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`New Thinking Spurs New Products
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`Christopher Glenn, Editor in Chief
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`PUBLISHED 15 FEBRUARY 2003
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`New Thinking Spurs New
`Products
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`With the market for dry-eye products already huge and growing,
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`the need for effective therapy is leading to novel approaches that
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`move beyond tear replacement. This article reviews some of
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`those efforts that have come to fruition in recent product
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`introductions.
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`Restasis, at Last
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`The late-December Food and Drug Administration approval of
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`A||ergan's Restasis (cyclosporine ophthalmic emulsion 0.5%)
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`ended years of development, testing and regulatory hurdles for
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`the company. The drug is the first therapeutic dry eye product
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`approved and may have paved the way for other competitors.
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`The product is a reflection of an evolving understanding of the
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`dry-eye disease process. Restasis was designed for patients
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`with inadequate tear production due to ocular inflammation
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`associated with keratoconjunctivitis sicca. The inflammatory
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`pathophysiology until recent years was thought to be limited to a
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`small subset of dry-eye conditions.
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`Regulatory fits and starts marked the history of Al|ergan's cyclosporin product, finally approved in December 2002.
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`Peter McDonnell, MD, of the University of California, Irvine, who
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`participated in the Restasis clinical trials, explains, "lt's been
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`known for some time that that diseases like rheumatoid arthritis
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`and Sjogrens are autoimmune conditions in which lymphocytes
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`essentially the attack the patient's own lacrimal gland, and there
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`is destruction of tissue and dysfunction of the gland. It was
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`thought that this was very much the exception, just one small
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`subset of dry-eye patients. The data that has been generated
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`over the last five to 10 years show is that this is not really a great
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`exception, that, in fact, a very common phenomenon in a great
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`number of patients with dry eye is an underlying local disorder of
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`immunity or inflammation that causes this same type of lacrimal
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`dysfunction."
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`Michael Lemp, MD, a clinical professor of ophthalmology at
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`Georgetown University School of Medicine, says the action of
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`cyclosporin-A downregulates the inflammatory response and
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`allows those cells to recover their normal activity. "By modulating
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`the immune response, which sets up inflammation, [cyclosporin-
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`] controls the inflammatory response," says Dr. Lemp. "That
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`response, particularly in the lacrimal glands, but probably also in
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`the meibomian glands of the eyelid, leads to a dysfunction of
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`acinar cells, the secreting cells in the lacrimal glands that
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`produce the aqueous portion of the tears. Those cells become
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`dysfunctional and do not produce tears either of normal quantity
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`or quality.''
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`‘ llergan calls the product a "partial immunomodu|ator," though
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`its exact mechanism of action is not known.
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`The Restasis Phase III submission was based on four
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`multicenter, randomized, controlled trials of 1,200 patients
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`diagnosed as suffering from moderate to severe
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`keratoconjunctivitis sicca. The most common side effects in the
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`trials were ocular burning (approximately 17 percent of patients),
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`and conjunctival hyperemia, discharge, epiphora, eye pain,
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`oreign body sensation, pruritus, stinging and blurring (1 to 5
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`percent).
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`It may take up to six months for the product to take full effect,
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`though Dr. Lemp points out that this is "not unreasonable when
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`you understand how it works. This is a disease process that
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`takes a long time for an inflammation to develop and for the cells
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`to become dysfunctional. And to restore the environment in
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`hich the cells can recover is going to take some time too."
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`Dave Power, A||ergan's director of Global Pharmaceutical
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`Marketing, points out that the emulsion vehicle in which the
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`cyclosporin is dissolved provides some comfort benefits fairly
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`quickly. "Certainly in our studies we saw improvements in patient
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`comfort at the first month and that continued to get better as the
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`disease heals," he says. "We need to educate the doctors on
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`how this drug works and why it takes some time for it to have its
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`ull effect. That's not a hard sell for the doctor to tell a patient who
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`has been coming to his office for several years and not gotten
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`the kind of relief that he's looking for to stick with this product,
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`because there's really nothing else out there for him."
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`With the addition of Endura, intended for moderate to severe cases, the Refresh line extends to all levels of dry eye.
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`Dr. McDonnell agrees. "|'ve felt for some time fairly impotent in
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`helping these patients with severe dry eye, whose lives are really
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`disordered by this condition," he says. "Now to have something
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`here we can finally address the underlying condition is pretty
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`exciting."
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`‘ New Landscape
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`Dr. Lemp believes the willingness of the FDA to reconsider data
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`based on the changing understanding of dry eye bodes well not
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`'ust for patients and physicians, but for industry as well.
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`"The data from the first two Phase III clinical trials has been
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`available for several years and [Restasis] did not receive
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`approval its first time around," says Dr. Lemp. In addition to the
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`two new trials that supported the drug's FDA submission, this
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`approval "involved the agency's willingness to relook at data and
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`reinterpret it in terms of defining efficacy," he says. "There has
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`been a gradual increasing awareness that [dry eye] is a difficult
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`nut to crack, a gradual recognition that has been coming on for
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`years. So this is absolutely a positive development for the
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`agency and entirely appropriate."
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`That willingness to reconsider dry-eye data may benefit Durham,
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`N.C.'s Inspire Pharmaceuticals, which is preparing to seek
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`approval on its own product, diquafosol tetrasodium (lNS365
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`Ophthalmic). One Phase II trial and two Phase III trials have
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`been conducted, and a Phase lllb trial is ongoing.
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`Inspire announced in October 2002 that the NDA filing would be
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`based on safety and efficacy data from the completed Phase II
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`and Phase III trials. As well as safety and tolerability, the trials of
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`lNS365 have demonstrated statistically significant improvement
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`compared to placebo in corneal and conjunctival staining.
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`The content and format of a New Drug Application for the
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`product submission were agreed to with the FDA in a pre-NDA
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`meeting held in January 2003.
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`"We believe this overall clinical package is strong, and we now
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`have clarity on FDA requirements for the content and format of
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`the NDA submission," said Christy L. Shaffer, PhD, CEO of
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`Inspire. "Our top priority is to prepare and submit a high-quality
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`NDA mid-year."
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`New in OTC
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`‘ nother new product introduced last year extended the Refresh
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`(Allergan) line of tear supplements. Refresh Endura. Unlike the
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`other preserved products in the Refresh line, Endura is
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`unpreserved and features an emulsion formula that keeps the
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`product active on the eye longer, says the company.
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`Erika Carlucci, product manager for the Refresh line, says,
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`"Endura is intended for the moderate to severe dry-eye patient,
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`the ones who tend to go their eye doctor." She calls the product
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`"a new type of technology that the over-the-counter market
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`hasn't seen."
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`Peter Simmons, PhD, senior scientist at Allergan R&D, explains,
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`"The big difference is this oil-based emulsion and the structure of
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`the emulsion is such that it's in a low electrolyte formula in the
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`container, then when it hits the eye and interacts with the tears,
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`the electrolytes in the tears cause the emulsion to break down,
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`and that releases the oil. So the oil can then migrate and
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`supplement the lipid layer in the tears."
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`Castor oil has been shown to be effective in treating patients with
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`meibomian gland dysfunction. A randomized, placebo-controlled
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`Japanese study used a low-concentration castor oil mixture in 40
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`eyes of 20 patients (7 male, 13 female, age 52.1 i 11.0 years)
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`ith noninflamed MGD whose symptoms had not improved with
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`conventional artificial tears, antibiotics, and corticosteroids.1
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`Nine patients demonstrated aqueous tear deficiency of Schirmer
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`testing, with four of these diagnosed with Sj6gren's. Excluded
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`ere patients with anterior blepharitis of more than moderate
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`severity, infectious conjunctivitis, acute MGD, and excessive
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`expression of meibum. For two separate two-week periods,
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`subjects were randomly assigned to receive oil eye drops or
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`placebo six times daily.
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`Pre- and post-study examination included tear evaporation
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`assessment, rose bengal and fluorescein staining, tear breakup
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`time and a subjective patient assessment of comfort. Symptom
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`scores, as well as each of the objective measures, showed
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`significant improvement in the treatment period vs. the placebo
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`period. The authors postulate several mechanisms for the
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`improvement in the tear stability including lipid spreading over
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`the ocular surface, greater ease of meibum expression,
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`prevention of tear evaporation and the lubricating effect of the oil.
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`Patients may notice an unusual sensation when they first
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`encounter Endura. "When that emulsion breaks down, within a
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`minute or so, some people get a sensation, a very transient bit of
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`a sting, or theyjust notice that something is there," says Dr.
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`Simmons. "|t behaves differently from most eye drops that are
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`usually very soothing initially and wear off rapidly as the fluid
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`tends to drain from the eye. The oil component, we think, will
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`reside on the lower lid, float on the tear fluid and stay around a
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`lot longer.''
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`Roanoke, Va., ophthalmologist John Sheppard says he's found
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`the solution especially effective for patients with lipid-deficiency
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`dry eye, such as those with blepharitis. ''It comes in a single-
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`dose unit, so it's preservative free, which is great. Because it's an
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`SDU, it's not as cost-effective and a little more inconvenient to
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`use, but in many cases, it's well worth those minor adaptations."
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`He's also adding it with good success to antibiotic therapy for
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`certain patients with meibomian disease or rosacea. For the
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`majority of patients who tolerate the doxycyclene he normally
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`prescribes, the therapy can take a few months to be fully
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`effective. In the interim, he says, Endura can provide
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`symptomatic relief.
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`Advanced Vision Research has added two products to its TheraTears line.
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`The Nutritional Route
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`‘ nother approach to improving tear film composition, this one
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`through nutritional means, is TheraTears Nutrition, one of two
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`new products from Advanced Vision Research, of Woburn, Mass.
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`The product contains flaxseed oil, an omega-3 essential fatty
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`acid.
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`In the body, omega-3s are acted on to produce prostaglandin E3
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`and leukotriene B5. These two eicosanoids decrease
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`inflammation. Omega 3s also decrease gene expression of
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`proinflammatory interleukins, tumor necrosis factor-alpha and
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`cylooxygenase, as well as decreasing the activity of
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`proteoglycan-degrading enzymes.
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`New Thinking Spurs New Products
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`In addition, the meibomian glands use essential fatty acids in the
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`production of the lipid component of the tear film, says Jeffrey
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`Gilbard, MD, founder of Advanced Vision Research. He cites
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`studies showing the polar lipid profiles of meibomian gland
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`secretions in female Sjogren's patients are controlled by the
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`dietary intake of omega-3 essential fatty acids, as well as clinical
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`reports of clearer and thinner oils with omega-3 treatment. EFAs
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`also play a role in inhibiting production of arachidonic acid and
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`promoting the production of prostaglandin E1, which has been
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`shown to stimulate aqueous tear production.
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`The company has also introduced TheraTears Liquid Gel, a
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`preservative-free, hypotonic electrolyte-balanced liquid gel for
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`dry eye. The gel, for nighttime or daytime use, is designed to
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`avoid lid crusting and blurred vision, according to the company.
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`1. Goto E, Shimazaki J, Monden, Y, et al. Low-concentration Homogenized Castor Oil Eye Drops for Noninflamed ObstructiveMeibomian Gland Dysfunction.
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`Ophthalmology 109:11;2030-2035.
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`Copyright © 2017 Jobson Medical Information LLC unless othenNise noted.
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`All rights reserved. Reproduction in whole or in part without permission is prohibited.
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`https://www.reviewofophthalmology.com/article/new-thinking-spurs-new-products
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