DEWS MANAGEMENT AND THERAPY
`
`IlL ASSESSMENT OF CURRENT DRY EYE ThERAPIES
`
`OUTliNE
`
`Introduction
`
`II Goals of the Management
`Subcommittee
`
`arid Therapy
`
`III Assessment of current dry eye therap3es
`
`Tear supplementation Iubncants
`
`General charactenstscs
`
`and eflècts
`
`.1
`
`Preservatives
`
`Electrolyte composaon
`
`Osmoiarity
`
`Viscosity agents
`
`Summary
`
`Teat Retention
`
`Punctal occlusion
`
`Rationale
`
`b.Types
`
`Clinical studies
`
`d1 lAdications and contraindications
`
`Compilcations
`
`Summary
`Mosture chamber spectacles
`
`Contact
`
`lenses
`
`Tear stimulation secretagogues
`
`tear substitutes
`
`Biological
`
`ISomm
`
`Sallvaiygiind autotransplantation
`
`AntWnfiarnrnatory
`
`therapy
`
`Cyclosporine
`
`Corticosteroids
`
`CliAlcal studies
`
`Basic research
`
`Tetracyclines
`
`Properties of tetra
`derivatives
`
`rnei and their
`
`Arthbactenal properties
`
`Mti4nflarnmatory
`
`Anti-anglcgenoc properties
`
`Chnccal applications
`
`of tetracycline
`
`Acne Rosacea
`
`Chronic posterior blepharitis
`meibomlanitis melbomian gland
`dysfunction
`
`Dosage aid safety
`
`Essential fatty acids
`
`Environmenta
`
`strategies
`
`IV Treatment
`
`recommendations
`
`Unanswered questions and future directions
`
`by afl subcommittee members and by the entire Dry Eye
`WorkShop membership Comments and suggested
`revi
`sions were discussed by the subcommittee members and
`incorporated into the report where deemed appropriate
`by consensus
`
`It
`
`it
`
`tests or
`
`Tear Supplementation Lubricants
`General Characteristics and Effects
`The term artificial
`tears is misnomer for most prod
`ucts that identify themselves as such because they do not
`mimic the composition of human tears Most
`function as
`formulations mimic
`lubricants although some more recent
`the electrolyte composition of human tears TheraTears
`Vision Research Woburn MA2 The ocular
`lubricants presently available in the United States are ap
`proved based on the US Food and Drug Administration
`FDA monograph on over-the-counter OTC products
`21 CFR 349 and are not based on clinical efficacy The
`specifies permitted active ingredients eg
`monograph
`demulcents emulsifiers surfactants and viscosity agents
`and concentrations
`on
`but gives only limited guidance
`inactive additives and solution parameters Certain iriac
`tive ingredients that are used in artificial
`tears sold in the
`Inc Irvine CA
`US eg castor oil
`in Endurat
`Ft Worth TX are not listed
`and guar in Systane
`in the monograph
`in an ocular
`is difficult
`to prove that any ingredient
`If there is an active in
`lubricant acts as an active agent
`is the polymeric base or viscosity agent but
`gredient
`to demonstrate This is either
`this has proved dfflcuit
`the effects or differences
`because it
`is not possible to detect
`trials with presently available clinical
`in clinical
`because the currently available agents do not have any
`lubrication effect
`discernable clinical activity beyond
`tears have demonstrated more
`Although certain artificial
`success than others in reducing symptoms of irritation
`or decreasing ocular surface dye staining in head-to-head
`there have been no large scale masked
`compansons
`trials to evaluate the wide variety of
`comparative clinical
`ocular lubricants
`What is the clinical effect of ocular lubricants or artificial
`tears Do they lubricate replace missing tear constituents
`tear film osmolarity dilute or wash out
`reduce
`elevated
`inflammatory or inflammation-inducing agents Do they
`in some instances actually wash out essential substances
`found in normal human tears These questions remain to
`tests become avail
`be answered as more sensitive clinical
`able to detect changes in the ocular surface
`The foremost objectives in caring for patients with dry
`eye disease are to improve the patienth ocular comfort and
`quality of life and to return the ocular surface and tear film
`to the normal homeostatic state Although symptoms can
`rarely be eliminated they can often be improved leading
`is more difficult
`to an improvement
`in the quality of life It
`to demonstrate that topical
`lubricants improve the ocular
`surface and the tear film abnormalities associated with dry
`eye Most clinical studies fail
`to demonstrate significant
`between symptoms and clinical
`correlation
`or between the clinical
`test values themselves.3-5 It
`is not
`dry eye with only mild symptoms to show
`rose bengal staining Until agents are developed
`significant
`that can restore the ocular surface and tear film to their
`
`unusual
`
`for
`
`test values
`
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`normal homeostatic state the symptoms and signs of dry
`eye disease will continue
`Ocular
`lubricants are characterized by hypotonic or
`isotonic buffered solutions containing electrolytes surfac
`tants and various types of viscosity agents In theory the
`lubricant should be preservative-free contain
`ideal artificial
`potassium bicarbonate and other electrolytes and have
`polymeric system to increase its retention time
`Physical
`to slightly alkaline pH
`properties should include
`neutral
`Osmolarities of artificial
`tears have been measured to range
`to 354 mOsmJL9 The main variables in the
`formulation of ocular lubricants regard the concentration
`of and choice of electrolytes the osmolarity and the type
`system the presence or absence of
`of viscosity/polymeric
`preservative and if present
`the type of preservative
`
`from about
`
`Preservatives
`The single most critical advance in the treatment of dry
`eye came with the elimination of preservatives
`such as benzal
`konium chloride BAK from OTC lubricants Because
`of the risk of contamination of multidose products most
`preservative or employ some mechanism
`either contain
`The FDA has required that
`for minimizing contamination
`muitidose artificial
`tears contain preservatives to prevent
`microbial growth Preservatives
`are riot required in unit
`single use The wide
`dose vials that are discarded after
`preparations allows
`of nonpreserved
`spread availability
`lubricants more frequently without
`patients to administer
`concern about the toxic effects of preservatives For patients
`with moderate-to-severe dry eye disease the absence of
`is of more critical
`importance than the particu
`preservatives
`lar polymeric agent used in ocular lubricants The ocular
`surface inflarrirtiation associated with dry eye is exacerbated
`by preserved lubricants however nonpreserved solutions
`are inadequate in themselves to improve the surface inflarn
`se
`mation and epithelial pathology seen in dry eye
`Benzaikonium chloride is the most
`frequently used
`preservative in topical ophthalmic preparations
`as well as
`toxic effects have been
`lubricants Its epithelial
`in topical
`well established2-7 The toxicity of BAK is related to its
`concentration the frequency of dosing the level or amount
`of tear secretion and the severity of the ocular surface
`disease In the patient with mild dry eye BAK-preserved
`drops are usually well tolerated when used 4-6 times
`day
`or less in patients with moderate-to-severe dry eye the
`for BAK toxicity is high due to decreased
`tear
`potential
`secretion and decreased turnover.7 Some patients may be
`using other topical preparations eg glaucoma medications
`that contain BAK increasing their exposure to the toxic
`effects of I-lAX Also the potential
`for toxicity exists with
`patient abuse of other OTC products that contain BAK
`such as vasoconstrictors
`BAK can damage the corneal and conjunctival epithe
`hum affecting cell-to-cell
`and cell shape and
`junctions
`rnicrovilli eventually leading to cell necrosis with sloughing
`of 1-2 layers of epithelial cells.7 Preservative-free formula
`for patients with severe dry
`tions are absolutely necessary
`
`eye with ocular surface disease and impairment of lacrirnal
`gland secretion or for patients on multiple preserved
`topical medications for chronic eye disease Patients with
`severe dry eye greatly reduced tear secretion and punctal
`occlusion are at particular
`risk for preservative toxicity In
`such patients the instilled agent cannot be washed out if
`this risk has not been appreciated by the clinician preserved
`drops might be used at high frequency
`Another additive used in OTC formulations is disodium
`EDTA lt augments the preservative efficacy of BAK and
`other preservatives but by itself
`is not
`sufficient pre
`servative Used in some nonpreserved solutions it may
`help limit microbial growth in opened unit-dose vials
`Although use of EDTA may allow lower concentration of
`preservative EDTA may itself be toxic to the ocular surface
`epithelium study comparing two preservative-free solu-
`tions Hypotears PP Novartis Ophthalmics East Hanover
`NJ containing EDTA and Refresh Allergan Inc Irvine
`CA without EDTA showed that both formulations had
`identical safety profiles and were completely nontoxic to
`the rabbit corneal epithelium Other studies found that
`EDTA-contairiing preparations increased corneal epithehial
`permeability920 The potential exists that patients with
`severe dry eye will find that EDTA-containing preparations
`increase irritation
`
`it
`
`single unit-dose tear substitutes are
`Nonpreserved
`to produce more
`more costly
`for the manufacturer
`costly for the patients to purchase and less convenient
`to use than bottled ocular
`lubricants For these reasons
`reciosable unit dose vials eg Refresh Free
`Inc
`Irvine CA Tears Natural Free
`Fort Worth
`TX were introduced Less toxic preservatives
`such as
`polyquad polyquaterniurn-1 sodium chlorite Purite
`and sodium perborate were developed to allow the use
`of muitidose bottled lubricants and to avoid the known
`The vanishing
`toxicity of BAlK-containing solutions.2122
`preservatives were sodium perborate and sodium chlorite
`Vision Research Woburn MAI
`TheraTears
`East 1-lanover NJ and Refresh Tears
`Genteal
`lAllergan Inc Irvine CA
`Sodium chlorite degrades to chloride ions and water
`upon exposure to UV light after instillation Sodium perbo
`rate is converted to water and oxygen on contact with the
`tear film For patients with severe dry eye even vanishing
`preservatives may not totally degrade due to decrease in
`tear volume and may be irritating
`Patients prefer bottled
`preparations for reasons of both cost and ease of use The
`lubricant would come in multidose easy--to-use
`ideal
`bottle that contains
`that completely dissipates
`preservative
`before reaching the tear film or is completely nontoxic arid
`nonirritating and maintains absolute sterility with frequent
`use One such multi-use preservative-free product has
`been introduced to the market Visine PureTears
`mc NJ
`Ocular ointments and gels are also used in treatment of
`dry eye disease Ointments are formulated with
`specific
`mixture of rumeral oil and petrolazum Some contain lanolin
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`which can be irritating to the eye and delay cornea wound
`heahng Individuals with sensitivity to wool may also be
`sensitive to lanolin.23 Some ointments contath paraberis as
`preservatives and these ointments are not well
`tolerated
`by patients with severe thy eye In general ointments do
`not support bacterial growth and therefore do not require
`preservatives Gels containing high molecular weight cross
`linked polymers of acrylic acid carbomers have longer
`retention times than artificial
`tear solutions but have less
`than petrolatum ointments
`
`visual blurring effect
`
`Electrolyte Composition
`Solutions containing electrolytes and or ions have been
`shown to be beneficial
`in treating ocular surface damage
`due to dry eye.6202425
`To date potassium and bicarbon
`ate seem to be the most critical Potassium is important to
`maintain cornea thickness.7
`In dry-eye rabbit model
`hypotonic tear-matched electrolyte solution TheraTears
`Vision Research Woburn MAD increased con
`junctival goblet cell density and corneal glycogen content
`and reduced tear osmolarity and rose bengal staining after
`weeks of treatment.25 The restoration of conjunctival goblet
`cells seen in the thy-eye rabbit model has been corroborated
`in patients with dry eye after LASIK28
`Bicarbonate-containing solutions promote the recovery
`of epithelial barrier ftinction in damaged comical epithelium
`and aid in maintaining normal epithelial ukrastructure
`for maintaining the mucin layer
`They may also be important
`of the tear film.6 Ocular lubricants are available that mimic
`the electrolyte composition of human tears eg TheraTears
`Advanced Vision Research Woburn MA and BION Tears
`Alcon Fort Mnth TX.2 These also contain bicarbonate
`which is critical
`for forming and maintaining the protec
`tive mucin gel
`in the stomach.27 Bicarbonate may play
`similar role for gel-forming mucins on the ocular surface
`Because bicarbonate is converted to carbon dioxide when
`in contact with air and can diffuse through the plastic unit
`dose vials foil packaging of the plastic vials is required to
`maintain stability
`
`artificial
`
`Osnrolarily
`Tears of patients with dry eye have
`tear film
`higher
`osmolarity crystalloid osmolarity than do those of normal
`patients.28.29 Elevated tear film osmolarity causes mor
`to the corneal and
`phological and biochemical
`changes
`conjunctival epithel urn8.3 and is pro-inflammatory3 This
`knowledge influenced the development of hypo-osmotic
`tears such as Hypotears 230 mOsmfL
`Ophthalmics East Hanover NJ and subsequently Thera
`Tears 181 rnOsrn/L
`Vision Research Woburn
`MA32
`Colloidal osmolality is another
`factor
`that varies in
`tear formulations While crystalloid osmolarity
`artificial
`is related to the presence of ions colloidal osmoiaiity is
`largely on macrornolecule content Colloidal
`dependent
`osmolarity also known as oncotic pressure is involved in the
`control of water transport in tissues Differences
`in colloidal
`
`osmolality affect the net water flow across membranes and
`water flow is eliminated by applying hydrostatic pressure
`to the downside of the water flow The magnitude of this
`osmotic pressure is determined by osmolality differences
`on the two sides of the membrane Epithelial cells swell
`due to damage to their cellular membranes or due to
`dysfunction in the pumping mechanism Following the
`addition of
`fluid with
`high colloidal osmolality to the
`damaged cell surface deturgescence
`occurs leading to
`return of normal cell physiology Theoretically an artificial
`tear formulation with high colloidal osmolality may be of
`value Holly and Esquivel evaluated many different artificial
`tear formulations and showed that Hypotears Novartis
`Ophthaimic.s East Hanover NJ had the highest colloidal
`osmolality of all of the formulations tested.33 Formulations
`with higher colloidal osmolality have since been marketed
`Eye Company Silverdale WAD
`Dwelle
`Protection against the adverse effects of increased os
`molarity osmoprotection has led to development of OTC
`drops incorporating compatible solutes such as glycerin
`erythritol and levocarnitine Optive
`Inc Irvine
`CA it
`is thought that the compatible solutes distribute be
`tween the tears and the intracellular fluids to protect against
`potential cellular damage from hyperosmolar
`tears.34
`
`as
`
`Viscosity Agents
`The stability of the tear film depends
`on the chemical-
`film interacting with the
`physical characteristics of that
`and cornea epithelium via the membrane
`conjunctival
`spanning mucths ie MUC 16 and MUC-4 In the classical
`the mucin layer is usually
`three-layered tear film model
`surfactant or wetting agent acting to lower
`thought of as
`tension of the relatively hydrophobic
`ocular
`the surface
`cells wet
`surface rendering the comical and conjunctival
`table.33 Currently the tear film is probably best described
`hydrated mucin gel whose mucin concentration
`decreases with distance
`from the epithelial cell surface It
`protective role similar to that of mucin in the
`may have
`stomach35 It may also serve as sink or storage vehicle
`secreted by the main and accessory lacrimal
`for substances
`glands and the ocular surface cells This may explain why
`most of the available water-containing lubricants are only
`in restoring the normal horneostasis
`minimally effective
`the ocular surface In addition to washing away and
`of
`diluting out irritating or toxic substances
`in the tear film
`lubricants hydrate gel-forming roucin While some
`patients with dry eye have decreased aqueous lacrimal gland
`secretion alterations or deficiencies involving mucin also
`cause dry eye
`Macromolecular complexes added to artificial
`lubricants
`act as viscosity agents The addition of
`viscosity agent in
`creases residence time providing
`longer interval of patient
`comfort For example when
`viscous anionic charged
`carboxymethyi-ceiluiose CIVIC 100000mw solution was
`compared with neutral hydroxyrnethylcellulose HPMC
`solution CMC was shown to have
`significantly slower rate
`of clearance from
`the eye.36 Viscous agents in active drug
`
`artificial
`
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`the surface
`
`in
`formulations may also prolong ocular surface contact
`creasing the duration of action and penetration of the drug
`Viscous agents may also protect
`the ocular surface
`is known that rose bengal stains abnormal
`epithelium It
`comeal and conjunctival epithelial cells expressing an al
`tered mucin glycocalytc.37 Agents such as hydrosymethycel.
`lulose HMC which decrease rose bengal staining in thy
`eye subjects38 may either coat and protect
`epithelium or help restore the protective effect of mucins
`In the US carboxymethyl cellulose is the most corn
`moniy used polymeric viscosity agent IRI Market Share
`Data Chicago 1L typically in concentrations fmm 025%
`to 1% with differences in molecular weight also contrib
`uting to final product viscosity Carboxymethyl
`cellulose
`has been found to bind to and be retained by human epi.
`thelial cells.39 Other viscosity agents included in the FDA
`monograph in various concentrations
`include polyvinyl
`alcohol polyethylene glycol glycol 400 propylene glycol
`hydroxymethyl cellulose and hydroxypropyl cellulose
`The blurring of vision and esthetic disadvantages of cak
`ing and thying on eyelashes are drawbacks of highly viscous
`agents that patients with mild to moderate dry eye will
`not
`tolerate l.ower molecular-weight
`viscous agents help
`to minimize these problems Because patient compliance
`comfort and convenience
`are important considerations
`range of tear substitute formulations with varying viscosi
`ties are needed
`Hydroxypropyl-guar HP-guar has been used as gel
`in solution containing glycol 400 and propyl
`ene glycol Systane Alcon Fort Worth TX It has been
`that HP.guar preferentially binds to the more
`suggested
`hydrophobic desiccated
`or damaged
`areas of the surface
`epithelial cells providing temporary protection for these
`cells.404 Several commercial preparations containing oil
`in
`inc Irvine CA
`the form of castor oil EnduraT
`L.ornb Rochester NY
`or mineral oil Soothe
`are purported to aid in restoring or increasing the lipid layer
`that
`of the tear film.4243 Hyaluronic acid is
`viscosity agent
`years as an active compound
`has been investigated for
`added to tear substitute formulations
`for the treatment of
`acid 0.2% has significantly
`thy eye Hyaluronic
`longer
`residence times than 0.3 percent HPMC
`ocular surface
`or 1.4 percent polyvinyl alcohol Some clinical studies
`reported improvement
`in
`dry eye in patients treated
`with sodium hyaluronate-contairting
`solutions compared
`to other
`lubricant solutions whereas others did not.48
`Although lubricant preparations containing sodium hyal
`uronate have not been approved for use in the US they are
`frequently used in some countries
`
`ling agent
`
`Swnmary
`lubricants with various viscos
`Although many topical
`ity agenis may improve symptoms and objective findings
`there is no evidence
`to another
`that any agent
`is superior
`Most clinical
`lubricant preparations
`trials involving topical
`will document some improvement but not resolution of
`subjective symptoms and improvement
`in some objective
`
`the improvements noted are not
`parameters.4 However
`necessarily any better than those seen with the vehicle or
`lubricants The elimination
`other nonpreserved artificial
`of preservatives and the development of newer
`less toxic
`preservatives have made ocular lubricants better tolerated
`lubricants which
`by dry eye patients However ocular
`have been shown to provide some protection of the ocular
`in patient symp
`surface epitheium and some improvement
`torus and objective findings have not been demonstrated
`trials to be sufficient
`in controlled clinical
`to resolve the
`ocular surface disorder and inflammation seen in most dry
`
`eye sufferers
`
`Tar Rtettkrn
`Puctat Ocdaon
`Rationdle
`While the concept of permanently occluding the lacri
`mual puncta with cautery to treat dry eye extends back 70
`years49 and although the first dissolvable implants were
`used 45 years ago5 the modem era of punctal plug use
`began in 1975 with the report by Freeman.5 Freeman de
`dumbbell-shaped silicone plug which
`scribed the use of
`rests on the opening of the punctum and extends into the
`canaliculus His report established concept of punctal oc
`clusion which opened the field for development of variety
`removable long-lasting plugs to retard tear clearance
`of
`to treat the ocular surface of patients with
`in an attempt
`tear production The Freeman style plug
`deficient aqueous
`remains the prototype for most styles of punctal plugs
`
`T3pes
`Punctal plugs are divided into two main types absorb
`able and nonabsorbable The former are made of collagen
`or polymers and last
`for variable periods of time
`days
`to months The latter nonabsorbable permanent plugs
`include the Freeman style which consists of
`surface collar
`neck and wider base In
`resting on the punctal opening
`the Herrick plug Lacrimedics
`contrast
`tee and is designed to reside within
`like
`is shaped
`golf
`the canaliculus It is blue for visualization other variations
`
`newly designed cylindrical Smartpiugm
`
`are radiopaque
`CA expands and increases
`Medermium Inc
`diameter
`in situ following insertion into the canaliculus
`due to thermodynamic properties of its hydrophilic acrylic
`composition
`
`in
`
`CThücaI SLides
`
`fall
`
`variety of clinical studies evaluating the efficacy of
`punctal plugs have been reported.52 These series generally
`into Level
`II evidence Their use has been associated
`with objective and subjective improvement
`with both Sjogren and non-Sjogren aqueous
`dry eye filamentary keratitis contact
`lens intolerance
`StevensJohnson disease severe trachoma neurotrophic
`keratopathy post-penetrating keratopiast diabetic kera
`topathy and post-photorefractive
`keratectomy or laser in
`situ keratomileusis Several studies have been performed
`
`in patients
`
`tear deficient
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`to evaluate the effects of punctai plugs on the efficacy of
`glaucoma medications in reducing intraocular pressure
`and these studies have reported conflicting
`results.755
`Beneficial outcome in dry eye symptoms has been reported
`in 74-86% of patients treated with punctal plugs Objective
`reported with the use of punctal
`indices of improvement
`plugs include improved comeal staining prolonged tear
`film breakup time TEBUT decrease in tear osmolarity
`and increase in goblet cell density Overall the clinical util
`ity of punctal plugs in the management of dry eye disease
`has been well documented
`
`that
`
`Schirrner
`
`Indk4tions and Contindicatmas
`review on punctal plugs it was reported
`In
`recent
`in major eye clinic punctal plugs are considered
`indicated in patients who are symptomatic of dry eyes
`test with anesthesia result less than
`have
`mm at minutes and show evidence
`dye staining.55
`to the use of punctal plugs include
`Contraindications
`allergy to the materials used in the plugs to be implanted
`punctal ectropion and pre-existing riasalacrimal duct ob
`struction which would presumably negate the need for
`punctal occlusion It has been suggested
`that plugs may
`be contraindicated in dry eye patients with clinical ocular
`inflammation because occlusion of tear outflow
`surface
`would prolong contact of
`the abnormal
`tears contain
`ing proinflammatory cytokines with the ocular surface
`Treatment of
`the ocular surface inflammation prior to
`plug insertion has been recommended Acute or chronic
`infection of the lacrimal canaliculus or lacrimal sac is also
`
`of ocular surface
`
`contraindication
`
`to use of
`
`plug
`
`CopUctions
`The most common complication
`of punctal plugs is
`spontaneous plug extrusion which is particularly common
`with the Freeman-style plugs Over time an extrusion rate
`of 50% has been reported but many of these extrusions
`took place after extensive periods of plug residence Most
`for incon
`extrusions are of small consequence except
`and expense More troublesome complications
`venience
`include internal migration of plug bioflim formation and
`infection and pyogenic granulorna formation Removal of
`migrated canalicular plugs can be difficult and may require
`surgery to the nasolacrimal duct system.606
`
`Sunrnay
`The extensive literature on the use of punctal plugs in
`the management of dry eye disease has documerted their
`recent reports however
`Several
`have suggested
`utility
`that absorption of tears by the nasolacrimal ducts into sur
`rounding tissues and blood vessels may provide
`feedback
`mechanism to the lacrimal gland regulating tear produc
`tion.62 In one study placement of punctal plugs in patients
`significant decrease
`with normal tear production caused
`weeks after plug insertion.53
`in tear production for up to
`This cautionary note should be considered when deciding
`
`whether
`
`to incorporate punctal occlusion into
`disease management plan
`
`dry eye
`
`Moistnre Chambex Spectacles
`The wearing of moisture-consewing spectacles has for
`to alleviate ocular discomfort
`many years been advocated
`the level of evidence sup
`associated with dry eye However
`for dry eye treatment has been relatively
`porting its efficacy
`limited Taubota et al using
`sensitive moisture sensor
`reported an increase
`in periocular humidity in subjects
`wearing such spectacies Addition of side panels to the
`spectacles was shown to further increase the humidity65
`The clinical efficacy of moisture chamber spectacles
`has
`been reported in case reports.8567 Kurihashi proposed
`for dry eye patients in the farm of wet
`related treatment
`gauze eye mask Conversely Nichols et al recently report
`ed in their epidemiologic study that spectacle wearers were
`twice as likely as emmetropes to report dry eye disease
`The reason for this observation was not explained
`There have been several
`with relatively high
`reports
`level of evidence describing the relationship between
`environmental humidity and dry eye Korb et
`in periocular humidity caused
`increases
`significant
`increase in thickness of the tear film lipid layer.7 Dry eye
`showed significantly
`subjects wearing spectacles
`longer
`interblink intervals than those who did not wear spectacles
`and duration of blink blinking time was significantly
`longer in the latter subjects.7 Instillation of artificial
`tears
`
`reported
`
`that
`
`caused
`increase in the interblink interval and
`significant
`decrease in the blink rate.71 Maruyama et al reported that
`lens wearers
`dry eye symptoms worsened in soft contact
`when environmental humidity decreased.72
`
`corneal
`
`Contact Lenses
`lenses may help to protect and hydrate the
`Contact
`corneal surface in severe dry eye conditions Several differ
`ent contact
`lens materials and designs have been evaluated
`including silicone rubber lenses and gas permeable scieral
`lenses with or without
`fenestmtion.777
`bearing hard contact
`visual acuity and comfort decreased
`improved
`and healing of persistent cornea epithelial
`epitheliopathy
`defects have been reported.7377 Highly oxygen-permeable
`materials enable overnight wear in appropriate circum
`stances.75 There is
`small risk of corneal vascularization
`and possible corneal
`infection associated with the use of
`lenses by dry eye patients
`contact
`Tha 8dm to scretogogsn
`Several potential
`agents may
`topical pharmacologic
`secretion mucous secretion or both
`stimulate aqueous
`The agents currently under investigation by pharmaceuti
`cal companies are diquafosol one of the P212 receptor
`agonists rebamipide gefamate ecabet sodium mucous
`secretion stimulants and 15S-HETE Mud stimulant
`Among them diquafósol eye drop has been favorably
`trials 2% diquafosol 1NS365 DE-089
`evaluated in clinical
`Osaka Japan Inspire Durharn NC proved to
`
`168
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`THE OCULAR SURFACE
`
`APRIL 2007 VOL
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`NO
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`www.theocuIarsurface.com
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`FAMY CARE - EXHIBIT 1004-0349
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`
`DEWS MANAGEMENT AND THERAPY
`
`be effective
`
`in the treatment of dry eye in randomized
`in humans to reduce ocular surface
`double-masked trial
`
`similar study demonstrated the ocular safety
`staining.78
`double-masked placebo-
`and tolerability of diquafosol
`in
`controlled randomized study79 This agent
`is capable of
`stimulating both aqueous and mucous secretion in animals
`and humans.803 Beneficial effects on corneal epithelial
`barrier function as well as increased
`tear secretion has
`been demonstrated in the rat dry eye rnodel Diquafosol
`also has been shown to stimulate mucin release from goblet
`cells in rabbit thy eye modei.85
`The effects of rebamipide OPC 12759 LOtsuka Rock
`vile MD Novartis
`Switer1and have been evalu
`
`ated in human clinical
`trials in animal studies rebamipide
`increased the mucin-like substances on the ocular surface
`It also bad hy
`rabbit eyes.87
`effects on UVB-induced conical
`
`trials
`
`keratocon
`
`of N-acetyicysteine-treated
`droxyl radical scavenging
`damage in mice.as
`Ecabet sodium Senju
`Japan ISTA
`CA is being evaluated in clinical
`trials internationally
`but oniy limited results have yet been published
`single
`instillation of ecabet sodium ophthalmic solution elicited
`increase in tear mucin in thy eye
`statistically significant
`Japan has been
`patients.89 Gefarnate Santen
`in animal studies Gefarnate promoted mucin
`evaluated
`injury in monkeys.9 Gefar
`production after conjunctival
`nate increased PAS-positive cell density in rabbit conjunc
`tiva and stimulated mucin-like glycoprotein stimulation
`from rat cultured conical epithelium.9192 An in viva rabbit
`similar result93
`experiment showed
`The agent 15S-HETE
`unique molecule can
`stimulate MUC1 mucin expression on ocular surface
`protected the cornea in rabbit
`epitheiium.9515S-HETE
`model of desiccation-induced
`injury probably because of
`mucin secretion.9 It has been shown to have beneficial
`effects on secretion of mucin-like glycoprotein by the rab
`bit conical epitheiiurn.97 Other laboratory studies confirni
`the stimulatory effect of 15S-HETE.98 Some of these
`agents may become useful clinical
`therapeutic modalities
`in the near future
`Two orally administered cholinergic agonists pilocar
`pine and cevilemine have been evaluated
`in clinical
`for treatment of Sjogren syndrome associated
`junctivitis sicca KCS Patients who were treated with pi
`dose of mg QID experienced
`locarpine at
`significantly
`than placebo-treated patients
`improvement
`greater overall
`in ocular problems in their ability to focus their eyes dur
`ing reading and in symptoms of blurred vision compared
`with placebo-treated patients.2 The most commonly
`from this medication was excessive
`reported side effect
`sweating which occurred in over 40% of patients Two
`percent of the patients taking pilocarpine withdrew from
`the study because of drug-related side effects Other stud
`ies have reported efficacy of pilocarpine for ocular signs
`and symptoms of Sjogren syndrome
`an increase in conjunctival goblet cell density after
`months of
`
`that
`
`Cevilemine is another oral cholinergic agonist
`was found to significantly improve symptoms of dryness
`and ocular surface
`and aqueous
`disease
`tear production
`compared to placebo when taken in doses of 15 or 30 rag
`TID.709 This agent may have fewer adverse systemic side
`effects than oral pilocarpine
`ooca Tear
`
`ttut
`
`ie nonpharmaceuticai
`Naturally occurring biological
`fluids can be used to substitute For natural rears The use
`of serum or saliva for this purpose has been reported in
`humans They are usually unpreserved When of autologous
`origin they lack antigenicity and contain various epithe
`liotrophic factors such as growth factors neurotrophins
`and extraceliular matrix
`vitamins immunoglobulins
`proteins involved in ocular surface maintenance Biologi
`cal tear substitutes maintain the morphology and support
`the proliferation of priniasy human conical epithelial cells
`tear substitutes.109 However
`than pharmaceutical
`better
`despite biomechanical
`and biochemical similarities rel
`differences compared with normal
`e.vant compositional
`tears exist and are of clinical
`Additional
`practical problems concern sterility and stability and
`surgical procedure
`labor-intensive production process or
`saliva is required to provide the natural
`the ocular surface
`
`tear substitute to
`
`Serum
`Serum is the fluid component of Full blood that remains
`after clotting Its topical use for ocular surface disease