R E V I E W Effectiveness of twice daily azelastine nasal spray in patients with asonal allergic rhinitis
Friedrich Horak
incentiveMedical University Vienna,
ENT – Univ. Clinic, Vienna, Austria Correspondence: Friedrich Horak HNO – Univ. Klinik Wien, Waehringer Guertel 18–20, A-1090 Vienna, A ustria T el +43 1 404 003 336
Fax +43 1 789 76 76
Email friedrich.horak@vienna.at Abstract: Azelastine nasal spray (Allergodil®, Lastin®, Afl uon®; Meda AB, Stockholm, Sweden) is a fast-acting, effi cacious and well-tolerated H1-receptor antagonist for the treatment of rhinitis. In addition it also has mast-cell stabilizing and anti-infl ammatory properties, reducing the concentration of leukotrienes, kinins and platelet activating factor in vitro and in vivo, as well as infl ammatory cell migration in rhinitis patients. Well-controlled studies in patients with asonal allergic rhinitis (SAR), perennial rhinitis (PR) or vasomotor rhinitis (VMR) confi rm that azelastine nasal spray has a rapid ont of action, and improves nasal symptoms associated with rhinitis such as nasal congestion and post-nasal drip. Azelastine nasal spray is effective at the lower do of 1 spray as well
at a do of 2 sprays per nostril twice daily, but with an improved tolerability profi le compared to the 2-spray per nostril twice daily regimen. Compared with intranasal corticosteroids, azelastine nasal spray has a faster ont of action and a better safety profi le, showing at least comparable effi cacy with fl uticasone propionate (Flona®; GSK, USA), and a superior effi cacy to mometasone furoate (Nasonex®; Schering Plough, USA). In combination with fl uticasone propionate, azelastine nasal spray exhibits greater effi cacy than either agent ud alone, and this combination may provide benefi t for patients with diffi cult to treat asonal allergic rhinitis. In addition, azelastine nasal spray can be ud on an as-needed basis without compromising clinical effi cacy. Compared with oral antihistamines, azelastine nasal spray also demonstrates superior effi cacy and a more rapid ont of action, and is effective even in patients who did not respond to previous oral antihistamine therapy. Unlike most oral antihistamines, azelastine nasal spray is effective in alleviating nasal congestion, a particularly bothersome symptom for rhinitis sufferers. Azelastine nasal spray is well tolerated in both adults and children with allergic rhinitis. Bitter taste which ems to be associated with incorrect dosing technique is the most common side effect reported by patients, but this problem can be minimized by correct dosing technique.雅思作文句子
Keywords: azelastine nasal spray, rhinitis, intranasal corticosteroids, oral antihistamines, asonal allergic rhinitis
Introduction
have
Rhinitis is an inflammatory dia of the upper airways, affecting approximately 58 million people only in the United States alone (Settipane 2001) and its prevalence is increasing. The cost of the dia is signifi cant with between US$2 and US$5 billion incurred annually in both direct and indirect costs (Ray et al 1999; Reed et al 2004). In the US, the number of lost workdays is estimated as approximately 3.5 million a year (Mahr and Sheth 2005). It can be classifi ed as allergic, non-allergic or mixed upper respiratory disorder (Berstein 2007). It is classifi ed as allergic if symptoms occur in association with a specifi c IgE-mediated respon; as non-allergic if symptoms are induced by irritant triggers, but without an IgE-mediated respon; and as of mixed etiology if IgE-mediated respons occur in conjunction with symptoms induced by both allergens and non-allergic irritant triggers. Allergic rhinitis (AR) is further classifi ed as asonal or perennial (Dykewicz et al 1998). Seasonal allergic rhinitis
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(SAR) symptoms are induced by exposure to pollens from trees, grass, weeds or asonal mould spores, whilst peren-nial rhinitis (PR) is associated with environmental allergens which are generally prent on a year-round basis such as hou dust, animal dander and inct droppings (Dykewicz et al 1998). In contrast, the “Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines” recommend a classifi cation in intermittent allergic rhinitis and persistent allergic rhinitis according to the frequency and persistence of symptoms (Bousquet et al 2001).
Symptoms of SAR include nasal congestion, runny no, nasal and nasopharyngeal itching, ear symptoms, sneezing and ocular symptoms in many patients, including itchy and watery eyes (Bielory and Ambrosio 2002). The symptoms of sneezing, itching and rhinorrhea are less common with PR (Economides and Kaliner 2002). As many as half of all patients diagnod with rhinitis have non-allergic dia (sometimes called vasomotor rhinitis [VMR]) where an allergic component cannot be identifi ed (Dykewicz et al 1998). Symptoms are often induced by irritant triggers such as tobacco smoke, strong odors and temperature and pres-sure changes (Devyani and Corey 2004). The symptoms of VMR are similar to tho of AR (Devyani and Corey 2004). To further complicate rhinitis classifi cation, as many as half of all patients with AR are also nsitive to non-allergic triggers; a condition referred to as mixed rhinitis (Settipane and Settipane 2002; Liberman et al 2005)
. Symptoms of rhinitis can have a major impact on patients’ quality of life (QoL) by interfering with sleep which caus fatigue, and impairing daily activities and cognitive function (Dykewicz et al 1998). Patients often complain of an inability to concentrate, and in the ca of SAR often avoid outdoor activities in order to avoid exposure to symptom-inducing allergen(s). The Joint Task Force on Allergy Practice and Parameters advis that improving the negative impact on daily life in rhinitis patients defi nes successful treatment as much as providing symptom relief (Dykewicz et al 1998). Indeed, Juniper (1997) recommends that for most patients with rhinitis, improving patient well-being and QoL should be the primary goal of treatment.
Treatment guidelines from the Joint Task Force and WHO recommend that antihistamines, both topical (eg, azelastine [Allergodil®; Meda AB, Stockholm, Sweden]) and oral cond-generation (eg, loratadine [Claritin®, Schering Plough, USA], desloratadine [Clarinex®; Schering Plough, USA], fexofenadine [Allegra®; Sanofi Aventis, USA] or cetirizine [Zyrtec®; Pfi zer, USA], and levocetirizine [Xyzall®; UCB, EU]) be ud as fi rst-line therapy for AR (Dykewicz et al 1998; Bousquet et al 2001). Intranasal corticosteroids (eg, fl uticasone propionate [Flona®, GSK, USA], mometasone furoate [Nasonex®; Schering Plough, USA]) may also be considered as initial therapy for AR in patients with more vere symp-toms, particularly nasal congestion [(Dykewicz et al 1998; LaForce 1999). The All
ergic Rhinitis and its Impact on Asthma (ARIA) guidelines recommend a stepped approach to therapy bad upon the frequency and verity of symptoms (Table 1) (Bousquet et al 2001). Interestingly, a recent US nationwide survey incorporating approximately 2500 adult allergy suf-ferers, revealed that 66% were dissatisfi ed with their current allergy medication due to lack of effectiveness (Anon 2006). Furthermore, more than two-thirds of primary care physicians reported patient dissatisfaction with therapy as the main reason for stopping or switching medications (Anon 2001). Clearly, effective therapies with a good safety profi le are needed to treat AR sufferers.
Azelastine
广州伊利莎白医院Azelastine nasal spray is a topically administered cond-generation antihistamine and lectively antagonizes the H
1
-receptor (Zechel et al 1981) being approximately tenfold more potent than chlorpheniramine in this regard (Casale 1989). It has one of the fastest onts of action (15 min with nasal spray and up to 3 min with eye drops) among the currently available rhinitis medications (Baumgarten et al 1994; Greiff et al 1997). The effect of azelastine lasts at least 12 hours, thus allowing for a once or twice daily do
sing regimen (Greiff et al 1997). It has proven effi cacy in treating both allergic and non-allergic rhinitis, and is the only pre-scription antihistamine approved in the US, Portugal and the Netherlands for the treatment of both SAR (1996) and VMR (1999). In SAR patients azelastine therapy (two sprays per nostril twice daily), improved both total symptom and major symptom complex scores to a signifi cantly greater extent than placebo (McTavish and Sorkin 1989; Storms et al 1994; LaForce et al 1996; Ratner and Sacks 2007). Similarly, in PR patients, azelastine nasal spray signifi cantly improved sleep-ing, reduced daytime somnolence and nasal congestion com-pared with placebo (Golden et al 2000). Liberman et al (2005) were the fi rst to show that azelastine was also effective in the management of VMR and even in mixed rhinitis. Azelastine nasal spray signifi cantly (p Ͻ 0.01) reduced the total VMR symptom score (TVRSS) compared with placebo after 21-day double-blind treatment, and was associated with clinical improvement in each symptom of the TVRSS (ie, rhinorrhea, sneezing, nasal congestion, and post-nasal drip). In a large open-label trial 4364 patients received azelastine nasal spray
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Azelastine nasal spray
(2 sprays per nostril twice daily) as monotherapy for 2 weeks. 78% of VMR patients reported some or complete control of post-nasal drip which ro to 90% of SAR patients for the symptom of sneezing. Of patients reporting sleep diffi culties or impaired daytime activities becau of rhinitis symptoms, 85% experienced improvements in the parameters with azelastine. Baline sleep diffi culties and impairment of daytime activities were signifi cant (p Ͻ 0.01) predictors of a positive treatment effect with azelastine nasal spray. Female patients (p = 0.02), patients with SAR (p Ͻ 0.01) and patients with SAR plus nsitivity to non-allergic triggers (p = 0.03) were identifi ed as being most likely to respond to azelastine nasal spray (Liberman et al 2005) Due to its rapid ont of action, azelastine nasal spray continues to control rhinitis symptoms when ud on an as-needed basis (Ciprandi et al 1997). This property of azelastine is discusd later. First marketed in the UK in 1991 for the treatment of both SAR and PR, it is currently available in more than 70 countries world-wide.
Mode of action
企业英语培训H owever, azelastine is more than just an anti-histamine. It exhibits a very fast and long-acting effect bad on a triple mode of action, with anti-infl ammatory and mast cell stabilizing properties in addition to its anti-allergic effects (Bernstein 2007; Lee and Corren 2007). For example, azelas-tine i
nhibits the activation of cultured mast cells and relea of interleukin (IL)-6, trypta, and histamine (Kempuraj et al 2002). It also reduces mediators of mast cell degranu-lation such as leukotrienes which are involved in the late pha allergic respon (Howarth 1997), in the nasal lavage fl uid of patients with rhinitis (Shin et al 1992). It does this possibly by reducing the production of leukotriene (LT)B
4 and LTC
4
, inhibiting phospholipa A
2
and LTC
4
syntha (H amasaki et al 1996). Leukotrienes are associated with dilation of vesls, incread vascular permeability and edema which results in nasal congestion, mucus production and recruitme
x atr
nt of infl ammatory cells (Golden et al 2006). Substance P and bradykinin concentrations which are formed in biological fl uids and tissues during infl ammation, are also reduced by azelastine (Shin et al 1992; Nieber et al 1993; Shinoda et al 1997). The agents are associated with the AR symptoms of nasal itching and sneezing, but may also contribute to the ont of non-allergic VMR symptoms. Other anti-infl ammatory properties of azelastine include inhibition of tumor necrosis factor alpha (TNFα) relea
T able 1 Summary of ARIA allergic rhinitis management guidelines
Rhinitis verity ARIA recommendation
Mild intermittent • Oral/intranasal antihistamines OR
watchdog是什么意思• Decongestants (10 days maximum)
Moderate/vere intermittent • Intranasal antihistamines
• Oral antihistamines AND/OR
• Decongestants
汉堡包英语单词
• Intranasal corticosteroids
• Cromones
Mild persistent • Intranasal antihistamines
• Oral antihistamines AND/OR
• Decongestants
• Intranasal corticosteroids
• Cromones
A stepwi approach is advid with reasssment after 2 weeks. If symptoms
are controlled and the patient is on intranasal corticosteroid, the do should
be reduced, but otherwi treatment continued. If symptoms persist and the
patient is on antihistamines or cromones, a change should be made to an
intranasal corticosteroid.
Moderate/vere persistent • Intranasal corticosteroid (fi rst line treatment)
If symptoms are uncontrolled after 2–4 weeks, medication should be added
depending on the persistent symptom, eg, add an antihistamine if the major
symptom is rhinorrhea, pruitis, or sneezing, double the do of intranasal
深圳化妆培训steroid for persistent nasal blockage and add ipratropium for prominent
strongestcomplaint of rhinorrhea.
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(Hide et al 1997; Matsuo and Takayama 1998), reduction of granulocyte macrophage colony-stimulating factor (GM-CSF) generation, as well as a reduction in the number of a range of infl ammatory cytokines including interleukin (IL)-1β, IL-6, IL-4 and IL-8 (Y oneda et al 1997; Ito et al 199
8; Beck et al 2000). The cytokines perpetuate the infl ammatory respon (Settipane 2001). Finally, in SAR patients, azelastine nasal spray has been shown to lower neutrophil and eosinophil counts and decrea intercel-lular adhesion molecule-1 (ICAM-1) expression on nasal epithelial cell surfaces in both the early and late phas of the allergic reaction (Ciprandi et al 1996). It also decreas free-radical production by human eosinophils and neutrophils (Bus et al 1989; Umeki 1992) and calcium infl ux induced by platelet-activating factor in vitro (Nakamura et al 1988; Morita et al 1993).
The u of a topical treatment has many advantages over a systemic treatment. Firstly, with a nasal spray, medication can be delivered directly to the site of allergic infl ammation. Secondly, the higher concentrations of antihistamines that can be achieved in the nasal mucosa by topical as oppod to oral administration should enhance the anti-allergic and potential anti-infl ammatory effects of the agents. Thirdly, a do of 0.28 mg intranasally has a faster ont of action than a do of 2.2 mg administrated orally (Horak et al 1994). And fi nally, with topical administration the risk of interaction with concomitant medication is minimized (Davies et al 1996) and the potential of systemic effects reduced.
Dosage
Recent results from 2 studies have shown that azelastine nasal spray at a dosage of 1 spray per nostril twice daily is effec-tive and has a better tolerability profi le compared to 2 sprays per nostril twice daily in patients (Ն12 years; n = 554) with moderate to vere SAR (Lumry et al 2007). The total nasal symptom score (TNSS) improved by 14.1% in study 1 and by 22.1% in study 2 with azelastine nasal spray (1 spray per nostril twice daily) compared with 4.5% and 12.0% with placebo in study 1 (p = 0.01) and 2 (p Ͻ 0.01) respectively. This compares with a 24%–29% improvement in rhinitis symptoms scores with a 2-spray dosage of azelastine (Ratner et al 1994; Storms et al 1994; LaForce et al 1996). For individual symptoms, itchy no, runny no, sneezing, and nasal congestion were all signifi cantly improved after the 1-spray azelastine regimen compared with placebo. One spray per nostril twice daily of azelastine was also associ-ated with signifi cant improvements in the Rhinitis Quality of Life Questionnaire (RQLQ) daily activity and nasal symptoms domains and patient global evaluations compared with placebo. In addition, the incidence of a bitter taste after azelastine application more than halved and the incidence of somnolence decread almost 30 times in the 1-spray group versus the labeled incidence with the 2-spray regimen (Lumry et al 2007). Although an earlier study showed an improve-ment in rhinitis symptoms versus placebo with azelastine 1 spray per nostril twice daily, this improvement failed to reach statistical signifi cance. However, a global evaluation noted a signifi cant clinical improvement versus placebo (49%) i
n the 1-spray regimen (75%, p Ͻ 0.001) as well as a 2-spray once daily (89%, p = 0.028) and a 2-spray twice daily regimen (83%, p Ͻ 0.001) (Weiler et al 1994).
From the results one can conclude that a greater degree of effectiveness would be expected with two sprays per nostril twice daily. Although one spray per nostril twice daily may provide somewhat less effi cacy this is compensated for by an improved tolerability profi le compared with the 2-spray regimen. Therefore, the choice of dosage of azelastine nasal spray should be bad on the verity and persistence of symptoms as well as the patient’s acceptance of the nasal spray (Bernstein 2007). For example, the 2-spray do could be ud as the starting do for patients with vere symptoms of SAR, and either maintained or tapered to the 1-spray do as required. The 1-spray do could be ud as a starting do in patients with mild-to-moderate symptoms, and if necessary the do incread to 2 sprays per nostril twice daily if symptom control proved to be inadequate (Lumry et al 2007).
As-needed
Becau azelastine starts working within 15 minutes of application investigators wondered how effective an as-needed regimen would be in controlling the symptoms of rhinitis (Ciprandi et al 1997).
A randomized controlled study was car-ried out in 30 patients nsitized to Parietaria pollen or grass. Patients were treated with the standard European do of azelas-tine (0.56 mg/day), half this do (0.22 mg/day), or as-needed. Both groups who received the standard and half-standard dos showed an improvement in their rhinitis symptoms, with a concomitant reduction in markers of infl ammation, namely neutrophil and eosinophil counts as well as ICAM-1 expression in nasal scrapings. However, patients who ud azelastine nasal spray on an as-needed basis also showed an improvement in their rhinitis symptoms, but without a reduction in the markers of infl ammation. The results of this small study suggest that although regular treatment with azelastine is superior at controlling symptoms, as-needed therapy may be
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