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Keywords:

  • ARIA;
  • asthma;
  • GA2LEN;
  • IgE;
  • pharmacotherapy;
  • rhinitis

Abstract

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Conclusions
  7. Acknowledgments
  8. References

The pharmacologic treatment of allergic rhinitis proposed by ARIA is an evidence-based and step-wise approach based on the classification of the symptoms. The ARIA workshop, held in December 1999, published a report in 2001 and new information has subsequently been published. The initial ARIA document lacked some important information on several issues. This document updates the ARIA sections on the pharmacologic and anti-IgE treatments of allergic rhinitis. Literature published between January 2000 and December 2004 has been included. Only a few studies assessing nasal and non-nasal symptoms are presented as these will be discussed in a separate document.


Abbreviations:
ARIA

Allergic Rhinitis and its Impact on Asthma

BID

twice a day

CAM

complementary and alternative medicine

HPA

hypothalamic-pituitary-adrenal

OD

once a day

PAF

platelet activating factor

PRN

as needed

QOL

quality-of-life

RQLQ

rhinoconjunctivitis quality of life questionnaire (Juniper)

Background

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Conclusions
  7. Acknowledgments
  8. References

The management of allergic rhinitis includes patient education, allergen and pollutant (e.g. tobacco) avoidance, pharmacotherapy and allergen-specific immunotherapy (1–3).

Pharmacologic treatment encompasses efficacy, safety and cost-effectiveness of medications, patient preference and the objective of treatment (4), likely adherence to recommendations (5), severity of the disease as well as the presence of co-morbidities. Medications used for rhinitis are usually administered intranasally or orally. The efficacy of medications may differ among patients.

The pharmacologic treatment of allergic rhinitis proposed by ARIA is an evidence-based and step-wise approach based on the classification of the symptoms. The ARIA workshop, held in December 1999, published a report in 2001 (2) and new information has subsequently been published. The initial ARIA document lacked some important information on issues such as complementary and alternative medicine (CAM) and occupational rhinitis.

Objectives

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Conclusions
  7. Acknowledgments
  8. References

This document updates the ARIA sections on the pharmacologic and anti-IgE treatments of allergic rhinitis. Literature published between January 2000 and December 2004 has been included. Complementary and alternative medicine is not evaluated in this document as it is discussed in a separate section (G. Passalacqua, unpublished data). Moreover, only a few studies assessing nasal and non-nasal symptoms are presented as these will also be discussed in a separate document (A.A. Cruz et al., unpublished data).

Methods

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Conclusions
  7. Acknowledgments
  8. References

Search strategy

  • Studies were sought from MEDLINE (1 January 2000 to 31 December 2004) and EMBASE. Moreover, we used the expert group database to assess whether certain papers may not have been retrieved by the electronic search.
  • The following key words were used for the search strategy:
  • Antihistamine, H1-blocker, (intra)nasal corticosteroid, intranasal steroid, anti-cholinergic, decongestant, immunotherapy, leukotriene receptor antagonist, Azelastine, Beclomethasone, Budesonide, Cetirizine, Chlorpheniramine, Clemastine, Cromoglycate, Desloratadine, Diphenhydramine, Ebastine, Emedastine, Fexofenadine, Fluticasone, Ipratropium, Ketotifen, Levocetirizine, Loratadine, Mizolastine, Mometasone, Montelukast, Olopatadine, Omalizumab, Oxatomide, Pranlukast, Pseudoephedrine, Rupatadine, Triamcinolone and Zafirlukast.
  • [AND] rhinitis.
  • [AND] conjunctivitis.
  • [AND] placebo.
  • Moreover, we searched for rhinitis [OR] conjunctivitis [AND] systematic review.

Selection criteria

  • Only randomized, double-blind, placebo-controlled clinical trials published as full papers were selected including some key studies on safety.
  • Key case reports and observational studies were used for drug safety information.
  • Full manuscripts published in peer-reviewed journals. Abstracts were not considered.

Exclusion criteria

  • Studies using methods which make it very difficult to assess efficacy and/or safety.
  • Challenge studies including chamber and park models (6–13).
  • Skin test studies.
  • Methodological papers using single-blind trials (14–19).
  • Reviews in which the methodology was not clearly stated (20).
  • Studies on non-allergic rhinitis, rhino-sinusitis or nasal polyposis (21–28) or sleep disordered breathing (29, 30).

All studies meeting the search strategy were examined by two of the experts, reviewed by the chair of the group and discussed during plenary sessions of the ARIA Scientific Committee.

Pharmacologic treatment of allergic rhinitis

Oral H1 antihistamines.  H1-blockers or H1-antihistamines block histamine at the H1 receptor level (neutral antagonists or inverse agonists) (31). Some also possess additional anti-allergic properties. During the last 20 years, pharmacologic research has produced compounds with minimal sedative effect and impairment: the so-called second-generation H1-antihistamines, as opposed to the first-generation H1-antihistamines (32). The term ‘third’ generation should be reserved for an H1-antihistamine with novel properties.

Oral H1-antihistamines improve the quality-of-life of patients by their effectiveness against symptoms mediated by histamine, including rhinorrhea, sneezing, nasal itching and eye symptoms. They are, however, less effective on nasal congestion.

Long-term treatment (years) with an oral H1-antihistamine is safe, including little or no sedation or impairment. Some, but not all, oral H1-antihistamines undergo hepatic metabolism via the cytochrome P450 system and are prone to drug interactions. Although cardiotoxicity is not a class effect (33), major concerns existed about the arrhythmogenic action of terfenadine, astemizole and high doses of diphenhydramine, which have rarely been associated with fatalities.

H1-antihistamines have been approved for young children (34).

Table 1 summarizes the desirable characteristics of an anti-histamine medication for use in allergic rhinitis (35).

Table 1.   Optimal properties of oral H1-antihistamines
Pharmacologic properties
 Potent and selective H1 receptor blockage
 Additive anti-allergic activities
 No clinically relevant pharmacokinetic interference by foods, medications or intestinal transport proteins
 No known interaction with cytochrome P4503A (CYP3A)
 No known interaction with other diseases to avoid toxic reactions
Efficacy
 Effective in the treatment of intermittent and persistent rhinitis as defined in the ARIA document (2)
 Effective for all nasal symptoms including nasal obstruction
 Improvement of allergic eye symptoms
 If a claim for asthma is made
 Improvement of asthma symptoms (short-term studies)
 Reduction of asthma exacerbations (long-term studies)
 An improvement of the pulmonary function tests, even though in pollen-induced bronchial symptoms, FEV1 and peak flow rates are usually not altered
 If a claim for a preventive effect is proposed, appropriate trials should be conducted
 Studies should be carried out in young children and old age patients to assess efficacy
Side effects
 No sedation, cognitive or psychomotor impairment
 No anti-cholinergic effects
 No weight gain
 No cardiac side effects (prolongation of the QT interval)
 Possible use in pregnancy and breast feeding
 Studies should be carried out in young children and old age patients to assess safety
Pharmacodynamics
 Rapid onset of action, so that clinical benefits are noted quickly and so drugs can be used also prn
 Long duration of action, at least persistence of clinical effects over 24 h, so the drug can be administered once a day
 No likelihood of development of tolerance (tachyphylaxis).
Comparison with other drugs used to treat rhinitis (conjunctivitis)

Recently, Loratadine, a major second-generation anti-histamine medication in the USA, has taken on a non-prescription or over the counter (OTC) status (36). This has resulted in increased out of pocket expenses for patients as OTC medications are not part of an insurance or drug benefit program. Insurers are continuing to adjust drug benefits for other anti-histamines in view of the 44% drop in anti-histamine use by patients who have lost drug benefits for anti-histamine medications (37).

Cetirizine.  Cetirizine provides a positive impact on work/school-related productivity and activity impairment in patients with pollen-induced rhinitis (38).

Long-term (6 months) treatment with Cetirizine reduces allergic symptoms and the need for rescue medication in children with mite allergy as compared with placebo (39).

In infants 6–11 months of age, a double-blind, placebo-controlled study has demonstrated the safety of Cetirizine (40). Another study produced no adverse effects on behavior, and learning processes were associated with the prolonged use of Cetirizine in young children with atopic dermatitis (41).

Although, in children, Chlorpheniramine and Cetirizine increased P300 latency (an event-related potential used as an objective test of sedation) when compared with baseline (42), the significant increase in P300 latency was not accompanied by a change in subjective somnolence as measured on a visual analog scale.

Cetirizine, compared with placebo, delays or, in some cases, prevents the development of asthma in a subgroup of infants with atopic dermatitis sensitized to grass pollen and, to a lesser extent, house dust mite (43). Further studies are required focusing specifically on sensitized groups to substantiate this finding.

Desloratadine.  Desloratadine in 5 mg dosage provided significant 24 h relief of seasonal allergic rhinitis signs and symptoms. There were no statistically significant differences among the four largest doses suggesting that Desloratadine 5 mg OD offers the best therapeutic profile (44). Recommended OD doses of Fexofenadine and Desloratadine were equally effective in improving nasal peak flow and nasal symptoms in seasonal allergic rhinitis (45). Desloratadine reduces nasal congestion (46), rapidly and safely reduces the symptoms of perennial allergic rhinitis, and its efficacy did not diminish during 4 weeks of treatment (47). In two studies, Desloratadine also reduced bronchial symptoms during the pollen season in patients with seasonal asthma and seasonal rhinitis (48, 49).

At the recommended dose of 5 mg, Desloratadine appears to be free of adverse effects on psychomotor performance, daytime sleep latencies, and subjective sleepiness and could prove suitable for those involved in skilled activity and transportation (50). Desloratadine at a therapeutic dose does not impair driving performance (51). Desloratadine has no clinically relevant electrocardiographic or pharmacodynamic interactions with Ketoconazole (52), Erythromycin (53) or Azithromycin (54).

Ebastine.  In pollen-induced rhinitis, Ebastine 20 mg OD was significantly superior to Loratadine 10 mg OD. It improved the total rhinitis symptom score throughout the day and in the morning when awakening at the end of the 24 h dosing interval over a 4-week period (55–57).

At its recommended therapeutic dose, it did not alter objective measures of psychomotor and cognitive function (58, 59). At five times the recommended therapeutic dose, it did not cause clinically relevant changes in the QTc interval (60). There is no effect of food intake in the efficacy of Ebastine (61).

Fexofenadine.  In one study, Fexofenadine (120 mg OD) was significantly more effective than Loratadine in relieving eye symptoms and nasal congestion and was significantly better than Loratadine in improving the rhinitis-quality-of-life questionnaire (RQLQ) (62).

In 259 patients, no differences were found between the Fexofenadine and placebo groups on reaction times, decision-making or driver behaviour (63).

Fexofenadine was efficacious and safe in 6- to 11-year-old children with seasonal allergic rhinitis (64, 65).

Emedastine.  Emedastine was studied in a double-blind, randomized, parallel-group trial without a placebo group (66).

Levocetirizine.  In the treatment of seasonal allergic rhinitis, by comparison with other dosages, Levocetirizine 5 mg OD has an optimal benefit/risk ratio (67). Levocetirizine is effective for the relief of nasal congestion in adolescents and adults (perennial allergic rhinitis) sensitized to house dust mites (68). In this study, somnolence was reported in 2.8% of the placebo group and in 6.0% of the Levocetirizine group.

An important trial examined the effect of Levocetirizine given for over 6 months to 551 patients with moderate to severe persistent allergic rhinitis (XPERT® study). It was found that, compared with placebo, Levocetirizine improves nasal symptoms including nasal obstruction and quality of life (RQLQ and SF-36) and reduces medical costs involved in the long-term management of these patients (69). Levocetirizine is currently the only antihistamine with the indication of persistent allergic rhinitis in Europe.

Single and repeated doses of Levocetirizine have no effect on cognitive and psychomotor functions in healthy volunteers (70–72) and on driving performance (73).

Loratadine.  Loratadine syrup 5 or 10 mg OD was effective in improving the symptom scores of children aged 3–12 years with allergic rhinitis without side effects (74). Loratadine was well tolerated by a selected group of children aged 2–5 years at a dose similar to the adult dose (i.e. 10 mg per day) (75). Learning and response time in children attending a laboratory school were not significantly affected by Loratadine or Diphenhydramine (76). This report differs from previous studies (38, 77).

Mizolastine.  Over a 4-week period, Mizolastine 10 mg OD was as effective as Loratadine 10 mg OD in relieving symptoms of perennial allergic rhinitis in adult patients, and the tolerability was good (78).

Rupatadine.  Rupatadine is a new second-generation H1-antihistamine with OD dosing that may have the potential to provide better control of symptoms than the currently used oral H1-antihistamines. This is due to its dual pharmacologic profile (anti-PAF and anti-H1) which does, however, require testing in controlled comparative studies. Rupatadine 10 mg per day was superior to placebo and non-significantly superior to Ebastine 10 mg in alleviating the symptoms of seasonal allergic rhinitis over a 2-week period (79). Somnolence was reported in 2.4% of patients treated with placebo, 10.8% with Ebastine and 17.7% with Rupatadine.

Topical H1-antihistamines.  Intranasal H1-antihistamines are effective in reducing itching, sneezing, runny nose and nasal congestion. Given ocularly, they are effective in reducing allergic eye symptoms. They can be effective within 20 min of administration. Topical H1-antihistamines require twice a day dosing. In general, topical H1-antihistamines are well tolerated. However, both oral and topical antihistamines are significantly less effective than intranasal glucocorticosteroids for the treatment of allergic rhinitis, particularly for the symptom of nasal congestion.

Nasal administration.  Azelastine nasal spray was found to be an effective treatment for patients with seasonal allergic rhinitis who do not respond to loratadine and is an alternative to switching to another oral antihistamine or to using multiple antihistamines (80). Azelastine nasal spray is effective in treating severe seasonal allergic rhinitis patients who remain symptomatic after treatment with Fexofenadine (81).

Ocular administration.  A 10-week, randomized, double-blind, parallel group compared olopatadine 0.1% ophthalmic solution BID vs placebo in 131 patients with pollen-induced rhinitis and conjunctivitis. Olopatadine controlled ocular and nasal symptoms and was well tolerated (82).

Epinastine has been tested in a randomized, double-blind, parallel-group study without a placebo arm in patients with allergic conjunctivitis (83).

Intranasal glucocorticosteroids.  Glucocorticosteroids are the most efficacious medications available for the treatment of allergic and non-allergic rhinitis. The rationale for using intranasal glucocorticosteroids in the treatment of allergic rhinitis is that high drug concentrations can be achieved at receptor sites in the nasal mucosa, with minimal risk of systemic adverse effects. Because of their mechanism of action, efficacy appears after 7–8 h of dosing, but maximum efficacy may require up to 2 weeks. These medications are effective at improving all symptoms of allergic rhinitis. For nasal congestion or frequent symptoms, an intranasal glucocorticosteroid is the most appropriate first-line treatment. Intranasal glucocorticosteroids are well tolerated and adverse effects are uncommon, of mild severity and have approximately the same incidence as placebo. Evidence shows that the long-term use of intranasal glucocorticosteroids is free of the concerns associated with the long-term use of oral glucocorticosteroids.

Ideal properties which should be met by intranasal Glucocorticosteroids are listed in Table 2 (35).

Table 2.   Optimal properties of intranasal glucocorticosteroids
Pharmacologic properties
 Potent action on transcription factors
 Inhibition of cytokine synthesis
 First pass hepatic metabolism
 Limited systemic bioavailability
Efficacy
 Effective in the treatment of intermittent and persistent rhinitis as defined in the ARIA document (2)
 Effective for all nasal symptoms
 Improvement of eye symptoms
 If a claim for asthma is proposed
 Improvement of asthma symptoms (short-term studies)
 Reduction of asthma exacerbations (long-term studies)
 An improvement in pulmonary function tests, even though in pollen-induced bronchial symptoms, FEV1 and peak flow rates are usually not altered
 If a claim for nasal polyposis or sinusitis is proposed, adequate appropriate trials should be conducted
 If a claim for a preventive effect is proposed, appropriate trials should be conducted
Side effects
 Minimal local side effects
 No HPA axis effects
 Especially in children
 And in association with the inhaled (intrabronchial) form
 No long-term effect on growth in children
 No eye or bone side effects
 Possible use in pregnancy
Pharmacodynamics
 Assessment of the onset of action
 Long duration of action, at least 24 h, ability to be administered once a day
 If a claim for a prn use is proposed, appropriate trials should be conducted
Comparison with other drugs used to treat rhinitis

Clinical and pharmacologic effects.  The onset of action of intranasal corticosteroids may be shorter than previously thought (84, 85). Budesonide is effective after 12 h of administration (86).

Cost-effectiveness studies of intranasal corticosteroids are important but may depend on local costs. Few studies are available.

Side effects of intranasal glucocorticosteroids.  In children, the rate of growth was slightly reduced in those regularly treated twice a day with intranasal Beclomethasone over 1 year (87). However, no growth slowing has been observed in 1 year follow-up studies of children treated with Fluticasone propionate (88) or Mometasone furoate (89–91). Moreover, a pharmacokinetic/pharmacodynamic model of the relationship between systemic corticosteroid exposure and growth velocity has been proposed and may be useful for the development of future locally acting corticosteroids (90, 91).

Budesonide aqueous nasal spray does not affect the HPA-axis in children with allergic rhinitis (92). Concurrent use of intranasal and orally inhaled Fluticasone propionate does not affect hypothalamic-pituitary-adrenal-axis function (93).

In a study of 360 patients with allergic rhinitis, Fluticasone propionate, Mometasone furoate and Beclomethasone dipropionate caused variations in the intraocular pressure measured by Goldman's tonometry at 3 weeks, 6 weeks, 3 months, 6 months and 1 year, but the variations were within normal limits (94).

In the elderly, intranasal corticosteroids, at the recommended dose, have not been associated with an increased risk of fractures (95).

Budesonide.  Allergic contact dermatitis has occasionally been reported after the intranasal or inhaled administration of Budesonide (96, 97).

Fluticasone propionate.  Fluticasone propionate aqueous nasal spray [when used as needed (PRN) (84, 85)] improves nasal symptoms of seasonal allergic rhinitis. PRN has a lower incidence of adverse events than typically associated with regular one per day use (85). The PRN use of Fluticasone propionate has been approved in some countries. Future studies are still needed to show the optimal use of intranasal glucocorticosteroids in the controlling of nasal symptoms, especially in persistent allergic rhinitis. It has been confirmed by one of the studies that a significant difference of total symptom scores between the treatment of fluticasone propionate aqueous and placebo was found only after 5 days of treatment (84). Whether there is a need for a minimum duration of treatment by intranasal glucocorticosteroids in PRN remains to be investigated.

A randomized placebo-controlled trial compared Fluticasone propionate aqueous nasal spray in mono-therapy, Fluticasone propionate plus Cetirizine, Fluticasone propionate plus Montelukast and Cetirizine plus Montelukast for seasonal allergic rhinitis (98). The results of this comparative study showed that Fluticasone propionate is highly effective for treating patients with allergic rhinitis, with an efficacy exceeding that of Cetirizine plus Montelukast in combined therapy. This study also suggested that there was little advantage in adding Cetirizine or Montelukast to Fluticasone propionate.

Intranasal Fluticasone propionate is also effective for treating perennial non-allergic rhinitis with or without eosinophilia (99) and significantly improves ocular symptoms in patients with seasonal allergic rhinitis (100).

The effect of drugs on sleep in allergic rhinitis has already been reported. A recent study reported an improvement in subjective sleep disturbances in perennial allergic rhinitis treated with intranasal Fluticasone propionate for 8 weeks. However, polysomnography, the current gold standard for sleep studies, was unchanged (101).

Rhinitis during pregnancy, a common condition with longstanding nasal congestion, is troublesome for the mother. A study of 53 pregnant women showed no effect of Fluticasone propionate on fetal growth or pregnancy outcome (102). Although safe in pregnant women, it was not very effective for this condition.

Intranasal Fluticasone propionate was tested for its effect on the bioavailability and pharmacokinetics of single-dose intranasal Hydromorphone hydrochloride in patients with allergic rhinitis (103). Hydromorphone was rapidly absorbed after nasal administration, with maximum concentrations occurring for most subjects within 30 min suggesting that Fluticasone propionate does not modify its absorption.

Mometasone furoate.  Mometasone furoate nasal spray relieves cough and nasal symptoms associated with seasonal allergic rhinitis (104).

Triamcinolone acetonide.  Intranasal Triamcinolone acetonide given for 4 weeks improves symptom scores and RQLQ in patients with perennial allergic rhinitis. The ability of Triamcinolone to relieve nasal congestion symptoms was correlated with improvements in RQLQ (105). The Food and Drug Administration (FDA) recently approved the HFA formulation of Triamcinolone acetonide.

Decongestants.  The decongestant effect of an H1-antihistamine Pseudoephedrine fixed-dose combination was demonstrated by using the novel method of endoscopic inferior turbinate photography, in addition to acoustic rhinometry and visual analogue scale scores (106). Pseudoephedrine has been banned for Olympic athletes. This has important implications for the correct and prominent labeling of pharmacologic treatments for rhinitis, particularly for over-the-counter remedies.

Antileukotrienes.  Several pivotal studies of seasonal allergic rhinitis compared Montelukast and placebo, and in some studies the combination Montelukast-Loratadine (107–111). Montelukast, in trials involving a large number of patients, was consistently more effective than placebo for all nasal and ocular symptoms and there was no significant difference between Montelukast and Loratadine, even for nasal obstruction. Moreover, contrary to the first study (112), the combination Montelukast-Loratadine did not provide any statistically significant additive beneficial effect to the two drugs given alone. In all these studies, Montelukast improved all nasal symptoms of rhinitis, symptoms of conjunctivitis and RQLQ, and was well tolerated. Montelukast is equally effective in patients exposed to low and high pollen counts (111). In a study carried out in patients with seasonal allergic rhinitis and asthma, Montelukast was found to improve nasal and bronchial symptoms (113). As-needed beta-agonist use (puffs/day) was also reduced with Montelukast. Combined Montelukast and Cetirizine treatment, when started 6 weeks before the pollen season, is effective in preventing AR symptoms and reduces allergic inflammation in the nasal mucosa during natural allergen exposure (114).

Leukotriene receptor antagonists are less effective in allergic rhinitis than intranasal corticosteroids and have an efficacy similar to oral H1-antihistamines (98, 115, 116).

Montelukast does not modify skin prick test results (117, 118) and therefore does not need to be discontinued before skin testing.

Humanized monoclonal antibodies against IgE

The recombinant humanized monoclonal anti-IgE antibody (Omalizumab) forms complexes with free IgE, blocking its interaction with mast cells and basophils and lowering free IgE levels in the circulation. In a large pivotal trial, Omalizumab decreased serum free IgE levels and provided clinical benefit in a dose-dependent fashion in patients with seasonal allergic rhinitis (119). Omalizumlab was found to decrease all nasal symptoms and improve RQLQ in patients with rhinitis induced by birch and ragweed pollens as well as in patients with sensitization to outdoor allergens (adults and adolescents) (120, 121). Moreover, the treatment was safe and well tolerated (122, 123). In patients with asthma and rhinitis, Omalizumab improved nasal and bronchial symptoms and reduced unscheduled visits to physicians for asthma (124). The clinical benefit of treatment with Omalizumab is associated with an anti-inflammatory effect on cellular markers in blood and nasal tissue (125, 126) as well as a reduction in mast cell FcɛRI expression and function (127). Omalizumab inhibits allergen challenge-induced nasal response (128). Omalizumab rapidly decreases nasal allergic response and FcɛRI on basophils (129) and dendritic cells (130). The relative efficiency of this treatment compared to H1-antihistamines and intranasal glucocorticosteroids needs to be established.

Specific immunotherapy (SIT) and treatment with monoclonal anti-IgE antibodies have complementary modes of action. Omalizumab conferred a protective effect independent of the type of allergen. Additional clinical benefit was demonstrated in both pollen seasons, whether there was coverage by SIT or not (131). The co-seasonal application of Omalizumab after pre-seasonal SIT decreases ocular and nasal symptom scores and rescue medication use in grass pollen allergic children (132). This combination might prove useful for the treatment of allergic rhinitis, particularly for polysensitized patients.

Treatment of infants and young children

Perennial rhinitis in children under 4 years of age is a difficult problem to treat safely and effectively. A randomized, multicentre, double-blind, double dummy, placebo-controlled study compared intranasal Fluticasone propionate and ketotifen (133). Generally, except for nasal itching/rubbing over weeks 1–3, the patients taking Fluticasone propionate had lower recorded symptom scores for all individual symptoms measured. Nasal blockage, in particular, was significantly reduced over the 4–6-week periods. There were no reports of serious adverse events, the incidence of drug-related adverse events was low and there was no statistical difference in regard to safety between the groups.

Conclusions

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Conclusions
  7. Acknowledgments
  8. References

New studies have been performed since the ARIA workshop report and they are listed in this report. A revised level of evidence can be proposed (Table 3). It is clear that studies using the new ARIA classification (intermittent and persistent rhinitis) should be carried out for all treatments in order to fully appreciate the efficacy of treatments used in allergic rhinitis.

Table 3.   Level of evidence
 Seasonal rhinitisPerennial rhinitisPersistent rhinitis†
AdultChildrenAdultChildren
  1. B*: by extension of studies in persistent allergic rhinitis of 4 weeks and longer, but studies using the new classification have to be performed to confirm efficacy in this indication.

  2. B**: by extension of studies in seasonal allergic rhinitis of 4 weeks.

  3. A***: most studies included small numbers of patients.

  4. †Adolescents and adults.

Oral H1-antihistaminesAAAAA
Intranasal H1-anthistaminesAAAAB*
Intranasal corticosteroidsAAAAB*
Intranasal chromonesA***A***A***A*** 
Anti-leukotrienesAA  B**
Anti-IgE mabAAAAB*

Acknowledgments

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Conclusions
  7. Acknowledgments
  8. References

The authors would like to thank Drs R Dubakiene and V Lund for their valuable comments.

References

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Conclusions
  7. Acknowledgments
  8. References
  • 1
    Bousquet J, Lockey R, Malling H. WHO Position Paper. Allergen immunotherapy: therapeuticvaccines for allergic diseases. Allergy 1998;53(Suppl. 54):155.
  • 2
    Bousquet J, Van Cauwenberge P, Khaltaev N. Allergic rhinitis and its impact on asthma. J Allergy Clin Immunol 2001;108(Suppl. 5):S147S334.
  • 3
    ARIA in the pharmacy: management of allergic rhinitis symptoms in the pharmacy. Allergic rhinitis and its impact on asthma. Allergy 2004;59:373387.
  • 4
    Marinker M. From compliance to accordance: achieving shared goals in medicine taking. Report of the Royal Pharmaceutical of Great Britain Working party, 1998.
  • 5
    Bousquet J, Lund VJ, Van Cauwenberge P, Bremard-Oury C, Mounedji N, Stevens MT et al. Implementation of guidelines for seasonal allergic rhinitis: a randomized controlled trial. Allergy 2003;58:733741.
  • 6
    Horak F, Stubner UP, Zieglmayer R, Harris AG. Effect of desloratadine versus placebo on nasal airflow and subjective measures of nasal obstruction in subjects with grass pollen-induced allergic rhinitis in an allergen-exposure unit. J Allergy Clin Immunol 2002;109:956961.
  • 7
    Horak F, Stubner P, Zieglmayer R, Kavina A, De Vos C, Burtin B et al. Controlled comparison of the efficacy and safety of cetirizine 10 mg o.d. and fexofenadine 120 mg o.d. in reducing symptoms of seasonal allergic rhinitis. Int Arch Allergy Immunol 2001;125:7379.
  • 8
    Horak F, Stubner P, Zieglmeyer R, Harris AG. Comparison of the effects of desloratadine 5-mg daily and placebo on nasal airflow and seasonal allergic rhinitis symptoms induced by grass pollen exposure. Allergy 2003;58:481485.
  • 9
    Deruaz C, Leimgruber A, Berney M, Pradervand E, Spertini F. Levocetirizine better protects than desloratadine in a nasal provocation with allergen. J Allergy Clin Immunol 2004;113:669676.
  • 10
    Day JH, Briscoe MP, Rafeiro E, Ratz JD. Comparative clinical efficacy, onset and duration of action of levocetirizine and desloratadine for symptoms of seasonal allergic rhinitis in subjects evaluated in the Environmental Exposure Unit (EEU). Int J Clin Pract 2004;58:109118.
  • 11
    Day JH, Briscoe MP, Rafeiro E, Hewlett D Jr, Chapman D, Kramer B. Randomized double-blind comparison of cetirizine and fexofenadine after pollen challenge in the Environmental Exposure Unit: duration of effect in subjects with seasonal allergic rhinitis. Allergy Asthma Proc 2004;25:5968.
  • 12
    Perry TT, Corren J, Philip G, Kim EH, Conover-Walker MK, Malice MP et al. Protective effect of montelukast on lower and upper respiratory tract responses to short-term cat allergen exposure. Ann Allergy Asthma Immunol 2004;93:431438.
  • 13
    Stubner P, Zieglmayer R, Horak F. A direct comparison of the efficacy of antihistamines in SAR and PAR: randomised, placebo-controlled studies with levocetirizine and loratadine using an environmental exposure unit – the Vienna Challenge Chamber (VCC). Curr Med Res Opin 2004;20:891902.
  • 14
    Wilson A, Dempsey OJ, Sims EJ, Coutie WJ, Paterson MC, Lipworth BJ. Evaluation of treatment response in patients with seasonal allergic rhinitis using domiciliary nasal peak inspiratory flow. Clin Exp Allergy 2000;30:833838.
  • 15
    Wilson AM, Sims EJ, Orr LC, Coutie WJ, White PS, Gardiner Q et al. Effects of topical corticosteroid and combined mediator blockade on domiciliary and laboratory measurements of nasal function in seasonal allergic rhinitis. Ann Allergy Asthma Immunol 2001;87:344349.
  • 16
    Wilson AM, Orr LC, Sims EJ, Lipworth BJ. Effects of monotherapy with intra-nasal corticosteroid or combined oral histamine and leukotriene receptor antagonists in seasonal allergic rhinitis. Clin Exp Allergy 2001;31:6168.
  • 17
    Wilson AM, Orr LC, Coutie WJ, Sims EJ, Lipworth BJ. A comparison of once daily fexofenadine versus the combination of montelukast plus loratadine on domiciliary nasal peak flow and symptoms in seasonal allergic rhinitis. Clin Exp Allergy 2002;32:126132.
  • 18
    Lee DK, Gardiner M, Haggart K, Fujihara S, Lipworth BJ. Comparative effects of desloratadine, fexofenadine, and levocetirizine on nasal adenosine monophosphate challenge in patients with perennial allergic rhinitis. Clin Exp Allergy 2004;34:650653.
  • 19
    Lee DK, Jackson CM, Soutar PC, Fardon TC, Lipworth BJ. Effects of single or combined histamine H1-receptor and leukotriene CysLT1-receptor antagonism on nasal adenosine monophosphate challenge in persistent allergic rhinitis. Br J Clin Pharmacol 2004;57:714719.
  • 20
    Bender BG, Berning S, Dudden R, Milgrom H, Tran ZV. Sedation and performance impairment of diphenhydramine and second-generation antihistamines: a meta-analysis. J Allergy Clin Immunol 2003;111:770776.
  • 21
    Meltzer EO, Charous BL, Busse WW, Zinreich SJ, Lorber RR, Danzig MR. Added relief in the treatment of acute recurrent sinusitis with adjunctive mometasone furoate nasal spray. The Nasonex Sinusitis Group. J Allergy Clin Immunol 2000;106:630637.
  • 22
    Keith P, Nieminen J, Hollingworth K, Dolovich J. Efficacy and tolerability of fluticasone propionate nasal drops 400 μg once daily compared withlacebo for the treatment of bilateral polyposis in adults. Clin Exp Allergy 2000;30:14601468.
  • 23
    Penttila M, Poulsen P, Hollingworth K, Holmstrom M. Dose-related efficacy and tolerability of fluticasone propionate nasal drops 400 μg once daily and twice daily in the treatment of bilateral nasal polyposis: a placebo-controlled randomized study in adult patients. Clin Exp Allergy 2000;30:94102.
  • 24
    Parikh A, Scadding GK, Darby Y, Baker RC. Topical corticosteroids in chronic rhinosinusitis: a randomized, double-blind, placebo-controlled trial using fluticasone propionate aqueous nasal spray. Rhinology 2001;39:7579.
  • 25
    Dolor RJ, Witsell DL, Hellkamp AS, Williams JW Jr, Califf RM, Simel DL. Comparison of cefuroxime with or without intranasal fluticasone for the treatment of rhinosinusitis. The CAFFS Trial: a randomized controlled trial. Jama 2001;286:30973105.
  • 26
    Lavigne F, Cameron L, Renzi PM, Planet JF, Christodoulopoulos P, Lamkioued B et al. Intrasinus administration of topical budesonide to allergic patients with chronic rhinosinusitis following surgery. Laryngoscope 2002;112:858864.
  • 27
    Bucher HC, Tschudi P, Young J, Periat P, Welge-Luussen A, Zust H et al. Effect of amoxicillin-clavulanate in clinically diagnosed acute rhinosinusitis: a placebo-controlled, double-blind, randomized trial in general practice. Arch Intern Med 2003;163:17931798.
  • 28
    Lund VJ, Black JH, Szabo LZ, Schrewelius C, Akerlund A. Efficacy and tolerability of budesonide aqueous nasal spray in chronic rhinosinusitis patients. Rhinology 2004;42:5762.
  • 29
    Kiely JL, Nolan P, McNicholas WT. Intranasal corticosteroid therapy for obstructive sleep apnoea in patients with co-existing rhinitis. Thorax 2004;59:5055.
  • 30
    Mansfield LE, Diaz G, Posey CR, Flores-Neder J. Sleep disordered breathing and daytime quality of life in children with allergic rhinitis during treatment with intranasal budesonide. Ann Allergy Asthma Immunol 2004;92:240244.
  • 31
    Leurs R, Church MK, Taglialatela M. H1-antihistamines: inverse agonism, anti-inflammatory actions and cardiac effects. Clin Exp Allergy 2002;32:489498.
  • 32
    Bousquet J, Van-Cauwenberge P, Bachert C, Canonica G, Demoly P, Durham S et al. Requirements for medications commonly used in the treatment of allergic rhinitis. Allergy 2003;58:192197.
  • 33
    Passalacqua G, Canonica GW, Bousquet J. Structure and classification of H1-antihistamines and overview of their activities. Clin Allergy Immunol 2002;17:65100.
  • 34
    Simons FE. Advances in H1-antihistamines. N Engl J Med 2004;351:22072217.
  • 35
    Bousquet J, Van Cauwenberge P, Bachert C, Canonica GW, Demoly P, Durham SR et al. Requirements for medications commonly used in the treatment of allergic rhinitis. European Academy of Allergy and Clinical Immunology (EAACI), Allergic Rhinitis and its Impact on Asthma (ARIA). Allergy 2003;58:192197.
  • 36
    Sullivan PW, Nichol MB. The economic impact of payer policies after the Rx-to-OTC switch of second-generation antihistamines. Value Health 2004;7:402412.
  • 37
    Goldman DP, Joyce GF, Escarce JJ, Pace JE, Solomon MD, Laouri M et al. Pharmacy benefits and the use of drugs by the chronically ill. Jama 2004;291:23442350.
  • 38
    Murray JJ, Nathan RA, Bronsky EA, Olufade AO, Chapman D, Kramer B. Comprehensive evaluation of cetirizine in the management of seasonal allergic rhinitis: impact on symptoms, quality of life, productivity, and activity impairment. Allergy Asthma Proc 2002;23:391398.
  • 39
    Ciprandi G, Tosca M, Passalacqua G, Canonica GW. Long-term cetirizine treatment reduces allergic symptoms and drug prescriptions in children with mite allergy. Ann Allergy Asthma Immunol 2001;87:222226.
  • 40
    Simons FE, Silas P, Portnoy JM, Catuogno J, Chapman D, Olufade AO et al. Safety of cetirizine in infants 6 to 11 months of age: a randomized, double-blind, placebo-controlled study. J Allergy Clin Immunol 2003;111:12441248.
  • 41
    Stevenson J, Cornah D, Evrard P, Vanderheyden V, Billard C, Bax M et al. Long-term evaluation of the impact of the h1-receptor antagonist cetirizine on the behavioral, cognitive, and psychomotor development of very young children with atopic dermatitis. Pediatr Res 2002;52:251257.
  • 42
    Ng KH, Chong D, Wong CK, Ong HT, Lee CY, Lee BW et al. Central nervous system side effects of first- and second-generation antihistamines in school children with perennial allergic rhinitis: a randomized, double-blind, placebo-controlled comparative study. Pediatrics 2004;113:e116e121.
  • 43
    Warner JO. A double-blinded, randomized, placebo-controlled trial of cetirizine in preventing the onset of asthma in children with atopic dermatitis: 18 months treatment and 18 months posttreatment follow-up. J Allergy Clin Immunol 2001;108:929937.
  • 44
    Salmun LM, Lorber R. 24-hour efficacy of once-daily desloratadine therapy in patients with seasonal allergic rhinitis. BMC Fam Pract 2002;3:14.
  • 45
    Wilson AM, Haggart K, Sims EJ, Lipworth BJ. Effects of fexofenadine and desloratadine on subjective and objective measures of nasal congestion in seasonal allergic rhinitis. Clin Exp Allergy 2002;32:15041509.
  • 46
    Nayak AS, Schenkel E. Desloratadine reduces nasal congestion in patients with intermittent allergic rhinitis. Allergy 2001;56:10771080.
  • 47
    Simons FE, Prenner BM, Finn A Jr. Efficacy and safety of desloratadine in the treatment of perennial allergic rhinitis. J Allergy Clin Immunol 2003;111:617622.
  • 48
    Berger WE, Schenkel EJ, Mansfield LE. Safety and efficacy of desloratadine 5 mg in asthma patients with seasonal allergic rhinitis and nasal congestion. Ann Allergy Asthma Immunol 2002;89:485491.
  • 49
    Baena-Cagnani CE, Berger WE, Dubuske LM, Gurne SE, Stryszak P, Lorber R et al. Comparative effects of desloratadine versus montelukast on asthma symptoms and use of beta 2-agonists in patients with seasonal allergic rhinitis and asthma. Int Arch Allergy Immunol 2003;130:307313.
  • 50
    Nicholson AN, Handford AD, Turner C, Stone BM. Studies on performance and sleepiness with the H1-antihistamine, desloratadine. Aviat Space Environ Med 2003;74:809815.
  • 51
    Vuurman EF, Rikken GH, Muntjewerff ND, De Halleux F, Ramaekers JG. Effects of desloratadine, diphenhydramine, and placebo on driving performance and psychomotor performance measurements. Eur J Clin Pharmacol 2004;60:307313.
  • 52
    Banfield C, Herron J, Keung A, Padhi D, Affrime M. Desloratadine has no clinically relevant electrocardiographic or pharmacodynamic interactions with ketoconazole. Clin Pharmacokinet 2002;41(Suppl. 1):3744.
  • 53
    Banfield C, Hunt T, Reyderman L, Statkevich P, Padhi D, Affrime M. Lack of clinically relevant interaction between desloratadine and erythromycin. Clin Pharmacokinet 2002;41(Suppl. 1):2935.
  • 54
    Gupta S, Banfield C, Kantesaria B, Marino M, Clement R, Affrime M et al. Pharmacokinetic and safety profile of desloratadine and fexofenadine when coadministered with azithromycin: a randomized, placebo-controlled, parallel-group study. Clin Ther 2001;23:451466.
  • 55
    Ratner PH, Lim JC, Georges GC. Comparison of once-daily ebastine 20 mg, ebastine 10 mg, loratadine 10 mg, and placebo in the treatment of seasonal allergic rhinitis. The Ebastine Study Group. J Allergy Clin Immunol 2000;105(6 Pt 1):11011107.
  • 56
    Hampel F Jr, Howland W III, Van Bavel J, Ratner P. A randomized, double-blind, placebo-controlled study comparing the efficacy and safety of ebastine (20 and 10 mg) to loratadine 10 mg once daily in the treatment of seasonal allergic rhinitis. J Investig Allergol Clin Immunol 2004;14:5663.
  • 57
    Ratner P, Hampel F Jr, Van Bavel J, Howland W III. Efficacy and safety of ebastine 20 mg compared to loratadine 10 mg once daily in the treatment of seasonal allergic rhinitis: a randomized, double-blind, placebo-controlled study. Int Arch Allergy Immunol 2004;133:371379.
  • 58
    Hindmarch I, Shamsi Z. The effects of single and repeated administration of ebastine on cognition and psychomotor performance in comparison to triprolidine and placebo in healthy volunteers. Curr Med Res Opin 2001;17:273281.
  • 59
    Tagawa M, Kano M, Okamura N, Higuchi M, Matsuda M, Mizuki Y et al. Differential cognitive effects of ebastine and (+)-chlorpheniramine in healthy subjects: correlation between cognitive impairment and plasma drug concentration. Br J Clin Pharmacol 2002;53:296304.
  • 60
    Gillen MS, Miller B, Chaikin P, Morganroth J. Effects of supratherapeutic doses of ebastine and terfenadine on the QT interval. Br J Clin Pharmacol 2001;52:201204.
  • 61
    Frank H Jr, Gillen M, Rohatagi SS, Lim J, George G. A double-blind, placebo-controlled study of the efficacy and safety of ebastine 20 mg once daily given with and without food in the treatment of seasonal allergic rhinitis. J Clin Pharmacol 2002;42:10971104.
  • 62
    Van Cauwenberge P, Juniper EF. Comparison of the efficacy, safety and quality of life provided by fexofenadine hydrochloride 120 mg, loratadine 10 mg and placebo administered once daily for the treatment of seasonal allergic rhinitis. Clin Exp Allergy 2000;30:891899.
  • 63
    Potter PC, Schepers JM, Van Niekerk CH. The effects of fexofenadine on reaction time, decision-making, and driver behavior. Ann Allergy Asthma Immunol 2003;91:177181.
  • 64
    Wahn U, Meltzer EO, Finn AF Jr, Kowalski ML, Decosta P, Hedlin G et al. Fexofenadine is efficacious and safe in children (aged 6–11 years) with seasonal allergic rhinitis. J Allergy Clin Immunol 2003;111:763769.
  • 65
    Meltzer EO, Scheinmann P, Rosado Pinto JE, Bachert C, Hedlin G, Wahn U et al. Safety and efficacy of oral fexofenadine in children with seasonal allergic rhinitis – a pooled analysis of three studies. Pediatr Allergy Immunol 2004;15:253260.
  • 66
    Horak F, Stubner P, Zieglmayer R, Kavina A, Corrado ME, Assandri A et al. Clinical study of the therapeutic efficacy and safety of emedastine difumarate versus cetirizine in the treatment of seasonal allergic rhinitis. Arzneimittelforschung 2004;54:666672.
  • 67
    Leynadier F, Mees K, Arendt C, Pinelli ME. Efficacy and safety of levocetirizine in seasonal allergic rhinitis. Acta Otorhinolaryngol Belg 2001;55:305312.
  • 68
    Potter PC. Levocetirizine is effective for symptom relief including nasal congestion in adolescent and adult (PAR) sensitized to house dust mites. Allergy 2003;58:893899.
  • 69
    Bachert C, Bousquet J, Canonica GW, Durham SR, Klimek L, Mullol J et al. Levocetirizine improves quality of life and reduces costs in long-term management of persistent allergic rhinitis. J Allergy Clin Immunol 2004;114:838844.
  • 70
    Gandon JM, Allain H. Lack of effect of single and repeated doses of levocetirizine, a new antihistamine drug, on cognitive and psychomotor functions in healthy volunteers. Br J Clin Pharmacol 2002;54:5158.
  • 71
    Hindmarch I, Johnson S, Meadows R, Kirkpatrick T, Shamsi Z. The acute and sub-chronic effects of levocetirizine, cetirizine, loratadine, promethazine and placebo on cognitive function, psychomotor performance, and weal and flare. Curr Med Res Opin 2001;17:241255.
  • 72
    Verster JC, Volkerts ER, Van Oosterwijck AW, Aarab M, Bijtjes SI, De Weert AM et al. Acute and subchronic effects of levocetirizine and diphenhydramine on memory functioning, psychomotor performance, and mood. J Allergy Clin Immunol 2003;111:623627.
  • 73
    Verster JC, De Weert AM, Bijtjes SI, Aarab M, Van Oosterwijck AW, Eijken EJ et al. Driving ability after acute and sub-chronic administration of levocetirizine and diphenhydramine: a randomized, double-blind, placebo-controlled trial. Psychopharmacology (Berl) 2003;169:8490.
  • 74
    Yang YH, Lin YT, Lu MY, Tsai MJ, Chiang BL. A double-blind, placebo-controlled, and randomized study of loratadine (Clarityne) syrup for the treatment of allergic rhinitis in children aged 3 to 12 years. Asian Pac J Allergy Immunol 2001;19:171175.
  • 75
    Salmun LM, Herron JM, Banfield C, Padhi D, Lorber R, Affrime MB. The pharmacokinetics, electrocardiographic effects, and tolerability of loratadine syrup in children aged 2 to 5 years. Clin Ther 2000;22:613621.
  • 76
    Bender BG, McCormick DR, Milgrom H. Children's school performance is not impaired by short-term administration of diphenhydramine or loratadine. J Pediatr 2001;138:656660.
  • 77
    Vuurman EF, Van-Veggel LM, Uiterwijk MM, Leutner D, O'Hanlon JF. Seasonal allergic rhinitis and antihistamine effects on children's learning. Ann Allergy 1993;71:121126.
  • 78
    Freche C, Leynadier F, Horak F, Hide D, Gracia FD, Goos M et al. Mizolastine provides effective symptom relief in patients suffering from perennial allergic rhinitis: a double-blind, placebo-controlled study versus loratadine. Ann Allergy Asthma Immunol 2002;89:304310.
  • 79
    Guadano EM, Serra-Batlles J, Meseguer J, Castillo JA, De Molina M, Valero A et al. Rupatadine 10 mg and ebastine 10 mg in seasonal allergic rhinitis: a comparison study. Allergy 2004;59:766771.
  • 80
    Berger WE, White MV. Efficacy of azelastine nasal spray in patients with an unsatisfactory response to loratadine. Ann Allergy Asthma Immunol 2003;91:205211.
  • 81
    Laforce CF, Corren J, Wheeler WJ, Berger WE. Efficacy of azelastine nasal spray in seasonal allergic rhinitis patients who remain symptomatic after treatment with fexofenadine. Ann Allergy Asthma Immunol 2004;93:154159.
  • 82
    Abelson MB, Turner D. A randomized, double-blind, parallel-group comparison of olopatadine 0.1% ophthalmic solution versus placebo for controlling the signs and symptoms of seasonal allergic conjunctivitis and rhinoconjunctivitis. Clin Ther 2003;25:931947.
  • 83
    Whitcup SM, Bradford R, Lue J, Schiffman RM, Abelson MB. Efficacy and tolerability of ophthalmic epinastine: a randomized, double-masked, parallel-group, active- and vehicle-controlled environmental trial in patients with seasonal allergic conjunctivitis. Clin Ther 2004;26:2934.
  • 84
    Jen A, Baroody F, De Tineo M, Haney L, Blair C, Naclerio R. As-needed use of fluticasone propionate nasal spray reduces symptoms of seasonal allergic rhinitis. J Allergy Clin Immunol 2000;105:732738.
  • 85
    Dykewicz MS, Kaiser HB, Nathan RA, Goode-Sellers S, Cook CK, Witham LA et al. Fluticasone propionate aqueous nasal spray improves nasal symptoms of seasonal allergic rhinitis when used as needed (prn). Ann Allergy Asthma Immunol 2003;91:4448.
  • 86
    Fokkens WJ, Cserhati E, Dos Santos JM, Praca F, Van Zanten M, Schade A et al. Budesonide aqueous nasal spray is an effective treatment in children with perennial allergic rhinitis, with an onset of action within 12 hours. Ann Allergy Asthma Immunol 2002;89:279284.
  • 87
    Skoner D, Rachelefsky G, Meltzer E, Chervinsky P, Morris R, Seltzer J et al. Detection of growth suppression in children during treatment with intranasal belcomethasone dipropionate. Pediatrics 2000;105:e23.
  • 88
    Allen DB, Meltzer EO, Lemanske RF Jr, Philpot EE, Faris MA, Kral KM et al. No growth suppression in children treated with the maximum recommended dose of fluticasone propionate aqueous nasal spray for one year. Allergy Asthma Proc 2002;23:407413.
  • 89
    Schenkel EJ, Skoner DP, Bronsky EA, Miller SD, Pearlman DS, Rooklin A et al. Absence of growth retardation in children with perennial allergic rhinitis after one year of treatment with mometasone furoate aqueous nasal spray. Pediatrics 2000;105:E22.
  • 90
    Daley-Yates PT, Richards DH. Relationship between systemic corticosteroid exposure and growth velocity: development and validation of a pharmacokinetic/pharmacodynamic model. Clin Ther 2004;26:19051919.
  • 91
    Fink RS, Pierre LN, Daley-Yates PT, Richards DH, Gibson A, Honour JW. Hypothalamic-pituitary-adrenal axis function after inhaled corticosteroids: unreliability of urinary free cortisol estimation. J Clin Endocrinol Metab 2002;87:45414546.
  • 92
    Kim KT, Rabinovitch N, Uryniak T, Simpson B, O'Dowd L, Casty F. Effect of budesonide aqueous nasal spray on hypothalamic-pituitary-adrenal axis function in children with allergic rhinitis. Ann Allergy Asthma Immunol 2004;93:6167.
  • 93
    Sheth KK, Cook CK, Philpot EE, Prillaman BA, Witham LA, Faris MA et al. Concurrent use of intranasal and orally inhaled fluticasone propionate does not affect hypothalamic-pituitary-adrenal-axis function. Allergy Asthma Proc 2004;25:115120.
  • 94
    Bross-Soriano D, Hanenberg-Milver C, Schimelmitz-IDI J, Arrieta-Gomez JR, Astorga Del Toro R, Bravo-Escobar G. Effects of three nasal topical steroids in the intraocular pressure compartment. Otolaryngol Head Neck Surg 2004;130:187191.
  • 95
    Suissa S, Baltzan M, Kremer R, Ernst P. Inhaled and nasal corticosteroid use and the risk of fracture. Am J Respir Crit Care Med 2004;169:8388.
  • 96
    Isaksson M, Bruze M. Allergic contact dermatitis in response to budesonide reactivated by inhalation of the allergen. J Am Acad Dermatol 2002;46:880885.
  • 97
    Bennett ML, Fountain JM, McCarty MA, Sherertz EF. Contact allergy to corticosteroids in patients using inhaled or intranasal corticosteroids for allergic rhinitis or asthma. Am J Contact Dermat 2001;12:193196.
  • 98
    Di Lorenzo G, Pacor ML, Pellitteri ME, Morici G, Di Gregoli A, Lo Bianco C et al. Randomized placebo-controlled trial comparing fluticasone aqueous nasal spray in mono-therapy, fluticasone plus cetirizine, fluticasone plus montelukast and cetirizine plus montelukast for seasonal allergic rhinitis. Clin Exp Allergy 2004;34:259267.
  • 99
    Webb DR, Meltzer EO, Finn AF Jr, Rickard KA, Pepsin PJ, Westlund R et al. Intranasal fluticasone propionate is effective for perennial nonallergic rhinitis with or without eosinophilia. Ann Allergy Asthma Immunol 2002;88:385390.
  • 100
    Bernstein DI, Levy AL, Hampel FC, Baidoo CA, Cook CK, Philpot EE et al. Treatment with intranasal fluticasone propionate significantly improves ocular symptoms in patients with seasonal allergic rhinitis. Clin Exp Allergy 2004;34:952957.
  • 101
    Craig TJ, Mende C, Hughes K, Kakumanu S, Lehman EB, Chinchilli V. The effect of topical nasal fluticasone on objective sleep testing and the symptoms of rhinitis, sleep, and daytime somnolence in perennial allergic rhinitis. Allergy Asthma Proc 2003;24:5358.
  • 102
    Ellegard EK, Hellgren M, Karlsson NG. Fluticasone propionate aqueous nasal spray in pregnancy rhinitis. Clin Otolaryngol 2001;26:394400.
  • 103
    Davis GA, Rudy AC, Archer SM, Wermeling DP, McNamara PJ. Effect of fluticasone propionate nasal spray on bioavailability of intranasal hydromorphone hydrochloride in patients with allergic rhinitis. Pharmacotherapy 2004;24:2632.
  • 104
    Gawchik S, Goldstein S, Prenner B, John A. Relief of cough and nasal symptoms associated with allergic rhinitis by mometasone furoate nasal spray. Ann Allergy Asthma Immunol 2003;90:416421.
  • 105
    Potter PC, Van Niekerk CH, Schoeman HS. Effects of triamcinolone on quality of life in patients with persistent allergic rhinitis. Ann Allergy Asthma Immunol 2003;91:368374.
  • 106
    McFadden EA, Gungor A, Ng B, Mamikoglu B, Moinuddin R, Corey J. Loratadine/pseudoephedrine for nasal symptoms in seasonal allergic rhinitis: a double-blind, placebo-controlled study. Ear Nose Throat J 2000;79:254, 257–258, 260 passim.
  • 107
    Nayak AS, Banov C, Corren J, Feinstein BK, Floreani A, Friedman BF et al. Once-daily mometasone furoate dry powder inhaler in the treatment of patients with persistent asthma. Cochrane Database Syst Rev 2000;2:417424.
  • 108
    Philip G, Malmstrom K, Hampel FC, Weinstein SF, Laforce CF, Ratner PH et al. Montelukast for treating seasonal allergic rhinitis: a randomized, double-blind, placebo-controlled trial performed in the spring. Clin Exp Allergy 2002;32:10201028.
  • 109
    Van Adelsberg J, Philip G, Pedinoff AJ, Meltzer EO, Ratner PH, Menten J et al. Montelukast improves symptoms of seasonal allergic rhinitis over a 4-week treatment period. Allergy 2003;58:12681276.
  • 110
    Van Adelsberg J, Philip G, Laforce CF, Weinstein SF, Menten J, Malice MP et al. Randomized controlled trial evaluating the clinical benefit of montelukast for treating spring seasonal allergic rhinitis. Ann Allergy Asthma Immunol 2003;90:214222.
  • 111
    Chervinsky P, Philip G, Malice MP, Bardelas J, Nayak A, Marchal JL et al. Montelukast for treating fall allergic rhinitis: effect of pollen exposure in 3 studies. Ann Allergy Asthma Immunol 2004;92:367373.
  • 112
    Meltzer EO, Malmstrom K, Lu S, Prenner BM, Wei LX, Weinstein SF et al. Concomitant montelukast and loratadine as treatment for seasonal allergic rhinitis: a randomized, placebo-controlled clinical trial. J Allergy Clin Immunol 2000;105:917922.
  • 113
    Philip G, Nayak AS, Berger WE, Leynadier F, Vrijens F, Dass SB et al. The effect of montelukast on rhinitis symptoms in patients with asthma and seasonal allergic rhinitis. Curr Med Res Opin 2004;20:15491558.
  • 114
    Kurowski M, Kuna P, Gorski P. Montelukast plus cetirizine in the prophylactic treatment of seasonal allergic rhinitis: influence on clinical symptoms and nasal allergic inflammation. Allergy 2004;59:280288.
  • 115
    Pullerits T, Praks L, Ristioja V, Lotvall J. Comparison of a nasal glucocorticoid, antileukotriene, and a combination of antileukotriene and antihistamine in the treatment of seasonal allergic rhinitis. J Allergy Clin Immunol 2002;109:949955.
  • 116
    Wilson AM, O'Byrne PM, Parameswaran K. Leukotriene receptor antagonists for allergic rhinitis: a systematic review and meta-analysis. Am J Med 2004;116:338344.
  • 117
    Simons FE, Johnston L, Gu X, Simons KJ. Suppression of the early and late cutaneous allergic responses using fexofenadine and montelukast. Ann Allergy Asthma Immunol 2001;86:4450.
  • 118
    Hill SL III, Krouse JH. The effects of montelukast on intradermal wheal and flare. Otolaryngol Head Neck Surg 2003;129:199203.
  • 119
    Casale TB, Condemi J, Laforce C, Nayak A, Rowe M, Watrous M et al. Effect of omalizumab on symptoms of seasonal allergic rhinitis: a randomized controlled trial. Jama 2001;286:29562967.
  • 120
    Adelroth E, Rak S, Haahtela T, Aasand G, Rosenhall L, Zetterstrom O et al. Recombinant humanized mAb-E25, an anti-IgE mAb, in birch pollen-induced seasonal allergic rhinitis. J Allergy Clin Immunol 2000;106:253259.
  • 121
    Chervinsky P, Casale T, Townley R, Tripathy I, Hedgecock S, Fowler-Taylor A et al. Omalizumab, an anti-IgE antibody, in the treatment of adults and adolescents with perennial allergic rhinitis. Ann Allergy Asthma Immunol 2003;91:160167.
  • 122
    Nayak A, Casale T, Miller SD, Condemi J, McAlary M, Fowler-Taylor A et al. Tolerability of retreatment with omalizumab, a recombinant humanized monoclonal anti-IgE antibody, during a second ragweed pollen season in patients with seasonal allergic rhinitis. Allergy Asthma Proc 2003;24:323329.
  • 123
    Berger W, Gupta N, McAlary M, Fowler-Taylor A. Evaluation of long-term safety of the anti-IgE antibody, omalizumab, in children with allergic asthma. Ann Allergy Asthma Immunol 2003;91:182188.
  • 124
    Vignola AM, Humbert M, Bousquet J, Boulet LP, Hedgecock S, Blogg M et al. Efficacy and tolerability of anti-immunoglobulin E therapy with omalizumab in patients with concomitant allergic asthma and persistent allergic rhinitis: SOLAR. Allergy 2004;59:709717.
  • 125
    Plewako H, Arvidsson M, Petruson K, Oancea I, Holmberg K, Adelroth E et al. The effect of omalizumab on nasal allergic inflammation. J Allergy Clin Immunol 2002;110:6871.
  • 126
    Bez C, Schubert R, Kopp M, Ersfeld Y, Rosewich M, Kuehr J et al. Effect of anti-immunoglobulin E on nasal inflammation in patients with seasonal allergic rhinoconjunctivitis. Clin Exp Allergy 2004;34:10791085.
  • 127
    Beck LA, Marcotte GV, MacGlashan D, Togias A, Saini S. Omalizumab-induced reductions in mast cell Fce psilon RI expression and function. J Allergy Clin Immunol 2004;114:527530.
  • 128
    Hanf G, Noga O, O'Connor A, Kunkel G. Omalizumab inhibits allergen challenge-induced nasal response. Eur Respir J 2004;23:414418.
  • 129
    Lin H, Boesel KM, Griffith DT, Prussin C, Foster B, Romero FA et al. Omalizumab rapidly decreases nasal allergic response and FcepsilonRI on basophils. J Allergy Clin Immunol 2004;113:297302.
  • 130
    Prussin C, Griffith DT, Boesel KM, Lin H, Foster B, Casale TB. Omalizumab treatment downregulates dendritic cell FcepsilonRI expression. J Allergy Clin Immunol 2003;112:11471154.
  • 131
    Kuehr J, Brauburger J, Zielen S, Schauer U, Kamin W, Von Berg A et al. Efficacy of combination treatment with anti-IgE plus specific immunotherapy in polysensitized children and adolescents with seasonal allergic rhinitis. J Allergy Clin Immunol 2002;109:274280.
  • 132
    Rolinck-Werninghaus C, Hamelmann E, Keil T, Kulig M, Koetz K, Gerstner B et al. The co-seasonal application of anti-IgE after preseasonal specific immunotherapy decreases ocular and nasal symptom scores and rescue medication use in grass pollen allergic children. Allergy 2004;59:973979.
  • 133
    Fokkens WJ, Scadding GK. Perennial rhinitis in the under 4s: a difficult problem to treat safely and effectively? A comparison of intranasal fluticasone propionate and ketotifen in the treatment of 2-4-year-old children with perennial rhinitis. Pediatr Allergy Immunol 2004;15:261266.