Allergy Update
Recent studies offer new information about five frequently prescribed ocular medications.
INTRODUCTION BY GREGG J. BERDY, M.D., F.A.C.S.

This is an exciting time for both ocular allergy sufferers and ophthalmologists. In the past, most drugs used to treat allergic conjunctivitis were uncomfortable -- even painful -- to use. In addition, they had to be instilled at least four times a day to maintain control of symptoms.

The following article summarizes five recently completed clinical studies that evaluate Alocril, Alrex, Alamast, Zaditor and Patanol. Some have already been published; others have been submitted for publication. These studies demonstrate that each of these agents is safe and effective for the treatment of allergic conjunctivitis. In addition, some of the studies show that the medications are safe when used for an extended period, that they may provide unexpected benefits for the corneal and conjunctival surface, and that they may play a role in alleviating the symptoms of allergic rhinitis in addition to providing ocular relief.

What's next? Treatment of allergic conjunctivitis is moving toward immuno-modulation of the host response to disease. Therapy may target not only the mast cell and its products, but also interleukines, cytokines, T-helper lymphocytes and anti-IgE.

These reviews offer a glimpse into what is to come. 

Nedocromil Sodium: Fewer Doses Just as Effective

Numerous studies have shown that nedocromil sodium 2% (Alocril) used twice daily is an effective treatment for symptoms of seasonal allergic conjunctivitis. However, Michael Alexander, FRCPC, et al., working in Ontario, Canada, hypothesized that because nedocromil sodium inhibits late phases of the allergic response, which prevents the characteristic heightened sensitivity to allergens normally seen in this phase, it might not be necessary to continue BID dosing to maintain the effectiveness of the treatment.

To determine whether the dose could be reduced to once daily -- following an initial period of BID dosing intended to bring acute symptoms under control -- Alexander et al. conducted an 8-week, open-label, prospective study at a medical center in Ontario, Canada.

Thirty patients suffering from ocular itching, as a result of grass pollen allergy, instilled nedocromil sodium 2% BID (morning and evening) for 5 days, and then once a day for 4 to 8 weeks. Doctors evaluated subject symptoms at the end of the 5-day period and every 2 weeks thereafter until grass pollen season ended.

Patients kept a daily record of their symptoms, and were allowed to use rescue medications (nedocromil or oral antihistamines only) if necessary for additional relief.

Results were as follows:

Change in symptoms. After the initial period, dropping to once-daily dosing caused no statistically significant change in patients' self-reported symptoms. Physicians conducting clinical exams agreed.

Symptom control. After the switch to once-daily dosing, doctors rated the symptom control as moderate or full for 100% of patients; 93% of patient self-ratings agreed.

Willingness to continue. 83% of subjects were willing to continue the same regimen during the next allergy season.

Use of rescue medications. The data showed:

• Overall, use of rescue medications (nedocromil or antihistamine capsules) did not change enough during the study to achieve statistical significance.
• Ten of the 30 participants used no rescue medication. Three subjects used less rescue medication during the second (once-daily) phase of the study; 8 subjects used more.
• Only five out of 30 subjects increased their use of rescue medications by more than two doses per week after switching to once-daily dosing of the primary medication.

The data clearly support the contention that once acute symptoms have been brought under control, once-a-day use of nedocromil sodium is sufficient to maintain symptom relief.

(The complete study can be found in Advances in Therapy, Vol. 19, No. 1.)

Loteprednol Etabonate: Steroid Safety

According to Charles B. Slonim, M.D., clinical professor of ophthalmology at the University of South Florida College of Medicine in Tampa, a retrospective, multicenter, long-term safety study of loteprednol etabonate 0.2% (Alrex) was recently completed. This is the first study of its kind to evaluate the long-term safety of Alrex (an ester corticosteroid) in multiple clinics across the country. Alrex is the only ophthalmic steroid approved by the Food and Drug Administration (FDA) for the temporary relief of the signs and symptoms of seasonal allergic conjunctivitis.

The study looked at the safety of the drug when used chronically over an extended period of time for the treatment of both seasonal and perennial allergic conjunctivitis in a clinical setting.

Preliminary results from this study showed no evidence of clinically significant IOP elevations, cataract formations or exacerbations of any infectious disease with long-term use of loteprednol etabonate 0.2%.

Findings and results from this study have been submitted for publication.

Pemirolast Potassium: Phase III Trial Results

In an effort to determine the safety and efficacy of pemirolast potassium (Alamast) in preventing symptoms of allergic conjunctivitis, Mark B. Abelson et al. conducted a pooled analysis of data from two prospective, randomized, double-masked, placebo-controlled, multicenter, phase III clinical trials. Both studies tested the effectiveness of pemirolast under two different conditions: during environmental exposure, and when instilled 20 minutes before a conjunctival allergen challenge (CAC).

The studies were conducted simultaneously during ragweed season (July through November) in seven different U.S. centers. After an initial CAC to determine the quantity of ragweed antigen necessary to provoke a positive bilateral reaction, qualified subjects received either pemirolast potassium 0.1% or placebo. Beginning 1 to 2 weeks before the historical start of ragweed season, subjects instilled 1 to 2 drops of medication (or placebo) in each eye QID, and this was continued until 5 to 30 days after the first killing frost, signaling the end of ragweed season.

Subjects recorded their daily use of medication in a diary, along with daily evaluations of ocular itching and redness. Subjects were also examined by doctors at least four times during this part of the trials. Finally, at the end of allergy season, subjects were subjected to another CAC, 20 minutes after receiving a dose of their medication (or placebo).

The pooled analysis found:

Ocular itching. Pemirolast was significantly better at reducing itching than placebo during allergy season:

• For every 7-day period, subjects receiving pemirolast recorded more days with no ocular itching. The difference was statistically significant in 10 of 16 periods.
• Analyzed by 14-day periods, subjects again recorded more days without itching in every period, and the difference was significant in 7 of 8 periods.
• Subjects receiving pemirolast reported more days without itching at bedtime in 88% of evaluated periods (analyzed in either 7- or 14-day periods). However this difference was only statistically significant during a few of these periods.

Redness at bedtime. No significant difference was found in number of days with no ocular redness at bedtime.

Response to CAC. Subjects were checked 3, 10 and 20 minutes after the final CAC:

• pemirolast reduced ocular itching more effectively than placebo at all time points, although the difference was only significant at the first checkpoint.
• The worst itching during the 10 minutes following the CAC was scored significantly lower by subjects receiving pemirolast.
• No significant differences between the two groups were noted for ciliary, episcleral or conjunctival injection, or for chemosis, lid swelling or tearing.

Safety. Adverse ocular events during the trials were infrequent and mild, and were similar in subjects receiving pemirolast and placebo.

Comfort. Ninety-seven percent of subjects receiving pemirolast reported no burning, stinging or ocular discomfort. This may account for the high compliance rate displayed by the subjects.

The authors note that the effectiveness of pemirolast appeared to increase as ragweed season progressed; nevertheless, a statistically significant superiority over placebo was noted even in the first week after ragweed season began.

(The complete study can be found in the Journal of Ocular Pharmacology and Therapeutics, Vol. 18, No. 5.)

Ketotifen Fumarate: Treating Nasal Symptoms

Jerome Crampton, M.D., associate clinical professor of ophthalmology at Boston University, recently conducted a study to determine whether ketotifen fumarate (Zaditor), which has previously demonstrated its ability to prevent ocular itching in the conjunctival allergen challenge model of induced allergic conjunctivitis, could aid in the treatment of acute nasal allergy symptoms.

Dr. Crampton observed that significant nasal signs and symptoms are induced following conjunctival allergic challenge, as the allergen and allergic mediators drain from the eye into the inferior turbinate of the nose. He reasoned that because the early stages of nasal allergic reaction are pharmacologically similar to the early stages of allergic reaction in ocular tissue, drainage of ketotifen into the nose could reduce nasal symptoms as well.

To test this theory, Dr. Crampton enrolled 32 subjects in a randomized, double-blind, single-center study. Qualified subjects (those demonstrating a positive reaction in prior testing) underwent a bilateral ocular conjunctival challenge with allergens. Fifteen minutes before instilling the allergens, 19 subjects received ketotifen fumarate bilaterally; 13 received placebo (HypoTears). Subjects evaluated their nasal allergic symptoms using standardized scales at 10, 20 and 30 minutes after the allergens were instilled.

The results supported Dr. Crampton's supposition; subjects who had received ketotifen reported significantly fewer baseline-corrected nasal symptoms than subjects receiving placebo. This was true at all three time points following instillation of the allergens.

Dr. Crampton notes that this can be attributed both to the pharmacological action of ketotifen fumarate, and to its drainage into the nasal passages.

Olopatadine Hydrochloride: Treating Epithelial and Stromal Disease

Most studies of olopatadine hydrochloride 0.1% (Patanol) -- one of a new class of allergy relief drugs combining antihistamine and mast-cell-stabilizing actions -- have focused on the drug's effectiveness at reducing allergy symptoms, or effectiveness compared with other ocular allergy medications. To move in a different direction, Murat Dogru, M.D., Ph.D., et al., in Bursa, Turkey, conducted a study to determine two things. First, they sought to quantify the disruptions in tear function and the ocular surface caused by allergic conjunctivitis, as demonstrated by corneal sensitivity, the Schirmer test of tear quality, tear film breakup time (BUT) and conjunctival impression cytology. Second, they wanted to determine the effect topical olopatadine has on these variables.

They conducted a single-center, prospective, open-label study involving 42 eyes of 21 patients suffering from allergic conjunctivitis, and a control group of 70 eyes of 35 healthy subjects. (No vehicle-treated or untreated control group was possible because no subject consented to allow this option.) Patients received one drop of topical olopatadine hydrochloride BID for 3 weeks. Tear film and ocular surface were assessed before treatment, 1 week after starting treatment, and at the end of treatment. Control patients received the same exams, but no treatment.

Significant differences in tear function and ocular surface characteristics were found between healthy controls and allergy sufferers:

Corneal sensitivity. Allergy sufferers had lower mean corneal sensitivity than controls (42.5 mm vs. 57.5 mm), as measured using a Cochet-Bonnet aesthesiometer. (Below 50 mm was considered low sensitivity.)

Tear film breakup time. On average, allergy patients had faster tear film breakup time (8.1 seconds) than controls (14.9 seconds).

Fluorescein staining score. Subjects with allergic conjunctivitis scored significantly higher on this test: 1.5, vs. 0.5 for healthy patients.

Schirmer test. Patients with allergic conjunctivitis had drier eyes, averaging 17.9 on the Schirmer test, vs. 20.8 for controls. However, this difference was not statistically significant.

Impression cytology. Allergy patients had a mean squamous metaplasia grade of 2.5, compared with 0.5 for controls. Mean goblet cell density was significantly lower in allergy patients: 545 cells/mm², vs. 1818 cells/mm².

Differences noted in allergic patients as a result of treatment with olopatadine included:

Corneal sensitivity. Before treatment, 47.6% of allergic subjects had low corneal sensitivity; after treatment only 11.9% did. Mean pretreatment score was 42.5; after treatment the mean score was 55.0.

Tear film breakup time. Allergy patients' average BUT rose from 8.1 seconds to 14.0 seconds by the end of the 3 weeks of treatment. The data showed, however, that little change occurred in the first week; BUT was nearly the same after only 1 week of treatment.

Fluorescein staining score. Allergy patients showed a steady decrease in this score during treatment. Before treatment, 64% scored below 1.0; only 14.3% did after treatment. The mean score of 1.5 before treatment dropped to 1.0 after 1 week of treatment, and dropped to 0.5 -- the same as control subjects -- by the end of the third week.

Schirmer test. No significant change in the allergy patients' Schirmer test scores was noted as a result of treatment with olopatadine.

Impression cytology. Mean squamous metaplasia grade among tested allergy patients dropped from 2.5 to 1.0 by the end of the study. Goblet cell density rose from 545 cell/mm² to 1090 cells/mm².

Treatment with olopatadine clearly helped alleviate most of the studied symptoms.

Authors of the study believe their findings suggest that allergic conjunctivitis may be associated with corneal epithelial/stromal disease, and that treatment should be directed at both the epithelium and the tear film. Also, the authors note that some patients still had symptoms at the end of treatment, suggesting the need for possible alternative treatments aimed at treating conjunctival and corneal epithelial disease.

(The complete study can be found in Clinical Therapeutics, Vol. 24, No. 8.)