DEWS MANAGEMENT AND THERAPY
`DEWS MANAGEMENT AND THERAPY
`
`SUTURE
`OtrfUNE
`t. int'ocSuctiori
`I. Introduction
`M. Goals of the Managerrie.it arid
`llierapy
`II. Goals of the Management and Therapy
`Subcorrsmfttee
`Subcommittee
`:N« Assessment of current, dry eye
`therapies
`Ill. Assessment of current dry eye therapies
`A. Tear siippiemerstation: liibriGsnts
`A. Tear supplementation: lubricants
`1. Genersi characteristics and effects
`1. General characteristics and effects
`2. Preservatives
`2. Preservatives
`3. Electrolyte composrtiofi
`3. Electrolyte composition
`4. Gsrnolarity
`4. Osmolarity
`5. Viscosrty agersts
`5. Viscosity agents
`6. Summary
`8. StfrrifTiary
`8. Tear Retention
`R. Tear Retention
`.1.. Pisridai occiusion
`1. Punctal occlusion
`a. Rationsie
`a. Rationale
`b. Types
`b. Types
`c. Ciinfca! studies
`c. Clinical studies
`d. Indications snd cssntrairidlcations
`d. Indications and contraindications
`6. Ccrripiicstlons
`e. Complications
`f. Summary
`f. Summary
`2. Moisture chamber spectecies
`2. Moisture chamber spectacles
`3. Contact lenses
`3. Contact lenses
`C. Tear stimii'ation: secretagogues
`C. Tear stimulation: secretagogues
`D. Bioioglcal tear substitutes
`D. Biological tear substitutes
`1. Serum
`1. Serum
`2. Salivary gland autotranspiantatlon
`2. Salivary gland autotransplarrtation
`E. Anti-irifiamnnatory tlierapy
`E. Arrti-inflarnmatory therapy
`1. Cyclosporins
`1. Cyclosporine
`2. Corticosteroids
`2. Corticosteroids
`a. Ciifiical studies
`a. Clinical studies
`b. Basic research
`b. Basic research
`3. TetracyclSnes
`3. Tetracyclines
`a. Properties of tetracyciines and their
`a. Properties of tetracyclines and their
`derivath^es
`derivatives
`1) Antibacterial properties
`1) Antibacterial properties
`2) Anti-inflamrristory
`2) Anti-inflammatory
`3) Anti-angiogersle properties
`3) Anti-anglogenic properties
`b. Ciirsical appiicatlons of
`tetracycline
`b. Clinical applications of tetracycline
`1) Acne Rosacea
`1) Acne Rosacea
`2} Chronic posterior blephsritis:
`2) Chronic posterior blepharitis:
`meibomianltis, meibomian gland
`rneibomianitis, meibomian gland
`dysfonction
`dysfunction
`3) Dosage and safety
`3) Dosage and safety
`F. EssefEtlai fatty acids
`F. Essential fatty acids
`G. Envirorsmentai stnrtegies
`G. Environmental strategies
`Tv. Treatmerit recommendations
`IV. Treatment recommendations
`V. Unariswered qiiestions and future directions
`V. Unanswered questions and future directions
`
`by all subcommittee members and by the entire Dry Eye
`by all subcommittee members and by the entire Dry Eye
`Workshop membership. Comments and suggested revi­
`WorkShop membership. Comments and suggested revi-
`sions were discussed by the subcommittee members and
`sions were discussed by the subcommittee members and
`incorporated into the report where deemed appropriate
`incorporated into the report where deemed appropriate
`by consensus.
`by consensus.
`
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`THE OCULAR SURFACE / APRIL 2007, VOL, 5, NO, 2 / www.theocuiarsurface.coni
`THE OCULAR SURFACE I APRIL 2007, VOL. 5, NO. 2 / www.theocularsurface.com
`
`States
`
`are
`
`ap­
`
`ill. ASSESSgyigNT OF OURRENT DRY EYE THERAPIES
`1111. ASSESSMENT OF CURRENT DRY EYE THERAPIES
`A. Tsar Supptemefstafisrs: Lssbrieassts
`A. Tear Supplementation: Lubricants
`1. Gesera! Clias-acierfetics
`asd Effects
`
`1. General Characteristics and Effects
`The term "artificial tears" is a misnomer for most prod­
`The term "artificial tears" is a misnomer for most prod-
`ucts that identify themselves as such, because they do not
`ucts that identify themselves as such, because they do not
`mimic the composition of human tears. Most function as
`mimic the composition of human tears. Most function as
`lubricants, although some more recent formulations mimic
`lubricants, although some more recent formulations mimic
`the electrolyte composition of human tears (TheraTears®
`the electrolyte composition of human tears (TheraTears®
`[Advanced Vision Research, Wobum, MAS).1'2 The ocular
`[Advanced Vision Research, Woburn, MA]).1.2 The ocular
`lubricants presently available in
`the
`United
`lubricants presently available in the United States are ap-
`proved based on the US Food and Drug Administration
`proved based on the US Food and Drug Administration
`(FDA) monograph on over-the-counter (OTC) products
`(FDA) monograph on over-the-counter (OTC) products
`(21 CFR 349) and are not based on clinical efficacy The
`(21 CFR 349) and are not based on clinical efficacy. The
`monograph specifies permitted active ingredients (eg,
`monograph specifies permitted active ingredients (eg,
`demulcents, emulsifters, surfactants, and viscosity agents)
`demulcents, emulsifiers, surfactants, and viscosity agents)
`and concentrations, but gives only limited guidance on
`and concentrations, but gives only limited guidance on
`inactive additives and solution parameters. Certain inac­
`inactive additives and solution parameters. Certain inac-
`
`tive ingredients that are used in artificial tears sold in the
`tive ingredients that are used in artificial tears sold in the
`US (eg, castor oil in Endura™ [Allergan, Inc., Irvine, CA]
`US (eg, castor oil in Endure [Allergan, Inc., Irvine, CA]
`
`and guar in Systane® [Alcon, Ft Worth, TX]) are not listed
`and guar in Systane® [Alton, Ft Worth, TX]) are not listed
`in the monograph.
`in the monograph.
`It is difficult to prove
`
`that ingredient in an ocular any
`
`It is difficult to prove that any ingredient in an ocular
`lubricant acts as an
`
`active agent. If there is an active in­
`lubricant acts as an active agent. If there is an active in-
`gredient, it is
`the polymeric base or viscosity agent, but
`gredient, it is the polymeric base or viscosity agent, but
`this has proved difficult to demonstrate. This is either
`this has proved difficult to demonstrate. This is either
`because it is not possible to detect the effects or differences
`because it is not possible to detect the effects or differences
`in clinical trials with presently available clinical tests or
`in clinical trials with presently available clinical tests or
`because the currently available agents do not have any
`because the currently available agents do not have any
`discernable clinical activity beyond a lubrication effect.
`discernable clinical activity beyond a lubrication effect.
`Although certain artificial
`tears
`have
`demonstrated
`Although certain artificial tears have demonstrated more
`success than others in reducing symptoms of irritation
`success than others in reducing symptoms of irritation
`or decreasing ocular surface dye staining in head-to-head
`or decreasing ocular surface dye staining in head-to-head
`comparisons, there have been no large scale, masked,
`comparisons, there have been no large scale, masked,
`comparative clinical trials to evaluate the wide variety of
`comparative clinical trials to evaluate the wide variety of
`ocular lubricants.
`ocular lubricants.
`What is the clinical effect of ocular lubricants or artificial
`What is the clinical effect of ocular lubricants or artificial
`tears? Do they lubricate, replace missing tear constituents,
`tears? Do they lubricate, replace missing tear constituents,
`reduce elevated tear film osmolality, dilute or wash out
`reduce elevated tear film osmolarity, dilute or wash out
`infiammatoiy or inflammation-inducing agents? Do they,
`inflammatory or inflammation-inducing agents? Do they,
`
`in some instances, actually wash out essential substances
`in some instances, actually wash out essential substances
`remain
`found in normal human
`
`tears? These questions to
`found in normal human tears? These questions remain to
`be answered as more sensitive clinical
`tests
`become
`avail­
`he answered as more sensitive clinical tests become avail-
`able to detect changes in
`the
`ocular
`surface.
`able to detect changes in the ocular surface.
`The foremost objectives in
`
`caring for patients with dry
`The foremost objectives in caring for patients with dry
`eye disease are to improve the patient's ocular comfort and
`eye disease are to improve the patients ocular comfort and
`quality of life, and to return the ocular surface and tear film
`quality of life, and to return the ocular surface and tear film
`to the normal homeostatic
`state. Although
`symptoms
`to the normal homeostatic state. Although symptoms can
`rarely be eliminated,
`they can
`often be
`improved,
`rarely be eliminated, they can often be improved, leading
`to an improvement in the quality of life. It is more difficult
`to an improvement in the quality of life. It is more difficult
`to demonstrate, that topical lubricants
`
`
`the improve ocular
`to demonstrate that topical lubricants improve the ocular
`surface and the tear film abnormalities associated with dry
`surface and the tear film abnormalities associated with dry
`eye. Most clinical studies fail to demonstrate significant
`eye. Most clinical studies fail to demonstrate significant
`correlation between symptoms and clinical test values
`correlation between symptoms and clinical test values
`or between the clinical test values themselves.3-5 It is not
`or between the clinical test values themselves.3-5 It is not
`unusual for a dry eye with only mild symptoms to show
`unusual for a dry eye with only mild symptoms to show
`significant rose bengal staining. Until agents are developed
`significant rose bengal staining. Until agents are developed
`that can restore the ocular surface and tear film to their
`that can restore the ocular surface and tear film to their
`
`more
`
`can
`leading
`
`0345
`
`TEVA - EXHIBIT 1004 (PART 3 OF 4)
`
`

`
`DEWS MANAGEMENT AND THERAPY
`DEWS MANAGEMENT AND THERAPY
`
`eye with ocular surface disease and impairment of lacrimal
`
`
`of signs dry
`noriTiai. homeostatic state,
`the
`symptoms
`and
`normal homeostatic state, the symptoms and signs of dry
`eye with ocular surface disease and impairment of lacrimal
`gland secretion, or for patients on multiple, preserved
`eye disease will continue.
`gland secretion, or for patients on multiple, preserved
`eye disease will continue.
`Ocular iubricants are characterized by hypotonic or
`topical medications for chronic
`eye disease. Patients with
`Ocular lubricants are characterized by hypotonic or
`topical medications for chronic eye disease. Patients with
`isotonic buffered solutions containing electrolytes, surfac­
`severe dry eye, greatly reduced tear secretion, and punctal
`isotonic buffered solutions containing electrolytes, surfac-
`severe dry eye, greatly reduced tear secretion, and punctal
`occlusion are at particular risk for preservative toxicity. In
`tants, and various
`
`
`In types of viscosity agents. theory, the
`occlusion are at particular risk for preservative toxicity. In
`tants, and various types of viscosity agents. In theory, the
`ideal artificial lubricant should be preservative-free, contain
`such patients, the
`instilled agent
`
`cannot washed out; if be
`
`ideal artificial lubricant should be preservative-free, contain
`such patients, the instilled agent cannot be washed out; if
`this risk lias not been appreciated by the clinician, preserved
`potassium, bicarbonate, and
`other
`electrolytes and
`have
`a
`this risk has not been appreciated by the clinician, preserved
`potassium, bicarbonate, and other electrolytes and have a
`polymeric system to increase its retention time.''6-* Physical
`drops might be. used at high frequency.
`polymeric system to increase its retention time.1.68 Physical
`drops might be used at high frequency.
`Another additive used in OTC formulations is disodium
`properties should include a neutral to slightly alkaline pH.
`properties should include a neutral to slightly alkaline pH.
`Another additive used in OTC formulations is disodium
`(EDTA). It augments
`
`the preservative efficacy of BAK and
`Osmolarities of artificial tears have been measured to range
`(EDTA). It augments the preservative efficacy of BAK and
`Osmolarities of artificial tears have been measured to range
`other preservatives, but,
`
`by itself, it is not a sufficient pre­
`from about i 81 to 354 mOsm/L9 The main variables in the,
`from about 181 to 354 mOstn/L.9 The main variables in the
`other preservatives, but, by itself, it is not a sufficient pre-
`formulation of ocular lubricants regard the concentration
`servative. Used in some nonpreserved solutions, it may
`formulation of ocular lubricants regard the concentration
`servative. Used in some nonpreserved solutions, it may
`
`
`the of and choice of electrolytes, the osmolarity and type
`help limit microbial growth in opened unit-dose vials.
`help limit microbial growth in opened unit-dose vials.
`of and choice of electrolytes, the osmolarity and the type
`of viscosity/polymeric system,
`the
`
`presence or absence of
`Although use of EDTA may allow a lower concentration of
`of viscosity/polymeric system, the presence or absence of
`Although use of EDTA may allow a lower concentration of
`preservative, EDTA may itself be toxic to the ocular surface
`preservative, and,
`if present,
`the
`
`type of preservative.
`preservative, EDTA may itself be toxic to the ocular surface
`preservative, and, if present, the type of preservative.
`epithelium. A study comparing two preservative-free solu­
`epithelium. A study comparing two preservative-free solu-
`tions, Hypotears PF® (Novartis Ophthahmcs, East Hanover,
`tions, Hypotears PF® (Novartis Ophthalrnics, East Hanover,
`of dry
`NJ) containing EDTA and Refresh® (Allergan, Inc.,
`Irvine,
`NJ) containing EDTA and Refresh® (Allergan, Inc., Irvine,
`CA) without EDTA, showed that both formulations had
`CA) without EDTA, showed that both formulations had
`identical safety profiles and were completely nontoxic
`to
`identical safety profiles and were completely nontoxic to
`the rabbit corneal epithelium.18 Other studies found that
`the rabbit corneal epithelium.18 Other studies found that
`EDTA-containing preparations increased corneal epithelial
`EDTA-containing preparations increased corneal epithelial
`permeability. i9-2!) The potential exists that patients with
`permeability.19,2° The potential exists that patients with
`severe dry eye will find that EDTA-containing preparations
`severe dry eye will find that. EDTA-containing preparations
`unit
`increase irritation.
`increase irritation.
`Nonpreserved, single unit-dose tear substitutes are
`Nonpreserved, single unit-dose tear substitutes are
`more costly for the manufacturer to produce, more
`more costly for the manufacturer to produce, more
`costly for the patients to purchase, and less convenient
`costly for the patients to purchase, and less convenient
`to use than bottled ocular lubricants.
`
`For these reasons,
`to use than bottled ocular lubricants. For these reasons,
`reclosable unit dose vials (eg, Refresh Free [Allergan Inc.,
`reclosable unit dose vials (eg, Refresh Free (Allergan Inc.,
`Irvine, CA]; Tears Natural Free® [Alcon, Fort Worth,
`Irvine, CAI; Tears Natural Free® [Alcon, Fort Worth,
`ocular
`TX)) were introduced. Less toxic preservatives, such as
`TX)) were introduced. Less toxic preservatives, such as
`polyquad (polyquaternium-l), sodium chlorite (Purite®),
`polyquad (polyquatemium-1), sodium chlorite (Purite®),
`and sodium perborate were developed to allow the use
`and sodium perborate were developed to allow the use
`of multidose bottled lubricants and to avoid the known
`of multidose bottled lubricants and to avoid the known
`toxicity of BAK-containing solutions.21'22 The "vanishing"
`toxicity of BAK-containing solutions.21,22 The "vanishing"
`preservatives were sodium perborate and sodium chlorite
`preservatives were sodium perborate and sodium chlorite
`(TheraTears® [Advanced Vision Research, Woburn, MA],
`(TheraTears® (Advanced Vision Research, Woburn, MAI ,
`Genteal® [Novartis, East Hanover, Nj], and Refresh Tears®
`Genteal® (Novartis, East Hanover, NJ), and Refresh Tears®
`[Allergan Inc.,
`Irvine, CA]).
`(Allergan Inc., Irvine, CAD.
`Sodium chlorite degrades to chloride ions and water
`Sodium chlorite degrades to chloride ions and water
`upon exposure to UV light after instillation. Sodium perbo­
`upon exposure to UV light after instillation. Sodium perbo-
`rate is converted to water and
`oxygen on
`contact with
`rate is convened to water and oxygen on contact with the
`tear film. For patients with
`
`severe dry even vanishing eye,
`
`tear film. For patients with severe dry eye, even vanishing
`preservatives may not totally degrade, due to a decrease in
`preservatives may not totally degrade, due to a decrease in
`tear volume, and may be
`irritating. Patients prefer bottled
`tear volume, and may he irritating. Patients prefer bottled
`may be
`The
`preparations for reasons of both
`cost and
`ease of use.
`preparations for reasons of both cost and ease of use. The
`ideal lubricant would come in a multidose, easy-to-use
`ideal lubricant would come in a multidose, easy-to-use
`bottle, that contains a preservative diat completely dissipates
`bottle that contains a preservative that completely dissipates
`before reaching the tear film, or is completely nontoxic and
`before reaching the tear film, or is completely nontoxic and
`nonirritating and maintains absolute sterility with frequent
`nonirritating and maintains absolute sterility with frequent
`use. One such multi-use, preservative-free product has
`use. One such multi-use, preservative-free product has
`epithe­
`been introduced
`to the market (Visine Pure-Tears® [Pfizer,
`been introduced to the market (Visine PureTears® (Pfizer,
`Inc. NJ]).
`Inc, NJI).
`Ocular ointments and gels are also used in treatment of
`Ocular ointments and gels are also used in treatment of
`dry eye disease. Ointments are formulated with a specific
`dry eye disease. Ointments are formulated with a specific
`mixture of mineral oil and petrolatum. Some contain lanolin,
`mixture of mineral oil and petrolatum. Some contain lanolin,
`
`2. Preservatives
`2. Preservatives
`The single most critical advance in
`the
`treatment
`The single most critical advance in the treatment of dry
`eye came wish the elimination of preservatives, such as benzal-
`eye came with the elimination of preservatives, such as benzal-
`konium chloride (BAK), from OTC lubricants. Because
`konium chloride (BAIT), from OTC lubricants. Because
`of the risk of contamination of multidose products, most
`of the risk of contamination of multidose products, most
`either contain a preservative or employ some mechanism
`either contain a preservative or employ some mechanism
`for minimizing contamination. The FDA has required
`that
`for minimizing contamination. The FDA has required that
`multidose artificial tears contain preservatives to prevent
`multidose artificial tears contain preservatives to prevent
`microbial growth.30 Preservatives are not
`required
`in
`microbial growth. 30 Preservatives are not required in unit
`dose vials that are discarded after a single use. The wide­
`dose vials that are discarded after a single use. The wide-
`spread availability of nonpreserved preparations allows
`spread availability of nonpreserved preparations allows
`patients to administer
`lubricants more
`
`frequently without
`patients to administer lubricants more frequently without
`concern about the toxic effects of preservatives. For patients
`concern about the toxic effects of preservatives. For patients
`with moderate-to-severe dry eye disease, the absence of
`with moderate-to-severe dry eye disease, the absence of
`preservatives is of more critical importance than the particu­
`preservatives is of more critical importance than the particu-
`lar polymeric agent used in ocular lubricants. The
`lar polymeric agent used in ocular lubricants. The ocular
`surface Lnfiamroation associated with dry eye. is exacerbated
`surface inflammation associated with dry eye is exacerbated
`
`by preserved lubricants; however, nonpreserved solutions
`by preserved lubricants; however, nonpreserved solutions
`are inadequate in themselves to improve the surface inflam­
`are inadequate in themselves to improve the surface inflam-
`
`mation and epithelial pathology seen in dry eye, disease.51
`mation and epithelial pathology seen in dry eye disease.
`Benzalkonium chloride is the most frequently used
`Benzalkonium chloride is the most frequently used
`preservative in
`topical ophthalmic preparations, as well as
`preservative in topical ophthalmic preparations, as well as
`in topical lubricants. Its epithelial toxic effects have been
`in topical lubricants. Its epithelial toxic effects have been
`well established.S2"17 The toxicity of BAK is related to its
`well established."-" The toxicity of BAK is related to its
`concentration, the frequency of dosing, the level or amount
`concentration, the frequency of dosing, the level or amount
`of tear secretion, and the severity of the ocular surface
`of tear secretion, and the severity of the ocular surface
`disease. In the patient with mild dry eye, BAK-preserved
`disease. In the patient with mild dry eye, BAK-preserved
`
`drops are usually well tolerated when used 4-6 times a day
`drops are usually well tolerated when used 4-6 times a day
`or less. In patients with moderate-to-severe dry eye, the
`or less. In patients with moderate-to-severe dry eye, the
`potential for BAK toxicity is high, due to decreased tear
`potential for BAK toxicity is high, due to decreased tear
`secretion and decreased turnover.®7 Some
`patients
`secretion and decreased turnover." Some patients may be
`using other topical preparations (eg, glaucoma medications)
`using other topical preparations (eg, glaucoma medications)
`that contain BAK, increasing their exposure to the toxic
`that contain BAK, increasing their exposure to the toxic
`effects of BAK. Also, the potential for toxicity exists with
`effects of BAK. Also, the potential for toxicity exists with
`patient abuse of other OTC products that contain BAK,
`patient abuse of other OTC products that contain BAK,
`such as vasoconstrictors,
`such as vasoconstrictors.
`BAK can damage the corneal
`and
`conjunctival
`BAK can damage the corneal and conjunctival epithe-
`lium, affecting cell-to-cell junctions and cell shape and
`lium, affecting cell-to-cell junctions and cell shape and
`microvilli, eventually leading to cell necrosis with sloughing
`microvilli, eventually leading to cell necrosis with sloughing
`of 1-2 layers of epithelial cells.17 Preservative-free formula­
`of 1-2 layers of epithelial cells." Preservative-free formula-
`
`
`with tions are absolutely necessary for patients severe dry
`tions are absolutely necessary for patients with severe dry
`
`
`
`/ THE OCULAK SURFACE / APRIL 2007, VOL. 5, NO. 2 ww.dseociikrsurface.com
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`DEWS MANAGEMENT AND THERAPY
`DEWS MANAGEMENT AND THERAPY
`
`which can be irritating to the eye and delay corneal wound
`which can be irritating to the eye and delay corneal wound
`healing.23 Individuals with
`sensitivity
`
`
`wool to may also be
`healing.23 Individuals with sensitivity to wool may also be
`sensitive to lanolin.23 Some ointments contain parabens as
`sensitive to lanolin.23 Some ointments contain parabens as
`preservatives, and these ointments are not well tolerated
`preservatives, and these ointments are not well tolerated
`by patients with severe dry
`eye. In
`general,
`by patients with severe dry eye. In general, ointments do
`not support bacterial growth and, therefore, do not require
`not support bacterial growth and, therefore, do not require
`preservatives. Gels containing high molecular weight cross-
`preservatives. Gels containing high molecular weight cross-
`linked polymers of acrylic acid (carbomers) have longer
`linked polymers of acrylic acid (carbomers) have longer
`retention times than
`artificial tear
`solutions,
`but
`retention times than artificial tear solutions, but have less
`visual blurring effect than
`petrolatum
`ointments.
`visual blurring effect than petrolatum ointments.
`
`4. Osmdbsily
`4. Osmolarity
`Tears of patients with dry eye have a higher tear film
`Tears of patients with dry eye have a higher tear film
`osmoiarity (crystalloid osmoiarity) than do those, of normal
`osmolarity (crystalloid osmolarity) than do those of normal
`patients. 28>29 Elevated tear film osmoiarity causes mor­
`patients.28•Z9 Elevated tear film osmolarity causes mor-
`phological and biochemical changes to the corneal and
`phological and biochemical changes to the corneal and
`
`conjunctival epithelium18'30 and is pro-infiammatory.31 This
`conjunctival epithelium' 8•3° and is pro-inflammatory.31 This
`knowledge influenced the development of hypo-osmotic
`knowledge influenced the development of hypo-osmotic
`artificial tears such as Hypotears® (230 mOsm/L [Novartis
`artificial tears such as Hypotears® (230 mOsni/L [Novartis
`Ophthalmics, East Hanover, NJ]) and subsequently Thera­
`Ophthalmics, East Hanover, NJ]) and subsequently Thera-
`Tears® (181 mOsm/L [Advance Vision Research, Wobum,
`Tears® (181 mOsm/L. [Advance Vision Research, Woburn,
`MA]).32
`MA]).32
`Colloidal osmolality is another factor that varies in
`Colloidal osmolality is another factor that varies in
`artificial tear formulations. While crystalloid osmoiarity
`artificial tear formulations. While crystalloid osmolarity
`is related to the presence of ions, colloidal osmolality is
`is related to the presence of ions, colloidal osmolality is
`dependent largely on macromolecule content. Colloidal
`dependent largely on macromolecule content. Colloidal
`osmoiarity, also known as oncotic pressure, is involved in the
`osmolarity, also known as oncotic pressure, is involved in the
`control of water transport in tissues. Differences in colloidal
`control of water transport in tissues. Differences in colloidal
`
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`osmolality affect the net water flow across membranes, and
`osmolality affect the net water flow across membranes, and
`water flow is eliminated by applying hydrostatic pressure
`water flow is eliminated by applying hydrostatic pressure
`to the downside of the water flow. The magnitude of this
`to the downside of the water flow. The magnitude of this
`osmotic pressure is determined by osmolality differences
`osmotic pressure is determined by osmolality differences
`on the two sides of the membrane. Epithelial ceils swell
`ointments
`do
`on the two sides of the membrane. Epithelial cells swell
`due to damage to their cellular membranes or due to a
`due to damage to their cellular membranes or due to a
`dysfunction in the pumping mechanism. Following the
`dysfunction in the pumping mechanism. Following the
`addition of a fluid with a high colloidal osmolality to the
`addition of a fluid with a high colloidal osmolality to the
`have
`less
`damaged cell surface, deturgescence occurs, leading to a
`damaged cell surface, deturgescence occurs, leading to a
`return of normal cell physiology. Theoretically, an artificial
`return of normal cell physiology. Theoretically, an artificial
`tear formulation with a high colloidal osmolality may be of
`tear formulation with a high colloidal osmolality may be of
`3. Ekclroiyte C®mpesMosi
`value. Holly and Esquivel evaluated many different artificial
`3. Electrolyte Composition
`value. Holly and Esquivel evaluated many different artificial
`tear formulations and showed that Hypotears® (Novartis
`Solutions containing electrolytes and or ions have been
`Solutions containing electrolytes and or ions have been
`tear formulations and showed that Hypotears® (Novartis
`shown to be beneficial in treating ocular surface damage
`Ophthalmics, East Hanover, NJ) had
`the highest colloidal
`shown to be beneficial in treating ocular surface damage
`Ophthalmics, East Hanover, NJ) had the highest colloidal
`due to dry eye.1,6,20.24,25 To date, potassium and bicarbon-
`osmolality of all o! the formulations tested.33 Formulations
`due to dry eye.®-6'20-24'23 To date,
`bicarbon­
`potassium
`and
`osmolality of all of the formulations tested.33 Formulations
`to
`ate seem to be the most critical. Potassium is
`important
`with higher colloidal osmolality have since been marketed
`ate seem to be the most critical. Potassium is important to
`with higher colloidal osmolality have since been marketed
`(Dwelle® [Dry Eye Company, Silverdale, WA]).
`maintain corneal thickness.7 In a dry-eye rabbit model, a
`maintain corneal thickness.'" In a dry-eye rabbit model, a
`(Dwelle [Dry Eye Company, Silverdale, WA]).
`Protection against the adverse effects of increased os­
`hypotonic tear-matched electrolyte solution
`(TheraTears®
`hypotonic tear-matched electrolyte solution (TheraTears®
`Protection against the adverse effects of increased os-
`[Advanced Vision Research, Wobum, MA]) increased con­
`moiarity (osmoprotection) has led to development of OTC
`[Advanced Vision Research, Woburn, MA]) increased con-
`molarity (osmoprotection) has led to development of OTC
`junctival goblet cell density and corneal glycogen content,
`drops incorporating compatible
`solutes
`
`(such as glycerin,
`junctival goblet cell density and corneal glycogen content,
`drops incorporating compatible solutes (such as glycerin,
`erythritoi, andlevocamitine (Optive® [Allergan Inc., Irvine,
`and reduced tear osmoiarity and rose bengal staining after 2
`and reduced tear osmolarity and rose bengal staining after 2
`erythritol, and levocamitine (Optive® [Allergan Inc., Irvine,
`weeks of treatment.25 The restoration of conjunctival goblet
`CAj). It is thought that the compatible solutes distribute be­
`weeks of treatment.25 The restoration of conjunctival goblet
`CA] ). It is thought that the compatible solutes distribute be-
`tween the tears and the intracellular fluids to protect against
`cells seen in the diy-eye rabbit model has been co rroborated
`cells seen in the dry-eye rabbit model has been corroborated
`tween the tears and the intracellular fluids to protect against
`in patients with dry eye after LAS1K.26
`potential cellular damage from hyperosmolar
`tears.34
`in patients with dry eye after LASIK.26
`potential cellular damage from hyperosmolar tears.34
`Bicarbonate-containing solutions promote the recovery
`Bicarbonate-containing solutions promote the recovery
`5. Viscosiiy Agezste
`of epithelial barrier function in damaged corneal epithelium
`of epithelial barrier function in damaged corneal epithelium
`5. Viscosity Agents
`The stability of the
`tear film depends
`on
`the. chemical-
`and aid in maintaining normal epithelial ultrastructure.
`and aid in maintaining normal epithelial ultrastructure.
`The stability of the tear film depends on the chemical-
`They may also be important for maintaining the mucin layer
`physical characteristics of that film interacting with the
`They may also be important for maintaining the mucin layer
`physical characteristics of that film interacting with the
`of the tear film.6 Ocular
`conjunctival and corneal epithelium via the. membrane-
`
`lubricants are. available that mimic
`of the tear film.' Ocular lubricants are available that mimic
`conjunctival and corneal epithelium via the membrane-
`the electrolyte composition of human tears, eg, TheraTears®
`spanning mucins (ie, MUC-16 and MUC-4). In the classical
`the electrolyte composition of human tears, eg, TheraTears®
`spanning mucins (ie, MU& 16 and MUC-4). In the classical
`(Advanced Vision Research, Wobum, MA) and BION Tears®
`three-layered tear film model, the mucin layer is usually
`(Advanced Vision Research, Woburn, MA) and BION -fears®
`three-layered tear film model, the mucin layer is usually
`(Akon, Fort Worth, TX).1 '2 These also contain bicarbonate,
`thought of as a surfactant or wetting agent, acting to lower
`(Alcon, Fort Worth, TX).' •2 These also contain bicarbonate,
`thought of as a surfactant or wetting agent, acting to lower
`protec­
`which is critical for forming and maintaining
`the
`the surface tension of the relatively hydrophobic ocular
`which is critical for forming and maintaining the protec-
`the surface tension of the relatively hydrophobic ocular
`the corneal and conjunctival cells "wet-
`tive mucin gel in the stomach.27 Bicarbonate may play a
`surface, rendering
`tive mucin gel in the stomach.27 Bicarbonate may play a
`surface, rendering the corneal and conjunctival cells "wet-
`similar role, for gel-forming mucins
`on
`the
`ocular
`surface.
`table."33 Currently, the tear film is probably best described
`table."33 Currently, die
`film is probably
`tear
`best described
`similar role for gel-forming mucins on the ocular surface.
`Because bicarbonate is
`conve