UPDATE: Treating Ocular Allergy
Current options are plentiful, and many new alternatives are in the pipeline.
BY PETER A. D'ARIENZO, M.D., FACS

Back in the 1980s, ocular anti-allergy therapy was a very small niche in the pharmaceutical industry, with a total market share of only about $30 million in the United States. Treatment was based on empirical formulas of antihistamine/decongestant products, cromolyn sodium, or steroids. At the same time, clinical studies in ocular and systemic allergy were fraught with error and lack of reproducibility, creating a nearly impossible obstacle for new products to overcome.

Two developments triggered a change. First, FDA regulations regarding combination products were amended to require proof that both components significantly contributed to a product's total efficacy. This mandate spurred a great many clinical studies on the effects and duration of action of the available combination drugs. Second, the development of the allergen challenge model of allergic conjunctivitis -- a model sensitive enough to overcome problems of intersubject and intrasubject variability -- provided a way for the pharmaceutical industry to more easily evaluate and compare these agents and their components. Before long, new, more efficacious products began to surface, and interest in ocular allergy rose sharply.

Today, diagnosis and treatment of ocular allergy has become a significant part of most practices. Here, I'd like to briefly describe the main categories of drugs currently available for topical treatment of allergic conjunctivitis, new treatments on the horizon, and new trends in the field.

Currently available medications for allergy fall into several categories, which can be considered either single action or dual action. Single action categories include:

Antihistamines. These compounds compete with histamine for binding at the H1 receptors, thus reducing symptoms such as itching and tearing. This category encompasses first-generation products such as antazoline or pheniramine (which have relatively less selectivity and limited duration of action), and more advanced antihistamines such as levocabastine (Livostin) and emedastine (Emadine), which last longer and cause less discomfort. (The first-generation compounds are now available OTC, often marketed in combination with a decongestant that constricts blood vessels and whitens the eye.)

Mast cell stabilizers. These compounds inhibit the release of mast-cell mediators. They include cromolyn sodium (Crolom) -- the first to become available -- and more recently, nedocromil sodium (Alocril), lodoxamide tromethamine (Alomide), and pemirolast potassium (Alamast). These agents may also inhibit other cells such as eosinophils, as exemplified by the indication of Alomide for keratitis in vernal keratoconjunctivitis (VKC).

Although used widely for the treatment of allergic conjunctivitis, these are primarily effective when taken for at least 2 weeks; they don't alleviate signs or symptoms of allergy once a reaction has begun. (Some OTC products combine drugs from these two categories to alleviate immediate symptoms while providing longer-term protection.)

Dual Action Agents

Compounds in this category include olopatadine (Patanol), ketotifen (Zaditor), azelastine (Optivar) and epinastine (Elestat). These medications incorporate both selective antihistamic activity and mast cell stabilization.

► Olopatadine was the first to be developed; it was designed specifically for ocular use through screening using human conjunctival mast cells. Its mast cell stabilizing efficacy has been confirmed using the allergen challenge model to show inhibition of tear histamine, ICAM-a expression and other mast cell derived mediators in clinical study (Leonardi et al. Clin Ther 2003: 25(10): 2539-52). It's the only agent in this category approved for relief of all signs and symptoms of allergic conjunctivitis.

► Ketotifen, approved for the relief of ocular itching, was originally used as an asthma medication. It's been shown to inhibit mast cell degranulation in vitro, stabilize eosinophils, and inhibit leukotriene and platelet activating factor release (Schoch, J Ocul Pharmacol Ther 2003 Feb; 19(1): 75-81). Both ketotifen and olopatadine have been shown to suppress nasal symptoms such as rhinorrhea, sneezing and itching when applied topically to the eye, as a result of draining through the nasolacrimal ducts into the nose. (Abelson et al., Clin Ther 2003 Mar; 25(3): 931-47.; Crampton HJ., Clin Ther Nov. 2002; 24(11)).

► Azelastine was first used in Europe to treat asthma and rhinitis; it has a rapid onset of action and is indicated for b.i.d. use. Its mast cell stabilization ability was studied in blood-derived and skin mast cells. (Ciprandi et al., Ann Allergy Asthma Immunol 2003 Apr; 90(4): 434-8; James et al., Curr Med Res Opin. 2003; 19(4): 313-20; or Canonica et al., Curr Med Res Opin. 2003; 19(4): 321-9.)

► Epinastine (Elestat) was first synthesized in 1975. It was used for allergic rhinitis for many years, but was recently approved as a topical product for ocular allergy. Elestat's efficacy as a mast cell stabilizer originates from experiments involving lung, skin and peritoneal mast cells. Clinical studies using allergen challenge have shown epinastine to have an 8- to 12-hour duration. (For more information, see Schiffman et al., Invest. Ophthalmol. Vis. Sci. 2002 43: E-Abstract 107. Also, studies on this topic were reported by Whitcup et al. at the May 2003 ARVO meeting in Fort Lauderdale, Fla., and Friedlander et al., at the Western Society of Allergy, Asthma, and Immunology [WSAAI] meeting in Maui, HI, Jan. 2004.)

New Alternatives

Several new options are under investigation:

► A new formulation of olopatadine with a higher concentration of the active ingredient (0.2%) has recently been developed. This formulation has undergone testing to determine if once-daily dosing significantly inhibits signs and symptoms. Studies by Abelson et al. and Lichtenstein et al. (both reported during presentations at the WSAAI meeting on January 18, 2003 in Maui, HI) have indicated that it's safe and well-tolerated, with higher potency and a duration of action of at least 24 hours. (Because most available anti-allergy agents are dosed b.i.d., this could set a new standard for allergy therapy.)

Other new possibilities are also under investigation:

► Murata et al. have shown that topical protease in-hibitors effectively inhibit eosinophil conjunctival migration and degranulation in animal models of allergic conjunctivitis (Curr Eye Res 2003 May; 26(5): 271-6). Sodhi et al. have demonstrated that topical mitomycin C is effective in these models as well (Cornea 2003 Apr; 22(3): 210-3).

► Recent studies have shown that diclofenac, a non-steroidal anti-inflammatory medication, and montelukast, a leukotriene receptor antagonist, are effective at treating vernal conjunctivitis. These medications, which affect the arachidonic acid pathways, are effective in chronic allergy where prostaglandins and leukotrienes play a larger role. (See D'Angelo et al., Graefes Arch Clin Exp Ophthalmol 2003 Mar; 241(3): 192-5; and Lambiase et al. Arch Ophthalmol 2003 May; 121(5): 615-20.) This suggests that several of the other mediators released may contribute to causing VKC.

► Tacrolimus has been shown to be effective in combating eyelid-dermatologic allergic disease. (Rikkers et al., Am J Ophthalmol 2003 Mar; 135(3): 297-302; and Tomida et al., Adv Exp Med Biol 2002; 506(Pt B): 805-12.) This compound, like cyclosporine, works by inhibiting cytokine gene transcription in T-lymphocytes. The involvement of T-cells in chronic allergic conditions makes these drugs likely candidates to combat the increased infiltration of mediators such as eosinophils.

► Apafant, a potent platelet activating factor antagonist, was found to significantly inhibit conjunctival vascular permeability in an animal model of ocular allergy, blocking both redness and swelling. (Kato et al., J Ocul Pharmacol Ther 2003 Aug; 19(4): 315-24.)

► Novel transglutamase inhibitors (nonapeptides or antiflammins) are being synthesized using recombinant techniques. They appear to safely inhibit allergic and inflammatory reactions in the first allergy models. (Sohn et al., J Clin Invest 2003 Jan; 111(1): 121-8.)

► Research into the genetic basis of allergic conjunctivitis may also prove fruitful. The use of immunostimulatory sequences of DNA (ISSS-ODN) as an allergy treatment has been tested, and proven effective in inhibiting allergic responses in a mouse model with systemic or conjunctival administration (Ono SJ et al., Invest Ophthalmol Vis Sci 2000 Nov; 41(12): 3850-5.)

In addition, research into eosinophils and anti-inflammatory activity may play a role in treating more chronic/severe cases of allergy.

Changes for the Better

How important are these developments? In addition to doing a better job of alleviating patient allergy symptoms, side benefits often result. For example, it's becoming increasingly evident that inhibiting mast cells can have broad-ranging effects by blocking the release of so many mediators.

This realization has motivated some new approaches to evaluating ocular allergy. The degranulation of mast cells releases several vasoactive molecules (including histamine) which can act to induce gaping of the endothelial cells and exudation of fluid in the affected tissue. This can cause the chemosis sometimes seen with allergic conjunctivitis; it can also lead to lid swelling, which can result in permanent micro-damage to the fragile skin and collagen fibers surrounding the eye. As a result, researchers have recently begun to focus on the importance of eyelid swelling as an objective sign and parameter more specific to vascular permeability changes than conjunctival redness. To facilitate this promising approach, researchers have developed new objective methods for measuring lid swelling. (Abelson et al., Clin Ther. 25(7): 2003: 2070-2084.)

Also, allergy problems impact other procedures, such as LASIK. Studies such as those by Boorstein et al. (Ophthalmology 2003; 110(1): 131-7) are indicating that allergy may be a risk factor for an imperfect outcome in LASIK -- and that topical treatment prior to surgery may provide protection against this risk.

The profound impact this mild but ubiquitous disease has on other disease states and procedures demands the highest attention from both practitioners and the pharmaceutical industry. I look forward to seeing what developments the next 15 years will bring.

Peter A. D'Arienzo, M.D., is a clinical assistant professor of ophthalmology at New York Medical College, Valhalla, New York. He also serves as clinical director of the Department of Ophthalmology, Saint Vincent Catholic Medical Centers, Brooklyn & Queens Region. He is in private practice at Manhasset Ophthalmology in New York.