Many treatments for dry eye have failed to rise above simply being palliative. However, a new generation of longer-lasting and more effective agents is emerging to help. Two of these new treatments, Restasis (Allergan) and Systane (Alcon) will make their debut this spring. Here is a look at them.

Restasis Arrives
Dry eye is common, especially among the elderly, where it has been estimated to affect 4.3 million Americans aged 65 and older.1 However, everyone has experienced its symptoms.

Previously, the predominant treatment strategy for dry eye focused upon replacing tears,   and was rooted in simplistic notions of dry eye's causes. Over the last few decades, researchers have investigated the mechanisms of dry eye. As a result of this research, they have sought remedies to the disease based on new knowledge of its mechanisms.

This research bore fruit when Allergan received approval from the U.S. Food and Drug Administration for Restasis (cyclosporine ophthalmic emulsion, 0.05%) in December of 2002. This Cyclosporin A (CsA) emulsion is the first treatment in what could be an expanding arsenal of prescription dry-eye therapies. It's indicated to increase tear production in patients whose production is presumed to be suppressed due to ocular inflammation associated with keratoconjunctivitis sicca.2 In its trials, researchers didn't find tear production in patients taking topical anti-inflammatory drugs or who had punctal plugs.2

Restasis is sterile and preservative-free.2 The dosage regimen is b.i.d. and it can be used concomitantly with artificial tears.2 Its active ingredients include cyclosporine 0.05%. Its inactive ingredients are glycerin, castor oil, polysorbate 80, carbomer 1342, purified water and sodium hydroxide.2 The most frequently reported adverse event with Restasis is ocular burning (17 percent).2

The indication for Restasis is based upon four multicenter studies of 1,200 patients with moderate to severe keratoconjunctivitis sicca. Restasis showed statistically significant increases over vehicle in Schirmer's strip wetting of 10 mm.2 This increase was seen at six months in a population who presumably suffered from suppressed tear production due to inflammation.2 The increases in Schirmer's strip wetting were seen in 15 percent of Restasis treated patients compared to only 5 percent of vehicle-treated subjects.2

Restasis was developed to address dry-eye's inflammatory cascade. The exact workings of this inflammation are still being examined, but researchers believe that it involves the activation of the immune response, release of inflammatory mediators and apoptosis. Unchecked, the cascade can destroy the lacrimal glands.3

In this cascade, the surface of the eye is irritated. When the tear reflex is inadequate at minimizing the irritation, the nervous stimulation triggers a mechanism of regulation and repair.3 T-cells residing within the ocular surface and its contributory structures, such as the lacrimal gland, become activated and release cytokines that can damage host tissues. This affects the quality and quantity of tears and may affect the neural connections that drive reflex tearing.3,4 These effects cause more damage, resulting in the activation of more T-cells, generating an inflammatory response that can kill the lacrimal glands and conjunctival epithelium.4

The exact mechanism of action for Restasis is unknown, though it's believed to be a partial immunomodulator. The agent possibly limits T lymphocyte activation by inhibiting the expression of HLA-DR and other signals that activate the T lymphocytes.5 By affecting the activation of T-cells, Restasis can modulate inflammation.5

Restasis also is believed to be an anti-inflammatory, by preventing T-cells from releasing cytokines.6 Inhibiting cytokine release leaves the tissue of the lacrimal glands and the ocular surface intact and prevents further triggering of T lymphocytes by cytokines.7,8 By affecting the inflammatory cascade, the ocular surface and the lacrimal gland both recover, promoting normal tear production.

 • Remaining questions. The approval of Restasis as the first prescription medication for the therapy of the underlying inflammation associated with chronic dry eye is an important first step in the development of dry-eye therapies, though it's not the end of the line. Once Restasis becomes available to physicians, some questions must be addressed. For example, how does the clinician identify who would best benefit from the therapy? The answer is unclear. The subject population during the Phase III clinical trial was diagnosed as having moderate to severe dry-eye disease based upon questionnaires, Schirmer's strip wetting and corneal surface staining.8 These are commonly used diagnostic tools of clinical practice. However, only 15 percent of those subjects selected by these diagnostic criteria and who received the Restasis formulation had the relevant increase in Schirmer's strip wetting.

Clinicians should consider additional, and perhaps more sensitive, diagnostic tests, since we know Schirmer's test can lack sensitivity. In fact, Michael Lemp, MD, of George Washington University has suggested taking multiple Schirmer's in a patient to get a clearer idea of tear production over time. And Claes Dohlman, former chief of ophthalmology at the Massachusetts Eye and Ear Infirmary, has suggested ignoring the reading completely. Since Restasis is thought to act as an anti-inflammatory, perhaps testing for the presence of some of the more pronounced dry eye related inflammatory markers like IL-6 is a necessary step. According to the FDA, the clinical relevance of such testing still remains to be seen.

Another incentive for us to use better techniques to identify the best patient population to receive treatment is that Restasis takes six months to improve Schirmer's strip wetting.

It's also important to consider that 17 percent of the patients experienced ocular burning, while only 15 percent had a treatment effect. Before initiating at least a six-month course of treatment, the clinician should consider whether it's the best treatment strategy to risk adding discomfort to already moderate or severe dry eyes without ensuring a better than 15 percent chance of an effect. In the face of the diagnostic challenges, the clinician should recommend the patient use artificial tears with Restasis during the initial six months.

Also preparing to debut this spring is Systane, a novel sterile aqueous tear solution preserved with Polyquad, a preservative many think is safer to the corneal epithelium than benzylkonium chloride (BAK).9 Polyquad preserves a formulation that includes monograph demulcents, potassium, calcium, magnesium, sodium and 0.18% hydroxypropyl guar (HP-guar). Since these are monograph ingredients, or ingredients that the government allows to be mixed in any amount to create a new agent, Systane didn't require an FDA trial for approval. The Systane dry-eye therapy promotes a healthy corneal epithelium by prolonging tear film dwell time, maintaining a protective ocular shield.

Rather than replacing tears, Systane integrates with the tear film by using HP-guar as a gelling agent. A water-soluble polysaccharide even in low concentrations, natural guar galactomannan causes increased viscosity when dissolved in solutions. HP-guar is derived from natural guar galactomannan treated with propylene oxide.10 The HP-guar derivative maintains many of the essential properties of natural guar, but is more soluble.10

The properties of HP-guar are what place Systane in the new generation of treatments. When administered topically to the eye, HP-guar binds to the hydrophobic surface. It also binds to the borate in the Systane formulation, so that when Systane interacts with the pH of the ocular surface, which is approximately 7.4,11 a network with a soft, gelatinous consistency is formed. The increased viscosity of the gelatinous network improves lubrication, inhibiting mechanical destruction of the ocular surface. Furthermore, the crosslinking of HP-guar and borate preferentially adheres to disrupted epithelial cells, so the dwell time of the highly viscous gelatinous network is improved. These properties promote corneal and conjunctival healing.

In a comparative environmental trial conducted by Alcon against a leading tear substitute, Systane reduced the signs and symptoms of dry eye. In the 87-patient trial, it demonstrated a very good safety profile and was well-tolerated. Six-week treatment with Systane reduced conjunctival staining and trends were seen towards the reduction in corneal staining. Systane also demonstrated statistically significant reduction in morning dryness, end-of-day dryness and foreign body sensation.

Restasis and Systane complement each other. While Restasis may take six months to show efficacy and is sometimes accompanied by burning, Systane is well-suited to address comfort, and dwells long enough to prevent irritation as Restasis inhibits inflammation. This two-pronged treatment also hedges against the possibility that Restasis might not be effective in individual dry-eye patients. Clinicians will ultimately evaluate these products in their patients, which will establish the agents' roles. 

Dr. Abelson, an associate clinical professor of ophthalmology at Harvard Medical School and senior clinical scientist at Schepens Eye Research Institute, consults in ophthalmic pharmaceuticals. Mr. Casavant is a clinical researcher in the dry-eye department at Ophthalmic Research Associates in North Andover.

1. Schein OD, Mu-oz B, Tielsch JM, et al. Prevalence of Dry Eye Among the Elderly. Amer J of Ophthalmol 1997;124: 723-728.
2. Restasis package insert. 2002 Allergan, Inc.
3. Baudouin, C. The Pathology of Dry Eye. Surv Ophthalmol 2001;45:S211-S220.
4. Stern ME, Beuerman RW, Fox RI, et. al. A Unified Theory of the Role of the Ocular Surface in Dry Eye. In: Lacrimal Gland, Tear Film, and Dry Eye Syndromes 2. Sullivan D, ed. Plenum: New York 1998. 643-651.
5. Kunert KS, Tisdale AS, Stern ME. Analysis of topical cyclosporine treatment of patients with dry eye syndrome. Arch Ophthalmol 2000;118:1489-1496.
6. Turner K, Pflugfelder SC, Ji Z, et. al. Interleukin-6 levels in the conjunctival epithelium of patients with dry eye disease treated with cyclosporine ophthalmic emulsion. Cornea 2000;19:4: 492-496.
7. Rosenbaum JT, Brito B, Han YB, et. al. Cytokines: An Overview. In: Lacrimal Gland, Tear Film, and Dry Eye Syndromes 2. Sullivan D, ed. Plenum: New York, 1998. 441-446.
8. Sall K, Stevenson OD, Mundorf TK, et. al. Two multicenter, randomized studies of the efficacy and safety of cyclosporine ophthalmic emulsion in moderate to severe dry eye disease. Ophthalmol 2002;107:4: 631-639.
9. Lopez B, Ubel J. Quantitative evaluation of the corneal epithelial barrier: effect of artificial tears and preservatives. Curr Eye Res 1991;10:7:645-56.
10. Cheng Y, Brown KM, Prud'homme RK. Characterization and intermolecular interactions of hydroxypropyl guar solutions. Biomacromolecules 2002;3:456-461.
11. Khurana AK, Chaaudhary R, Ahluwalia BK, Gupta S. Tear film profile in dry eye. Acta Ophthalmologica 1991;09:1:79-86.

The Side Effects of Losing a Drug Patent
Mark B. Abelson MD, FRCS (C)
The expiration of a drug's patent has many implications. Though some of these effects may be beneficial in the short term, there could be others that are bad in the long run. An example of how these effects can play out is the recent experience of Schering-Plough and its $3 billion-per-year anti-allergy drug Claritin, which lost its patent in 2002.
After Schering was denied Claritin's patent extension, it was allowed to sell the drug over the counter. As the company works to keep the drug profitable, the atmosphere in pharmaceuticals is one of intense competition from generic antihistamines, more conservative attitudes on drug development from Congress and money-saving tactics from managed care.
In the short term, consumers benefit from a drug's over-the-the counter availability. However in the future, withdrawing a patent decreases the number of R&D dollars available to a drug's maker to re-invest in the development of new drugs. And, as these dollars diminish, a pharmaceutical company needs more time to develop drugs. The slowing of the new drug development process could ultimately be detrimental to consumers.
• Managed care's response. An interesting effect of Claritin's OTC status is the decision of some managed-care groups to deny the use of all other systemic antihistaminics that had been developed after Claritin, and may even have benefits that surpass it. Despite the fact that these medications are in the same class as Claritin, they may not even be on a managed care's formulary. And if they are on a formulary, a plan's subscribers are sometimes faced with co-payments of up to $50 for them. Clearly, this is a case of managed care attempting to tighten its purse strings by dropping the agents.
• Systemic antihistamines extend their claims. With Claritin off patent, there's the question of how the remaining antihistamines in the prescription market will respond. Under pressure, they're scrambling to find a niche in the market to which they have no real claim. This is behind the recent proliferation of misguided advertising for agents like Allegra (Aventis), in which the drug is positioned as adequate for ocular allergy. Such ads are making unsubstantiated claims of ocular efficacy as a way to differentiate the drugs and maintain their positions on managed-care formularies. These claims must seem specious to readers of both this column and the ophthalmic literature in general, as well as to those with experience in treating ocular allergy, since no systemic antihistaminic has ever worked well enough to receive approval for an ophthalmic indication from the FDA. By utilizing summed scores of itching, redness and tearing, as well as vague complaints gleaned from large studies, however, systemic antihistamines have obtained subtle differences between each other as far as ocular allergy is concerned. These differences, though real, don't reach the level of clinical relevance that we practitioners and the FDA Ophthalmic Division would require for the approval of an allergic drug such as Patanol, Zaditor, Alamast and Alrex.
Not only don't the systemic agents work on ocular allergy, but they all produce ocular drying with a 50-percent decrease in tear flow and volume.1,2 Tear-film reductions translate into loss of barrier protection, diluent effect and an inadequate wash over the eye. The tear film is therefore critical not only in dry-eye patients, but also in patients with allergy.
The optimal therapy to treat the ocular component of allergy for patients with rhinoconjunctivitis is a topical drop. Research shows that nasal symptoms can also be reduced by topically treating the eye.3,4 Eyedrops and steroid nasal sprays, used in combination, are superior against allergic rhinitis when compared to systemic allergics used in combination with a spray.5 Also, drops alone are superior to systemic agents for ocular allergy.6-8 Only with a drop do you get the highest concentrations of drug and the appropriate pharmacokinetics to deliver the maximum amount of antihistaminic and mast cell stabilizing effects.
Issues of legislative or economic concern should be superceded by the question of proper selection of agents for patients based on efficacy. For these studies alone and in total, topical treatment for ocular allergy is better. It will be interesting to see how the story unfolds as the might of the managed care formularies runs head on into clinical reality.

1. Nally L, Emory TB, Welch DL. Ocular drying associated with oral antihistamines (loratadine) in the normal population –effect on tear flow and tear volume as measured by fluorophotometry. ARVO 2002, Abstract No. 92.
2. Gupta G, Ousler GW, Pollard SD, Abelson MB. The comparative ocular drying effects between Claritin and Zyrtec in normal adults. ARVO 2002, Abstract No. 70.
3. Abelson MB, Turner FD, Amin D. Patanol is effective in the treatment of the signs and symptoms of allergic conjunctivitis and allergic rhinoconjunctivitis. Invest Ophthalmol Vis Sci. 2000;41(S): 4922.
4. Crampton HJ. A comparison of the relative clinical efficacy of a single dose of ketotifen fumarate 0.025% ophthalmic solution versus placebo in inhibiting the signs and symptoms of allergic rhinoconjunctivits as induced by conjunctival allergen challenge. Clinical Therapeutics 2002;24:11:1800-08.
5. Lanier BQ, Abelson MB, Berger WE, Granet DB, D'Arienzo PA, Spangler DL, Kagi MK. Comparison of the efficacy of combined fluticasone propionate and olopatadine versus combined fluticasone propionate and fexofenadine for the treatment of allergic rhinoconjunctivitis induced by the conjunctival allergen challenge. Clinical Therapeutics 2002;24:7:1161-74.
6. Abelson MB, Welch DL. An evaluation of onset and duration of action of Patanol (olopatadine hydrochloride ophthalmic solution 0.1%) compared to Claritin (loratadine 10 mg) tablets in acute allergic conjunctivitis in the conjunctival allergen challenge model. Acta Ophthalmol Scand 2000:78:60-63.
7. Abelson MB, Kaplan AP. A randomized, double-blind, placebo-controlled comparison of emedastine 0.05% ophthalmic solution with loratadine 10 mg and their combination in the human conjunctival allergen challenge model. Clinical Therapeutics 2002;24(3):445-56.
8. Crampton HJ. An evaluation of the efficacy of ketotifen fumarate 0.025% ophthalmic solution compared to desloratadine 5 mg compared to ketotifen fumarate 0.025% ophthalmic solution used with desloratadine 5 mg in inhibiting the signs and symptoms of seasonal allergic rhinoconjunctivitis in the allergen challenge model [in press].