Ординатура / Офтальмология / Английские материалы / Clinical Ocular Pharmacology 5th edition_Bartlett, Jaanus_2008

observation as compared with the first group. The first group showed a small initial pressure increase that did not continue to rise during subsequent weeks of the study.

The degree of response to topical corticosteroid thus appears to be genetically determined. Patients with primary open-angle glaucoma and their relatives show a remarkably high prevalence of pressure elevations with topical steroids. Approximately 70% of the first-degree offspring of individuals with glaucoma have IOP elevations of at least 5 mm Hg. Information regarding patient or family history of glaucoma, therefore, becomes important when considering the use of steroids. In addition to genetic tendencies, other factors can contribute to the pressure elevations resulting from topical steroid administration.These can include patient age, myopia of 5D or more, and Krukenberg’s spindles.

Long-term systemic steroid therapy can also cause IOP elevations. Patients treated with systemic cortisone, 25 mg or its equivalent, for rheumatoid arthritis and other collagen vascular diseases showed significantly higher mean applanation pressures as compared with untreated individuals. A decreased facility of outflow and changes in ocular rigidity in steroid-treated patients were also observed.

Corticosteroid-induced ocular hypertension appears to relate not only to the individual patient but to the specific steroid used. In general, dexamethasone 0.1%, betamethasone 0.1%, and prednisolone acetate appear more likely to induce significant IOP elevations than do fluorometholone alcohol and medrysone. Clinical studies with rimexolone and LE indicate that they have less potential to elevate IOP than does dexamethasone phosphate or prednisolone acetate.

A masked study using male volunteers compared ocular pressure elevations with dexamethasone phosphate 0.1%, fluorometholone alcohol 0.1%, and medrysone 1% applied four times daily for 6 weeks. Figure 12-3 shows the relative ability of these steroids to raise IOP. At the end of 6 weeks of treatment, the mean pressure increases for dexamethasone, fluorometholone, and medrysone were 63.1%, 33.8%, and 8.3%, respectively. Additional studies have compared the effects of fluorometholone alcohol suspension 0.25% with dexamethasone sodium phosphate solution 0.1% in steroidresponsive patients. Subjects received the medication in one eye four times daily for up to 6 weeks.Although both drugs elevated IOP, mean pressure increases from baseline in eyes treated with fluorometholone were significantly lower than those in eyes treated with dexamethasone at weeks 2, 4, and 6. Further studies are needed to compare the effects of the alcohol and acetate derivatives of fluorometholone on IOP in both nonsteroid and steroid responders.

With a significant elevation of IOP defined as equal to or greater than 10 mm Hg at any visit, analysis of pooled data from 1,442 patients and 206 volunteers treated for 28 days with LE 0.2% or 0.5%, prednisolone acetate 1%, or

STUDY DAY

Figure 12-4 Mean intraocular pressure response in known corticosteroid responders to loteprednol etabonate (LE) 0.5% or prednisolone acetate (PA) 1.0%. (Reprinted with permission from Bartlett JD, Horowitz B, Laibovitz R, et al. Intraocular pressure response to loteprednol etabonate in known steroid responders. J Ocul Pharmacol 1993;9:161.)

placebo showed a 0.6%, 1.0%, and 6.7% rise in IOP, respectively. The effect of LE 0.5% and prednisolone acetate 1.0% has been compared in known steroid responders. Four-times-daily administration of LE for 6 weeks increased IOP by 24% as compared with baseline pressure (Figure 12-4). In contrast, prednisolone acetate increased IOP by 50% as compared with baseline. The pressure rise was statistically significant for prednisolone but not for LE. The IOP of rimexolone has also been compared with fluorometholone alcohol in known steroid responders. The drugs were instilled four times daily for 4 weeks. Rimexolone was reported to be equivalent to fluorometholone in its IOP-elevating potential.

Factors contributing to the reduced propensity of some steroids to raise IOP could include their intraocular bioavailability, considerably shorter pharmacokinetic halflife, and greater susceptibility to metabolism as compared with dexamethasone and prednisolone. In addition to the individual steroid’s effect on IOP, concentration, frequency, and length of administration may play a role in IOP elevation.

The molecular mechanism whereby corticosteroids increase resistance to aqueous humor outflow is not fully understood. Human trabecular cells possess receptors that are responsive to steroids. A direct action on meshwork cells could mediate alterations in outflow facility. Electron microscope studies of steroid-treated trabecular specimens have indicated the presence of extracellular materials (including glycosaminoglycans) in eyes with corticosteroid-induced glaucoma. These materials are different from those seen in eyes with open-angle glaucoma. Experimental studies of cultured human eyes or trabecular cells also indicate that corticosteroids can cause changes in the proteoglycans of the extracellular

232 CHAPTER 12 Anti-Inflammatory Drugs

matrix, alter protein synthesis, stabilize the actin microfilament network within cells, and decrease phagocytic capacity.

Infection

Because steroids reduce one’s immunologic defense mechanisms, these drugs lower resistance to many types of infection. In addition, inhibiting the inflammatory response may mask symptoms of disease. Evidence indicates that steroid administration can increase susceptibility to viral, fungal, and bacterial infections.

The use of steroids in ocular infections requires caution to avoid interfering with reparative processes. If the appropriate antibiotic is selected and if the course of therapy is relatively short, steroids can help to reduce inflammation and prevent possible scarring. In general, however, steroids should be avoided in cases of routine bacterial infections of the eyelids and conjunctiva when no scarring is anticipated, because steroids provide relatively little benefit in the healing process.

Steroids may prolong the clinical course of dendritic keratitis caused by herpes simplex virus. Experiments with rabbits have confirmed these observations.

There is general agreement that topical use of steroids enhances ocular susceptibility to fungal infection. Treatment of minor ocular injuries with steroids or steroid–antibiotic combinations has resulted in fungal keratitis. Indirect evidence indicates that steroids decrease human resistance to fungal infections.Therefore for patients using topical or systemic steroid therapy in whom discontinuation of the steroid is not feasible, elimination of the infection can be difficult and prolonged. The enhanced risk of superinfection by bacteria, fungi, and viruses emphasizes the need to maintain a balance between the steroid and the chemotherapeutic agent. Although steroids decrease the amount of tissue damage caused by the inflammatory response, preserving the ocular structures requires the use of specific anti-infective therapy to eradicate the replicating organism. It is generally accepted that steroids should never be the sole therapeutic agent in conditions caused by actively replicating microorganisms.

Retardation of Corneal Epithelial Healing

Both systemic and topical ocular steroid therapy can retard corneal healing. Persistent punctate staining of the cornea can indicate epithelial damage by the corticosteroid if the original disease has been eliminated. Effects on collagen synthesis and fibroblast activity have been proposed as a possible mechanism.

In recent studies topical corticosteroids have shown promising results in treating dry eye and epithelial damage from inflammatory medications. Steroids may help increase goblet cell density and reduce the accumulation of inflammatory cells within the ocular tissues.

Topical LE 0.5% (Lotemax) four times a day may benefit patients with keratoconjunctivitis sicca that has at least a moderate inflammatory component. Currently, however, the use of topical steroids for dry eye treatment is strictly “off label.”

Corticosteroid Uveitis

It seems paradoxical that the topical use of corticosteroids can lead to acute inflammation of the anterior segment. However, since the first association of the development of anterior uveitis during provocative testing with steroids for glaucoma, additional cases have been reported.The incidence is higher in blacks (5.4%) than in whites (0.5%). Symptoms include pain, photophobia, blurred vision, and perilimbal (ciliary) hyperemia; anterior chamber cells and flare can be observed. The corticosteroid itself, rather than its vehicle, appears to cause the condition. Treatment includes discontinuation or reduction of the steroid medication and using steroidsparing agents such as nonsteroidal anti-inflammatory or immunosuppressive agents to reduce the inflammation. It does not appear to be related to a particular steroid preparation, because it can occur with either the sodium phosphate or alcohol derivatives of dexamethasone and prednisolone acetate.

Mydriasis and Ptosis

Dilation of the pupil and ptosis can occur with topical steroid administration. Application of dexamethasone 0.1% in human volunteers produced mydriasis as early as 1 week after the drug’s initial use.The average increase in pupillary diameter was approximately 1 mm. The effect disappears on cessation of drug therapy.

The mydriatic effect of topically applied corticosteroids was investigated in living monkey eyes. Instillation of dexamethasone 0.1% (Decadron) produced pupillary dilation and ptosis as well as elevation of IOP. When the steroids were tested without their vehicles but in saline solution, the effects on IOP, pupil size, and upper eyelid did not occur. Thus it has been suggested that an excipient in the vehicle mixture causes the effects, possibly by altering cell membrane permeability to the steroid.

Other Side Effects

Transient ocular discomfort can ensue after topical application of steroids to the eye. Mechanical effects of the steroid particles in suspension, the vehicle itself, and the severity of the inflammatory condition can all be causative factors.

Steroid-induced calcium deposits in the cornea have been reported. Patients with such persistent epithelial defects such as postoperative inflammation, penetrating keratoplasty, and a history of herpetic keratitis and dry eye have developed a calcific band keratopathy after topical use of a steroid phosphate formulation.

SYSTEMIC EFFECTS OF LOCALLY ADMINISTERED CORTICOSTEROIDS

Topical or periocular steroids cause few systemic effects. When topical dexamethasone sodium phosphate was administered four times daily for 6 weeks, subjects showed reduced plasma levels of cortisol. However, elevation of 11-deoxycortisol with the oral metyrapone tartrate test indicated that the pituitary-adrenal axis was intact.

Intralesional injection of steroid can lead to adrenal suppression. Infants and small children are especially susceptible, because a given amount of steroid is distributed in a smaller volume of fluid and tissue compartments. Infants injected with mixtures of triamcinolone acetonide and betamethasone or dexamethasone for periocular hemangiomas exhibited depressed serum cortisol and adrenocorticotropic hormone levels. The adrenal suppression can last up to 5 months and can result in weight loss and growth retardation. It is not known whether other corticosteroid preparations would produce similar effects or which other factors might influence these results. In general, topical and periocular use of steroids produces minimal systemic effects. Withdrawal of topical or periocular steroids does not generally cause adrenal crisis.

CONTRAINDICATIONS TO

CORTICOSTEROID USE

Because side effects can complicate the use of corticosteroids, a careful history and certain tests may be advisable, particularly if a patient may require prolonged ocular therapy. Steroids should be used with great caution in patients with diabetes mellitus, infectious disease, chronic renal failure, congestive heart failure, and systemic hypertension. Systemic administration is generally contraindicated in patients with peptic ulcer, osteoporosis, or psychoses. Topical steroids should be used with caution and only when necessary in patients with glaucoma.

Patients receiving prolonged systemic therapy usually lack sufficient adrenal reserve to respond appropriately to such stresses as trauma or surgery. These individuals may need supplementary corticosteroids to cover the period of stress.

Concurrent administration of other drugs may interfere with the metabolism and alter the effects of corticosteroids. Some of the effects appear to result from increased metabolism of administered steroid.Barbiturates, phenylbutazone, and phenytoin may enhance metabolism and reduce the anti-inflammatory and immunosuppressive potential of systemic steroids. Additionally, the response to anticoagulant therapy may be reduced by simultaneous administration of steroids.

Patients receiving topical ocular steroids must be examined periodically for corneal, lens, and IOP changes. Slitlamp examination for punctate, herpetic, or fungal keratitis

is necessary. Patients receiving systemic therapy should be monitored for systemic hypertension, glaucoma, and cataracts. If prolonged systemic therapy is necessary, blood glucose levels should be evaluated at appropriate intervals.

NONSTEROIDAL ANTI-INFLAMMATORY DRUGS

Topical ophthalmic steroids represent the gold standard for mediating ocular inflammation. Because steroids have the potential for increased incidence of adverse events, judicious application is indicated. The most notable among these is elevation of IOP. NSAIDs offer some advantages over steroids in reducing inflammation. In perspective, there are some disadvantages as well.Topical NSAIDs may be inferior candidates for suppressing ante- rior-chamber inflammation after ocular surgery. However, no topical NSAID has ever been reported to increase IOP. One strong point of oral NSAIDs is that they can be costeffective alternatives (rescue medications) to topical forms by offering antipyretic, analgesic, and anti-inflammatory activity without the potential to increase IOP.

To understand the mechanism of action of NSAIDs, it is important to explore pathways of inflammation. The inflammatory response involves production of prostaglandins. These mediators of inflammatory activity are ubiquitous throughout the body. In addition,they mediate other cellular and tissue responses that are crucial to homeostasis,such as platelet aggregation and renin release. Because of these necessities, prostaglandins are produced on demand and consequently have a short half-life.

The omega-6 fatty acid pathway is the source for the cascade of inflammatory prostaglandin production. From linolenic acid, the enzyme delta-6-desaturase is responsible for producing gamma-linolenic acid. This then becomes the source of arachidonic acid, which under the influence of cyclooxygenase is converted to the so-called series 2 prostaglandins, which are inflammatory (Figure 12-5).

Under the influence of omega-3 fatty acids, the pathway proceeds to produce series 1 prostaglandins, which are anti-inflammatory, and leukotrienes (less inflammatory). From alpha-linolenic acid, enzymes eventually synthesize eicosapentaenoic acid. Cyclooxygenase, given this substrate, can synthesize series 3 prostaglandins, which are also anti-inflammatory (Figures 12-6 and 12-7).

What this allows is targeting of either the cyclooxygenase or leukotriene arms of the prostaglandin pathways. Although this is a convenient separation of mechanisms, there is often overlap. It is for this reason, for example, that postoperative cataract patients are administered both topical steroids and NSAIDs.

Pharmacology of Nsaids

The cyclooxygenase pathway may be interrupted at a number of stages. Two cyclooxygenase enzyme isoforms

have been identified to date, cyclooxygenase-1 and cyclooxygenase-2. Cyclooxygenase-1 inhibits thromboxane production and thus platelet aggregation.The resultant blood thinning may lead to bleeding ulcers when the gastric mucosa is sufficiently disrupted. An advantage of cyclooxygenase-2 is that it is less disruptive of mucosal surfaces but may adversely affect hemostatic balance and favor thrombosis.

Although oral NSAIDs have application to ophthalmic pain management, topical NSAIDs have the more immediate utility. Some of the earliest indications for topical NSAIDs were prophylaxis and treatment for cystoid macular edema (CME) as well as pain and inflammation management after cataract surgery.This pioneering work was done before the introduction of less traumatic procedures such as clear corneal incisions.The seminal investigations using

Figure 12-7 Simplified concept of prostaglandin and leukotriene synthesis pathway from eicosapentaenoic acid. Note the enzymes involved in this process (cyclooxygenase and lipoxygenase), which become the target for anti-inflammatory drugs. (From http://www.asthmaworld.org/OMEGA3.htm)

topical indomethacin also demonstrated higher intraocular levels than provided by the oral route and showed the efficacy of topical indomethacin for CME. Prophylaxis for CME has been demonstrated in studies worldwide, as well. Topical NSAIDs offer analgesic, anti-inflammatory, and antipyretic effects as their primary application, although other attributes and applications exist.

Side Effects of and Contraindications to NSAIDS

In general, when administered orally these medications are rapidly absorbed into systemic circulation (30 to 120 min). Because prostaglandins, the mediators of inflammation, are produced extemporaneously, dosing schedules are based on the peak plasma drug levels (i.e., every 4 to 6 hours). For the sake of precaution, it is important to note that oral NSAIDs are metabolized in the kidneys.

Drug interactions with the oral NSAIDS include aspirin, which with concomitant administration increase the unbound circulating fraction of an orally administered NSAID. For patients taking warfarin, there is risk of prolonged clotting times and the potential consequences of decreased platelet aggregation. A similar precaution should be observed for those taking Ginkgo biloba. Patients who are dosing with antacids, however, require no increased dosages of oral NSAIDs,because these will not interfere with absorption.These interactions are not applicable to topically applied NSAIDs because significantly lower amounts reach the systemic circulation.

With regard to topical NSAIDs, there are few significant contraindications. One reported interaction is between oral indomethacin and topical brimonidine. Patients taking this oral medication were found to have escape of IOP control when using brimonidine. However, the study failed to demonstrate such loss of IOP-lowering control with latanoprost.

Another potential contraindication to topical NSAIDs is concomitant administration of topical prostaglandin analogues used for lowering IOP. In studies reporting small numbers of normal and glaucoma patients, slight and perhaps clinically insignificant IOP increases

were noted. Clinicians should be aware of this potential, but, perhaps more importantly, the studies may reflect additional mechanisms for IOP reduction by the prostaglandin analogues.

Burning and stinging are the most prevalent side effects of topically administered NSAIDs.The original FDA approval for ketorolac, for example, was modulation of postoperative refractive surgery pain and inflammation. Ketorolac, however, has application in a variety of ocular inflammatory conditions, including seasonal allergic conjunctivitis, giant papillary conjunctivitis, as prophylaxis, postoperatively in ophthalmic surgery, and pain modulation for managing corneal abrasions. It has been demonstrated that although the potential for delayed wound healing exists, this is not a practical impediment to administering topical ketorolac (0.4%) to patients with small corneal abrasions. In addition, the lower concentration (0.5% was the original) is responsible for fewer instances of minor and transient ocular irritation on instillation.

A more significant side effect has been reported with topical diclofenac ophthalmic solution. Keratolysis (corneal melting) was associated with a small number of cases in high-risk patients after ophthalmic surgery. Responsibility for this side effect has been attributed subsequently to the vitamin E–based solubilizer/preservative in the generic formulation, which has been withdrawn from the marketplace.

Clinical Uses

The most widely prescribed topical NSAID is ketorolac (Acular-LS 0.4%). Its FDA labeling is for the reduction of ocular pain and discomfort after corneal refractive surgery. Among its off-label applications are treatment of acute and chronic postoperative CME, seasonal allergic conjunctivitis, giant papillary conjunctivitis, and inflamed pterygia.

FDA approval of Ocufen (0.03% flurbiprofen, Allergan) in 1986 represented the first approved topical ophthalmic NSAID in the United States. The indication was maintenance of pupil dilation during cataract surgery. Off-label uses were rapidly discovered and reported. These included postoperative pseudophakic CME management. A trial to mitigate the inflammatory component of dry eye syndrome, however, has proven flurbiprofen less useful than either tear supplements alone or in combination with topical ophthalmic steroids. Other adjunctive paradigms such as topical ketorolac with topical cyclosporine A may show a more favorable outcome.

Suprofen 1% (Profenal, Alcon) was approved also for the maintenance of pupil dilation during cataract surgery. It, too, has found may other applications. These include treatment of pseudophakic CME.

Diclofenac sodium 0.1% (Voltaren,Ciba),one of the topical ophthalmic NSAIDs derived from oral formulations,

236 CHAPTER 12 Anti-Inflammatory Drugs

was also approved initially for the maintenance of pupil dilation during cataract surgery. However, it too has found a host of alternative applications, such as management of post–refractive surgery (photorefractive keratectomy and laser in situ keratomileusis [LASIK]) pain and photophobia. In addition,Voltaren has been reported as an alternative treatment for postoperative cataract surgery inflammation and may have a prophylactic role in contact lens care because it has been shown to inhibit the adherence of Staphylococcus epidermidis to soft lens material. Topical diclofenac has also been demonstrated to be superior to dexamethasone or ketorolac for post–strabismus surgery pain management. However, diclofenac has been used in the postoperative period after cataract surgery with mixed results. When combined with gentamicin, it controlled anterior chamber cells and flare at least as well as a topical steroid (dexamethasone), but there was greater superficial punctate staining. Voltaren has also found application in filamentary keratitis.Topical application four times per day for 30 days has been reported to eliminate filaments.

Bromfenac 0.09% (Xibrom, ISTA) has been approved for topical application outside the United States for many years. Bromfenac has compiled an excellent safety record with only 13 reported postmarketing adverse events among 6 million prescriptions written. Perhaps its greatest advantage is reported less initial stinging on instillation (1.5% vs. 20% to 45% for ketorolac 0.4%).The current FDA approval is for the management of postoperative cataract surgery pain.

The first nonsteroidal prodrug for topical ophthalmic application is nepafenac 0.1% (Nevanac, Alcon). It is hydrolyzed to amfenac in the anterior chamber. By this mechanism it reaches higher intraocular concentrations than other topical NSAIDs. In animal models nepafenac has been shown to inhibit prostaglandin synthesis in the retina and choroid after topical administration. For this reason it may have a clinical role in conditions that are caused by prostaglandin-mediated vascular leakage. Nepafenac has been FDA approved for treatment of pain and inflammation associated with cataract surgery.

The topical NSAIDs as a group have demonstrated adjunctive efficacy in several clinical situations. These include synergistic activity with topical cortical steroids after cataract surgery.Amelioration of pain, inflammation, and resolution of CME after cataract surgery has been demonstrated. A similar effect on the mitigation of post–photorefractive keratectomy pain has also been shown. Ketorolac specifically has been suggested for concomitant application with cyclosporine A for the initial treatment of chronic dry eye disease.

In summary, topical NSAIDs currently have application for their analgesic, anti-inflammatory, and antipyretic effects in a variety of ocular inflammatory conditions (Table 12-6). These versatile drugs may be used prophylactically before cataract and other refractive surgical procedures. In addition, suppression of inflammation

Table 12-6

Contemporary Topical NSAIDs

aNot commercially available in the United States. bNot commercially available in Canada.

before glaucoma surgery with topical NSAIDs may become routine. Postoperatively, ketorolac has been shown to be useful for treatment of postoperative CME. In the future topical NSAIDs may be combined with antibiotics for other prophylactic and active treatment applications.

CYCLOSPORINE A: IMMUNOMODULATOR OF OCULAR SURFACE INFLAMMATION

Cyclosporine A (CsA, Restasis 0.05%) was approved in 2002 by the FDA as an ocular therapeutic for patients with keratoconjunctivitis sicca (dry eye). Until 2002 the therapy of choice for the treatment of dry eye was artificial tears and punctal plugs and the occasional use of pulse doses of topical steroids.Artificial tears and punctal plugs brought some temporary relief to patients, but the underlying cause of dry eye, inflammation, was not affected. Steroids carried the threat of a multitude of side effects.With as many as 7.1 million people in the United States alone encountering dry eye symptoms, the development of a therapy that eliminates the inflammatory events associated with the disease has been a significant benefit.

Pharmacology

Inflammation of the ocular surface is characterized by acute inflammatory events that occur within 24 hours of being exposed to an offending stimulus and if not controlled can transform into a chronic inflammatory state. In an acute response, in both the cornea and conjunctiva, physical injury to the eye can damage the epithelium, resulting in the release of proinflammatory cytokines from these cells (Figures 12-8 and 12-9). Cytokines are proteins that serve as the main intermediaries of communication among cells of the immune

system and are responsible for many of the functions of immune cells. These inflammatory cytokines upregulate vascular endothelial adhesion molecules such as vascular cell adhesion molecule-1 and platelet endothelial cell adhesion molecule-1, thereby enhancing the movement of immune cells from the limbal vessels into the ocular surface (see Figure 12-9).

In a susceptible individual, a chronic response develops after the acute response, if the irritant cannot be eliminated or is constantly recurring and inflammatory cytokine levels persist. Chronic inflammation can result in tissue damage due to the irritant itself, but also by the constant presence of inflammatory cytokines. Immunemediated inflammation can be characterized by the types

of phlogistic proteins present at the site of tissue damage. Ocular surface inflammation can be associated with CD4+ T-cell activation. In 1986 the existence of two subsets of T cells were reported, called T helper 1 (TH1) and T helper 2 (TH2) cells.These cells were classified into either TH1 or TH2 type T helper cells based on the types of cytokines they produced. TH1 cells produce interferon-γ (IFN-γ) and tumor necrosis factor-α. TH2 cells produce interleukin (IL)-4, IL-5, and IL-13. T cells are activated by recognizing antigen in the context of MHC class II molecules on antigen-presenting cells such as macrophages. Antigen-presenting cells infiltrate the inflamed tissue toward the end of the acute response.These cells engulf the foreign antigen, process the antigen into peptides, and present these peptides in the context of their MHC class II molecules.T cells with antigen-specific T-cell receptors

recognize the antigen in the MHC class II molecule, and in combination with interaction of costimulatory molecules the T cell becomes activated (Figure 12-10). The differentiation of CD4+ T cells into TH1 or TH2 cells is controlled by the cytokine expression at the site of injury. For dry eye the desiccating atmosphere on the ocular surface promotes a TH1-inducing environment.

Dry eye results from an unstable tear film or tear evaporation, which results in damage to the ocular surface. The Unified Theory published in 1998 provided the basis for understanding dry eye as an inflammatory disease of the integrated lacrimal functional unit.The lacrimal functional unit consists of the ocular surface (cornea, meibomian glands, and conjunctiva), main and accessory lacrimal glands, and their interconnecting nerves. In the healthy state the lacrimal functional unit maintains a

healthy stable tear film on the ocular surface. A healthy patient secretes a normal tear film when the dense population of free nerve endings of the corneal surface is stimulated. This stimulation induces afferent nerve impulses to the central nervous system.Within the central nervous system these impulses are integrated through cortical and other systems and then result in the efferent secretomotor impulses that are sent to the main and accessory lacrimal glands. If the components of the lacrimal functional unit face an inflammatory environment, the secreted tear film constituents are altered, thereby destabilizing the tear film that is required for maintaining, protecting,and supporting the ocular surface.Inflammatory cytokines can be secreted by epithelial cells of the ocular surface and infiltrating lymphocytes into the lacrimal functional unit. These inflammatory cytokines have the ability to hinder neural transmission both directly and indirectly. The composition of the tear

film changes from “ocular surface supportive” to “proinflammatory.”

Dry eye patients express a number of inflammatory cytokines in the tear fluid, including tumor necrosis factor-α and IFN-γ, displaying a classical TH1 response. IL-1, IL-6, and IL-8 have also been detected in the tear fluid of dry eye patients. Patients with allergic conjunctivitis express IL-4, a TH2 type cytokine. For many years this clear-cut classification was applied to diseases such as systemic lupus erythematosus, which was believed to be TH2 in nature due to the high levels of autoantibodies. Recent reports, however, have contradicted this classification, instead showing the absolute requirement of the TH1 cytokine IFN-γ in systemic lupus erythematosus. In another example, allergic conjunctivitis has been thought to be a TH2-mediated disease. New research has shown the importance of IFN-γ and IL-12 in allergic conjunctivitis in a murine model of allergic conjunctivitis.

240 CHAPTER 12 Anti-Inflammatory Drugs

Another example is the role of TH2 in enhancing graft rejection, in which TH2 cytokines are found to play an important role in corneal graft rejection in atopic individuals. Ocular surface inflammation can be exacerbated when both TH1 and TH2 type diseases occur simultaneously. For example, many dry eye patients experience severe ocular allergy.

Cyclosporine binds to cyclophilin within T cells. The CsA–cyclophilin complex then binds to calcineurin and inhibits calcineurin’s activity required for the dephosphorylation of regulatory proteins necessary for the transcription and production of proinflammatory cytokines (IL-2, IL-4, IFN-γ, and tumor necrosis factor-α) from T-helper cells. CsA prevents pathologic apoptosis of the tear-secreting epithelia by preventing the ability of the mitochondrial permeability transition pore to open, a required step in the apoptotic process.

Clinical Uses

CsA is used in transplant patients by oral administration. Although CsA is a positive therapeutic for transplantation patients, complete body immunosuppression is neither required nor desired for treating ocular surface inflammatory events. To avoid potential side effects of systemic immunosuppression, an emulsion was designed to permit a suitable vehicle for drug delivery topically to the ocular surface. Because of the lipid-soluble properties of cyclosporine, it is capable of residing in the epithelium of the cornea after topical administration.Topical treatment with cyclosporine results in accumulations of CsA on the ocular surface at 0.236 mg/kg. Cyclosporine is a hydrophobic cyclic undecapeptide. Because of the hydrophobicity of cyclosporine, the ophthalmic formulation includes a caster oil–water emulsion, glycerin, and polysorbate 80 and the pH is buffered with sodium hydroxide. This formulation permits the maintenance of ocular retention time at about 2 hours. High levels of cyclosporine were detectable in the conjunctiva, cornea, and lacrimal glands (502, 452, and 89.3 ng/ml, respectively) of dogs treated twice daily with 35 mcl of 0.05% CsA in castor oil–water emulsion at 20 minutes to 1 hour after topical application. Intraocular levels were very low (9 ng/ml or less). Based on the observation that cyclosporine is not metabolized in dog or rabbit eyes, humans are not anticipated to metabolize cyclosporine on the ocular surface.

Animal Models of Ocular

Surface Inflammation

The original beneficial properties of CsA for ocular surface inflammation were first determined in dogs with dry eye. Conjunctival biopsies taken from dogs with spontaneous chronic idiopathic dry eye contained numerous CD3+ T cells.The lacrimal acinar and conjunctiva epithelial cells of dogs with dry eye underwent apoptosis, whereas the infiltrating inflammatory CD4+ T cells

had a much lower rate of apoptosis comparatively. This lack of apoptosis within the lymphocytic population allows for amassing of these inflammatory cells. CsA was shown to enhance the apoptosis of inflammatory lymphocytes on the ocular surface, and lacrimal acinar and conjunctival epithelial cell survival was restored.

Dry eye can result from a single phenomenon or as a secondary event associated with different types of autoimmune diseases. The autoimmune disease that is most closely associated with dry eye is Sjögren’s syndrome, with the phenotype of the disease including CD4+ T-cell infiltration into the lacrimal and submandibular glands. The MRL/lpr mouse, which contains a defective Fas receptor, has severe CD4+ T-cell infiltration into the lacrimal gland. Female mice of this strain have more severe lacrimal gland cellular infiltration as compared with male mice. Animal models of dry eye that induce inflammation in the lacrimal functional unit in pathologic ways similar to that seen in humans provide a platform to evaluate the mechanisms of dry eye disease.

Human Studies

For treatment of dry eye, topical cyclosporine (Restasis) is supplied as a 0.05% ophthalmic emulsion in 32 preser- vative-free vials per tray. Dosage is one drop twice daily. In an FDA phase II clinical trial, both eyes of 129 patients were treated with CsA (0.05%, 0.1%, 0.2%, and 0.4%) twice daily. Of these, 33 patients received vehicle. A subgroup consisting of 90 patients had moderate to severe dry eye at baseline. Thirty-two percent of the patients in this subgroup had Sjögren’s syndrome. At all CsA concentrations tested, a significant improvement in ocular signs and symptoms, including rose bengal staining, superficial punctate keratitis, and a feeling of grittiness, dryness, and itching at the ocular surface, were reported. For objective end points, 0.1% CsA gave the best results. The most improvement seen with patient symptoms was reported at 0.05%. There was no identifiable dose–response in this study.

Two FDA phase III clinical trials evaluated 0.05% CsA, 0.1% CsA, or vehicle in 877 patients with moderate to severe dry eye over a 6-month treatment period. With both 0.05% and 0.1% CsA, there was a significant improvement in categorized Schirmer values and corneal fluorescein staining as compared with the vehicle-treated group. In 15% of the patients receiving CsA, patients had high Schirmer values with anesthesia test scores that were 10 mm or greater than baseline.The vehicle group had only 5% of patients with a Schirmer value that improved more than 10 mm (p <.01). Both 0.05% and 0.1% CsA had high safety profiles and no adverse systemic effects, except 17% of patients did experience a burning sensation after CsA treatment. In an extension study of these patients,it was reported that continued use of CsA for 1 to 3 years was safe and well tolerated, with no association with systemic side effects. In dry eye