
`drugs, especially in those patients receiving a multiple drop
`regimen, may be detrimental as a dose- and time-dependent
`consequence to benzalkonium chloride exposure (Serle et al.,
`2004) There is now increasing evidence to demonstrate that a
`sizable portion of local side effects may result from the preser-
`vatives rather than from the active compounds. There may be
`a direct correlation between the presence of preservatives and
`the surface symptoms provoked by anti-glaucoma therapy
`(Serle et al., 2004); reducing such exposure could improve
`the patient’s comfort and thus his compliance.
`
`3. Antiglaucoma drugs and allergic reactions
`
`Topical IOP-lowering drugs can cause different reactions on
`ocular structures, especially on the ocular surface. Proper
`allergic reactions can be clinically serious, however, their inci-
`dence is definitely lower than the non-allergic alterations
`caused by the chronic use of such drugs. The incidence of
`proper allergic reactions is very different, depending on the
`compound. Immediate allergic reactions are less frequent with
`timolol than with other hypotensive drugs (Osborne et al.,
`2005).
`Some authors reported an incidence of 1.5% of allergic
`reactions with latanoprost, when used as a second-line therapy
`(Haverkamp et al., 2004).
`Allergic reactions with brimonidine have been reported to
`be between 4.2% and 25.7% (Manni et al., 2004); a lower
`incidence has been reported with the use of the fixed combi-
`nation brimonidine-timolol (Manni et al., 2004; Motolko,
`2008).
`Severe periocular dermatitis, possibly associated with atyp-
`ical likenoid reactions was reported to be associated with the
`use of dorzolamide, even months after the beginning of the
`therapy; the incidence of this type IV hypersensitivity reactions
`are over all quite uncommon (Mullins et al., 2004; Delaney
`et al., 2002).
`
`4. Antiglaucoma drugs and ocular surface
`
`Several epidemiological studies demonstrated that patients on
`local IOP-lowering therapies complained about local discom-
`fort (Jaenen et al., 2007; Pisella et al., 2002). The occurrence
`of ocular surface disease (OSD) may be related to different
`factors, such as age, sex, race, the presence of blepharitis and
`the use of preserved eye drops (Brewitt and Sistani, 2001;
`Baudouin and de Lunardo, 1998; Leung et al., 2008). Besides
`the allergic reactions caused by the active compounds, preser-
`vatives contained in the preparations may trigger an inflamma-
`tory response. As with all patients affected by OSD, signs and
`symptoms are not always related and many glaucomatous pa-
`tients that complain of dry eye symptoms do not have any
`measurable damage and vice-versa (Hay et al., 1998); however,
`the discomfort related to antiglaucoma eyedrops use has been
`reported as one of the most common causes of request for an
`ophthalmological consultation. The symptoms may be related
`either to the instillation or to the period between different ins-
`tillations. Stinging and burning are common just after the
`instillation of the eye-drops. Up to 25% of patients complain
`
`the occurrence of side effects such as ‘‘pain’’ immediately after
`the beginning of the therapy. The percentage rises up to 40% if
`the symptom sought for is ‘‘burning’’ that might also cause
`tearing. Other common symptoms are dry-eye sensation and
`itching of
`the palpebral margin. Conjunctival hyperemia
`related to topical prostaglandin application is usually consid-
`ered disagreeable by the patient. It is caused by a local vasodi-
`latation and its gravity is related to the compound and to
`individual reactivity (Hollo` , 2007). Usually the degree of
`hyperemia is apparently more severe than the symptoms (burn-
`ing, stinging and itching).
`Glaucoma patients are at high risk for developing ocular
`surface disease because:
` Both glaucoma and OSD incidence increases with the age.
` A large portion of glaucomatous patients are treated with
`preservative-containing pressure lowering eyedrops.
` The treatment is usually prolonged for years since glaucoma
`is a chronic disease.
`
`Besides OSD related discomfort and anatomical alterations,
`several authors found a correlation between chronic topical
`long-term therapy and a higher rate of subsequent filtration
`surgery failure (Leung et al., 2008; Broadway et al., 1994;
`Yee, 2007). Immediately after surgery fibroblasts tend to prolif-
`erate, in order to repair the incised tissues, thus reducing the
`filtration of aqueous humor to the subconjunctival space. An
`increase in inflammatory response leads to faster recruitment
`of fibroblasts that produce extracellular matrix. Long-term
`therapy with preserved local hypotensive drugs leads to con-
`junctival migration of macrophages and lymphocytes.
`The conjunctival inflammatory reaction in glaucomatous
`patients seems to be related both to the number of eye-drops
`instillation and to the duration of the therapy. The toxic effect
`of preservatives is likely to play a relevant role in the conjunc-
`tival cicatricial response after surgery (Baudouin, 1996, 2008).
`
`5. Antiglaucoma drugs and preservatives
`
`There is increasing evidence to demonstrate that a sizeable por-
`tion of local side-effects may result from the preservatives
`rather than from the active compounds. The most commonly
`used preservative in anti-glaucoma medications is benzalkoni-
`um chloride (BAK). BAK has been shown (Baudouin et al.,
`1999) to induce significant inflammatory and histopathological
`changes in both the ocular surface and deeper ocular struc-
`tures, and to induce apoptosis in conjunctival cells (Debbasch
`et al., 2001).
`As a quaternary ammonium, BAK, is most commonly asso-
`ciated with irritant toxic reactions (8% in OVID and PubMED
`based researches), whereas the organomercurials, such as thi-
`merosal, and the alcohols, such as chlorobutanol, have the
`highest associations with allergic responses
`(respectively,
`19% of OVID and 14% of PubMED based researches and
`20% of OVID and 11% of PubMED based researches). Such
`reactions appear mainly like an irritant effect for alcohols,
`whereas the organo-mercurials appear to truly interact with
`the immune system as neoantigens (Hong and Bielory, 2009).
`Non-quaternary ammonium preservatives seem to cause oxi-
`dative stress to a significantly lesser extent and to induce lower
`cell death rate than BAK (Debbash et al., 2001).
`
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`392
`
`A. Bagnis et al.
`
`The mechanism causing tear film instability, loss of globlet
`cells, conjunctival squamous metaplasia and apoptosis, disrup-
`tion of the corneal epithelium barrier and damage of deep ocu-
`lar tissues are far from being fully elucidated, but
`the
`involvement of immunoinflammatory reactions was proposed.
`The release of proinflammatory cytokines, apoptosis, oxidative
`stress as well as direct interactions with the lipid layer of the
`tear film and cell membranes are well established (Baudouin
`et al., 2010).
`
`6. Antiglaucoma drugs: how to reduce the exposure to
`preservatives?
`
`Despite consistent data confirming its potential toxic effects,
`especially for a chronic use, BAK is still used as the main pre-
`servative in eye drops. Considerable efforts have been made by
`the pharmaceutical industry in the recent past, however, to de-
`velop new antiglaucoma formulations that would bring about
`efficacy, safety and compliance. The most part of the antiglau-
`coma drugs that have been commercialized during the last
`years allows for a lower BAK exposure.
`Different strategies can be considered in order to reduce the
`amount of BAK administered when prescribing a therapeutic
`antiglaucoma regimen.
`
`6.1. Reducing the number of drops
`
`As BAK toxicity is mainly dose-dependent, reducing the num-
`ber of instillations can improve ocular tolerance (Baudouin
`et al., 2010).
`Prostaglandins and long-acting preparations of timolol are
`given once rather than twice a day, thus reducing the amount
`of BAK administered by 50% (Easty et al., 2006).
`The same occurs with the use of fixed-combined drugs prep-
`arations. Fixed combinations of timolol and prostaglandins,
`carbonic anhydrase inhibitors and brimonidine are currently
`on the market and represent an important tool in order to opti-
`mize glaucoma therapy. When two or more active molecules
`are necessary to obtain an adequate IOP, fixed-dose combina-
`tion eye drops may offer advantages for patients, while
`maintaining at least the same effect on IOP than separate
`instillation of the same two products (European Glaucoma
`Society, 2008c). As a general rule, compliance with any given
`medical therapy in glaucoma, like other chronic diseases, is
`better when regimens are simple rather than complex and
`reducing the number of daily administrations can positively
`affect patients’ quality of life (Olthoff et al., 2005). Moreover,
`
`the higher costs from more bottles seem to promote non-com-
`pliance and reduce persistence (Soumerai et al., 2006). Besides
`possible improved compliance, quality of life, costs saving and
`also additional IOP lowering effect for some molecules (Higg-
`inbothan, 2010), fixed combinations allow for halving the daily
`amount of BAK and related side-effects. Although no defini-
`tive data exist, at least some of the currently available fixed
`combination have shown a better safety profile and tolerability
`when compared with the same molecules used separately
`(Sleath et al., 2006; Hommer, 2007).
`
`6.2. Using of preserved formulation not containing BAK
`
`Overall, BAK has an apparently good safety/efficacy profile; it
`is weakly allergenic and has a high rate of antimicrobial prop-
`erties. Worth to remember is that the Pharmacopoeia recom-
`mends that eye drops must contain an antimicrobial agent
`(preservative) to avoid or limit microbial proliferation after
`opening of the bottle, which could induce a risk of potentially
`severe eye infection as well as alteration of the formulation
`(Baudouin et al., 2010). Conversely, definitive data suggest that
`avoiding its toxicity should be of benefit for a large portion of
`glaucomatous patients. Extensive research has been conducted
`to discover and develop less toxic preservatives than quaternary
`ammoniums. However, since preservatives must be potent anti-
`microbial agents while not being cytotoxic, only few agents
`have been proposed and are commercially available (Baudouin
`et al., 2010). PuriteÒ is a stabilized oxychloro complex acting as
`an oxidative preservative that is converted into natural tear
`components when exposed to light (Kim et al., 2007). This mol-
`ecule has shown a wide spectrum of antimicrobial activity and a
`very low-level toxicity in mammalian cells (Grant et al., 1996).
`When PuriteÒ was used in formulations of brimonidine 0.15%
`it resulted in significantly better tolerance as compared to BAK
`containing brimonidine 0.2%, especially in irritated eyes (Mun-
`dorf et al., 2003). SofziaÒ is a preservative system composed of
`boric acid, propylene glycol, sorbitol and zinc chloride that
`causes oxidative damage and consequent death to organisms
`that lack the enzymes cytochrome oxidase and catalase, such
`as most species of bacteria; human cells posses these enzymes
`and are thus not similarly harmed (Ammar et al., 2010). Henry
`and coworkers found significant improvement of ocular surface
`symptoms and hyperemia and similar IOP lowering effect when
`patients treated with latanoprost or bimatoprost were switched
`to Sofzia-preserved travoprost (Henry et al., 2008). Polyquad
`(polyquaternium-1) belongs to the family of plycationic poly-
`mers named polyquaternium and is commonly used as a multi-
`
`Table 1
`
`Summary of the antiglaucoma drugs currently available in either preservative- and/or BAK-free formulations.
`
`Category
`
`b-Blockers
`
`Carbonic anhydrase inhibitors
`a-Agonists
`Prostaglandin analogues/prostamides
`
`Parasympathomimetics
`Fixed combinations:
`
`Molecule
`
`Timolol 0.5–0.1%
`Betaxolol 0.25%
`Levobunol 0.5%
`Carteolol 1–2%
`Dorzolamide 2%
`Brimonidine 0.1–0.15%
`Tafluprost 0.0015%
`Travoprost 0.004%
`Pilocarpine
`Timolol-Dorzolamide
`
`Pharmaceutical form
`Single dose container/ABAKÒ, COMODÒ system
`Single dose container
`Single dose container
`Single dose container/ABAKÒ system
`Single dose container
`BAK-free solution (preservative: PuriteÒ)
`Single dose container
`BAK-free solution (preservative: SofziaÒ, Polyquad)
`Single dose container
`Single dose container
`
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`
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`Antiglaucoma drugs: The role of preservative-free formulations
`
`393
`
`purpose solution for contact lenses and is currently used in eye
`drops as an alternative to BAK (Lipener, 2009). Labbe et al
`showed higher toxic effects in the ocular surface of rats treated
`with BAK than those exposed to Polyquad (Labbe et al., 2006).
`Similarly, Ammar et al found that the substitution of BAK with
`Polyquad resulted in significantly higher percentages of human
`live conjunctival and corneal cells (Ammar et al., 2011).
`
`6.3. Preservative-free formulations
`
`The only way to completely eliminate BAK/preservative-
`related side effects is obviously to remove them from the
`eyedrops. However, due to the above mentioned Pharmaco-
`poeia recommendations, this approach raises industrial and
`regulatory concerns since non-preserved eyedrops in multidose
`bottles could enhance the risk of contamination.
`To address this concern, single-dose units are the most fre-
`quently used preservative-free formulations. Different beta-
`blockers, pilocarpine and more recently a fixed combination
`of timolol and dorzolamide as well as the prostaglandin ana-
`logue tafluprost have been commercialized as single-dose units
`(Hommer and Kimmich, 2011). Less cost-effectiveness and dif-
`ficult handling have been pointed out regarding these formula-
`tions and their use by older patients and with inappropriate
`finger manipulation could be associated with an increased risk
`of contamination. However, Kim et al reported that even in
`the worst conditions of poor administering technique of unpre-
`served artificial tears, only 2% of 242 reclosable containers had
`bacterial contamination after three times or more instillation
`within 10 h (Kim et al., 2008). Conversely, Tasli and Cosar
`found a 35% rate of contamination after 15 days in a multi-
`ple-use setting of bottles preserved with BAK (Tasli and
`Cosar, 2001).
`Newer multidose formulations have been developed: either
`by allowing for preservative filtration and adsorption on a por-
`ous membrane or by using a valve system that hinders penetra-
`tion of bacteria into the bottle (Baudouin et al., 2010).
`Different beta-blockers have been available with the ABAKÒ
`or COMODÒ systems for a number of years. Different clinical
`studies confirmed substantial
`improvement of the patient’s
`ocular surface after starting the use of BAK-free drops
`(Baudouin et al., 2010).
`
`7. Conclusions
`
`When selecting medical treatment for glaucoma it is impor-
`tant to understand not only the primary aim of the therapy
`but also contraindications and side effects of each medication
`for every single patient. Besides efficacy, the choice of therapy
`must take into account tolerability, related quality of life and
`adherence to treatment (European Glaucoma Society, 2008c).
`Preservatives contained within topical eye drop preparations
`may cause inflammatory conjunctival side effects and toxicity
`of the ocular surface (Blondin et al., 2003; Baratz et al.,
`2006).
`The use of preservative-free preparations/delivery systems,
`the reduction of the number of instillation or the choice of for-
`mulations containing preservatives less toxic than BAK should
`be considered to lessen such problems. This should lead to bet-
`ter tolerability and possibly higher adherence to the treatment
`and improvement of patients’ quality of life.
`
`Within the past 5–7 years, a number of ocular hypotensive
`drugs have been re-formulated in preservative-free versions
`and some have changed preservatives, while maintaining
`equally effective IOP-lowering effects. Preservative free formu-
`lations of timolol, betaxolol, dorzolamide, a fixed combination
`of timolol-dorzolamide and tafluprost are actually available;
`formulations of travoprost and brimonidine containing preser-
`vatives less toxic than BAK are also available (see Table 1).
`As a general rule, preservative-free eyedrops could be partic-
`ularly beneficial to patients with the following characteristics
`(Baudouin, 2008; Bagnis et al., 2011; European Glaucoma
`Society, 2008a,b,c):
` pre-existing or concomitant dry eye/ocular surface disease
` those receiving a multidrug topical treatment
` those whose treatments are expected to last over several
`years/decades
` those who are about to undergo glaucoma surgery.
`
`Patients showing one or more of these features are likely to
`benefit from BAK-free formulations as well as from minimiz-
`ing the exposure to BAK by the use of fixed combined
`preparations.
`
`References
`
`Ammar, D.A., Noecker, R.J., Kahook, M.Y., 2010. Effects of
`benzalkoium chloride-preserved, polyquad-preserved, and Sofzia-
`preserved topical glaucoma medications on human ocular epithelial
`cells. Adv. Ther. 27, 837–845.
`Ammar, D.A., Noecker, R.J., Kahook, M.Y., 2011. Effects of
`benzalkonium chloride- and polyquad-preserved combination
`glaucoma medications on cultured human ocular surface cells.
`Adv. Ther. 28, 501–510.
`Bagnis, A., Papadia, M., Scotto, R., Traverso, C.E., 2011. Current and
`emerging medical therapies in the treatment of glaucoma. Expert
`Opin. Emerging Drugs 16, 293–307.
`Baratz, K.H., Nau, C.B., Winter, E.J., McLaren, J.W., Hodge, D.O.,
`Herman, D.C., Bourne, W.M., 2006. Effects of glaucoma medica-
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