DEWS MANAGEMENT AND TllEl-ZAPY
`
`ill. AS$EsS§l‘J’lEll‘§' GF CURRENT 33%‘! EYE WEAPEES
`
`A. Test supplementation: Lubricants
`I. General Ebaraeteristim and Efiects
`
`The term “artificial tears” is a misnomer for most prod-
`ucts that identify tlietnselves as such, because they do not
`mimic the composition of human tears, Most function as
`lubricants, although some more recent formulations rnirnic
`the electrolyte composition of human tears (Thera1‘ears®
`{Advanced Vision Research, ‘Woburn, MAl).l~2 The ocular
`lubricants presently available in the United States are ap-
`proved based on the US Food and Drug Administration
`(EBA) monograph on ovet«the-counter (ETC) products
`(21 CFR 349) and are not based on clinical efficacy The
`monograph specifies permitted active ingredients (cg,
`clemulcents, emulsifiers, surfactants, and viscosity agents)
`and concentrations, but gives only limited guidance on
`inactive additives and solution parameters. Certain ina-:~
`tive ingredients that are used in artificial tears sold in the
`US (cg, Castor oil in Endura” [Allergan, inc, lrvine, CA}
`and guar in Systanew létlcon, Ft Worth, TXE) are not listed
`in the monograph.
`lt 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 symptoms of irritation
`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 lubricants.
`What is the clinical effect of ocular lubricants or artificial
`
`tears? Do they lubricate, replace missing tear constituents,
`reduce elevated tear hlrn osmolarity, dilute or wash out
`inllarnrnatoty or inllatnrnation-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 patients ocular comfort and
`quality of life, and to return the ocular surface and tear him
`to the normal homeostatic state. Although symptoms can
`rarely be eliminated, they can often be improved, leading
`to an improvement in the quality of life. it is more difficult
`to detnonstrate that topical lubricants improve the ocular
`surface and the 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 theniselves.3‘5 it is not
`
`unusual for a dry eye with only mild symptoms to show
`significant rose bengal staining. Until agenu. are developed
`that can restore the ocular surface and tear film to their
`
`by all subcotntnittee members and by the entire Dry Eye
`'\Norl<Sl‘top 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 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
`ideal artificial lubricant should be preservative—free, contain
`potassium, bicarbonate, and other electrolytes and have a
`polymeric systern to increase its retention tirne.l~5“°-i Pliysical
`properties should include a neutral to slightly allealine pl-l.
`Osmolarities of artificial tears have been measured to range
`from about If 8 ii, to 354 rnOsm/L." The main variables in the
`
`formulation of ocular lubricants regard the concentration
`of and choice of electrolytes, the osrnolarity and the type
`of viscosity/polyineric system, the presence or al:2sence of
`preservative, and, if present, the type of preservative.
`
`2.. Frescrvativm
`
`The single most critical advance in the treatment of dry
`eye came with the elimination of preservatives, such as henzal-—
`konium chloride (BAX), from OTC lubricants. Because
`of the risk of contamination of rriultidose products, inost
`either contain a preservative or employ‘ some rnecliaraisrn
`for minimizing coritamination. The FDA has required that
`rnultidose 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 arlrninister lubricants more frequen.tly without
`concern about the toxic effects of preservatives. For patients
`with inoderate~to—severe dry eye disease, the absence of
`preservatives: is of more critital importance than the particu-
`lar polymeric agent used in ocular luhricants. The ocular
`surface inilaniniatiori associated with dry eye is exacerbated
`hy preserved lubricants; however, nonpreserved solutions
`are inadequate in themselves to improve the surface inilarn~
`rnation and epithelial pathology seen in dry eye disease.“
`Berizalleoniurn chloride is the most frequently used
`preservative in topical ophthalmic preparations, as well as
`in topical lubricants. in; epithelial toxic effects have been
`well established.”‘” The toxicity of BAK is related to its
`concentration, the frequency of closing, 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 tunes a day
`or less. in patients with rrioderatoto-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 (cg, glaucoma medications)
`that contain BAK, increasing their exposure to the toxic
`effects of BAR. Also, the potential for toxicity erdsts with
`patient ahuse of other OTC products that. contain BAK,
`such as vasoconstrictors.
`
`BAR can damage the cortical and conjunctival epithe-
`lium, affecting cell~to~cell junctions and cell shape and
`tnicrovilli, eventually leading to cell necrosis with sloughing
`of L2 layers of epithelial cells. 17 Preservativedree formula-
`tions are absolutely necessary for patients with severe dry
`
`eye with ocular surface disease and irnpairrnent of lacrimal
`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
`occl.usiori are at pari'.icular rislr 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). It augrnerits the preservative efficacy of BAX and
`other preservatives, hut, ‘by itself, it is not a sufficient pre-
`servative. Used in some nonpreserved solutions, it may
`help limit nncrohial growth in opened unit—dose vials.
`Although use of EDTA may allow a lower concentration of
`preservative, EDTA rnay itself he toxic to the ocular surface
`epitheliuni. A study comparing two preservative free solu-
`tions, l-lypotears Pl“ (Novartis Ophthalrnics, East Hanover,
`NJ) containing EDTA and Refresh@ (Allergan, lncx, lrvine,
`CA) without El’.‘2'l.‘A, showed that hoth formulations had
`identical safety profiles and were completely rioritoiclc to
`the rabbit corneal epitheliutn.'”3 Other studies found that
`EDTEZAA-contai.ning preparatioris; increased. corneal epithelial
`permeability. 1939 The potential exists that patients with
`severe dry eye will find that EDT.A—C0l‘ll;2ll!’l.ll1g preparations
`increase irritation.
`
`Nonpreserved, single ur1it—dose tear substitutes are
`more costly for the nianufacturer to produce, more
`costly for the patients to purchase, and less convenient
`to use than bottled ocular lubricants. For these reasons,
`reclosahle unit dose vials (cg, Refresh Free {Allergan inc,
`lrvine, CA}; Tears Natural Freef’ lillcon, Fort Worth,
`TXE) were introduced. Less toxic preservatives, such as
`polyquad (polyquaterniurm 1), sodium ehlotitc (Purite®),
`and sodium perborate were developed to allow the use
`of rriul.titlose ‘oottled lubricants and to avoid the known
`
`toxicity of BA.l{-containing solutions.1l=23 The “vanishing”
`preservatives were sodium perhorate and sodium chiorite
`Cfheralearsfi {Advanced Vision Research, Wo‘ourn., MA],
`Gentealfl‘ lNovartis, East Hanover, Nil, and Refresh Tears”?
`lAllergan inc, lrvine, CAD.
`Sodium chlorite degrades to chloride ions and water
`upon exposure to UV light after instillation. Sodium perho~
`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 he irritating. i’atient;s prefer hottled
`preparations for reasons of hoth cost and ease of use. The
`ideal lubricant would come in a tnultidose, easy--to-use
`hottl.e. that contains a preservative that completely dissipates
`before reaching the tear film, or is completely nontoxic and
`tionirritating and niaiutairxs absolute sterility with frequent
`use. One such rnulti—use, preservative-free product has
`been introduced to the market (Vsine l’ure~'l'ears® lPiizer,
`inc, hill).
`Ocular ointments and gels are also used in treatment of
`dry eye disease. Ointrnents are formulated with a specific
`rniicture of niineral oil and petrolatum. Sorne contain lanolin,
`
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`DEWS MANAGEMENT AND THERAPY
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`which can be irritating to the eye and delay corneal wound
`healing.” individuals with sensitivity to wool may also be
`sensitive to lanolin.” Sorne ointrnents contain parabens as
`preservatives, and these ointrnerits are not well tolerated
`by patients with severe dry eye. in general, ointrnents do
`not support bacterial growth and, therefore, do not require
`preservatives; Gels containing high molecular weight cross-
`linlced polymers of acrylic acid (carboiners) have longer
`retention times than artificial tear solutions, but have less
`visual blurring ellect than petrolaturn ointments.
`
`3. Elecmolyte Composition
`Solutions containing electrolytes and or ions have been
`shown to be beneficial in treating ocular surface damage
`due to dry ey'e.l~‘3»"—°»l‘”5 To date, potassiuin and bicarbon-
`ate seem to he the most critical. Potassium is important to
`maintain corneal thicl«tness.7 ln a dry—eye rabbit model, a
`hypotonic teamnatched electrolyte solution (”l‘hera'.lears®
`lAdvanced Vision Research, Woburn, MAD increased con~
`junctival goblet cell density and corneal glycogen content,
`and reclucetl tear osrnolarity and rose bengal staining after 2
`weclts of treatment.” The restoration of conjunctival goblet
`cells seen in the clry—eye rabbit model has been corroborated
`in patients with dry eye alter l....“iSll{.2"’
`Bicarbonate—containing solutions promote the recovery
`of epithelial barrier function in damaged corneal epitheliurn
`and aid in maintaining normal epithelial ultrastructure.
`They may also be important for maintaining the nriuciri layer
`oi the tear film.“ Ocular lubricants are available that mimic
`
`the electrolyte composition of human tears, cg, Theralearsd
`(Advanced Vision Research, Woburn, MA.) and BlON '.lhars®
`(Alcon, ‘Fort Won;h, TX}. 5 >2 These. also contain bicarbonate,
`which is critical for forming and maintaining the protec~
`rive niucin gel in the stoinach.“ Bicarbonate may play a
`similar role for gel~lorming tnucins on the ocular surface.
`Because bicarbonate is converted to carbon dioxide when
`
`in contact with air and can dilluse. through the plastic unit
`dose vials, foil ‘packaging of the plastic vials is required to
`maintain stability
`
`-ll. Osmolarity
`Tears of patients with dry eye have a higher tear iilrn
`osrnolarity (crystalloid osrnolarityl than do those. of normal
`pat.ients.33~29 Elevated tear film osrnolarity causes mor-
`phological and biochemical changes to the corneal and
`conjunctival epi.tlieliurnl3-3° and is pro—in.llammatory.3l This
`knowledge influenced the development of liypo—osrnotic
`artificial tears such as l~lypotears® (230 rntflsm/I. lhlovartis
`Ophthaltnics, East Hanover, Njll and subsequently Theta»
`Tcarsg’ (181 rnDsrnfl_ {Advance Vision Research, Wohurn,
`MAD}:
`Colloidal osrnolality is another factor that varies in
`artificial tear iorniulations. ‘While crystalloitl osrnolarity
`K; related to the presence of ions, colloidal osinolality is
`dependent largely on inacroruoleculc content. Colloidal
`osrnolarity, also known as omzotic pressure, is involved in the
`control oi water transport in tissues. Differences in colloidal
`
`osrnolality affect the net water llow across rnernbranes, and
`water llow is eliminated by applying hydrostatic pressure
`to the downside of the water llow. The magnitude of this
`osmotic pressure is determined by ostnolality differences
`on the two sides of the membrane. Epithelial cells swell
`due to damage to their cellular membranes or clue to a
`dysfunction in the pumping niechanisrn. Following the
`addition of a fluid with a high colloidal osmolality to die
`darnaged cell surface, deturgesccnce 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 formulations and showed that llypotears‘l° (Novartis
`Ophthalniics,
`liariover, NJ) had the highest colloidal
`osmolality of all of the formulations tested.” Formulations
`with higher colloidal osrnolality have since been ‘znarlceted
`Cllwellell’ llilry Eye Company, Silvertlale, WAD.
`Protection against the adverse effects of increased os~
`rnolarity losmoprotectionl has led to development of OTC
`drops incorporating compatible solutes (such as glycerin,
`erythritol, and levocarnitine (Optive°3’ lilllergan lnc., lrvine,
`CAD. it is thought that the compatible solutes distribute be-
`tween the tears and the intracellular fluids to protect against.
`potential cellular damage from liyperosmolar tears.“
`
`5. ‘Viscosity Agents
`The stability of the tear lilrn depends on the cliernical—
`physical characteristics of that film interacting with the
`conjunctival and corneal epithelium via the membrane-
`spanning rnucins (ie, MUG lo and MUC4}. In the classical
`tliree—layered tear film model, the rnucin 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-~
`talile.”33 Currently, the tear film is probably best described
`as a hydrated, mucin gel whose tnucin concentration
`decreases with distance from the epithelial cell suriface. it
`may have a protective role. similar to that of rnucin in the
`stornachgls it may also serve as a “sink” or storage vehicle
`for substances secreted by the main and accessory lacrirnal
`glands and the ocular surface cells. Tliis may explain why
`niost of the available water-containing lubncants are only
`minimally effective in restoring the normal homeostasis
`of the ocular surface.
`lri addition to washing away and
`diluting out irritating or toxic substances in the tear film,
`artificial lubricants hydrate gel--forming rnucin. While some
`patients with dry eye have decreased aqueous laciiinal gland
`secretion, alterations or deficiencies involving rnucin also
`cause dry eye.
`Macromolecular complexes added to artiilcial lulciricants
`act as viscosity agents. The addition of a viscosity agent in-
`creases residence titne, providing a longer interval of patient
`comfort. For example, when a viscous, anionic charged
`carlioxyniethyhcellulose (CM (2, lO{),()O(3 mw) solution was
`cornpared with a neutral hydroxymethylcellulose (lll’MC)
`solution, CMC was shown to have a significaritly slower rate
`of clearance from the eye.” Viscous agents in active drug
`
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`DEWS l\!lAi‘\l.AC3lEl\/IENT AND Tl~lERAPY
`
`formulations may also prolong ocular surface contact, in-
`creasing the duration of action and penetration of the drug.
`Viscous agents may also protect the ocular surface
`epitheiiurn. it is known that rose hengal stains abnormal
`corneal and coniunctival epithelial cells expressing an al-
`tered rnucin glycocalyit. 37 Agents such as hydro:~:ymethycei--
`lulose (EEC), which decrease rose bengal staining in dry
`eye sub;Zects,3* may either “coat and protect” the surface
`epithelium or help restore the protective effect of niucins.
`In the US, carboxymethyl cellulose is the most com-
`monly used polymeric viscosity agent (IRI Market Share
`Data, Chicago, IL), typically in concentrations from 0.23%
`to 1%, with differences in molecular weight also contrih~
`uting to final product viscosity Carboxyniethyl cellulose
`has been found to bind to and he ret.aincd. by human epi-
`thelial cells?" Other viscosity agents included in the FDA
`monograph (in various concentrations) include polyvinyl
`alcohol, polyethylene glycol, glycol 400, propylene glycol
`hydroxytncthyl cellulose and hydroxypropyl cellulose.
`The blurring of vision and esthctic disadvantages oi cak-
`ing and drying on eyelashes are drawbacks of highly viscous
`agents that patients with mild to moderate dry eye will
`not tolerate. Lower rnolecularnweight viscous agents help
`to minimize these problems. Because patient compliance,
`cornlort, and convenience are important considerations, a
`range of tear substitute forniulatioris with varying vist:osi~
`ties are needed.
`
`l~ly‘droxypropyl—guar (llP~guar) has been used as a gel-
`ling agent in a solution containing glycol 4:00 and propyl~
`ene glycol (Systane“‘, Alcon, Fort Worth, TX). it has been
`suggested that Ill’--guar prefe‘reritial.ly binds to the more
`hydrophobic, desiccated or damaged areas of the surface
`epithelial cells, providing temporary protection for these
`cellsfillr“ Several corrimercial preparations containing oil in
`the form ol castor oil (Enduram {Allergen inc, lrvine, CAB
`or mineral. oil (Soothe@ lliausch ézr Lornb, Rochester,
`are purported to aid in restoring or increasing the lipid layer
`of the tear iilrn.’*3=’*3 l-iyaluronic acid is a viscosity agent that
`has been investigated for years as an “active” compound
`added to tear sulzstitute. iorrnulations lor the treatment of
`
`dry eye. liyaluronic acid (0.2%) has significantly longer
`ocular surface residence times than 0.3 percent l-ll-’lviC
`or 1.4 percent polyvinyl alcohol.“ Sorne clinical studies
`reported improvement in ‘M5 dry eye in patients treated
`with sodium hyaluronate-containing solutions compared
`to other lubricant solutions, whereas others did not.“
`Although lul:>ticant preparations containing sodium hyal--
`uronate have not been approved for use in the US, they are
`frequently used in some countries.
`
`6. §
`Although many topical lubricants, with various viscos-
`ity agents, may improve syrnptorrts and objective findings,
`there is no evidence that any agent is superior to another.
`Most clinical trials involving topical lubricant preparations
`will. (l.C?(2iJi!3T1(’.E’it:513‘E1’i€.
`iniprovernent {but not resolution) of
`subjective symptoms and improvement in some objective
`
`parameters.‘ However, the improvements noted are not
`necessarily any better than those seen with the vehicle or
`other nonpreserved artificial lubricants. The elirnination
`of preservatives and the development of newer, less toxic
`preservatives have made ocular lubricants better tolerated
`hy 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 findirigs, have not been dernonstrated
`in controlled clinical trials to he sufficient to resolve the
`
`ocular surface disorder and irillainination seen in most dry
`eye sufferers.
`
`3. ‘Fear Retention
`1. Funeral (‘inclusion
`ta. Rationale
`
`While the concept of permanently occluding the lacri~
`rnal puricta with cautery to treat dry eye extends baclr 70
`years,‘‘‘9 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 Freeroan?‘ Freeman cle-
`scribed the use of a dumbbell—shaped silicone plug, which
`rests on the opening of the puncturn and extends into the
`canaliculus. l--iis report established a concept of punctal oc-
`clusion, which opened the field for development of a variety
`of removable, longulasting 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.
`
`ls. T3.-pan
`Punctal plugs are divided into two main types: absorb-
`able and nonahsorbable. The iorrner are made of collagen.
`or polymers and last for variable periods of time (3 days
`to 6 months). The latter nonahsorbable “permanent” plugs
`include the Freeman style, which consists of a surface collar
`resting on the punctal opening, a neclt, and a wider base, in
`contrast, the lierricl-t plug (Lacnmcdics lEastsottnd,\7‘v’Al)
`is shaped like a golf tee and is designed to reside within
`the canaliculus. it is blue for visualization; other variations
`are radiopaque. A newly designed cylindrical Smanplug“
`(Mcdenniurn inc llrvine, CAD expands and increases in
`diameter in situ following insertion into the canaliculus
`due to thermodynamic properties of its hydrophilic acrylic
`cotnpositiort.
`
`c. Clinical Studies
`
`A variety of clinical studies evaluating the efficacy of
`punctal plugs have been reported.35"5‘3 These series generally
`fall into level ll eviderice. Their use has been associated
`
`with objective and subjective improvement in patients
`with both Sjogren and non~Sjogren aqueous tear deficient;
`dry eye, fi.lament.ary lteratitis, contact lens intolerance,
`Stevens-_}ohnson disease, severe trachoma, neurotrophic
`kcratopathy, postpenetrating keratoplasty, diabetic l<era--
`topathy, and post-photoreiractive keratectorriy or laser in
`situ keratomileusis. Several studies have been performed
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`to evaluate the effects of punetal plugs on the efficacy of
`glaucoma medications in reducing intraocular pressure,
`and these studies have reported conflicting results?’-53
`l3eneficial outcome in dry eye syrnptoins has been reported
`in 74-86% of patients treated with punctal plugs. Olziective
`indices of improvement reported with the use ol punctal
`plugs include improved corneal staining, prolonged tear
`film breakup time (TEFBE317), decrease in tear osrnolarity,
`and increase in goblet cell density Overall, the clinical util-
`ity of punctal plugs in the rnanagernent of dry eye disease
`has been well documented.
`
`d.
`
`Iuslioations mid Contraindications
`
`In a recent review on punctal plugs, it was reported
`that in a major eye clinic, punctal plugs are considered
`inrlicated in patients who are syrnptornatic of dry eyes,
`have a Schirrner test (with. anesthexsia) resul.t less than 5
`min at 5 minutes, and show evidence of ocular surface
`dye stain.ing.‘5‘3
`Contraindications to the use of punctal plugs include
`allergy to the materials used in the plugs to be implanted,
`punctal ectropion, and pre-existing nasolactirnal duct ob~
`struction, which would. presumably, negate the need for
`pnnctal occlusion. lt has been suggested that plugs may
`be contraindicated in dry eye patients with clinical ocular
`surface inflammation, because occlusion of tear outflow
`would prolong contact of the abnormal tears corrtainn
`ing proinllarnrnatory cytokines with the ocular surface.
`Treatment of the ocular surface inflammation prior to
`plug insertion has been recornrnended. Acute or chronic
`infection of the lacrimal canaliculus or lacrimal sat: is also
`
`a contraindication to use of a plug.
`
`e. Comlicuttioras
`The most coninion cornplication of punctal plugs is
`spontaneous plug €.‘9€l‘E’ll$l€)Ii, which is particularly corrrrnon
`with the Freeman-style plugs. Over time, an extrusion rate
`of 56% has been reported, but many of these extrusions
`took place after extensive periods of plug residerice. Most
`extrusions are of small consequence, except for incon-
`venience and expense. More troublesome corriplications
`include internal migration of a plug, ‘oiofilrn formation and
`infection,” and pyogenic granuloma formation. Rernovai of
`rnigrated carialicular plugs can be dill'lr:ult and may require
`surgery to the nasolacrirnal duct systern.‘l°»"l
`
`p
`f. Simrmmry
`The extensive literature on the use of punctal plugs in
`the rnariagernent oi dry eye disease has docurriented their
`utility Several recent reports, however, have suggested
`that absorption of tears by the nasolacrirnal ducts into sur~
`rounclirig tissues and blood vessels may provide a feedbac
`mechanism to the lacrirnal gland regulating tear produc-
`tion.“ in one study, placement of punctal plugs in patients
`with normal tear production caused a si.g;rritlcarit decrease
`in tear production. lor up to 2 weeks alter plug insertion.“
`‘Ibis cautionary note should be considered when deciding
`
`whether to incorporate purictal occlusion into a dry eye
`disease rnanagernent plan.
`
`2. Moisture Chamber Spectacles
`The wearing of moisture-conserving spectacles has for
`many years been advocated to alleviate ocular discornfort
`associated with dry eye. However, the level of evidence sup-
`porting its efficacy ior 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 specmcles.“ Addition of side panels to the
`spectacles was shown to further increase the hurriidity."’5
`The clinical efficacy of moisture cliarnher spectacles has
`been reported in case reports.5"~57 l(urihashi proposed a
`related treatment for dry eye patients, in the loom of a wet
`gauze eye mask.“ Conversely, Nichols er al recently report-
`ed in their epidemiologic study that spectacle wearers were
`twice as liltely as emmetropes to report dry eye cliseasefil’
`The reason for this observation was not explained.
`There have been several reports with relatively high
`level of evidence describing the relationship between
`environrriental humidity and dry eye. 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
`interblinlr intervals than those who did not wear spectacles,
`and duration of blink (blinking time) was significaritly
`longer in the latter subjects.” lnstihatiori ol artificial tears
`caused a significant increase in the interhlink interval and
`a decrease in the lilirrk rate.“ Maruyarns 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 di€ler~
`ent contact lens materials and designs have been evaluated,
`including silicone rubber lenses and gas permeable scleral-—
`hearing hard contact lenses with or without lenestration.73"77
`improved visual acuity and comfort, decreased corneal
`epitheliopathy, and healing of persistent corneal epithelial
`defects have been reported.73‘77 Highly oxygen-perrneable
`materials enable overnight wear in appropriate circum--
`starices.” There is a small.
`of corneal vascularization
`
`and possible corneal infection associated with the use of
`Contact lenses by dry eye patients.
`
`3. ‘Fear ntimuiation: fieeretogomias
`Several potential topical ‘pharrriacologicz agents may
`stimulate aqueous secretion, mucous secretion, or both.
`The agents currently under investigation by phaririaceuti~
`cal cornpanies are diquafosol (one of the i’2Y2 receptor
`agonists), reharnipide, gelarriate, ecabet sodium (mucous
`secretion stimulants}, and l5(S)~liE1'E{l~/lUCl stimulant).
`Among them, a diquafosol eye drop has been favorably
`evaluated in clinical trials. 2% diciuafosol tlNS365, DE—089
`lsanien, Osal<a,japanl; inspire lliurharn, NC}? proved to
`
`158
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`DEWS MANAGEMENT AND THERAPY
`
`be ellective in the treatment of dry eye in a randomized,
`double—inwl«:e«:l trial in humans to reduce ocular surface
`
`staining,” A similar study demonstrated the ocular safety
`and tolerability of diqualosol in a clouble~rnasl<ed, placebo-
`controlled, randomized study.” This agent is capable of
`stimulating both aqueous and mucous secretion in animals
`and huntans.3933 Beneficial effects on corneal epithelial
`barrier function, as well as increased tear secretion, has
`been demonstrated in the rat dry eye n1odel.3‘* Diqualosol
`also has been shown to stimulate mucin release from goblet
`cells in a rabbit dry eye tnodel.35»3’5‘
`The effects of rebarnipide -(Oi"C- l.2759 lOtsul<a, Rock-
`ville, MD}; Novartis Ebasel, Switzerlandl) have been evalu~
`ated in human clinical trials. in animal studies, rebarnipide
`increased the mucirt--like substances on the ocular surface
`
`of N—acetylcysteine—treated rabbit eyes.” it also had hy-
`droxyl radical scavenging effects on ill/B—iuduced corneal
`damage in mice.”
`Ecabet sodium {Senju lflsaka, japan}; iSTA llrviue,
`CAD 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 signillcant increase in tear rnucin in dry eye
`patients.” Gelarriate (Sariten {Osal.«:a, japanl) has been
`evaluated in animal studies. Gefaruate promoted rnucin
`production. alter conjunctival injury in rnonlteysflll Gefar--
`riate increased PAS-positive cell density in rabbit conjunc-
`tiva and stimulated mucin—lil<e glycoproteiu stimulation
`from rat cultured corneal epitheli.unt.9‘~‘-*2 An in vivo rabbit
`experiment showed a similar result.93»9‘*
`Tlie agent
`l5(S)—HETE, a unique molecule, can
`stimulate MUC1 rtiucin expression on ocular surface
`epitheliurn.‘*‘5l5(S)—l-{EYE protected the cornea in a rabbit
`model oi desiccation—iuduced injury, probably because of
`ruucin secretion?“ it has been shown to have beneficial
`
`effects on secretion of mucindilte glycoprotein by the rab—
`bit corneal epithel.iuru.97 Other laboratory studies conlirru
`the stimulatory effect of l5(S)-l~lET’tE.9’5"°l Some of these
`agents may become useful clinical therapeutic modalities
`in the near future.
`
`Two orally administered cholinergic agonists, pilocar~
`pine and cevilernine, have been evaluated in clinical trials
`for treatment of Sjogren syndrome associated l«:eratocon-
`junctivitis sicca (RC5). Patients who were treated with pi~
`locarpiue at a dose of 5 mg QED experienced a signilicantly
`greater overall improvement than placebo-treated patients
`in “ocular problems” in their ability to focus their eyes dur~
`ing reading, and in syrnptotrts of blurred vision cornpared
`with placebo—treated patients.“ The most commonly
`reported side effect from this medication was excessive
`sweating, which occurred in over 40% oi patients, Two
`percent of the patients talting pilocarpine withdrew from
`the study because of drug~related side effects. (Ether stud
`ies have reported efficacy of pilocarpine for ocular signs
`and symptoms of Sjogren syndrome l{CS,l°3"°5 including
`an increase in conjunctival goblet cell density after 1 and
`2 months of therapy.195
`
`Cevilemine is another oral cholinergic agonist that
`was found to significantly improve symptoms of dryness
`and aqueous tear production and ocular surface disease
`cotnparecl to placebo when taller: in doses of 13 or 30 mg
`TlD.'*°7vl°3 This agent may have fewer adverse systemic side
`ellects than oral pilocarpine.
`
`D. Eloiogoai “fear Substitutes
`Naturally occurring biological, ie, nonplianuaceutical
`fluids, can be used to substitute for natural tears. The
`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 epitlie—
`liotrophic factors, such as growth factors, neurotrophins,
`vita