",“."EI'E "' "'
`
`'3 A. '."." E
`
`Flatt Murphy
`Managing Editor
`
`Up to 10 I‘1‘11lli0I‘1 Ameri-
`cans suffer the daily misery of
`chronic dry eye syndrome. Un-
`reienting ocular irritation and pho-
`tophobia are a way of life. Dry eye
`syndrome, whether stemming from
`aqueous deficiency or accelerated
`tear evaporation, is the most com-
`mon treatable eye condition you
`encounter in the ciinic. In the face
`of such a stubborn and implacable
`malady, savvy clinicians use every
`conceivable countermeasure to
`
`bring some relief to their patients.
`Current treatments are essentialiy
`palliative. New therapies target the
`root Causes of the disease.
`
`causes and Defects
`
`The first step in managing dry
`eye is to determine what’s causing
`it. Inflammation of the lacrimal
`
`gland and denervation of the cornea
`can curb tear production. Meibomi-
`an gland dysfunction and incom«
`plete lid closure are frequently to
`
`You have a broa..___ range of therapies -
`
`to alleviate
`
`the symptoms of dry eye. Researchers and drug man-
`
`ufacturers hope to expand your therapeutic arsenal.
`
`blame for rapid tear evaporation.
`Obtain a history for systemic health
`factors, medications, environmental
`factors and anything else that may
`trigger or worsen symptoms.
`“I see a lot of patients in this
`area who are taking a variety of
`over-the-counter medications for
`
`aliergies or sinus problems, and
`those typically are antihistamines
`and decongestants," says James L.
`Fanclli, O.D., of Wilmington, N.C.
`“These people will get a pharmaco-
`logically induced dry eye because of
`all the medications.”
`
`Encourage patients to avoid envi-
`ronments that may exacerbate their
`discomiort, say a smoky harroom
`or a dusty attic. Maybe they can
`change their environment. “One
`thing that helps for people with
`reaily severe dry eye is to have
`them use a humidifier in their
`
`bedroom at night and moisten
`the air,” Atlanta clinician Paul
`C. Ajamian, O.D., says.
`Do a careful check of the
`
`lids. Meibomian gland stenosis
`and blepharitis are common
`triggers of dry eye. “Look at
`the lid margins for signs of
`
`chronic staph lid disease,” Dr.
`Aiamian advises. “A lot of dry eye
`patients have chronic staph, and yet
`we just focus on the dry eye portion
`and ignore the lid-hygiene portion.”
`Many patients who have had
`LASIK experience dry eye. Dry eye
`researcher Jeffrey P. Gilba rd, M.D.,
`attributes this to corneal denerva-
`
`tion. “When you cut the flap, you
`cut the corneal nerves,” he says.
`“And just as irritated eyes tear
`more, eyes that are numb tear less.”
`A recent study in Australia found
`that 100% of LASIK patients
`receiving TheraTears—the artificial
`tears developed by Dr. Gilbard—
`were symptom-free at one month
`post-op compared to just 20% of
`the untreated control group. New
`York surgeon Eric D. Donnenfeld,
`M.D., is now investigating the effi-
`cacy of cyclosporine (Restasis,
`Allergan Pharmaceuticais} in treat-
`ing post-LASIK dry eye.
`
`what's Happening Now
`Dry eye therapy is a sequence of
`palliative measures tailored to the
`severity of the presentation. Clini-
`cians typically begin with non-pre-
`
`FIEVI EW DF DI:-TUMETFIY
`FEBFILIA.-=|Y ‘I5. ED-CED’
`
`are
`
`Copyright ©2000. All Rights Reserved.
`
`1
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`ALL 2009
`ARGENTUM PHARMACEUTICALS V. ALLERGAN
`IPR2016-01232
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`9A“E"EEN"§'° BAHE
`
`served low~v1scos1ty artificial tears
`prescribed every two hours or so.
`Among the more popular choices
`are GenTeai (CIBA Vision}, Hypo—
`tears PF (CIBA Vision}, Moisture
`Eyes (Bausch Sc Lomh Pharmaceu~
`ticals), Refresh Plus {Aliergan}.
`Refresh Tears (Allergam, Tears
`Naturale Free (Alcon) and Thera-
`Tears (Advanced Vision Research).
`Patients may especiaily like the con-
`venience of GenTea| and Refresh
`Tears, which come bottled in a
`rnulti-dose formulation with a rela-
`
`tively rion—toxic preservative that’s
`neutralized upon instillation. Look
`for a multi—dose formulation of
`
`TheraTears come spring.
`“TheraTears seems to be winning
`more and more support,” Dr.
`Fanelli says. Rabbit studies showed
`that its electrolyte solution lowers
`elevated tear osmolarity and
`improves the eye’s electrolyte bal-
`ance. Even so, while Dr. Faneili
`favors GenTeal and Refresh Plus, he
`says it usually comes down to trial-
`and-erron “Theres no magic
`involved,” he says. “It's a matter of
`finding the drop that gives you the
`longest-lasting and most-cornforb
`able relief.“ Seattie clinician Kathy
`Yang Williams, 0.[)., favors preser-
`vative- and lanolin—free Hypotears
`PF for those with associated atopic
`eye disease to reduce the potential
`for a hypersensitivity reaction.
`For more severe or refractory
`presentations, you may wish to
`graduate to moderate-viscosity arti~
`ficial tears such as Biou Tears
`
`@
`
`HEVJEW CH: DPTDNIETPY
`Fl-_—'BF|I_|AFiY '1 E. EDEIEI
`
`{Alcon} or OcuCoat PF (B&cL
`Pharmaceuticals), or high-viscos-
`ity products such as AquaSite
`{CIBA Vision}, Celluvisc (Aller-
`gan) or Murocel (B&L Pharma-
`ceuticals}. As an alternative, these
`patients may find relief with the
`newer gel formulations GenTeal
`Gel (CIBA Vision) or Tears Again
`{OcuSoft}. Ointrnents may work
`well for the most severe cases
`
`that require nighttime therapy.
`Punctal plugs can be effective for
`moderate to severe dry eye when
`artificial tears alone don’t bring
`relief. Some clinicians favor the
`
`CIBA Vision line of punctal plugs
`that come with a preloaded device
`that makes insertion easy. But don't
`wait too long to plug. “I don’t think
`twice anymore about plugging,” Dr.
`Fanelli says. “I’m not going to put
`
`them through this regimen where
`they have to use tears every hour
`and ointments at night." He iikes to
`do a monocular trial by plugging
`the upper and lower puncta of one
`eye for a few days to see if it works.
`Especially severe and recalcitrant
`keratoconjunctivitis sicca may call
`for a short-term course of topical
`steroids. A 1999 study published in
`Ophthalmology by Peter Marsh,
`M.D., and Stephen Pflugfeicler,
`M.D., found that a 2-week course
`of topical methylprednisolone
`relieved the irritation of dry eye, and
`in many patients that relief lasted
`weeks or months after they stopped
`therapy. Loteprcdnol etabonate
`0.2% (Airex, B&L Pharmaceuticals)
`or loteprednoi etabonate 0.5 %
`{Loternax, B851. Pharmaceuticals}
`may be weli—suited for this purpose
`
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`Copyright ©2000. All Rights Reserved.
`
`2
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`

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`E"ET_'E¥I_.i°;‘}_'3E -,
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`_
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`_
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`because they’re less likely than other
`steroids to increase intraocular pres-
`sure. “With the advent of some of
`
`the newer steroids, certainly it’s nice
`to be able to prescribe medications
`like that without the risk of more
`
`serious complications,” Dr. Williams
`says. Topical rnerhylprednisolone
`1% rid or qicl for 3-4 weeks can be
`a safe and effective regimen.
`You may need to address associ-
`ated lid disease. In cases of staph
`blepharitis, Dr. Ajamian prescribes
`lid scrubs and a broad—spectrum
`antibiotic ointment such as poly-
`sporin. For dry eye symptoms due
`to meibomian gland disease, Terri
`Rose, O.D,, of the Bascom Palmer
`Eye Institute in Miami, favors a 6-8
`week course of oral doxycycline.
`“Dosing varies by physician, but an
`average course might be '1 00mg bid
`for 6-8 weeks,” says Dr. Rose.
`“The use of an antibiotic in a non-
`infectious condition has to do with
`
`the effect of doxycycline on lipid
`production and its effectiveness as
`an anti-inflammatory agent.”
`
`Wl1flt'S {O Come
`
`The dry eye treatment thar‘s
`attracted the most attention in the
`
`last year is one that hasn’t even
`obtained FDA approval. Clinical
`investigators who have given their
`patients topical eyclosporine 0.05 %
`{Restasis, Allergen Pharmaceuticals)
`say this irnmunomodulatory agent
`effectively reduces the signs and
`symptoms associated with kerato-
`conjunctivitis sicca. Although
`Allergan was rebuffed in its bid
`last July to win FDA approval,
`the company has responded to
`the agency’s concerns and hopes
`to get the green light to market
`the product by summertime.
`Cyclosporine targets the immune-
`based inflammation that shuts
`
`down tear production in the
`lacrimal gland. “T—lymphocytes
`infiltrate the lacrimal gland, and
`
`they cause inflammation,” explains
`Dr. Donnenfeld, a clinical investiga-
`tor for cyclosporine. “The acinar
`celis——those are the ones that
`secrete the tears—fibi-ost: and die.
`
`-
`
`The rear production stops, and you
`end up with a dry eye. What
`cyclosporine does, it’s a specific T-
`cell modulator that inhibits T—lym-
`phocytes reversibly, and in doing so
`stops the inflammatory cycle so that
`the inflammatory cells die a normal
`death and stop secreting the in flam-
`matory mediators. The lacrimal
`gland tissue that’s still viable comes
`
`back so that the patient starts
`inducing their own tears.”
`Although the FDA-mandated
`phase III trials showed that cyclo-
`sporine was clinically effective with
`negligible side effects {transient
`burning), Dr. Donnenfeld and other
`ciinicians say it cloesn’t work for all
`patients. “One of the problems with
`cyclosporine is that we don’t know
`who is going to be a good candidate
`for its use and who is not, and
`that’s one of the things we're still
`working out right now,” he says.
`Further back in the pipeline is
`another potentially fruitful dry eye
`therapy, this one based on the sex-
`hormones known as androgens.
`Animal models show that andro-
`
`gens play a key role in regulating
`the function of both the lacrimal
`
`and meibomian glands. David A.
`Sullivan, Ph.D., of the Schepens Eye
`Research Institute in Boston recent-
`
`ly found that women who lack
`
`functioning androgen receptors had
`a significant increase in dry eye
`signs and symptoms. Another study
`revealed that patients with Sjogren’s
`syndrome were androgen-deficient.
`Both studies support Dr. Sullivan’s
`hypothesis that androgen—replace-
`rnent therapy may benefit patients
`with lacrimal and meibomian gland
`dysfunction.
`Allergan holds the license to any
`potential therapy based on Dr. Sulli-
`van’s research. The company put on
`hold a multicentet phase II study
`originally planned for last summer.
`Still, Dr. Sullivan remains opti-
`mistic. “We think it looks pro-
`mising,” he says. “Every study
`we’ve been able to throw at it,
`with every control we can, so far
`they’ve been consistent with the
`hypothesis."
`Keep an eye on what’s happen-
`ing at Bascom Pairner. Searching
`for a target at which to aim a po-
`tential therapy, Dr. Pflugfelder has
`been looking for molecules that
`are elevated in dry eye but normal in
`healthy individuals. He thinks he’s
`found a collagenase enzyme that fits
`the bill. “There’s one specifically
`called MMP9 that’s very high in dry
`eye patients in their tear fluid and
`almost nondetectable in normals,”
`he says. “For the first time, [have a
`market that goes up in dry eye and
`not in normal eyes. I think it’s defi-
`nitely something to look into,
`inhibiting that." Interestingly, we
`already have a medication that acts
`as a potent inhibitor of MMP9-—the
`tetracyclines. Dr. Pflugfelder hopes
`to develop other therapies based on
`what he's learning.
`
`Dry eye will remain fertile ground
`for research as long as patients con-
`tinue to suffer. Chronic keratocon-
`
`junctivitis sicca is a miserable way
`to go through life. just ask your pa-
`tients. They’il appreciate anything
`you can do to ameliorate their lot. 9
`
`Copyright ©2000. All Rights Reserved.
`
`REVIEW OF OPTOMETRY
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