Bromhexine

Here's an in-depth look at today's treatment options, including a new Rx drop that addresses the inflammatory process.

Dry eye is one of the most common - and frustrating - diseases in eye care. Occasionally debilitating to patients, dry eye resists effective treatment in many.

To treat dry eye, we've used a wide range of modalities. In this article, I'll review the common treatment options and discuss newly approved cyclosporine ophthalmic emulsion 0.05% (Restasis), which is a landmark treatment for dry eye.

First, let's take a look at the two main approaches we've traditionally taken for treating dry eye: Lubrication and tear preservation.

Lubrication

The three methods used to lubricate the eyes are artificial tears, ointments and lacriserts.

* Artificial tears. First used in the early 1970s, preserved tears help patients with mild to moderate disease by wetting the eye. Unfortunately, patients with severe dry eye worsen when they use the preserved solution more than four times a day.

Preservative-free tears, introduced a few years later, were an important advance because patients can use them every hour without the toxicity associated with preserved tears. For the most part, these drops use the same polymer as the preserved tears, usually carboxymethylcellulose or polyvinyl alcohol.

Early artificial tears had several drawbacks. They contained no electrolytes, and sometimes the pH and the osmolarity were incorrect. Surface tension could become a problem because of a lack of lipids.

Over the years, manufacturers formulated artificial tears that are slightly hypotonie in response to the belief that dry eye is associated with hypertonicity.

For both preserved and nonpreserved tears, the rate of application depends completely on patient administration. What's more, preservative-free tears can quickly become expensive for patients because there's 0.5 cc of tears in each single-use vial, which the patient is instructed to use once and throw away. (In reality, patients use the same vial all day.) Because the vial is small, some patients - those with rheumatoid arthritis, for example - have trouble instilling the drops.

* Ointments. Usually used for patients with more severe dry eye, ointments are comparable to artificial tears in efficacy. Because the first ointments for dry eye were preserved, toxicity was a problem for some patients.

Unfortunately, ointments contribute to significant blurring and decreased visual acuity, which limits their use other than at bedtime. Also, many products contain lanolin and petrolatum, to which patients can become allergic.

* Lacriserts. Now rarely used, these rodlike devices, which patients must place in the fornix, melt in the tear film for long-lasting, slow distribution of methylcellulose. Patients need a certain tear flow to dissolve the lacriserts, so only a few patients can tolerate these devices. What's more, patients often have difficulty inserting lacriserts and can experience a foreign-body sensation. In rare cases, lacriserts help stabilize the tear film.

Tear preservation

Among the devices and techniques used to preserve tears are punctal occlusion, moist chamber goggles and tarsorrhaphy.

* Punctal occlusion. Done either un a temporary or permanent basis, punctal occlusion uses ptuglike devices or cautery to occlude the puncta and help preserve patients'tears.

Various problems can occur. For instance, the procedure can result in epiphora. If the patient's tears contain a lot of inflammatory mediators, plugging the puncta will allow noxious tears to accumulate against the cornea, exacerbating the problem. Another draw-back is that because the area is difficult to anesthetize, punctal cautery is painful.

Originally, small plugs rested on the outside of the puncta. But in newer designs, plugs change shape with body heat to conform to the canaliculus, going from a long, thin rod to a shorter, thicker rod, thereby providing better occlusion.

* Moist chamber goggles. For patients with meibomian gland dysfunction, which causes evaporative dry eye, the external lipid layer of tear film may not be as stable as it should be, resulting in too much evaporation. The cornea and the conjunctiva will stain from this abnormal tear film.

Moist chamber goggles maintain increased humidity, addressing the evaporation problem, which is often beneficial for patients with keratoconjunctivitis sicca. Rarely used, the goggles are worn continually and, of course, present a cosmetic issue.

* Tarsorrhaphy. Suturing together the lateral half of the eyelids protects the patient's corneas from drying. By closing, say, 60% of the patient's ocular surface, tears are more effective. But this procedure is disfiguring, and patients may lose some peripheral vision.

Another less commonly used method of tear preservation for severe cases is application of bandage contact lenses. These occasionally stabilize the tear film and protect the cornea from dessication.

And finally, oral bromhexine and pilocarpine can stimulate tears, but may cause adverse effects, such as flushing, sweating and nausea.

Addressing the inflammatory process

Unlike all of these medications and procedures, which treat signs and symptoms, cyclosporine ophthalmic is the first treatment that gets to the root of dry eye disease.

During the last decade, investigators have learned that dry eye from aqueous insufficiency (keratocon-junctivitis sicca) involves T-cell inflammation in the lacrimal tissues. This results in a continual outpouring of inflammatory mediators, including cytokines, on the ocular surface.

That, in turn, leads to a vicious cycle of upregulation of inflammation on the ocular surface, causing denervation of the ocular surface. This results in less feedback to the central nervous system and less neural stimulation to the lacrimal tissues in the main and accessory lacrimal glands.

In the normal eye, lymphocytes live about 110 days before being replaced. But in dry eyes, the inflammatory process stimulates more lymphocytes that infiltrate tissues; their lifespan is prolonged to 180 days.

What's more, the acinar tissue starts dying much more rapidly than normal. Thus, the patient experiences a loss of the secretory component and an increase in the inflammatory component as time goes on.

Cyclosporine mechanism and safety

Cyclosporine ophthalmic prevents the activation of T cells by cyclophilin and thereby inhibits the production of cytokines and other agents of inflammation. It normalizes the effects of chronic dry eye disease by reversing apoptosis in T cells and lacrimal gland cells. Therefore, the lymphocytes die in about 110 days, and the acinar tissue in the lacrimal glands lives longer.

Topical cyclosporine is given as a 0.05% emulsion. The emulsion allows efficacy at low cyclosporine concentrations. If one drop is given to a patient twice daily to each eye and all of the drop is absorbed systemically, it would take 1,961 years to reach the minimum toxic level reported. Therefore, systemic side effects are highly unlikely.

Indeed, in an FDA study of 877 patients, no patient had detectable serum levels (measured in nanograms) after taking cyclosporine twice daily for 6 months.

Who benefits most?

Patients who benefit most from topical cyclosporine are those who use artificial tears at least 4 times daily and have both conjunctival and corneal staining.

If no acinar tissue is left in the accessory lacrimal glands, then cyclosporine ophthalmic won't have any effect. The patient must have some response to the Schirmcr 2 test. In other words, if a patient shows less than 3 mm wetting with nasal stimulation, the lacrimal glands are probably beyond restoration.

The medication also will have no impact on eyes that have experienced a diffuse loss of goblet cells, such as in ocular pemphigoid disease, Stevens-Johnson syndrome or chemical burns. In these cases, the entire ocular surface has been affected.

Cyclosporinc ophthalmic may help in ocular cicatricial pemphigoid (OCP) disease before it reaches its end stage. Recent evidence suggests that OCP may be a T cell-mediated disease.

More positive outcomes

With this new agent, clinicians can look forward to more positive outcomes among their dry eye patients, such as peri- and postmenopausal women and patients with autoimmune diseases, such as rheumatoid arthritis and Sjogren's syndrome.

By Henry D. Perry, M.D. Rockville Centre, N.Y.

Dr. Perry practices at Ophthalmic Consultants of Long Island in Ruckville Centre, N.Y. He's clinical associate professor of ophthalmology at the Weill School of Medicine at Cornell University, Ithaca, N.Y.

Copyright Boucher Communications, Inc. Jul 2003
Provided by ProQuest Information and Learning Company. All rights Reserved