comparison of the efficacy of combined fluticasone ... propionate and olopatadine versus combined...

CLINICAL THERAPEUTICS®/VOL. 24, NO. 7, 2002

Comparison of the Efficacy of Combined Fluticasone Propionate and Olopatadine Versus Combined Fluticasone Propionate and Fexofenadine for the Treatment of Allergic Rhinoconjunctivitis Induced by Conjunctival Allergen Challenge

Bob Q. Lanier, MD, t Mark B. Abelson, MD, e William E. Berger, AID, MBA, 3'4 David B. Granet, MD, FACS, s Peter A. D'Arienzo, MD, FACS, 6 Dennis L. Spangler, AID, 7 and Martin K. Kiigi, MD s tFort Worth Allergy Asthma Association, Fort Worth, Texas, 2Harvard Medical School and Schepens Eve Research Institute, Boston, Massachusetts, 3Department of Pediatrics, Division of Allergy and Immunology, University of California, Irvine, 4Southern California Research, Mission Viejo, 5Departments of Ophthalmology and Pediatrics, University of California, San Diego, 6Catholic Medical Center of Brooklyn, New York, 7Atlanta Allergy and Asthma Clinic, Atlanta, Georgia, and SDermatology/Allergy FMH, Zurich, Switzerland

ABSTRACT

Background: One approach to treating allergic rhinoconjunctivitis is the concomitant use of an intranasal spray such as fluticasone propionate to alleviate nasal symptoms and a topical or systemic agent to relieve ocular symptoms. It has not yet been determined whether a topical or systemic agent is more effective for the latter purpose.

Objective: This study compared the efficacy of combined use of fluticasone and olopatadine with combined use of fluticasone and fexofenadine in the treatment of the signs and symptoms of allergic rhinoconjunctivitis.

Methods: This 2-site, randomized, double-masked, placebo-controlled, parallel-group study employed the conjunctival allergen challenge (CAC) model, a standardized method of inducing ocular and nasal signs and symptoms of allergic rhinoconjunctivitis. At visit 1, subjects underwent CAC to determine the dose of allergen required to elicit a positive reaction. The allergen dose was confirmed at visit 2, and, according to a randomization schedule, subjects were dispensed fluticasone, olopatadine, and placebo pill; fluticasone, fexofenadine, and tear substitute; or placebo nasal spray, placebo pill, and tear substitute. CAC took place at visit 3, after patients had used the assigned medications for 2 weeks. Study medication was instilled 2 hours before CAC, after which allergic signs and symptoms were graded on standardized scales. The primary efficacy variables were ocular itching, ocular redness, and overall nasal symptoms.

Accepted for publication May 7, 2002. Printed in the USA. Reproduction in whole or part is not permitted.

0149-2918/02/Sl9.00 1161

CLINICAL THERAPEUTICS ®

Results: Eighty subjects completed the study: 30 received fluticasone and olopatadine, 30 fluticasone and fexofenadine, and 20 placebo. Women constituted 63.8% of the study population and men 36.3%; 91.3% were white, 3.8% black, 2.5% Hispanic, 1.3% Asian, and 1.3% other. Concomitant use of fluticasone and olopatadine produced significantly greater improvements in ocular itching at 3 and 7 minutes after CAC compared with fluticasone and fexofenadine (P < 0.05). There were no significant differences in redness scores between groups; however, concomitant use of fluticasone and olopatadine produced significantly greater improvements in redness at 2 time points in each of the 3 vessel beds (ciliary, conjunctival, and episcleral) compared with placebo, and fluticasone and fexofenadine produced significantly greater improvement in redness at 1 time point in 1 vessel bed compared with placebo (both com- parisons, P < 0.05). The 2 treatments had similar effects on total nasal symptom efficacy scores.

Conclusions: In this study, concomitant use of the topical agents fluticasone and olopatadine was more effective than concomitant use of fluticasone plus fexofenadine for overall treatment of the signs and symptoms of induced allergic rhinoconjunctivitis.

Key words: fluticasone, olopatadine, fexofenadine, conjunctival allergen challenge, ocular allergy. (Clin Ther. 2002;24: 1161-1174)

INTRODUCTION

More than one third of Americans experi- ence allergic rhinoconjunctivitis after ex- posure to specific allergens or pollensJ The allergen first binds allergen-specific

immunoglobulin E (IgE) on the surface of conjunctival or nasal mast cells, which ini- tiates the allergic cascade. The allergen- bound IgE then cross-links, leading to mast-cell degranulation and release of allergic and inflammatory mediators. Among these is histamine, the primary mediator of the ocular itching and hyper- emia associated with an early-phase allergic reaction. 2

One approach to relieving the nasal signs and symptoms of allergic rhinoconjunctivitis is combined use of an intranasal spray and a systemic antihistamine. A novel alternative is concomitant use of a topical ophthalmic preparation and a nasal spray, which has the advantages of avoid- ing the drying effects of systemic antihistamines 3 and delivering direct site-specific treatment for both ocular and nasal signs and symptoms. The relative efficacy of these 2 approaches is not well documented.

Some commonly used medications for allergic rhinoconjunctivitis were included in the present study. Fluticasone propionate* nasal spray is a corticosteroid approved for the treatment of nasal symptoms associated with perennial or seasonal allergic and nonallergic rhinitis. The exact mechanism of its anti-inflammatory action is unknown, but intranasal steroids have been shown to moderate the increase in serum levels of antigen-specific IgE antibodies during allergy season, 4 and fluticasone has been shown to reduce the num- ber of nasal mast cells in nasal provocation tests. 5 Fexofenadine hydrochloride] a second-generation antihistamine, is a non- sedating 6,7 selective antagonist of the his-

*Trademark: Flonase ® (GlaxoSmithKline, Research Triangle Park, North Carolina).

tTrademark: Allegra ® (Aventis Pharmaceuticals, Inc, Bridgewater, New Jersey).

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B.Q. LANIER ET AL.

tamine type 1 (Hi) receptor that has been approved for the relief of symptoms associated with seasonal allergic rhinitis. Olopatadine hydrochloride,* a topical ophthalmic solution, is a combination mast- cell stabilizer and antihistamine approved for treatment of the signs and symptoms of allergic conjunctivitis; it has demonstrated statistically significant efficacy in studies using the conjunctival allergen challenge (CAC) model (P < 0.05). 8.9

The objective of this study was to evaluate the relative efficacy of combined fluticasone and olopatadine, combined fluticasone and fexofenadine, and placebo in the treatment of the signs and symptoms of allergic rhinoconjunctivitis induced by CAC.

SUBJECTS AND METHODS

This was a 2-site, randomized, double- masked, placebo-controlled, parallel- group CAC study. Potential subjects were identified from an allergy patient data- base and recruited through telephone con- tact. The protocol was approved by the IntegReview Institutional Review Board, Austin, Texas. Written informed consent was obtained from all subjects, who received prorated reimbursement.

The study consisted of 3 visits per patient (Figure 1). CAC, which has been accepted by the US Food and Drug Ad- ministration as a clinically relevant model for evaluating the efficacy of antiallergic agents, was performed according to previously described methods, l° This model uses 25 txL of specific allergens (cat hair and/or dander, ragweed pollen, tree pollen, or grass pollen) to

*Trademark: Patanol ~'~ (Alcon Laboratories. Inc, Fort Worth, Texas).

initiate a reproducible inflammatory response that produces the ocular and nasal signs and symptoms of allergic rhinoconjunctivitis. The choice of allergen for each patient is based on the results of prior skin testing. Under these reproducible conditions, antiallergic agents can be evaluated for efficacy (change in mean scores between visit 2 and visit 3) using standardized scales.

Visit 1

At visit 1, demographic data, medication and medical histories, and visual acuity (Early Treatment of Diabetic Retinopa- thy Study lj methodology) were recorded. Subjects participating in this study may have participated in previous ocular allergen challenge studies, but those who had participated in a study evaluating nasal spray or involving evaluation of nasal symptoms were excluded. The presence of inclusion or exclusion criteria was re- viewed at the beginning and end of each study visit, and any subject found to be unqualified was discontinued. Subjects were excluded if they were aged < 18 years; if they were taking antihistamines, corti- costeroids, mast-cell stabilizers, deconges- tants, topical ophthalmic preparations, or nasal sprays; or if they had illnesses or ocular conditions or infections that might, in the investigators' opinion, interfere with study assessments. In addition, use of any investigational drug or device within 30 days, any known allergy or contraindica- tion to study medications, or any ocular and/or nasal surgery within 3 months of enrollment were exclusionary factors. A urine pregnancy test was given to all women of childbearing potential.

A slit-lamp examination was performed to exclude subjects having any disallowed

1163


Visit 1 (Day 0): Antigen

determination and titration

(N = 123)

Visit 2 (Day 7): Antigen

confirmation (n = 99)

Eye drop: Olopatadine Nasal spray: Fluticasone - - Systemic: Placebo

Eye drop: Placebo Nasal spray: Fluticasone Systemic: Fexofenadine

Eye drop: Placebo Nasal spray: Placebo Systemic: Placebo

All regimens 14 d BID

1 dose of each

) '4

1 dose of each

1 dose of each

2 h before CAC

Visit 3 (Day 21):

Evaluation of itching,

redness, nasal symptoms

(n = 80)

I Figure 1. Study design. CAC = conjunctival allergen challenge.

ocular conditions or exhibiting any signs of active allergic rhinoconjunctivitis (presence of itching in either eye, redness score >1 in any vessel bed, or nasal symptom score >3). The scales used to assess ocular itching, ocular redness, and nasal symptoms are described in the following section.

CAC was then performed by bilateral instillation of cat hair and/or dander, ragweed pollen, tree pollen, or grass pollen in buffered saline solution. Dosing was initiated at the lowest available concentration of the specific allergen. If, after 10 minutes, the patient's allergic reaction was insufficient, the allergen concentration was increased every 10 minutes until a qualifying reaction was obtained (ocular itching score :-2, redness score >2 in any vessel bed, and nasal symptom score 55).

Ocular itching was graded by subjects on a scale from 0 (no itching) to 4 (severe itching), and ocular redness in each vessel bed (ciliary, conjunctival, and episcleral) was graded by the investigator on a scale from 0 (no redness) to 4 (extremely severe redness). Nasal symptoms were graded by subjects over 10-minute periods using standardized scales for 4 categories:

sneezing (0 = <2 sneezes; 0.5 = 2 sneezes; 1.0 = 3 4 sneezes; 1.5 = 5 sneezes; 2.0 = >5 sneezes); rhinorrhea (0 --- no symptoms; 1 = either runny nose or postnasal drip; 3 = both runny nose and postnasal drip); pruritus (0 = absent; 1 = present in nose or ear/palate; 2 = present in both nose and ear/palate); and congestion (0 = breathing freely; 1 = breathing without difficulty; 2 = one nostril blocked; 3 = both nostrils blocked). The nasal scales and use of their summed scores as exclusion criteria and for data analysis were adapted from previous nasal allergen challenge studies. 12,13 Subjects who did not develop sufficient ocular itching, redness, or nasal symptoms to indicate active allergic rhinoconjunctivitis were excluded from the study. If needed, 1 drop of a cur- rently marketed topical antiallergic medication (naphazoline*t) was administered at the end of the visit to relieve immediate discomfort due to allergen challenge.

*Trademark: Vasocon ® (Novartis Ophthalmics, Du- luth, Georgia).

'~Trademark: Visine®-A '~ (Pfizer Inc, Morris Plains, New Jersey).

1164

B.Q. LANIER ET AL.

Visit 2

At visit 2, patients' medical and medication histories were updated, their visual acuity was measured as at visit 1, and slit-lamp examination was repeated. One drop of the allergen solution that had elicited a positive reaction at visit 1 was instilled bilaterally. Subjects were asked to evaluate ocular itching at 3, 7, and 10 minutes after challenge. Investigators evaluated redness in each of the 3 vessel beds at 10, 15, and 20 minutes after challenge. Subjects evaluated nasal symptoms at 10, 20, and 30 minutes after challenge.

Subjects who continued to meet the inclusion criteria at visit 2 were assigned to treatment groups according to a randomization schedule generated before com- mencement of the study by qualified staff uninvolved in the conduct or monitoring of the study. Subjects were randomized to treatment in a 3:3:2 ratio (fluticasone + olopatadine:fluticasone + fexofenadine: placebo), and sequential numbers were assigned to all qualified subjects before separation by site.

The treatment groups consisted of fluticasone, olopatadine, and placebo pill; fluticasone, fexofenadine, and tear substitute; or placebo nasal spray, placebo pill, and tear substitute. The active preparations were fluticasone propionate 50 Ixg/spray, olopatadine hydrochloride 0.1% ophthalmic solution, and fexofenadine hydrochloride 60 mg capsule. The placebo preparations were sugar pills, tear-substitute eye drops,* and saline nasal spray, respectively.

Patients were instructed to administer all study medications twice daily, in the morning (within 2 hours of waking) and

*Trademark: Tears Naturale ® (Alcon Laboratories, lnc, Fort Worth, Texas).

in the evening (8-12 hours after the morning dose), beginning on the morning after visit 2 and continuing for 2 weeks until the night before visit 3. Medications were to be administered as 1 drop in each eye, 1 spray in each nostril, and 1 pill each morning and evening. Within each medication type, all eye drops, nasal sprays, and pills were of identical appearance.

Visit 3

At visit 3, medical and medication histories were updated, visual acuity measured, and slit-lamp examination repeated. Study personnel administered the eye drops and observed patients' administration of nasal spray and pills. The medications were taken from the supply dispensed to each patient at visit 2. Two hours after administration of all medications, 1 drop of the allergen solution that had elicited a positive response at visit 1 was instilled bilaterally. Ocular itching, redness, and nasal symptoms were evaluated at the same time points as at visit 2. If needed, naphazoline was administered topically to relieve any immediate discomfort caused by the allergic reaction.

Statistical Analysis

Data from all subjects who completed the study were included in the efficacy analyses. Mean baseline-corrected scores for ocular itching, ocular redness in each vessel bed, and total nasal symptoms were calculated at visits 2 and 3, and the change from visit 2 to visit 3 was compared between treatments. Greater magnitude of change between visit 2 (untreated) and visit 3 CAC (treated) would indicate greater medication efficacy. Two-sided Wilcoxon rank sum tests were used to

1165

CLINICAL THERAPEUTICS ~

determine P values, and statistical signif- icance was set at P < 0.05.

RESULTS

Eighty subjects completed the study, of whom 30 received fluticasone, olopatadine, and placebo pill; 30 received fluticasone, fexofenadine, and tear substitute; and 20 received placebo nasal spray, placebo pill, and tear substitute. Forty- three subjects did not complete the study, either because of failure to meet the inclusion criteria at visit 1 or visit 2 (33) or because of limited allowed enrollment (80 patients were required to complete the randomization scheme) at visit 2 (10). The demographic characteristics of the study population are summarized in the table.

The combination of fluticasone and olopatadine produced significantly greater

improvement in ocular itching at 3 and 7 minutes after challenge compared with the combination of fluticasone and fexofenadine (P < 0.05) (Figure 2). Both treatments were significantly more effective than placebo at 3, 7, and 10 minutes after challenge (P < 0.05).

With respect to redness in the ciliary (Figure 3), conjunctival (Figure 4), and episcleral (Figure 5) vessel beds, there were no significant differences between combined fluticasone and olopatadine and combined fluticasone and fexofenadine at 10, 15, or 20 minutes after challenge. Fluticasone and olopatadine produced significantly greater improvements in redness at 10 and 15 minutes after challenge in all 3 vessel beds compared with placebo (all, P < 0.05); fluticasone and fexofenadine produced significantly greater improvement at 10 minutes after challenge

Table. Demographic characteristics.

Characteristic Fluticasone + Olopatadine Fluticasone + Fexofenadine Placebo

No. (%) of patients 30 (37.5) 30 (37.5) 20 (25.0)

Mean age, y 40.9 43.8 39.5

Sex, no. (%)* Male 11 (36.7) 7 (23.3) 11 (55.0) Female 19 (63.3) 23 (76.7) 9 (45.0)

Race, no. (%)* White 28 (93.3) 28 (93.3) 17 (85.0) Black - 2 (6.7) 1 (5.0) Hispanic 1 (3.3) - 1 (5.0) Asian - - 1 (5.0) Other I (3.3) - -

Allergen, no. (%)* Grass pollen 12 (40.0) 4 (13.3) 6 (30.0) Ragweed pollen 11 (36.7) 16 (53.3) 9 (45.0) Cat dander/hair 6 (20.0) 7 (23.3) 4 (20.0) Tree pollen 1 (3.3) 3 (10.0) 1 (5.0)

*Percentages may not total 100 due to rounding error.

1166

B.Q. LANIER ET AL.

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Figure 2. Change from visit 2 (untreated) to visit 3 (treated) in baseline-corrected mean ocular itching scores at (A) 3 minutes, (B) 7 minutes, and (C) 10 minutes after conjunctival allergen challenge. *P < 0.001 versus fluticasone and fexofenadine; t p < 0.001 versus placebo; ~P = 0.019 versus fluticasone and fexofenadine.

1167


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Figure 3. Change from visit 2 (untreated) to visit 3 (treated) in baseline-corrected mean ciliary redness scores at (A) 10 minutes, (B) 15 minutes, and (C) 20 minutes after conjunctival allergen challenge. *P = 0.002 versus placebo; t p = 0.043 versus placebo; *P = 0.035 versus placebo.

1168

B.Q. LANIER ET AL.

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-~ .c_ 1.5 r r ~

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1,43 1.28 _ _ ~ _ _

Figure 4. Change from visit 2 (untreated) to visit 3 (treated) in baseline-corrected mean conjunctival redness scores at (A) 10 minutes, (B) 15 minutes, and (C) 20 minutes after conjunctival allergen challenge. *P = 0.023 versus placebo; tp = 0.039 versus placebo.

1169


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Figure 5. Change from visit 2 (untreated) to visit 3 (treated) in baseline-corrected mean episcleral redness scores at (A) 10 minutes, (B) 15 minutes, and (C) 20 minutes after conjunctival allergen challenge. *P = 0.023 versus placebo; t p ___ 0.029 versus placebo.

1170

B.Q. LANIER ET AL.

in the ciliary vessel bed compared with placebo (P < 0.05).

In the analysis of total nasal symptoms (sneezing, rhinorrhea, pruritus, congestion), no statistically significant differences were demonstrated between the combination of fluticasone and olopatadine and the combination of fluticasone and fexofenadine (Figure 6). Combined fluticasone and olopatadine were significantly more effective than placebo at 20 and 30 minutes after challenge, and combined fluticasone and fexofenadine were significantly more effective than placebo at 10 and 20 minutes after challenge (all, P < 0.05).

DISCUSSION

It has been demonstrated that concomitant use of such allergy medications as olopatadine eye drops and loratadine tablets can produce greater improvements in rhinoconjunctival symptoms than a sin- gle agent. ~4 However, the comparable efficacy of specific combination regimens has not been determined. The present study was designed to compare the efficacy of combined use of 2 site-specific topical medications (fluticasone and olopatadine) with combined use of a topical and a systemic medication (fluticasone and fexofenadine) versus placebo in the CAC model of allergic rhinoconjunctivitis. The overall efficacy of these regimens was determined based on sel~arate evaluations of the ocular and nasal com- ponents of allergic rhinoconjunctivitis.

Fluticasone and olopatadine had greater efficacy against the ocular signs and symptoms of induced allergic rhinoconjunctivitis than did fluticasone and fexofenadine, whereas the 2 treatments exhib- ited comparable efficacy against nasal

symptoms. The combination of fluticasone and olopatadine provided greater overall relief. The intranasal steroid fluticasone, which was used in both treatment arms, specifically targets the nasal allergic reaction, and topical olopatadine specifically targets the signs and symptoms of allergy localized to the eye. It cannot be determined from this study what proportion of the relief of nasal discomfort was produced by each medication. It is highly unlikely that any ocular relief was produced by the nasal spray, because little medication (mean, 8.7%) is deliv- ered even as far as the middle meatus with nasal spray administration, 15 and the ma- jority (>60%) is cleared from the nose via rapid drainage and ciliary and mucosal clearance of drug? 6 However, olopatadine has been shown to be effective in re- ducing nasal symptoms, 17 since a certain amount of eye drop delivery to the infe- rior turbinate occurs as a result of the con- tiguity of the ocular and nasal membranes and their connection through the channels of the lacrimal drainage system.

In the present study, the strategy of specifically targeting therapy to the sites of allergic reaction produced greater overall relief from the signs and symptoms of induced allergic rhinoconjunctivitis. Treating the ocular component of allergic rhinoconjunctivitis with a systemic medication, which must travel through the bloodstream, results in delivery of only a fraction of drug to the intended site, whereas use of a topical medication, which disperses directly through the tear film, provides greater bioavailability at the site of actionJ 8'w Previous research has indicated that olopatadine alone produces greater and longer-lasting improvements in the ocular symptoms of allergic rhinoconjunctivitis compared with sys-

1171


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3,40

Visit 3

3.85

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Visit 3

~: 1.48 I

3.73

Visit 2 Visit 3

Figure 6. Change from visit 2 (untreated) to visit 3 (treated) in baseline-corrected mean total nasal symptom scores (including sneezing, rhinorrhea, pruritus, and congestion) at (A) 10 minutes, (B) 20 minutes, and (C) 30 minutes after conjunctival allergen challenge. *P = 0.003 versus placebo; tp = 0.014 versus placebo; *P = 0.015 versus placebo.

1172

B.Q. LANIER ET AL.

temic antihistamines. 18 Eye drops have the additional nonspecific antiallergic effect of stabilizing the ocular tear film, pro- viding a surface barrier against the binding of allergen to the conjunctiva. 3 In contrast, an ocular drying effect has been observed with use of second-generation systemic antihistamines, increasing the probability of allergen binding to the rel- atively dry, unprotected conjunctiva)

C O N C L U S I O N S

In the subjects in this CAC study, the use of combined fluticasone and olopatadine produced greater improvements in the ocular signs and symptoms of allergic rhinoconjunctivitis compared with combined use of fluticasone and fexofenadine. Both treatments produced comparable improvements in nasal symptoms. There- fore, the combination of the 2 topical medications provided greater overall relief.

A C K N O W L E D G M E N T

Study supplies, investigator and subject compensation, and publishing costs were supported by an unrestricted grant from Alcon Laboratories, Inc, Fort Worth, Texas.

REFERENCES

1. Katelaris CH. Allergic rhinoconjunctivitis-- an overview. Acta Ophthalmol Scand Suppl. 2000;230:66-68.

2. Collum LMT, Kilmartin DJ. Acute allergic conjunctivitis. In: Abelson MB, ed. Allergic Diseases of the Eye. Philadelphia: WB Saunders Co; 2000:108-132.

3. Nevius JM, Abelson MB, Welch DL. The ocular drying effect of oral antihistamines

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(loratadine) in the normal population: An evaluation. Invest Ophthalmol Vis Sci. 1999;40(Suppl):2898. Abstract.

Naclerio RM, Adkinson NF Jr, Creticos PS, et al. Intranasal steroids inhibit seasonal increases in ragweed-specific immunoglobulin E antibodies. J Allergy Clin Immunol. 1993;92:717-721.

Rak S, Jacobson MR, Sudderick RM, et al. Influence of prolonged treatment with topical corticosteroid (fluticasone propionate) on early and late phase nasal re- sponses and cellular infiltration in the nasal mucosa after allergen challenge. Clin Exp Allergy. 1994;24:930-939.

Bernstein DI, Schoenwetter WF, Nathan RA, et al. Efficacy and safety of fexofenadine hydrochloride for treatment of seasonal allergic rhinitis. Ann Allergy Asthma lmmunol. 1997;79:443--448.

Lee EE, Maibach HI. Treatment of ur- ticaria. An evidence-based evaluation of antihistamines. Am J Clin Dermatol. 2001 ; 2:27-32.

Spangler DL, Bensch G, Berdy GJ. Eval- uation of the efficacy of olopatadine hydrochloride 0.1% ophthalmic solution and azelastine hydrochloride 0.05% ophthalmic solution in the conjunctival allergen challenge model. Clin Ther. 2001;23: 1272-1280.

Abelson MB. Evaluation of olopatadine, a new ophthalmic antiallergic agent with dual activity, using the conjunctival allergen challenge model. Ann Allergy Asthma lmmunol. 1998;81:211-218.

Abelson MB, Chambers WA, Smith LM. Conjunctival allergen challenge. A clinical approach to studying allergic conjunctivitis. Arch Ophthalmol. 1990; 108:84-88.

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CLINICAL THERAPEUTICS ~

11. Early Treatment Diabetic Retinopathy 16. Study Group. Manual of Operations. Bal- timore, Md: ETDRS Coordinating Center; 1985.

12. Corren J, Rachelefsky G, Spector S, et al. 17. Onset and duration of action of levo- cabastine nasal spray in atopic patients under nasal challenge conditions. J Al- lergy Clin Immunol. 1999;103:574--580.

13. Bousquet J, Lebel B, Chanal 1, et al. An- tiallergic activity of H~-receptor antago- 18. nists assessed by nasal challenge. J Al- lergy Clin lmmunol. 1988;82:881-887.

14. Lanier BQ, Gross RD, Marks BB, et al. Olopatadine ophthalmic solution adjunc- tive to loratadine compared with loratadine alone in patients with active seasonal allergic conjunctivitis symptoms. Ann Al- lergy Asthma Immunol. 2001 ;86:641-648.

19. 15. Homer JJ, Maughan J, Burniston M. A

quantitative analysis of the intranasal delivery of topical nasal drugs to the middle meatus: Spray versus drop administration. J Laryngol Otol. 2002; 116:10-13.

McLean JA, Bacon JR, Mathews KP, et al. Distribution and clearance of radioac- tive aerosol on the nasal mucosa. Rhinol- ogy. 1984;22:65-75.

Abelson MB, Turner FD, Amin D. Patanol is effective in the treatment of the signs and symptoms of allergic conjunctivitis and allergic rhinoconjunctivitis. Invest Ophthalmol Vis Sei. 2000;41 (Suppl):4922. Abstract.

Abelson MB, Welch DL. An evaluation of onset and duration of action of Patanol (olopatadine hydrochloride ophthalmic solution 0.1%) compared to Claritin (loratadine 10 mg) tablets in acute allergic conjunctivitis in the conjunctival allergen challenge model. Acta Ophthalmol Scand Suppl. 2000;78:60-63.

Sharif NA, Xu SX, Miller ST, et al. Char- acterization of the ocular antiallergic and antihistaminic effects of olopatadine (AL- 4943A), a novel drug for treating ocular allergic disease. J Pharmaco[ Exp Ther. 1996;278:1252-1261.

Addre s s co r r e spondence to: Bob Lanier, MD, Fort Worth Allergy Asthma Association, 6407 Southwest Blvd, Fort Worth, TX 76132.

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comparison of the efficacy of combined fluticasone ... propionate and olopatadine versus combined...

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