Eur J Ophthalmol 2010 ; 20 ( 5): 811-818

ORIGINAL ARTICLE

Treatment of allergic conjunctivitis: results of a 1-month, single-masked randomized study

Michele Figus1, Paolo Fogagnolo2, Stefano Lazzeri1, Federica Capizzi3, Mariachiara Romagnoli4, Annalisa Canovetti1, Michele Iester5, Antonio Ferreras6, Luca Rossetti3, Marco Nardi1
Department of Neurosciences, Ophthalmology, University of Pisa, Pisa - Italy G.B. Bietti FoundationIRCCS (Istituto di Ricovero e Cura a Carattere Scientico), Roma - Italy 3 Eye Clinic, San Paolo Hospital, University of Milano, Milano - Italy 4 Ophthalmic Surgery, AOUP, Pisa - Italy 5 Clinica Oculistica, Dept. of Neurological Sciences, Ophthalmology and Genetics, University of Genova, Genova - Italy 6 Miguel Servet University Hospital, University of Zaragoza, Zaragoza - Spain
1 2

PURpOSE. To compare the effects of topical antiallergic eyedrops in relieving the signs and symptoms of patients with allergic conjunctival pathology. METHODS. In this multicenter, single-masked, randomized study, 240 patients with signs and symptoms of allergic conjunctivitis were randomized to receive 1 of the following 8 treatments twice daily: cromolyn sodium/chlorpheniramine maleate, diclofenac, epinastine, uorometholone, ketotifen, levocabastine, naphazoline/antazoline, and olopatadine. Clinical signs and symptoms were evaluated by a masked operator using a 10-point scale at the moment of enrollment (day 0) and at weeks 1, 2, and 4. The percentage of patients achieving at least a small (at least 50% reduction of the total scale score) or a good (at least 75%) improvement of signs and symptoms was calculated at each visit. Tolerability was also evaluated as the duration of discomfort after instillation. RESULTS. All drugs gave some improvement in symptoms in more than 85% of cases. Epinastine and olopatadine obtained at least a good relief of symptoms in 37% and 33% of cases at week 1. At the end of the study, good improvement of symptoms was obtained in at least 70% of patients by epinastine, ketotifen, uorometholone, and olopatadine, whereas a 75% improvement for signs was obtained only by uorometholone and ketotifen. Naphazoline/antazoline induced higher discomfort compared to the other study treatments (p<0.0001). CONcLUSIONS. The efcacy of epinastine, ketotifen, and olopatadine in the treatment of allergic conjunctivitis was comparable to uorometholone. Naphazoline/antazoline had lower tolerability than the other study treatments. (Eur J Ophthalmol 2010; 20: 811-8) KEY WORDS. Allergic conjunctivitis, Antihistamines, Mast-cell stabilizers, Steroids, Vasoconstrictors
Accepted: February 24, 2010

INTRODUCTION
The term allergic conjunctivitis refers to a group of hypersensitivity disorders involving the eyelid, conjunctiva, and cornea, sharing a common pathogenesis. The allergic reaction is the response to the exposure to an environmental allergen binding an E immunoglobulin

on the surface of conjunctival mast cells, and causing an immediate release of histamine, which triggers the inammatory cascade with a release of other inammatory molecules (principally tryptase, prostaglandins, leukotrienes). Histamine is a major inammatory molecule: binding to H1 receptors on the surface of many cells, it is responsible for ocular itching, the main symptom of allergic conjunctivitis 811

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(1). Mast cell degranulation also induces activation of vascular endothelial cells and the expression of chemokines and adhesion molecules, which initiate the recruitment phase of inammatory cells in the conjunctival mucosa, which leads to the ocular late-phase reaction (2). The late phase corresponds to the persistent clinical inammation that characterizes allergic disease (3), and is characterized by mucosal inltration by eosinophils, neutrophils, basophils, and T-lymphocytes (4). In addition, conjunctival and corneal epithelial cells and broblasts may worsen inammation by expressing cytokines, chemokines, adhesion molecules, and factors that maintain local inammation and lead to tissue remodeling (5-7). Ocular allergy comprises 2 main groups: the rst includes the most frequent allergic conditions, i.e. seasonal (SAC) and perennial allergic conjunctivitis (PAC); the second includes the less frequent chronic severe forms, i.e. vernal keratoconjunctivitis (VRK) and atopic keratoconjunctivitis (AKC), both of which may be complicated by corneal involvement (8). Clinical presentation of ocular allergy can be isolated or, more commonly, associated with rhinitis (50%), asthma (35%), atopic dermatitis (2%), or skin rash or angioedema (1%) (2). The severity of the disease ranges from mild to severe. While ocular allergy is associated with a reduced perception of quality of life even in the mild forms, severe, untreated ocular allergy may potentially result in impairment of visual acuity (8). Many molecules are available for the topical treatment of allergic conjunctivitis. Corticosteroids are effective anti-inammatory and immunosuppressive drugs but they should be used with caution due to side effects such as cataract, glaucoma, and corneal infections (9). Nonsteroidal antiinammatory drugs have a limited use in allergic conjunctivitis, although research shows that cyclo-oxygenase inhibitors reduce conjunctival inammation after arachidonic acid application. Mast-cell stabilizers inhibit degranulation of mast cells and prevent the release of histamine, leukotrienes, and other inammatory molecules (10). This preventive action requires an early (normally 4 weeks before the beginning of the allergic period) and prolonged treatment. These molecules do not have any signicant side effects and, if properly used, they can spare steroid treatment also in the acute phase (11, 12). Local vasoconstrictors, such as sympathicomimetic amines, only have a symptomatic effect (13). Antihistamine eyedrops are also largely used for topical treatment of allergic conjunctivitis. Levocabas812

tine is an antihistaminic drug with good efcacy in reducing itching and hyperemia after conjunctival provocation tests and in reducing symptoms in allergic inammation (14). Ketotifen is a non-competitive, relatively selective antagonist of H1 histamine receptor. Its action includes inhibition of inammatory-mediator release from mast cells, basophils, and eosinophils; modulation of chemotaxis and degranulation of eosinophils; inhibition of platelet-activating factor and endothelial synthesis and expression of cellular adhesion molecules (15). Olopatadine is a strong inhibitor of mast cell degranulation and a selective histamine H1 receptor antagonist, to manage the itching, redness, chemosis, tearing, and lid swelling of the ocular allergic reaction (16). Epinastine is a molecule with high afnity for H1 receptors but it has also afnity for the H2, 1, 2, and 5 HT2 receptors (17). It is also endowed with a stabilizing action on mast cells, neutrophils, and eosinophils, preventing inammatory molecule release and oxygen radical production (18). Although many clinical trials previously compared the effects of few antiallergic drugs, a study addressing the efcacy and tolerability of all available antiallergic treatments is needed. Thus, the purpose of our study was to compare the short-term response of the commercially available agents for the treatment of allergic conjunctival pathology.

MATERIALS AND METHODS

This study was conducted from April to September 2006 in 2 Eye Clinics: Santa Chiara Hospital, Pisa, Italy, and San Paolo Hospital, Milan, Italy. It adhered to the Declaration of Helsinki and to the laws for data protection. Informed consent was obtained from all participants. All patients referred to the centers with signs and symptoms of allergic conjunctivitis were informed about the aims of the study and invited to participate. Inclusion criteria were 1) age > 18 years; 2) active allergic conjunctivitis; 3) positive history of allergic conjunctivitis since at least an allergic season; and 4) willingness to participate in the study. Exclusion criteria were 1) concomitant, not allergic ocular pathologies; 2) use of antiallergic treatment (topical or systemic) during the week before enrollment; 3) known hypersensitivity to components of study drugs, including benzalkonium chloride; 4) condition of pregnancy or lactating for women; and 5) unwillingness to stop contact lens use for the study period. A total of 247 consecutive eligible patients were consid-

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ered for study participation; 7 patients did not agree to participate in the study owing to inability to adhere to the schedule visits. After baseline visit, 240 patients fullling inclusion and exclusion criteria were enrolled and randomized to one of the 8 study groups (30 patients for each group): cromolyn sodium 4%/chlorpheniramine maleate 0.2%, diclofenac 0.1%, epinastine hydrochloride 0.05%, uorometholone 0.2%, ketotifen fumarate 0.05%, levocabastine 0.05%, naphazoline 0.25/antazoline 5 mg/mL, and olopatadine hydrochloride 0.1%. During the study, each patient was followed by 2 operators: an unmasked data operator who explained the aims of the study to patients, collected informed consent, demographics, and symptoms scales, and took care of randomization and prescription of study treatments; and an ophthalmologist (clinical evaluator) performing all study visits and grading the signs of the disease, who was masked to study treatment and patient demographics and symptoms. At the end of the baseline visit, the data operator communicated the results of the visit to a coordinating operator (one for every center) who randomized patients by means of a list of random numbers using a 2-block randomization (seasonal and nonseasonal allergy) to minimize the differences between groups. The randomization sequence was not available to any other operator. Industry involvement was absent in the design, conduct, and analysis of the study. Patients did not have to pay for any visit or medication (free samples provided by the companies were used). Patients were aware of the treatment they received. For drugs commercially available both as multidose and preservative free, only multidose formulation was used in order to avoid a possible intergroup variability caused by the absence of preservative. Patients were instructed to start treatment the day after baseline visit and to use study treatment twice daily (8 Am and 8 pm); intervals of 30 minutes were tolerated. Each patient was evaluated by the same ophthalmologist at day 0 (enrollment), week 1, week 2, and week 4. At each visit, ophthalmologists addressed the following clinical signs: eyelid edema, eyelid hyperemia, conjunctival chemosis, conjunctival hyperemia, follicular reaction, corneal dysepithelization, and corneal ulcers. A continuous numeric scale ranging from 0 to 10 was used (0, absent; 3, mild; 6, moderate; 10, severe) for each sign, and a global score (ranging from 0 to 70) was calculated. Patients were given an autoevaluation test regarding symptoms and discomfort at eyedrops instillation. The following

symptoms were evaluated: itching, burning, foreign body sensation, tearing, and photophobia. During the rst visit, patients were asked to score their symptoms using a continuous numeric scale from 0 to 10; a global score (ranging from 0 to 50) was calculated. If present, the duration of discomfort after eyedrops instillation was recorded using a scale from 0 (no discomfort) to 10 (a discomfort lasting for more than 30 minutes after instillation). At the end of each visit, all clinical information were collected by the data operator and sent to the coordinating operator; so, they were not available to the clinical operator.

Primary outcome
We calculated the percentage of patients achieving at least a small or good improvement of signs and symptoms (see below for denitions) at each visit and during the whole study period.

Sample size calculation

The sample size was calculated to detect an intergroup (30 subjects per group) difference or efcacy (arbitrarily dened as 50% reduction of symptoms) of 25%, assuming a standard deviation of 10%.

Statistical analysis
All statistical analyses were calculated using SPSS (version 15.0; SPSS Inc., Chicago, IL) statistical software. The Kolmogorov-Smirnov test was applied to the data, which showed a normal distribution. Mean score at the beginning and the end of the study was compared in each group by means of t test for paired data. At follow-up visits, the global scores for signs and symptoms were compared to baseline. A reduction of at least 50% of the global score was deemed a small improvement, whereas a reduction of 75% or more was deemed a good improvement. At each visit, the percentages of patients achieving at least a small or good improvement of signs and symptoms with each treatment were calculated and compared by means of Yates chi-square test corrected for continuity. Such percentages were plotted over time and area under the curve (AUC) of patients achieving at least a small or good improvement of both signs and symptoms was calculated to summarize the effect of the treatments. 813

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RESULTS
At baseline, the groups had homogenous demographics and distribution of the types of allergies (Tab. I). Mean scores for signs and symptoms were similar (p>0.05, t test for unpaired data); mean sign sum was 17.99.2 (range 14.6-20.4) and mean symptoms sum was 32.33.8 (range 29.2-34.1). The study was completed by 232/240 subjects (97%); 5 subjects interrupted the treatment due to burning, and 3 could not attend the visits for personal reasons. No systemic adverse events were reported. The discomfort at instillation of study eyedrops is reported in Table II. Naphazoline/antazoline induced signicantly higher discomfort compared to the other study treatments (4.31.7 vs 2.71.3 or less, p<0.0001); 2 of 8 patients who discontinued the treatment were using naphazoline/ antazoline. Ketotifen fumarate was the drug with the least discomfort (mean score 1.61.5, with discomfort less than few seconds in all subjects). All study treatments induced a statistically signicant reduction in mean scores for both signs and symptoms compared to baseline (p<0.0001, Tab. I). At the end of the study, the mean score for signs was similar in the study

groups (ranging from 0.31.3 to 1.32.1, p>0.5), whereas diclofenac and naphazoline/antazoline showed less efcacy in decreasing symptoms (4.02.8 and 3.32.3, respectively) compared to the other treatments (ranging from 0.70.9 to 2.32.3, p<0.05). All drugs induced at least a small improvement of both signs and symptoms in at least 85% of the study population (Tabs. III and IV). At week 1, the effect of diclofenac on symptoms was signicantly less than any other eyedrop (0.32 vs 0.54-0.89, p<0.008), whereas no signicant differences were found for symptoms at weeks 2 and 4 and for signs during the whole study period. At week 1, epinastine, ketotifen, uorometholone, and olopatadine induced at least a small improvement in symptoms in more than 70% of patients, while this percentage of improvements was obtained by all treatments for the signs. Epinastine, ketotifen, and levocabastine obtained the best AUC (0.80 or more) for at least small improvements of both signs and symptoms. When considering the percentages of patients achieving at least good improvements of symptoms and signs, less uniform patterns of efcacy were found (Tabs. V and VI). Relief of symptoms was obtained by epinastine and olopatadine in 37% and 33% of cases at week 1, and these

TABLE I -  DEMOGRAPHICS, DIAGNOSIS AT BASELINE, AND MEAN SCORES FOR SIGNS AND SYMPTOMS AT THE BEGINNING AND THE END OF THE STUDY

Cromolyn Diclofenac Epinastine Fluorometholone Ketotifen Levocabastine Naphazoline Olopatadine sodium 0.1% 0.05% 0.2% 0.05% 0.05% 0.25/antazoline 0.1% 4%/chlorpheniramine 5 mg/mL 0.2%

Patients No. patients No. of discontinuations Discontinuation due to burning Discontinuation for inability to attend visits Age, y M/F Diagnosis Vernal Seasonal Giant-papillary Atopic Perennial Mean score for signs at the beginning of the study SD Mean score for symptoms at the beginning of the study SD Mean score for signs at the end of the study SD Mean score for symptoms at the end of the study SD

30 0 0 0 3715 15/15 2 24 1 1 2 19.25.4 33.06.8 0.81.6 2.22.0

30 0 0 0 4213 15/15 2 24 2 2 0 15.54.2 34.16.9 1.32.1 4.02.8

30 1 1 0 3911 12/18 3 25 1 1 0 18.79.5 31.19.3 0.61.8 1.61.6

30 2 0 2 3716 15/15 1 24 3 1 1 19.68.2 32.79.1 0.31.3 0.70.9

30 1 1 0 3915 12/18 2 25 3 0 0 20.47.6 33.99.8 0.41.1 1.72.1

30 1 0 1 3615 13/17 2 22 3 0 3 17.96.6 32.17.9 0.81.6 2.32.3

30 2 2 0 3515 14/16 3 22 2 1 2 17.19.2 32.47.1 0.81.3 3.32.3

30 1 1 0 3720 15/15 2 22 3 1 2 14.64.0 29.25.6 0.51.6 1.81.3

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TABLE II - SIDE EFFECTS: MEAN SCORE OF DISCOMFORT AFTER INSTILLATION (MEAN STANDARD DEVIATION)
Cromolyn Diclofenac Epinastine Fluorometholone Ketotifen Levocabastine Naphazoline Olopatadine sodium 4%/ 0.1% hydrochloride 0.2% fumarate 0.05% 0.25/antazoline hydrochloride chlorpheniramine 0.05% 5 mg/mL 0.1% maleate 0.2% 2.21.6 2.71.3 2.01.5 1.81.4 1.61.5 2.51.5 4.31.7 1.91.9

TABLE III - PERCENTAGE OF PATIENTS SHOWING AT LEAST 50% IMPROVEMENT OF SYMPTOMS

Drugs 1 week Cromolyn sodium 4%/chlorpheniramine maleate 0.2% Diclofenac 0.1% Epinastine hydrochloride 0.05% Fluorometholone 0.2% Ketotifen fumarate 0.05% Levocabastine 0.05% Naphazoline 0.25/antazoline 5 mg/mL Olopatadine hydrochloride 0.1%
AUC = area under the curve.

Symptoms 2 weeks 0.87 0.74 0.96 0.93 1.00 1.00 1.00 0.88 4 weeks 0.87 1.00 0.96 0.93 1.00 1.00 1.00 0.88 AUC 0.70 0.61 0.81 0.80 0.84 0.80 0.76 0.74

0.61 0.32 0.85 0.89 0.84 0.70 0.54 0.79

TABLE IV - PERCENTAGE OF PATIENTS SHOWING AT LEAST 50% IMPROVEMENT OF SIGNS

Drugs 1 week Cromolyn sodium 4%/chlorpheniramine maleate 0.2% Diclofenac 0.1% Epinastine hydrochloride 0.05% Fluorometholone 0.2% Ketotifen fumarate 0.05% Levocabastine 0.05% Naphazoline 0.25/antazoline 5 mg/mL Olopatadine hydrochloride 0.1%
AUC = area under the curve.

Signs 2 weeks 1.00 0.84 0.96 0.86 0.97 0.97 0.96 0.92 4 weeks 1.00 1.00 0.96 0.86 0.97 0.97 1.00 0.92 AUC 0.85 0.75 0.83 0.74 0.81 0.81 0.80 0.80

0.91 0.74 0.93 0.82 0.84 0.83 0.75 0.92

TABLE V - PERCENTAGE OF PATIENTS SHOWING 75% OR MORE IMPROVEMENT OF SYMPTOMS

Drug 1 week Cromolyn sodium 4%/chlorpheniramine maleate 0.2% Diclofenac 0.1% Epinastine hydrochloride 0.05% Fluorometholone 0.2% Ketotifen fumarate 0.05% Levocabastine 0.05% Naphazoline 0.25/antazoline 5 mg/mL Olopatadine hydrochloride 0.1%
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Symptoms 2 weeks 0.30 0.26 0.63 0.75 0.65 0.40 0.33 0.54 4 weeks 0.61 0.26 0.78 0.82 0.87 0.67 0.54 0.79 AUC 0.28 0.18 0.52 0.53 0.52 0.32 0.27 0.48

0.04 0.05 0.37 0.18 0.26 0.03 0.04 0.33

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TABLE VII - PERCENTAGE OF PATIENTS SHOWING 75% OR MORE IMPROVEMENT OF SIGNS

Drug 1 week Cromolyn sodium 4%/chlorpheniramine maleate 0.2% Diclofenac 0.1% Epinastine hydrochloride 0.05% Fluorometholone 0.2% Ketotifen fumarate 0.05% Levocabastine 0.05% Naphazoline 0.25/antazoline 5 mg/mL Olopatadine hydrochloride 0.1%
AUC = area under the curve.

Signs 2 weeks 0.22 0.16 0.15 0.68 0.48 0.27 0.13 0.42 4 weeks 0.43 0.32 0.59 0.86 0.84 0.53 0.50 0.50 AUC 0.19 0.14 0.21 0.51 0.41 0.24 0.17 0.32

0.00 0.00 0.04 0.18 0.06 0.03 0.00 0.17

percentages were signicantly higher than those obtained by cromolyn, diclofenac, levocabastine, and naphazoline/ antazoline (p<0.02); at week 4, the improvement induced by diclofenac (0.26) was signicantly less than the other treatments (0.61-0.87, p<0.03), apart from naphazoline/ antazoline (0.54). For signs, no statistically signicant differences were found at week 1, whereas uorometholone and ketotifen achieved better results at weeks 2 and 4 (0.68 and 0.86, respectively, p<0.05). At the end of the study, good improvement of symptoms was obtained in at least 70% of patients by epinastine, ketotifen, uorometholone, and olopatadine, whereas a 70% improvement in signs was obtained only by uorometholone and ketotifen. Globally, an AUC >0.30 for both symptoms and signs was achieved by uorometholone, ketotifen, and olopatadine; only uorometholone obtained AUC>0.50.

DISCUSSION
This is a clinic prospective study comparing commercially available treatments for ocular allergy. All treatments were effective and induced at least a small improvement in symptoms and signs after 1-month followup. On the basis of our analyses, epinastine, uorometholone, ketotifen, and olopatadine were the treatments that provided the best relief of symptoms; uorometholone and ketotifen obtained the best results for signs. Overall, diclofenac showed less efcacy than the other molecules. Our results conrm the results of previously published meta-analyses. Limited evidence suggests that antihistamines might have a faster therapeutic effect compared to 816

mast cell stabilizers (19). All the currently available topical drugs are effective in decreasing the acute signs and symptoms of allergic conjunctivitis (20, 21). Our data on tolerability indicate that naphazoline/antazoline is less tolerated than the other treatments, because it burned for more than 20 minutes after instillation in about 70% of patients. Two of 8 patients who discontinued the study were under treatment with naphazoline/antazoline. All the other treatments gave negligible discomfort at instillation, in particular ketotifen, uorometholone, and olopatadine, which induced discomfort lasting for a few seconds in all subjects. Owing to the multicenter design, our study recruited an adequate number of patients with active ocular allergy; our results may reect the real clinical efcacy of the treatments compared to other studies which used the conjunctival provocation test (22, 23). Also, owing to the 2-block randomization, all groups had similar characteristics for demographics and clinical ndings. The absence of a control group is a potential limitation of the study. As a simple dilution of allergens may decrease signs and symptoms (24), using lubricating eyedrops as one of the investigational drugs might have been an option. However, our intention was to compare clinically available antiallergy drugs, which we clearly showed to differ in discomfort as well as in clinical effectiveness. Simple observation could be advisable, but we did not consider this option for ethical reasons. In conclusion, this study shows the efcacy of drugs acting with a double mechanism (both as competitive antagonists of histamine receptors and as mast-cell stabilizers), such as ketotifen, olopatadine, and epinastine. In particular, they

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obtained very similar results to uorometholone at each visit, without the well-known side effects of corticosteroids. We cannot recommend the use of corticosteroids in the acute phase because, based on our data, this treatment did not guarantee a signicant advantage during the rst 1-2 weeks from presentation when compared to the above mentioned drugs. The topical ophthalmic solutions provided effective management of allergic ocular signs and symptoms. Treatment preferences should therefore be based on convenience of use (with reduced frequency of instillation for some preparations), patient preference, costs, and side effects.
The authors report no proprietary interest or nancial support.

Address for correspondence: Michele Figus, MD, PhD Via B. Buozzi, 19 55045 Pietrasanta, Lucca Italy gus@ocupisa.it

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