Dual-action therapy important for complete allergy control

The treatment of ocular allergy has evolved in Europe over the past 30 years, with our choices broadened and our targets far more defined than they once were in the days of "cromolyn vs. steroids."

Advances in allergy research have given us a clearer picture of the mast cell, the eosinophil and even the fibroblast and conjunctival epithelial cell, along with their products, as players in a complex tapestry of events. It has become clear that therapy in ocular allergy is either aimed at multiple targets or is doomed to fail. The patient’s need for immediate relief has to be taken seriously and coupled to the physician’s need to ameliorate underlying disease.

Olopatadine is a newcomer to the European market. It has been approved by European regulators but not yet launched in Europe by Alcon. The drug has been shown to inhibit the ocular allergic reaction through multiple mechanisms. It has the ability to successfully block the events at the root of the allergic reaction.

In this article, we will discuss the importance of dual action drugs in ocular allergy therapy. We will also discuss the pharmacology and clinical results obtained with olopatadine in an effort to introduce this exciting new drug to the European ophthalmologist.

Response to allergens

Seasonal and perennial ocular allergy is the result of IgE antibodies reacting with airborne antigens that find their way into the tear film. These antigens attach to receptors found on mast cells in the conjunctival mucosa. Receptor binding elicits changes in the mast cell membrane that lead to its degranulation, an event that is at the apex of the type 1 hypersensitivity response.

Preformed mediators stored in these granular packets, such as tryptase, heparin and histamine, are then released into the extracellular mucosal tissue. These altered cell membranes release phospholipids that bind with phospholipase A2 and initiate the cascade of biochemical events that leads to the formation of newly synthesized mediators such as prostaglandins and leukotrienes.

Mast cell degranulation also activates vascular endothelial cells and the release of chemokines and adhesion molecules, factors that in sufficient quantity may initiate the recruitment phase of inflammatory cells in the conjunctival mucosa.

In most patients the influx of inflammatory cells does not reach the threshold needed to cause clinical signs and symptoms; however, these cells do play a role, especially in severe chronic forms of ocular allergy, such as atopic keratoconjunctivits (AKC) and vernal keratoconjunctivitis (VKC).

Histamine, released upon mast cell degranulation, has long been known to be the most reactive of mast cell mediators, binding to H1 and H2 receptors on nerve and vascular endothelial cells. This results in the immediate signs and symptoms of itching, redness, swelling and tearing, and it begins a ripple effect that has implications much further in time throughout the conjunctival cellular immune system.

Mast cell types

Mast cells are the leading players in type 1 hypersensitivity reactions. In the eye, two subtypes are known to exist. These were initially classified according to their site of discovery: connective tissue mast cells (CTMC) or mucosal mast cells (MMC). This rather unsophisticated system was replaced by one based on specific cellular markers for mast cells, which contain different quantities and types of proteases: the tryptase mast cell (MCT, previously the MMC), and the chymase-tryptase mast cell (MCTC, previously the CTMC).

Conjunctival mast cells isolated from allergic conjunctivitis patients have been shown to be 100% MCTC type. While the immunological role of these cells in distinct tissue types is identical, they do have diverse morphology and staining characteristics, contain different preformed mediators and, most importantly for the clinician, respond differently to inhibitory drugs such as mast cell stabilizers.

This mast cell heterogeneity is also evident in different tissues and is also found to vary across species. Thus it is critical to identify exactly where an anti-allergic drug has been tested — what animal, what tissue. Scores of preclinical studies have been performed on anti-allergic drugs, yet the relevance of these data may be nil with regard to the conjunctiva. For example, the dual action antihistamine azelastine was evaluated in vitro using umbilical cord-derived human mast cells. In contrast, studies of olopatadine’s anti-allergic activity have involved human conjunctival mast cells.

Cromolyn and others

Cromolyn sodium was the first mast cell stabilizer for local treatment of allergic diseases in the lung, nose and eye. Initially, its need for a loading period and inconsistencies of clinical results led manufacturers to increase the concentration from 2% to 4%. While the higher dose improved efficacy, this first generation molecule is weaker than those that followed.

Lodoxamide tromethamine is a mast cell stabilizer 2,500 times more powerful than cromolyn in inhibiting the signs and symptoms of allergic disease. Pemirolast and nedocromil sodium are other second-generation mast cell stabilizers with improved efficacy.

Mast cell stabilizers are thought to supress type 1 hypersensitivity reactions by inhibiting mast cell degranulation, possibly via inhibition of calcium influx into mast cells after antigen stimulation. They have no direct vasoconstrictor, antihistaminic or anti-inflammatory activity. Thus they have no effect on the reactions induced by mast cells that do succeed in degranulating, a phenomenon that invariably occurs depending on the mast cell stabilizer’s potency, onset and duration of action and loading period.

Newer antihistamines

Levocabastine and emedastine are two newer-generation antihistamines, superior to earlier molecules such as pheniramine, antazoline and chlorpheniramine, used in combination products.

These drugs work by competitively blocking histamine receptors in the conjunctival mucosa. H1 receptors, found primarily on nerve endings but also on blood vessel walls, are responsible for itching and some redness and swelling. H2 receptors are found on the blood vessels and cause redness.

The result of antihistamine use is blockage of histamine’s C-fiber nervous stimulation and thus an inhibition of itching. The lesser H2 antagonism causes relief of conjunctival redness, swelling (chemosis and eyelid) and tearing.

The earlier antihistamines were always combined with a vasoconstrictor to eliminate the vascular component of the histamine reaction, while the newer molecules do a fairly good job at inhibiting both itching and redness on their own. Nevertheless, these drugs have a relatively short duration of action of about 2 hours and thus can not provide all-day relief. They are indicated for up to four times daily dosing. Further, none stabilizes the mast cell to prevent degranulation and the allergic reaction in a comprehensive manner.

Steroid limitations

Steroids are frequently used for the treatment of allergic diseases of the eye, although we are all aware of their side effects of increased intraocular pressure, decreased wound healing and superinfection. They have a broad range of effects in decreasing the proliferation and recruitment of mast cells. While newer molecules have been developed to minimize absorption, loading periods are still necessary, and thus these drugs are not effective against ongoing acute allergic reactions.

Even after a loading phase, a single drop of olopatadine was shown to be more effective than loteprednol in a controlled allergen challenge study. Steroids, however, should be considered useful tools for the treatment of severe chronic cases of allergy that do not respond to other therapy.

Need for dual action

Single-action drugs such as traditional antihistamines and mast cell stabilizers can lead to dissatisfaction, poor patient compliance and ultimately inadequate treatment of disease because of the lack of immediate or long-acting benefit, depending on the drug prescribed. What is needed for the treatment of allergic conjunctivitis is a drug that inhibits mast cell degranulation and additionally blocks mediator effects in the mucosa by direct competitive antagonism.

Olopatadine has been shown to be a more effective mast cell stabilizer in human conjunctival mast cells than cromolyn and nedocromil. It has also been shown to inhibit H1 receptor activity and to inhibit histamine-dependent cytokine production by conjunctival epithelial cells. This latter effect was more potent than would have been predicted by its histamine receptor antagonism alone, and this contributes to its enhanced action compared to old and new antihistamines.

The concept of dual therapy is not new if one considers combination products such as antihistamine/vasoconstrictor preparations. However, these drugs are not disease-altering, they need a high dosing frequency, and they contain alpha-adrenergic agonists of debatable safety.

An improvement to this concept is the combination of cromolyn with chlorpheniramine; however, again the safety profile of two drugs must be considered, and the choice of two first-generation molecules does not guarantee adequate efficacy, as the combination is no better than the individual ingredients alone.

The ideal dual therapy anti-allergic agent is found in one molecule, as is the case with ketotifen and olopatadine. An immediacy of relief is obtained with the histamine antagonism that relieves itching and redness, while consistent use ameliorates future events by preventing mast cell degranulation.

Olopatadine is currently available in the United States, Australia, Turkey, Latin America, and some Asian countries. It is approaching 12 million prescriptions worldwide.

Studies have shown that a single drop of the dual-acting olopatadine was more effective than a 2-week load (29 drops) of a conventional mast cell stabilizer, nedocromil. It was also shown to have the most comfortable formulation and to have favorable efficacy compared with other of its class.

Olopatadine has been approved for all the signs and symptoms of allergic conjunctivitis, not just itching, as is the case with other drugs of its class. It acts as a potent and selective H1 histamine antagonist that has been proven superior to single-action antihistamines approved for treatment of ocular allergy.

Coupled to this immediate activity is its mast cell stabilizing ability. Olopatadine is the first topical ophthalmic anti-allergy agent that has demonstrated preclinical and clinical effects on human conjunctival mast cells. In eyes of allergic patients, topical olopatadine blocked histamine release from mast cells and inhibited the release of chemotactic factors and expression of adhesion molecules.

This latter effect further demonstrates olopatadine’s mast cell stabilization, since mast cell mediators such as tumor necrosis factor stimulate the expression of adhesion molecules on the conjunctival surface. Adhesion molecules are important in the migration of leukoctyes into tissue. Adhesion molecules are found on the conjunctival epithelium and blood vessel endothelium, where they attract eosinophils, basophils, and neutrophils into the tissue. Furthermore, tear levels of eotaxin, important in the maturation of premature conjunctival mast cells and in eosinophil chemotaxis, are decreased after treatment with olopatadine. These results attests to the mast cell stabilizing activity of the drug.

Systemic therapy

Another issue that should be addressed is the question of systemic therapy for allergic conjunctivitis. In other local sites of allergic disease (eg, nose and skin), a systemic antihistamine is often effective, particularly for amelioration of itching. However, studies have shown that for the eye and ocular itching, systemic antihistamines are ineffective. This includes the newer molecules such as loratadine, which was shown to be inferior to topical therapy.

With these newer agents, and particularly with traditional antihistamines such as chlorpheniramine, ocular drying can be seen, with up to a 50% decrease in tear film breakup time and tear production, even in normal subjects. This is a serious side effect that can exacerbate the signs and symptoms of allergy and decrease the defensive barrier afforded by the tear film.

On the other hand, ophthalmic eye drops draining into the nasolacrimal duct might help to to alleviate nasal allergic symptoms of patients affected with multiple-site allergies, suggesting a role complementing topical nasal therapy. Thus more potent eyedrops may have a role in treating the entire rhinoconjunctivitis condition.

Identifying patients

Surprisingly, defining allergic patients from within the ophthalmologist’s practice is not always easy. Often patients seek the ophthalmologist for other complaints and not allergy, which they self-treat with systemic antihistamines, over-the-counter drops or herbal remedies, the latter particularly in Europe. The sporadic or seasonal nature of allergies also makes them difficult to treat if the patient does not seek help, even though the ocular component of these allergies can have a significant negative impact on quality of life.

To optimize care, practitioners should be proactive about identifying allergic subjects, even out of season, and prescribing in advance the best therapy available, to be filled when needed.

Itching should be remembered as an important symptom for diagnosing allergy. Itching is a bothersome symptom that will affect the patient’s quality of life.

Knowledge of the local pollen season, the patient’s history of atopy and his or her exposure to offending allergens can also help identify patients who might benefit from allergy treatment.

In conclusion, dual action anti-allergic agents, and particularly, olopatadine, are the new gold standard for the treatment of ocular allergy. Significant benefits are provided to the patient with immediate relief of symptoms coupled with a long-term mast cell stabilizing activity and an overall suppression of the immune response to seasonal allergies. Olopatadine has been shown to be the most comfortable, the longest acting, and the most effective anti-allergic agent of its class. With its imminent arrival here in Europe, improved control of ophthalmic signs and symptoms of allergic disease can be expected.

For Your Information:

• Andrea Leonardi, MD, can be reached at the Department of Ophthalmology, University of Padua, Padua, Italy.
• Murat Irkec, MD, can be reached at the department of ophthalmology, Hacettepe University Faculty of Medicine, Ankara Turkey.
• Mark B. Abelson, MD, can be reached at the Schepens Eye Research Institute, Harvard Medical School, Boston, and Ophthalmic Research Associates Inc., North Andover, MA U.S.A..

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