DEWS MANAGEMENT AND THERAPY
`
` Hi. ASSESSMENT OF CURRENT DRY EYE THERAPIES
`
`A. Tear Supplementation: Lubricants
`1. General Characteristics and Effects
`The term “artificial tears” is a misnomer for most prod-
`ucts that identify themselves as such, because they do not
`mimic the composition of human tears. Most function as
`lubricants, although some more recent formulations mimic
`the electrolyte composition of human tears (TheraTears®
`jAdvanced Vision Research, Woburn, MAP).! The ocular
`lubricants presently available in the United States are ap-
`proved based on the US Food and Drug Administration
`(FEA) monograph on over-the-counter (OTC) products
`(21 CFR 349) and are not based on clinical efficacy. The
`monograph specifies permitted active ingredients (eg,
`demulcents, emulsifiers, surfactants, and viscosity agents)
`and concentrations, but gives only limited guidance on
`inactive additives and solution parameters. Certain inac-
`tive ingredients that are used in artificial tears sold in the
`US (eg, castor oil in Endura™ [Allergan, Inc., Irvine, CA]
`and guar in Systane® [Alcon, Ft Worth, TX]) are notlisted
`in the monograph.
`It is difficult to prove that any ingredient in an ocular
`lubricant acts as an active agent. If there is an active in-
`gredient, it is the polymeric base or viscosity agent, but
`this has proved difficult to demonstrate. This is either
`because it is not possible to detect the effects or differences
`in clinical trials with presently available clinical tests or
`because the currently available agents do not have any
`discernable clinical activity beyond a lubrication effect.
`Although certain artificial tears have demonstrated more
`success than others in reducing symptorns ofirritation
`or decreasing ocular surface dye staining in head-to-head
`comparisons, there have been no large scale, masked,
`comparative clinical trials to evaluate the wide variety of
`ocular hubricants.
`Whatis the clinicaleffect of ocular lubricants orartificial
`tears? Do they lubricate, replace missing tear constituents,
`reduce elevated tear film osmolarity, dilute or wash out
`inflammatory or inflammation-inducing agents? Do they,
`in some instances, actually wash out essential substances
`found in normal human tears? These questions remain to
`be answered as more sensitive clinical tests become avail-
`able to detect changes in the ocular surface.
`The foremost objectives in caring for patients with dry
`eye disease are to improve the patient's ocular comfort and
`quality of life, and to return the ocular surface andtear film
`to the normal homeostatic state. Although symptoms can
`rarely be eliminated, they can often be improved, leading
`to an improvement in the qualityof life. It is more difficult
`to demonstrate that topical hibricants improve the ocular
`surface andthe tear film abnormalities associated with dry
`eye. Most clinical studies fail to demonstrate significant
`correlation between symptoms and clinical test values
`or between the clinical test values themselves.?It is not
`unusual for a dry eye with only mild symptoms to show
`significant rose bengalstaining. Until agents are developed
`that can restore the ocular surface and tear film to their
`
`by all 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.
`
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`normal homeostatic state, the synyptoms and signs of dry
`eye disease will continue.
`Ocular lubricants are characterized by hypotonic or
`isotonic buffered solutions containing electrolytes, surfac-
`tants, andvarious types of viscosity agents. In theory, the
`ideal artificial lubricant should be preservative-free, contain
`potassium, bicarbonate, and otherelectrolytes and have a
`polymeric system to increase its retention time.1°§ Physical
`properties should inchide a neutralto slightly alkaline pH.
`Osmolarities of artificial tears have been measuredto range
`from about 181 to 354 mOsm/L.? The main variables in the
`formulation of ocular hibricants regard the concentration
`of and choice of electrolytes, the osmolarity and the type
`of viscasity/polymeric systera, the presence or absence of
`preservative, and, if present, the type of preservative.
`
`2. Preservatives
`The single most critical advance in the treatment of dry
`eye came with the elimination ofpreservatives, such as benzal-
`konium chloride (BAK), frorm OTC hubricants. Because
`of the risk of contamination of multidose products, most
`either contain a preservative or employ sere mechanisxn
`for minimizing contamination. The FDA has required that
`multidose artificial tears contain preservatives to prevent
`microbial growth.’ Preservatives are not required in unit
`dose vials that are discarded after a single use. The wide-
`spread availability of nonpreserved preparations allows
`patients to administer lubricants more frequently without
`concern about the toxic effects of preservatives. Por patients
`with moderate-to-severe dry eye disease, the absence of
`preservatives is ofmorecritical importance than the particu-
`lar polymeric agent used in ocular lubricants. The ocular
`surface inflammation associated with dry eye is exacerbated
`bypreserved hibricants; however, nonpreserved solutions
`are inadequate in themselves to improve the surface inflam-
`mation and epithelial pathology seen in dry eye disease.!!
`Benzalkonium chloride is the most frequently used
`preservative in topical ophthalmic preparations, as weil as
`in topical hubricants. lts epithelial toxic effects have heen
`well established." 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 iclerated when used 4-6 times a day
`or fess. In patients with moderate-to-severe dry eye, the
`potential for BAK toxicity is high, due to decreased tear
`secretion and decreased turnover.!? Some patients may be
`using other topical preparations (eg, glaucoma medications}
`that contain BAK, increasing their exposure to the toxic
`effects of BAK. 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-
`lium, affecting cell-to-cell junctions and cell shape and
`ticrovilli, eventually leadingto cell necrosis with sloughing
`of 1-2 layers of epithelial cells!” Preservative-free formuutla-
`tions are absolutely necessary for patients with severe dry
`
`eye with ocular surlace disease and impairment oflacrimal
`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
`occhusionare 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.
`Anotheradditive used in OTC formulations is disodium
`(EDTA). It augments the preservative efficacy of BAK and
`other preservatives, but, by itself, it is not a 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 a lower concentration of
`preservative, EDTA mayitself be toxic to the ocular surlace
`epithelium. A study comparing two preservative-free solu-
`tions, Hypotears PF® (Novartis Ophthalmics, East Hanover,
`NP 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.'8 Other studies found that
`EDTA-containing preparations increasedcorneal epithelial
`permeability 52° The potential exists that patients with
`severe dry eye will find that EDTA-containing preparations
`increase irritation.
`Nonpreserved, single unit-dose tear substitutes are
`more costly for the manufacturer to produce, more
`costly for the patients to purchase, and less convenient
`to use than bottled ocular lubricants. For these reasons,
`reclosable unit dose vials (eg, Refresh Free [Allergan Inc.,
`irvine, CA]; Tears Natural Free® [Alcon, Fort Worth,
`TX) were introduced. Less toxic preservatives, such as
`polyquad (polyquaternium-1), sodium chlorite (Purite®),
`and sodium perborate were developed to allow the use
`of multidose botded lubricarus and te avoid the known
`toxicity of BAK-containing sohitions.?!? The “vanishing”
`preservatives were sodiurn perborate and sodium chlorite
`(TheraTears® [Advanced Vision Research,Woburn, MAI,
`Genteal® [Novartis, East Hanover, NJ], and Refresh Tears®
`{Allergan 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 a decrease in
`tear volume, and may be irritating. Patients prefer bottled
`preparations for reasons of both cost and ease of use. The
`ideal lubricant would come in a multidose, easy-to-use
`bottle that contains a preservative that completely dissipates
`before reaching thetear film,or is completely nontoxic and
`nonirritating and maintains absolute sterility with frequent
`use. One such multi-use, preservative-free product has
`been introduced to the market (Visine Pure-Tears® (Pfizer,
`Inc, NJ).
`Ocular ointments and gels are also used in treatment of
`dry eye disease. Ointments are formulated with a specific
`mixture ofmineral oil and petrolatum. Sore contain lanolin,
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`which can beirritating to the eye and delay commeal wound
`healing7 Individuals with sensitivity to wool mayalso be
`sensitive to lanolin.Some cinuments contain parabens as
`preservatives, and these ointments are not well tolerated
`by patients with severe dry 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
`visual blurring effect than petrolatum ointments.
`
`3. Electrolyte Composition
`Solutions containingelectrolytes and or ions have been
`shown to be beneficial in treating ocular surface damage
`due to dry eye.15704445 To date, potassium and bicarbon-
`ate seem to be the most critical. Potassium is important to
`maintain comeal thickness.’ In a dry-eye rabbit model, a
`hypotonic tear-matched electrolyte solution (TheraTears®
`[Advanced Vision Research, Woburn, MAJ) increased con-
`functival goblet cell density and cormeal glycogen content,
`and reducedtear osmolarity and rose bengal stainingafter 2
`weeks of treatment.2> The restoration of conjunctival goblet
`cells seenin the dry-eye rabbit model has beencorroborated
`in patients with dry eye after LASTK.26
`Bicarbonate-containing solutions promote the recovery
`of epithelial barrier function in damaged comeal epithelium
`and aid in maintaining normal epithelial ultrastructure.
`They may also be important for maintaining the mucin layer
`of the tear film.® Ocular lubricants are available that mimic
`the electrolyte composition of human tears, eg, TheraTears®
`(Advanced Vision Research, Woburn, MA) and BION Tears®
`(Alcon, Port Worth, TX}.!4 These also contain bicarbonate,
`which is critical for forming and maintaining the protec-
`tive myucin gel in the stomach.’ Bicarbonate may play a
`sitnilar role for gei-forming mucins on the ocular surface.
`Because bicarbonate is converted to carbon dioxide when
`in contact with air and can diffuse through theplastic unit
`dose vials, foil packaging of the plastic vials is required to
`maintain stability,
`
`4. Osmolarity
`Tears of patients with dry eye have a higher tear film
`osmolarity (crystalloid osmolarity} than do those of normal
`patients.282? Elevated tear film osmolarity causes mor-
`phological and biochemical changes to the corneal and
`conjunctival epithelium)?" andis pro-inflammatory.This
`knowledge influenced the development of hypo-osmotic
`artificial tears such as Hypotears® (230 mOsm/L [Novartis
`Ophthalmics, fast Hanover, NJ}) and subsequently Thera-
`Tears® (181 mOsnV/L [Advance Vision Research, Woburn,
`MA]).22
`Colloidal osmolality is another factor that varies in
`artificial tear formulations. While crystalloid osmolarity
`is related to the presence of ions, colloidal osmolality is
`dependent largely on macromolecule content. Colloidal
`osmolarity, also known as oncotic pressure,is involved in the
`control ofwater 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 asmolality differences
`on the two sides of the membrane. Epithelial cells swell
`due to damage to their cellular membranes or due to a
`dysfunction in the pumping mechanisrn. Following the
`addition of a fluid with a high colloidal osmolality to the
`damaged cell surface, deturgescence occurs, leading to a
`return of normal cell physiology. Theoretically, an artificial
`tear formulation with a high colloidal osmolality may be of
`value. Holly and Esquivel evaluated many different artificial
`tear forrwulations and showed that Hypotears® (Novartis
`Ophthalmics, East Hanover, ND had the highest colloidal
`osmolality ofail of the formulations tested.*> Formulations
`with higher colloidal osmolality have since been marketed
`(Dwelle® [Dry Eye Company, Silverdale, WAI).
`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® [Allergan Inc., Irvine,
`CAD. It is thoughtthat the cormpatible solutes distribute be-
`tween the tears and the intracellular fluids to protect against
`potential cellular damage from hyperosmolar tears.34
`
`3. Viscosity Agents
`The stability of the tear film depends on the chemical-
`physieal characteristics of that film interacting with the
`conjunctival and corneal epithelium via the membrane-
`spanning nrucins (ie, MUC-16 and MUC-4). In the classical
`three-layered tear flm model, the mucin layer is usually
`thought of as a surfactant or wetting agent, acting to lower
`the surface tension of the relatively hydrophobic ocular
`surface, rendering the corneal and conjunctival cells “wet-
`table.”"? Currently, the tearfilmis probably best described
`as a hydrated, mucin gel whose mucin concentration
`decreases with distance from the epithelial cell surface. It
`may have a protective role sirnilar to that of mucin in the
`stomach.” lt may also serve as a “sink” or storage vehicle
`for substances secreted by the main and accessory lacrimal
`glands and the ocular surface cells. This may explain why
`most of the available water-containing lubricants are only
`minimally effective in restoring the normal homeostasis
`of the ocular surface. In addition to washing away and
`dilating outirritating or toxic substances in the tear film,
`artificial lubricants hydrate gel-forming mucin. While some
`patients with dry eye have decreased aqueouslacrimalgland
`secretion, alterations or deficiencies involving mucin also
`cause dry eye.
`Macromolecular complexes added to artificial lubricants
`act as viscosity agers. The addition of a viscosity agentin-
`creases residence time, providing a longerinterval ofpatient
`comfort. For example, when a viscous, anionic charged
`carboxymethyl-cellulose (CMC, 100,000 mw) solution was
`compared with a neutral hydroxymethylcellulose (HPMC)
`sohition, CMC was shown to havea significantly slowerrate
`of clearance from the eye.** Viscous agents in active drug
`
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`formulations may alse prolong ocular surface contact, in-
`creasing the duration of action and penetration of the drug.
`Viscous agents may also protect the ocular surface
`epithelium, It is known that rose bengal stains abnormal
`comeal and conjunctival epithelial cells expressing an al-
`tered mucin glycocalyx.*’ Agents such as hydroxymethycel-
`lulose (HMC), which decrease rose bengal staining in dry
`eye subjects,may either “coat and protect” the surface
`epithelium or help restore the protective effect of raucins.
`In the US, carboxymethyl cellulose is the most com-
`monly used polymeric viscosity agent (RI Market Share
`Data, Chicago, 11), typically in concentrations from 0.25%
`to 1%, with differences in molecular weight also contrib-
`uting to final product viscosity. Carboxymethy! cellulose
`has been found to bind to and be retained by human epi-
`thelial celis.°° Other viscosity agents included in the FDA
`monograph (in various concentrations) include polyvinyl
`alcohol, polyethylene glycal, glycol 400, propylene glycol
`hydroxymethyl cellulose and hydroxypropyl cellulose.
`The blurring ofvision and esthetic disadvantages of cak-
`ing and drying on eyelashes are drawbacks ofhighly viscous
`agents that patients with mild to moderate dry eye will
`not tolerate. Lower molecular-weight viscous agents help
`to minimize these problems. Because patient compliance,
`comfort, and convenience are important considerations, a
`range of tear substitute formulations withvarying viscosi-
`ties are needed.
`Hvdroxypropyl-guar CAP-guar) has been used as a gel-
`ling agent in a solution containing glycol 400 and propyl-
`ene glycol (Systane®, Alcon, Fort Worth, TX). It has been
`suggested that HP-guar preferentially binds to the more
`hydrophobic, desiccated or damaged areas of the surface
`epithelial cells, providing temporary protection for these
`cells4-4! Several coramercial preparations containing oil in
`the form of castor oil (Endura™ [Allergan Inc., Irvine, CAD
`or mineral oil (Soothe® [Bausch & Lornb, Rochester, NYD
`are purported to aid in restoring or increasing the lipid layer
`of the tear film.*.*3 Hyaluronic acid is a viscosity agent that
`has been investigated for years as an “active” compound
`added to tear substitute formulations for the treatment of
`dry eye. Hyaluronic acid (0.2%) has significantly longer
`ocular surface residence tirnes than 0.3 percent HPMC
`or 1.4 percent polyvinyl alcohol.* Some clinical studies
`reported improvement in “8 dry eye in patients treated
`with sodium byaluronate-containing solutions compared
`to other lubricant sohitions, whereas others did not.‘
`Although lubricant preparations containing sadium hyal-
`uronate have not been approved for use in the US, they are
`frequently used in some countries.
`
`& Stm«,ary
`Although manytopical lubricants, with various viscos-
`ity agents, may improve symptoms and objective findings,
`there is no evidence that any agent is superior to another.
`Mostclinical trials involving topical lubricant preparations
`will document some improvement (but not resolution) of
`subjective symptoms and improvement in some objective
`
`parameters.* However, the improvements noted are not
`necessarily any better than these seen with the vehicle or
`other nonpreserved artificial lubricants. The elimination
`of preservatives and the development of newer, less toxic
`preservatives have made ocular lubricants better tolerated
`by dry eye patients. However, ocular lubricants, which
`have been shown to provide some protection of the ocular
`surface epithelium and some improvement in patient symp-
`toms and objective findings, have not been demonstrated
`in controlled clinical trials to be sufficient to resolve the
`ocular surface disorder and inflammation seen in most dry
`eye sufferers.
`
`8. Tear Retention
`1. Ponctal Occlusion
`a. Rationale
`While the concept of permanently occluding the lacri-
`mal puncta with cautery to treat dry eye extends back 70
`years,*® and, although the first dissolvable implants were
`used 45 years ago,the modern era of punctal plug use
`began in 1975 with the report by Freernan.?! Freeman de-
`scribed the use of a dumbbell-shapedsilicone plug, which
`rests onthe opening of the punctum and extends into the
`canaliculus. His report established a concept of punctal oc-
`clusion, which opened the field for developmentof a variety
`of removable, long-lasting plugs to retard tear clearance
`in an attempt to treat the ocular surface of patients with
`deficient aqueous tear production. The Freeman style plug
`remains the prototype for most styles of punctal plugs.
`
`Bb. Types
`Punctal plugs are divided into two main types: absorb-
`able and nonabsorbable. The former are made ofcollagen
`or polymers and last for variable periods of time (3 days
`to 6 months). Thelatter nonabsorbable “permanent” plugs
`include the Freemanstyle, which consists of a surface collar
`resting on the punctal opening, a neck, and a wider base, In
`contrast, the Herrick plug (Lacrimedics [Eastsound,WA}
`is shaped like a golf tee and is designed to reside within
`the canalicuhus. It is bhue for visualization; other variations
`are radiopaque. A newly designed cylindrical Smartplug™
`(Medennium Inc [Irvine, CA]) expands and increases in
`diameter in situ following insertion into the canaliculus
`due to thermodynamic properties of its hydrophilic acrylic
`composition.
`
`c, Clinical Studies
`A variety of clinical studies evaluating the efficacy of
`punctal plugs have been reported.**>* These series generally
`fall into Level Il evidence. Their use has been associated
`with objective and subjective improvement in patients
`with both Sjogren and non-Sjogren aqueous tear deficient
`dry eye, Hlamentary keratitis, contact lens intolerance,
`Stevens-Johnson. disease, severe trachoma, neurotrophic
`keratopathy, post-penetrating keratoplasty, diabetic kera-
`topathy, and post-photorefractive keratectomy or laser in
`situ keratomileusis. Several studies have been performed
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`to evaluate the effects of punctal plugs on the efficacy of
`glaucoma medications in reducing intraocular pressure,
`and these studies have reported conflicting results.°78
`Beneficial outcomein dry eye symptoms has beenreported
`in 74-86% of patients treated with punctal phigs. Objective
`indices of improvement reported with the use of punctal
`plugs include improved corneal staining, prolonged tear
`film breakup time (IFBUT), decrease in tear osmolarity,
`and increase in goblet cell density. Overall, the clinical util
`ity of punctal plugs in the management of dry eyedisease
`has been well documented.
`
`a.
`
`Indications and Contraindications
`In a recent review on punctal plugs, it was reported
`that in a major eye clinic, punctal plugs are considered
`indicated in patients who are symptomatic of dry eyes,
`have a Schirmer test (with anesthesia) result less than 5
`mm at 5 minutes, and show evidence of ocular surface
`dye staining.>®
`Contraindications to the use of punctal plugs include
`allergy to the materials used in the plugs te be implanted,
`punctal ectropion, and pre-existing nasolacrimal 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
`surface inflammation, because occhision of tear outflow
`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
`a contraindication to use of a plug.
`
`&. Complications
`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 alter extensive periods of phig residence. Most
`extrusions are of small consequence, except for incon-
`venience and expense. More troublesome complications
`inchide internal migration ofa phig, biohim formation and
`infection,” and pyogenic granuloma formation. Removalof
`migrated canalicular plugs can be dificult and may requite
`surgery to the nasolacrimal duct system.®°4!
`
`f Summary
`The extensive literature on the use of punctal plugs in
`the management of dry eye disease has documented their
`utility. Several recent reports, however, have suggested
`that absorption of tears by the nasolacrimal ducts into sur-
`rounding tissues and blood vessels may provide a feedbac
`mechanism to the lacrimal gland regulating tear produc-
`tion.In one study, placementof punctal phigs in patients
`with normal tear production causeda significant decrease
`in tear productionfor up to 2 weeks after plug insertion.©
`This cautionary note should be considered when deciding
`
`whether to incorporate punctal occlusion into a dry eye
`disease management plan.
`
`2. Moisture Chamber Spectacles
`The wearing of moisture-conserving spectacles has for
`many years been advocated to alleviate ocular discomfort
`associated with dry eye. However, the level of evidence sup-
`porting its efhicacy for dry eye treatment has been relatively
`limited. Tsubota et al, using a sensitive moisture sensor,
`reported an increase in periocular humidity in subjects
`wearing such spectacles.“ Addition of side panels to the
`spectacles was shown to further increase the humidity
`The clinical efficacy of moisture chamber spectacles has
`been reported in case reports.“Kurihashi propased a
`related treatment for dry eye patients, in the form of a wet
`gauze eye mask. Conversely, Nichols et al recently report-
`ed in their epidemiologic enidy 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 reports with relatively high
`level of evidence describing the relationship between
`environmental humidity and dry eve. Korb et al reported
`that increases in periocular humidity caused a significant
`increase in thickness of the tear film lipid layer. Dry eye
`subjects wearing spectacles showed significantly longer
`interblink intervals than those who did not wear spectacles,
`and duration of blink (blinking time) was significantly
`longerin the latter subjects.” Instillation of artificial tears
`caused a significant increase in the interblink interval and
`a decrease inthe blink rate. Maruyama et al reported that
`dry eye symptoms worsened in soft contact lens wearers
`when environmental humidity decreased.
`
`3. Contact Lenses
`Contact lenses may help to protect and hydrate the
`corneal surface in severe dry eye conditions. Several differ-
`ent contact lens materials and designs have been evaluated,
`includingsilicone rubberlenses and gas permeable scleral-
`bearing hard contact lenses with or without fenestration.7-77
`imaproved visual acuity and comfort, decreased corneal
`epitheliopathy, and healiag of persistent corneal epithelial
`defects have been reported.2-" Highly oxygen-permeable
`materials enable overnight wear in appropriate circum-
`stances.’? There is a small risk of corneal vascularization
`and possible corneal infection associated with the use of
`contact lenses by dry eye patients.
`
`©. Tear Stimulation: Secretogeguas
`Several potential topical pharmacologic agents may
`stimulate aqueous secretion, mucous secretion, or both.
`The agents currently under investigation by pharmaceuti-
`cal companies are diquafosol (one of the P2Y2 receptor
`agonists}, rebamipide, gefarnate, ecabet sodium Gnucous
`secretion stimulants}, and 15(S)-HETE (MUC1 stirnulant).
`Among thera, a diquafosol eye drop has been favorably
`evaluated in clinicaltrials. 2% diquafosol (INS365, DE-O89
`[Santen, Osaka, Japan|; Inspire (Durham, NC] provedto
`
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`DEWS MANAGEMENT AND THERAPY
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`be effective in the treatment of dry eye in a randomized,
`double-masked trial in humans to reduce ocular surface
`staining,’® A similar study demonstrated the ocularsafety
`and tolerability of diquafosol in a double-masked, placebo-
`controlled, randomized study’? This agent is capable of
`stimulating both aqueous and mucous secretion in animals
`and bumans.®°*3 Beneficial effects on corneal epithelial
`barrier function, as well as increased tear secretion, has
`been demonstrated in the rat dry eye madel.™ Diquafosal
`also has been shown to stimulate mucinrelease from goblet
`cells in a rabbit dry eye model55.86
`Theeffects of rebamipide (OPC-12759 [Otsuka, Rock-
`ville, MD]; Novartis [Basel, Switzerland]) have been evalu-
`ated in human clinicaltrials. In animal studies, rebamipide
`increased the mucin-like substances on the ocular surface
`of N-acetyleysteine-treated rabbit eyes.?” It also had hy-
`droxyl radical scavenging effects on UVE-induced corneal
`damage in mice.®
`Ecabet sodium (Senju [Osaka, Japan]; ISTA [Irvine,
`CA]) is being evaluated in clinical trials internationally,
`but only limited results have yet been published. A single
`instillation of ecabet sodium ophthalmic solution elicited
`a statistically significant increase in tear mucin in dry eye
`patients.2° Gefarnate (Santen [Osaka, Japan}) has been
`evaluated in animal studies. Gelarnate promoted mucin
`productionafter conjunctival injury in monkeys.** Gefar-
`nate increased PAS-positive cell density in rabbit conjunc-
`tiva and stimulated raucin-like glycoprotein stimulation
`frorn rat cultured comealepithelium.94%? An in vivo rabbit
`experiment showed a similar result.
`The agent 15(S)-HETE, a unique molecule, can
`stimulate MUC] mucin expression on ocular surface
`epithelium.15(S)-HETEprotected the cornea in a rabbit
`model of desiccation-induced injury, probably because af
`mucin secretion.it has been shown to have beneficial
`effects on secretion of mucin-like glycoprotein by the rab-
`bit corneal epithelium.*” Otherlaboratory studies confirm
`the stimulatory effect of 15(S)}-HETE.%*!°! 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 trials
`for treatment of Sjogren syndrome associated keratocon-
`junctivitis sicca (KCS). Patients who were treated with pi-
`locarpine at a dose of 5 mg QUID experienced a significantly
`greater overall improvement than placebo-treated patients
`in “ocular problems”in their ability to focus their eyes dur-
`ing reading, and in symptoms of blurred vision compared
`with placebo-treated patients.°? The most commonly
`reported side effect from this medication was excessive
`sweating, which cecurred 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 KCS,!°33 including
`an increase in conjunctival goblet cell density after 1 and
`2 months of therapy!
`
`Cevilemine is another oral cholinergic agonist that
`was found to significantly improve symptoms of dryness
`and aqueous tear production and ocular surface disease
`compared to placebo when taken in doses of 15 or 30 mg
`TID. 107.108 This agent may have fewer adverse systemic side
`effects than oral pilocarpine.
`
`D. Sleiegical Tear Substitutes
`Naturally occurring biological, ie, nonpharmaceutical
`fluids, can be used to substitute for natural tears. 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-
`Hotrophic factors, such as growth factors, neurotrophins,
`vitamins, immunaglobulins, and extracellular matrix
`proteins involved in ocular surface maintenance. Biologi-
`cal tear substitutes maintain the morphology and support
`the proliferation of primary hurnan corneal epithelial cells
`better than pharmaceutical tear substitutes.’ However,
`despite biomechanical and biochemical similarities, rel
`evant compositional differences compared with normal
`tears exist and are of clinical relevance.!° Additional
`practical problems concern sterility and stability, and a
`labor-intensive production process or a surgical procedure
`(saliva) is required to provide the natural tear substitute to
`the ocular surface.
`
`k. Serum
`Serumis the thrid component of full blood that remains
`after clotting. Its topical use for ocular surface disease was
`much stirnulated by Tsubota’s prolifi