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`Give Dry Eye a One-two Punch
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`Mark B. Abelson, MD and Jason Casavant
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`PUBLISHED 15 MARCH 2003
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`Give Dry Eye a One-two
`Punch
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`Many treatments for dry eye have failed to rise above simply
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`being palliative. However, a new generation of longer-lasting and
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`more effective agents is emerging to help. Two of these new
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`treatments, Restasis (Allergan) and Systane (Alcon) will make
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`their debut this spring. Here is a look at them.
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`Restasis Arrives
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`Dry eye is common, especially among the elderly, where it has
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`been estimated to affect 4.3 million Americans aged 65 and
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`older.‘ However, everyone has experienced its symptoms.
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`Previously, the predominant treatment strategy for dry eye
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`focused upon replacing tears, and was rooted in simplistic
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`notions of dry eye's causes. Over the last few decades,
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`researchers have investigated the mechanisms of dry eye. As a
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`result of this research, they have sought remedies to the disease
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`based on new knowledge of its mechanisms.
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`This research bore fruit when Allergan received approval from
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`https://www.reviewofophtha|mo|ogy.com/articlelgive-dry-eye-a-one-two-punch
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`ALL 2037
`MYLAN PHARMACEUTICALS v. ALLERGAN
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`ALL 2037
`MYLAN PHARMACEUTICALS V. ALLERGAN
`IPR2016-01128
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`the U.S. Food and Drug Administration for Restasis
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`(cyclosporine ophthalmic emulsion, 0.05%) in December of 2002.
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`This Cyclosporin A (CsA) emulsion is the first treatment in what
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`could be an expanding arsenal of prescription dry-eye therapies.
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`It's indicated to increase tear production in patients whose
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`production is presumed to be suppressed due to ocular
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`inflammation associated with keratoconjunctivitis sicca? In its
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`trials, researchers didn't find tear production in patients taking
`topical anti-inflammatory drugs or who had punctal p|ugs.2
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`.:
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`Restasis is sterile and preservative-free? The dosage regimen is
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`b.i.d. and it can be used concomitantly with artificial tears? Its
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`active ingredients include cyclosporine 0.05%. Its inactive
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`ingredients are glycerin, castor oil, polysorbate 80, carbomer
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`1342, purified water and sodium hydroxide? The most frequently
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`reported adverse event with Restasis is ocular burning (17
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`percent)?
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`The indication for Restasis is based upon four multicenter
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`studies of 1,200 patients with moderate to severe
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`keratoconjunctivitis sicca. Restasis showed statistically
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`significant increases over vehicle in Schirmer's strip wetting of 10
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`mm? This increase was seen at six months in a population who
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`presumably suffered from suppressed tear production due to
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`inflammation? The increases in Schirmer's strip wetting were
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`seen in 15 percent of Restasis treated patients compared to only
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`2
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`5 percent of vehicle-treated subjects.2
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`Restasis was developed to address dry-eye's inflammatory
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`cascade. The exact workings of this inflammation are still being
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`examined, but researchers believe that it involves the activation
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`of the immune response, release of inflammatory mediators and
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`apoptosis. Unchecked, the cascade can destroy the lacrimal
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`glands?
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`In this cascade, the surface of the eye is irritated. When the tear
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`reflex is inadequate at minimizing the irritation, the nervous
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`stimulation triggers a mechanism of regulation and repairf‘ T-cells
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`residing within the ocular surface and its contributory structures,
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`such as the lacrimal gland, become activated and release
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`cytokines that can damage host tissues. This affects the quality
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`and quantity of tears and may affect the neural connections that
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`drive reflex tearing.“ These effects cause more damage,
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`resulting in the activation of more T-cells, generating an
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`inflammatory response that can kill the lacrimal glands and
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`conjunctival epithelium.4
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`The exact mechanism of action for Restasis is unknown, though
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`it's believed to be a partial immunomodulator. The agent possibly
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`limits T lymphocyte activation by inhibiting the expression of
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`HLA-DR and other signals that activate the T lymphocytes.5 By
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`affecting the activation of T-cells, Restasis can modulate
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`inf|ammation.5
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`3
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`
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`Restasis also is believed to be an anti-inflammatory, by
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`preventing T-cells from releasing cytokinese Inhibiting cytokine
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`release leaves the tissue of the lacrimal glands and the ocular
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`surface intact and prevents further triggering of T lymphocytes by
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`cytokines.” By affecting the inflammatory cascade, the ocular
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`surface and the lacrimal gland both recover, promoting normal
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`tear production.
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`- Remaining questions. The approval of Restasis as the first
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`prescription medication for the therapy of the underlying
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`inflammation associated with chronic dry eye is an important first
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`step in the development of dry-eye therapies, though it's not the
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`end of the line. Once Restasis becomes available to physicians,
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`some questions must be addressed. For example, how does the
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`clinician identify who would best benefit from the therapy? The
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`answer is unclear. The subject population during the Phase III
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`clinical trial was diagnosed as having moderate to severe dry-
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`eye disease based upon questionnaires, Schirmer's strip wetting
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`and corneal surface stainingf’ These are commonly used
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`diagnostic tools of clinical practice. However, only 15 percent of
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`those subjects selected by these diagnostic criteria and who
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`received the Restasis formulation had the relevant increase in
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`Schirmer's strip wetting.
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`Clinicians should consider additional, and perhaps more
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`sensitive, diagnostic tests, since we know Schirmer's test can
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`4
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`
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`lack sensitivity. In fact, Michael Lemp, MD, of George
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`Washington University has suggested taking multiple Schirmer's
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`in a patient to get a clearer idea of tear production over time. And
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`Claes Dohlman, former chief of ophthalmology at the
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`Massachusetts Eye and Ear Infirmary, has suggested ignoring
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`the reading completely. Since Restasis is thought to act as an
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`anti-inflammatory, perhaps testing for the presence of some of
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`the more pronounced dry eye related inflammatory markers like
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`IL-6 is a necessary step. According to the FDA, the clinical
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`relevance of such testing still remains to be seen.
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`‘ nother incentive for us to use better techniques to identify the
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`best patient population to receive treatment is that Restasis
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`takes six months to improve Schirmer's strip wetting.
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`It's also important to consider that 17 percent of the patients
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`experienced ocular burning, while only 15 percent had a
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`treatment effect. Before initiating at least a six-month course of
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`treatment, the clinician should consider whether it's the best
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`treatment strategy to risk adding discomfort to already moderate
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`or severe dry eyes without ensuring a better than 15 percent
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`chance of an effect. In the face of the diagnostic challenges, the
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`clinician should recommend the patient use artificial tears with
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`Restasis during the initial six months.
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`Systane
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`‘ lso preparing to debut this spring is Systane, a novel sterile
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`aqueous tear solution preserved with Polyquad, a preservative
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`5
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`
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`many think is safer to the corneal epithelium than benzylkonium
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`chloride (BAK).9 Polyquad preserves a formulation that includes
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`monograph demulcents, potassium, calcium, magnesium,
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`sodium and 0.18% hydroxypropyl guar (HP-guar). Since these
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`are monograph ingredients, or ingredients that the government
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`allows to be mixed in any amount to create a new agent, Systane
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`didn't require an FDA trial for approval. The Systane dry-eye
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`therapy promotes a healthy corneal epithelium by prolonging tear
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`film dwell time, maintaining a protective ocular shield.
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`Rather than replacing tears, Systane integrates with the tear film
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`by using HP-guar as a gelling agent. A water-soluble
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`polysaccharide even in low concentrations, natural guar
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`galactomannan causes increased viscosity when dissolved in
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`solutions. HP-guar is derived from natural guar galactomannan
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`treated with propylene oxide.” The HP-guar derivative maintains
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`many of the essential properties of natural guar, but is more
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`soluble.“
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`The properties of HP-guar are what place Systane in the new
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`generation of treatments. When administered topically to the eye,
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`HP-guar binds to the hydrophobic surface. It also binds to the
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`borate in the Systane formulation, so that when Systane interacts
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`ith the pH of the ocular surface, which is approximately 7.4”‘ a
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`network with a soft, gelatinous consistency is formed. The
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`increased viscosity of the gelatinous network improves
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`6
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`
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`lubrication, inhibiting mechanical destruction of the ocular
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`surface. Furthermore, the crosslinking of HP-guar and borate
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`preferentially adheres to disrupted epithelial cells, so the dwell
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`time of the highly viscous gelatinous network is improved. These
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`properties promote corneal and conjunctival healing.
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`In a comparative environmental trial conducted by Alcon against
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`a leading tear substitute, Systane reduced the signs and
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`symptoms of dry eye. In the 87-patient trial, it demonstrated a
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`very good safety profile and was well-tolerated. Six-week
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`treatment with Systane reduced conjunctival staining and trends
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`ere seen towards the reduction in corneal staining. Systane
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`also demonstrated statistically significant reduction in morning
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`dryness, end-of-day dryness and foreign body sensation.
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`Restasis and Systane complement each other. While Restasis
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`may take six months to show efficacy and is sometimes
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`accompanied by burning, Systane is well-suited to address
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`comfort, and dwells long enough to prevent irritation as Restasis
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`inhibits inflammation. This two-pronged treatment also hedges
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`against the possibility that Restasis might not be effective in
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`individual dry-eye patients. Clinicians will ultimately evaluate
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`these products in their patients, which will establish the agents‘
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`roles.
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`Dr. Abelson, an associate clinical professor of ophthalmology at
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`Harvard Medical School and senior clinical scientist at Schepens
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`7
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`Eye Research Institute, consults in ophthalmic pharmaceuticals.
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`Mr. Casavant is a clinical researcher in the dry-eye department a
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`Ophthalmic Research Associates in North Andover.
`
`1. Schein OD, Mu-oz B, Tielsch JM, et al. Prevalence of Dry Eye Among the Elderly. AmerJ of Ophthalmol 1997;124: 723-728.
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`2. Restasis package insert. 2002 Allergan, Inc.
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`3. Baudouin, C. The Pathology of Dry Eye. Surv Ophthalmol 2001;45:S211-S220.
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`. 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
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`2. Sullivan D, ed. Plenum: New York 1998. 643-651.
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`5. Kunert KS, Tisdale AS, Stern ME. Analysis of topical cyclosporine treatment of patients with dry eye syndrome. Arch Ophthalmol 2000;118:1489-1496.
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`6. Turner K, Pflugfelder SC, Ji 2, et. al. Interleukin-6 levels in the conjunctival epithelium of patients with dry eye disease treated with cyclosporine ophthalmic
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`emulsion. Cornea 2000;19:4: 492-496.
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`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,
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`1998. 441-446.
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`8. Sail K, Stevenson OD, Mundorf TK, et. al. Two multicenter, randomized studies of the efficacy and safety of cyclosporine ophthalmic emulsion in moderate to
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`severe dry eye disease. Ophthalmol 2002;107:4: 631-639.
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`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.
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`10. Cheng Y, Brown KM, Prud'homme RK. Characterization and intermolecularinteractions of hydroxypropyl guarsolutions. Biomacromolecules 2002;3:456-
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`A 61.
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`11. Khurana AK, Chaaudhary R, Ahluwalia BK, Gupta S. Tearfilm profile in dry eye. Acta Ophthalmologica 1991;09:1:79-86.
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`The Side Effects of Losing a Drug Patent
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`Mark B. Abelson MD, FRCS (C)
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`The expiration of a drug's patent has many implications. Though
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`some of these effects may be beneficial in the short term, there
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`could be others that are bad in the long run. An example of how
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`8
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`these effects can play out is the recent experience of Schering-
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`Plough and its $3 billion-per-year anti-allergy drug Claritin, which
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`lost its patent in 2002.
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`‘ fter Schering was denied C|aritin's patent extension, it was
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`allowed to sell the drug over the counter. As the company works
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`to keep the drug profitable, the atmosphere in pharmaceuticals is
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`one of intense competition from generic antihistamines, more
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`conservative attitudes on drug development from Congress and
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`money-saving tactics from managed care.
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`In the short term, consumers benefit from a drug's over-the-the
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`counter availability. However in the future, withdrawing a patent
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`decreases the number of R&D dollars available to a drug's
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`maker to re-invest in the development of new drugs. And, as
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`these dollars diminish, a pharmaceutical company needs more
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`time to develop drugs. The slowing of the new drug development
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`process could ultimately be detrimental to consumers.
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`- Managed care's response. An interesting effect of C|aritin's
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`OTC status is the decision of some managed-care groups to
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`deny the use of all other systemic antihistaminics that had been
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`developed after Claritin, and may even have benefits that
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`surpass it. Despite the fact that these medications are in the
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`same class as Claritin, they may not even be on a managed
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`care's formulary. And if they are on a formulary, a plan's
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`subscribers are sometimes faced with co-payments of up to $50
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`for them. Clearly, this is a case of managed care attempting to
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`tighten its purse strings by dropping the agents.
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`- Systemic antihistamines extend their claims. With Claritin off
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`9
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`patent, there's the question of how the remaining antihistamines
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`in the prescription market will respond. Under pressure, they're
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`scrambling to find a niche in the market to which they have no
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`real claim. This is behind the recent proliferation of misguided
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`advertising for agents like Allegra (Aventis), in which the drug is
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`positioned as adequate for ocular allergy. Such ads are making
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`unsubstantiated claims of ocular efficacy as a way to differentiate
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`the drugs and maintain their positions on managed-care
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`formularies. These claims must seem specious to readers of
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`both this column and the ophthalmic literature in general, as well
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`as to those with experience in treating ocular allergy, since no
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`systemic antihistaminic has ever worked well enough to receive
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`approval for an ophthalmic indication from the FDA. By utilizing
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`summed scores of itching, redness and tearing, as well as vague
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`complaints gleaned from large studies, however, systemic
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`antihistamines have obtained subtle differences between each
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`other as far as ocular allergy is concerned. These differences,
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`though real, don't reach the level of clinical relevance that we
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`practitioners and the FDA Ophthalmic Division would require for
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`the approval of an allergic drug such as Patanol, Zaditor,
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`* lamast and Alrex.
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`Not only don't the systemic agents work on ocular allergy, but
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`they all produce ocular drying with a 50-percent decrease in tear
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`flow and volume.1,2 Tear-film reductions translate into loss of
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`barrier protection, diluent effect and an inadequate wash over the
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`eye. The tear film is therefore critical not only in dry-eye patients,
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`but also in patients with allergy.
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`10
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`
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`The optimal therapy to treat the ocular component of allergy for
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`patients with rhinoconjunctivitis is a topical drop. Research
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`shows that nasal symptoms can also be reduced by topically
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`treating the eye.3,4 Eyedrops and steroid nasal sprays, used in
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`combination, are superior against allergic rhinitis when compared
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`to systemic allergics used in combination with a spray.5 Also,
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`drops alone are superior to systemic agents for ocular allergy.6-8
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`Only with a drop do you get the highest concentrations of drug
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`and the appropriate pharmacokinetics to deliver the maximum
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`amount of antihistaminic and mast cell stabilizing effects.
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`Issues of legislative or economic concern should be superceded
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`by the question of proper selection of agents for patients based
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`on efficacy. For these studies alone and in total, topical treatment
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`for ocular allergy is better. It will be interesting to see how the
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`story unfolds as the might of the managed care formularies runs
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`head on into clinical reality.
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`1. Nally L, Emory TB, Welch DL. Ocular drying associated with oral antihistamines (loratadine) in the normal population -effect on tear flow and tear
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`olume as measured by fluorophotometry. ARVO 2002, Abstract No. 92.
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`2. Gupta G, Ousler GVlI, Pollard SD, Abelson MB. The comparative ocular drying effects between Claritin and Zyrtec in normal adults. ARVO 2002,
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`3. Abelson MB, Turner FD, Amin D. Patanol is effective in the treatment of the signs and symptoms of allergic conjunctivitis and allergic
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`rhinoconjunctivitis. Invest Ophthalmol Vis Sci. 2000;41(S): 4922.
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`4. Crampton HJ. A comparison of the relative clinical efficacy ofa single dose of ketotifen fumarate 0.025% ophthalmic solution versus placebo in
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`inhibiting the signs and symptoms ofallergic rhinoconjunctivits as induced by conjunctival allergen challenge. Clinical Therapeutics 2002;24:11:1800-
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`08.
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`5. Lanier BQ, Abelson MB, Berger WE, Granet DB, D'Arienzo PA, Spangler DL, Kagi MK. Comparison of the efficacy of combined fluticasone propionate
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`and olopatadine versus combined fluticasone propionate and fexofenadine for the treatment of allergic rhinoconjunctivitis induced by the conjunctival
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`Give Dry Eye a One-two Punch
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`allergen challenge. Clinical Therapeutics 2002;24:7:1161-74.
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`6. Abelson MB, Welch DL. An evaluation of onset and duration of action of Patanol (olopatadine hydrochloride ophthalmic solution 0.1%) compared to
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`Claritin (loratadine 10 mg) tablets in acute allergic conjunctivitis in the conjunctival allergen challenge model. Acta Ophthalmol Scand 2000:78:60-63.
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`7. Abelson MB, Kaplan AP. A randomized, double-blind, placebo-controlled comparison ofemedastine 0.05% ophthalmic solution with loratadine 10 mg
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`and their combination in the human conjunctival allergen challenge model. Clinical Therapeutics 2002;24(3):445-56.
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`8. Crampton HJ. An evaluation of the efficacy of ketotifen fumarate 0.025% ophthalmic solution compared to desloratadine 5 mg compared to ketotifen
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`fumarate 0.025% ophthalmic solution used with desloratadine 5 mg in inhibiting the signs and symptoms of seasonal allergic rhinoconjunctivitis in the
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`allergen challenge model [in press].
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`Copyright © 2017 Jobson Medical Information LLC unless otherwise noted.
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`All rights reserved. Reproduction in whole or in part without permission is prohibited.
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`https://wwwreviewofophthalmology.com/article/give-dry-eye-a-one-tvvo-punch
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