Azelastine Hydrochloride and Fluticasone Propionate in the

Alleviation of Allergic Rhinitis

Xiangkun Xu

Vision Academy, Shanghai, 200050, China

Keywords: Allergic Rhinitis, Azelastine Hydrochloride, Fluticasone Propionate.

Abstract: Allergic rhinitis is a global health problem. Although it does not endanger the life of patients with allergic

rhinitis, its symptoms, such as rhinorrhea, sneezing, nasal itching, and nasal obstruction, can seriously affect

the patients' quality of daily life and cause an economic burden to individual and country. In this paper, I

summarize the pathology of allergic rhinitis, as well as introduce three classes of drugs used to treat allergic

rhinitis, which includes corticosteroids, H1 receptor antagonists, leukotriene receptor antagonists. Among

them, azelastine hydrochloride and fluticasone propionate are taken as examples to introduce their respective

targets and specific pharmacological effects when contrasting H1 receptor antagonists and corticosteroids.

The reasons why corticosteroids became first-line drugs and their limitations are elaborated.

1 INTRODUCTION

Allergic rhinitis is a nasal symptomatic disease

caused by nasal mucositis after allergen exposure.

It belongs to type Ⅰ hypersensitivity

reactions(Vaillant et al 2020) and contains an early-

phase and late-phase allergic response (Sin, Togias

2011, Min 2010). The hallmark of allergic rhinitis is

nasal congestion, which often causes sleep

disturbances in patients. Approximately one-quarter

of 2500 adults in America reported that they would

wake up or be unable to sleep at night because of the

symptoms in a research in 2012(Meltzer et al 2012).

A survey of 35757 families in the United States

reported sleep disruption due to nasal allergic

symptoms in up to 45% of children in 2009(Meltzer

et al 2009). This phenomenon leads to mental fatigue

and low mood of people. It also causes cognitive

impairment, depression, and anxiety in patients by the

combination with other symptoms, which leads to a

decrease in work productivity of adults, and learning

disabilities of children, an inability of children to get

along better with their peers. As a result, there is a

negative impact on patients' quality of life (Meltzer,

2001, Muñoz-Cano R et al 2018).

2 THE DISEASE

2.1 Significance in China and Other

Countries in the World

Allergic rhinitis is a common disease that affects up

to 40% of the global population with about 23% to

30% of Europeans with a prevalence of 25% in

Sweden in 2012 (Bauchau, Durham 2004), and 12%

- 30% of the population in the United States (Nathan

et al 2008). People with allergic rhinitis are obliged

to ease their symptoms by using medicines. For

example, in 2017, fluticasone propionate that is a

drug to alleviate symptoms of allergic rhinitis was the

15th most commonly prescribed medication in the

United States, with more than 32 million

prescriptions (up from 16th place & 29 million in

2016). In 2018, azelastine hydrochloride that is also a

drug to alleviate symptoms of allergic rhinitis was the

240th most commonly prescribed medication in the

United States, with more than 2 million prescriptions.

The prevalence of allergic rhinitis is increasing

globally (Dykewicz, Hamilos 2010). It is usually a

long-standing disease and often goes unnoticed by

people due to its high universality of symptoms at its

initial stage. Although it is not life-threatening, its

symptoms are often bothersome and reduce the

quality of life and work of people, and it also causes

a significant burden on the individual and the country

916

Xu, X.

Azelastine Hydrochloride and Fluticasone Propionate in the Alleviation of Allergic Rhinitis.

DOI: 10.5220/0011313100003443

In Proceedings of the 4th International Conference on Biomedical Engineering and Bioinformatics (ICBEB 2022), pages 916-925

ISBN: 978-989-758-595-1

(Canonica et al 2007). The burden on society is the

costs associated with the treatment of allergic rhinitis

(Simoens, Laekeman 2009). Although the direct cost

of treating allergic rhinitis is not obvious, it incurs

substantial indirect costs (Bousquet et al 2008).

In 2016, the total cost of allergic rhinitis was

estimated at € 1.3 billion per year in Sweden, which

has a population of 9.5 million people. The total cost

per person per year due to allergic rhinitis was €

961.1, which includes mean direct and indirect costs

of € 210.3 and € 750.8, respectively in

Sweden(Cardell et al 2016)]. In Germany, the total

cost of allergic rhinitis was € 240 million in 2000,

which included both direct and indirect costs (Bachert

et al. 2006). It is difficult to search the prevalence of

allergic rhinitis in China in recent years because of

the paucity of relevant data on allergic rhinitis.

According to the data of The National Bureau of

Statistics of China, China had a population of 1.37

billion at the end of 2014. The prevalence of allergic

rhinitis reported in 18 major cities in China was

17.6%.

The overall prevalence in the four major cities of

Western China (Chengdu, Chongqing, Nanning, and

Urumqi) is 34.3%, 34.3% in Chengdu, 32.3% in

Chongqing, 30.3% in Nanning, and 37.9% in Urumqi

(Figure 1). The overall prevalence of allergic rhinitis

in several areas in northern China (rural areas of

Qingxian, Hebei; coastal fishing village of Bohai

Bay, Huanghua; area of Wuling Mountain, Chengde;

urban areas of Tianjin) are about 9.2% (Zhang, Zhang

2014). This preliminary suggests that different

geographical and climatic contribute to the

differences in prevalence. Meanwhile, occupational

factors are also considered as one of the reasons for

the different prevalence. For example, farmers have a

2.32-fold increased risk (Wang et al 2011, 2012).

Although there is variation in prevalence across

regions, the prevalence has generally increased in

both adults and children over the past 20 years. The

epidemic trends of allergic rhinitis in China and the

trends of other developing countries are the same.

Figure 1: Prevalence of allergic rhinitis in adults and children in different cities in China in 2008 (Zhang, Zhang 2014)].

Azelastine Hydrochloride and Fluticasone Propionate in the Alleviation of Allergic Rhinitis

917

2.2 The Pathology of Allergic Rhinitis

and Its Symptoms

Antigens that cause hypersensitivity reactions are

called allergens, which contain certain drugs, plant

pollen, dust mites, fungal spores, animal dander or

feathers, insects or their venoms as well as foods,

such as fish, shrimp, eggs, milk, and certain enzymes

classes, such as subtilisin.

When the allergens enter the human body, they

stimulate B-lymphocytes to convert into plasma cells

which can produce immunoglobulin E (IgE)

antibodies. IgE is found at very low levels in normal

human serum and is significantly increased in the

serum of hypersensitive patients, so it is often

considered by doctors as an important indicator for

the diagnosis of allergic diseases (Ansotegui et al.

2020).

IgE has a high affinity for basophils and mast

cells, so they can bind to high-affinity IgE receptors

(FcεRI) on the surface of tissue mast cells and blood

basophils (Turner, Kinet 1999). When there is a

reappearance of the same allergen and cross-links to

IgE on the cell surface, FcεRI activates mast cells or

basophils by signal transduction and releases

intragranular active mediators, such as histamine,

kinins, proteases, chemokines, and heparin

(Siraganian 2003), and several types of type 2

cytokines like interleukin (IL)-3. This process is

called degranulation (Figure 2), which is the feature

of the early-phase reaction (Figure 3). At the same

time, arachidonic acid is released from cell

membrane phospholipids of activated mast cells and

basophils, then it is catalyzed by lipoxygenases or

cyclooxygenases to form the inflammatory lipid

mediators that include leukotrienes (composed of

LTC4, LTD4, and LTE4) and prostaglandins,

respectively (Moon, Befus, Kulka 2014). Symptoms

triggered by histamine-mediated anaphylaxis and

inflammatory mediators in the early-phase response

include bronchoconstriction, vasodilation, smooth

muscle contraction, etc.

Late-phase allergic responses (Figure 3) appear

several hours after exposure to the allergen. The

responses are characterized by the cellular

recruitment of basophils, neutrophils, T-

lymphocytes, monocytes, and eosinophils. They can

release several mediators, including cytokines,

prostaglandins, and leukotrienes, which increase the

duration of the inflammatory response (Sin, Togias

2011, Min 2010). This means that the late-phase

response is related to the development and

persistence of tissue edema and nasal congestion.

Figure 2: Degranulation processes 1 - antigen; 2 - IgE

antibody; 3 - FcεRI receptor; 4 - preformed mediators

(histamine, proteases, chemokines, heparin); 5 - granules; 6

- mast cell; 7 - newly formed mediators (prostaglandins,

leukotrienes).

Figure 3: Early-phase and late-phase allergic response of allergic rhinitis (Bjermer, Westman, Holmström, Wickman 2019).

ICBEB 2022 - The International Conference on Biomedical Engineering and Bioinformatics

918

The main symptoms of patients with allergic

rhinitis are runny nose, sneezing, nasal itching, and

nasal congestion, it is usually accompanied by ocular

pruritus, redness, and/or lacrimation in 60% - 70% of

patients (Canonica et al 2007, Bousquet et al 2008,

Schatz 2007). Subsequent disease development may

lead to related conjunctivitis, postnasal drip,

eustachian tube dysfunction, otitis media, etc. At the

same time, about 20% - 50% of patients with allergic

rhinitis suffer from clinical asthma (Strachan et al

1997), which shows allergic rhinitis often coexists

with asthma.

2.3 Drugs Used to Treat the Disease

and Their Origins

There are three categories of drugs that are used to

treat allergic rhinitis. They have different modes of

action and different interactions in allergic rhinitis

cases.

a) H1 receptor antagonists

The first-generation of H1 receptor antagonists

(Figure 4), diphenhydramine (Benadryl),

carbinoxamine (Clistin), clemastine (Tavist),

chlorpheniramine (Chlor-Trimeton), and

brompheniramine (Dimetane) that were marketed

before the 1980s (Berdy et al 1991, Welch et al 2002)

can cross the blood-brain barrier and enter the central

nervous system because of their high lipid solubility,

which causes the side effects of central depression

and sedation(Kay 2000). At the same time, the

selectivity to the H1 receptor of the first generation of

H1 receptor antagonists is not strong enough

(Kalpaklioglu, Baccioglu 2012), so there are the side

effects, such as anti-cholinergic, anti-adrenergic,

analgesic effects (Ali Habibi ETR 1991).

Second-generation H1 receptor antagonists

(Figure 4), such as cetirizine, terfenadine, astemizole,

loratadine, azelastine, and acrivastine (Aaronson

1991), were invented to overcome these side effects

as much as possible. They are more hydrophilic and

less lipophilic, and they also have a higher selectivity

for the H1 receptor, which means that the possibility

of the drugs crossing the blood-brain barrier is greatly

reduced and the central side effects are attenuated

compared with the first generation of H1 receptor

antagonists (Kay 2000).

Figure 4: Chemical structures of H1 receptor antagonists (Simons, Simons 1994) The treatment of allergic rhinitis generally

requires intranasal and oral H1 receptor antagonists. After oral administration, the concentration of the drug in the nasal cavity

often cannot reach the effective value (Molimard, Diquet, Benedetti 2004, Urien et al 1999), so it is necessary to increase the

concentration through intranasal injection (Horak, Zieglmayer 2009).

Azelastine Hydrochloride and Fluticasone Propionate in the Alleviation of Allergic Rhinitis

919

b) Corticosteroids

Corticosteroids are considered a safe and effective

first-line treatment for allergic rhinitis, although it

was initially reserved as a second-line agent (Group

IRMW 1994). Several intranasal corticosteroids are

available for allergic rhinitis (Figure 5), such as

beclomethasone dipropionate, budesonide,

flunisolide, fluticasone propionate, mometasone

furoate, and triamcinolone acetonide (Trangsrud,

Whitaker, Small 2002). The following contents

include the relationships of structure-activity of

corticosteroids.

The carbon skeleton of each corticosteroid

consists of three 6-carbon rings (rings A, B, and C)

and one 5-carbon ring (ring D). Common features

among each other are the ketone oxygen group at

position 3, unsaturated double bond between carbons

4 and 5, hydroxyl group at position 11, and a ketone

oxygen group on carbon 20. The changes at positions

16, 17, and 21, outside the D-loop, are the largest

differences between the individual molecules (Szefler

2001).

For example, the furoate group of mometasone

furoate can enhance the molecular affinity to the

glucocorticoid receptor binding site. Other groups

improve the activity of corticosteroid compounds.

Figure 5: Chemical structures of corticosteroids.

Modes of administration include intranasal

administration and systemic administration. The

common way is intranasal administration because

anti-inflammatory effects of the drugs can be

problematic if systemic concentrations of these drugs

are excessive, and intranasal administration can

achieve the efficacy of systemic administration while

minimizing side effects by oral administration for

patients with allergic rhinitis (Pichler, Klint, Blaser,

Graf, Sauter, Weiss et al.1988).

c) Leukotriene receptor antagonists

Leukotriene receptor antagonists, such as

montelukast, zafirlukast, and pranlukast, can block

the activity or secretion of cysteinyl leukotriene

(CysLT) that is an inflammatory mediator and

include leukotriene C4(LTC4), leukotriene

D4(LTD4), and leukotriene E4(LTE4) (Peters-

Golden, Henderson 2005). There are two ways to

block the action of leukotrienes. The first way is to

inhibit the synthetic pathway of leukotriene

metabolism by inhibiting 5-lipoxygenase. The second

way is to rely on the antagonistic effect of drugs on

cysteinyl-leukotriene type 1 (CysLT1) receptors,

such as montelukast and zafirlukast, which can block

the effect of CysLT on CysLT1 receptor of target

cells, such as bronchial smooth muscle. Therefore, it

can alleviate the symptoms of allergic rhinitis (Singh

2013).

3 AZELASTINE

HYDROCHLORIDE AND

FLUTICASONE PROPIONATE

3.1 Basic Information on Azelastine

Hydrochloride and Fluticasone

Propionate

a) Azelastine hydrochloride

The IUPAC name of azelastine hydrochloride is

4-[(4-chlorophenyl)methyl]-2-(1-methylazepan-4-

yl)phthalazin-1-one;hydrochloride. ‘Hydrochloride’

means that it is the hydrochloride salt of azelastine.

The molecular formula of azelastine

hydrochloride is C22H24ClN3O.HCl. Figure 6 and

figure 7 show the chemical structure of azelastine

hydrochloride.

ICBEB 2022 - The International Conference on Biomedical Engineering and Bioinformatics

920

Figure 6: Chemical structure of azelastine hydrochloride

(2D).

Figure 7: Chemical structure of azelastine (3D).

Azelastine hydrochloride is a racemic mixture

with a melting point of 225°C, so it is a white

crystalline powder at room temperature with a

molecular weight of 418.37. It is sparingly soluble in

water, methanol, and propylene glycol, and slightly

soluble in ethanol, octanol, and glycerine. It is sold as

a form of the solution under the brand name Optivar.

b) Fluticasone propionate

The IUPAC name of fluticasone propionate is

[(6S,8S,9R,10S,11S,13S,14S,16R,17R)-6,9-

difluoro-17-(fluoromethylsulfanylcarbonyl)-11-

hydroxy-10,13,16-trimethyl-3-oxo-

6,7,8,11,12,14,15,16-

octahydrocyclopenta[a]phenanthren-17-yl]

propanoate. Fluticasone Propionate is the propionate

salt form of fluticasone.

The molecular formula of fluticasone propionate

is C25H31F3O5S. Figure 8 and figure 9 show the

chemical structure of fluticasone propionate.

Figure 8: Chemical structure of fluticasone propionate

(2D).

Figure 9: Chemical structure of fluticasone propionate

(3D).

The melting point of fluticasone Propionate is

261-273 °C, so it is solid at room temperature with a

molecular weight of 500.6. It is insoluble in water and

sold under the brands of Flovent and Florase. So, it is

not easy to dissolve in human bronchial fluid, the

deposition of drugs in the airways increases. The

release of drugs is slower, and the local action time is

longer.

3.2 Pharmacology of Azelastine

Hydrochloride and Fluticasone

Propionate

a) Azelastine hydrochloride

H1 histamine receptors belong to the family of

rhodopsin-like G-protein-coupled receptors. They are

activated by histamine and are expressed in smooth

muscles, vascular endothelial cells, the heart, and the

central nervous system. It can trigger anaphylaxis

mediated by histamine.

In the type Ⅰ hypersensitivity allergic reactions

process, once histamine is released from mast cells or

basophils by cellular degranulation, it can bind to H1

histamine receptors to initiate allergic reactions

(Lytina et al 2002, Tamaoki et al 1999). Azelastine

Azelastine Hydrochloride and Fluticasone Propionate in the Alleviation of Allergic Rhinitis

921

hydrochloride is useful in the treatment of allergic

rhinitis by competing with histamine for H1

histamine receptors (Figure 10).

Therefore, histamine-mediated symptoms of

anaphylaxis, such as rhinorrhea, itching, and sneezing

are reduced. This drug also has the effects of

stabilizing mast cells, anti-leukotrienes, and anti-

inflammatory (Horak, Zieglmayer 2009).

Azelastine hydrochloride can effectively block

the calcium channel regulated by IgE in the

degranulation process of mast cells and stabilize mast

cells, so it can prevent the release of histamine and

other mediators, such as prostaglandins, kinin, and

interleukin (Van Hoecke, Vandenbulcke, Van

Cauwenberge 2007, Kempuraj et al 2003).

Azelastine hydrochloride can inhibit

phospholipase A2 and LTC4 synthase and prevents

the release of leukotriene (LTB4 and LTC4) by

stabilizing mast cells (Hamasaki et al. 1996).

Anti-inflammatory properties of azelastine

hydrochloride are resulted from inhibiting the release

of inflammatory cells and mediators. These include

eosinophils and neutrophils as well as mediators.

Figure 10: The process of preventing mast cell

degranulation.

b) Fluticasone propionate

The glucocorticoid receptor (GR) is the receptor

to which cortisol that is the endogenous

glucocorticoid hormone and is produced in many

animals, mainly by the zona fasciculata of the adrenal

cortex in the adrenal gland (Thau, Gandhi, Sharma.

Physiology, cortisol. 2019.), and other glucocorticoid

receptor agonists (GC) bind. It is expressed in almost

every cell in the body. When cortisol or GC bind to

GR, it achieves anti-inflammatory effects by

regulating gene transcription (Lu et al 2006, Rhen

2005).

Glucocorticoid receptor agonists that have often

been used to treat allergic rhinitis belong to

corticosteroids. Fluticasone propionate, one of the

glucocorticoid receptor agonists (GC molecules),

binds to and activates glucocorticoid receptors (GR),

thereby activating lipocortins. Lipocortins can inhibit

cytosolic phospholipase A2 that can trigger a cascade

of responses involved in the synthesis of

inflammatory mediators, such as prostaglandins and

leukotrienes. The transcriptional activity of nuclear

factor kappa-B(NF-κB) is blocked, thereby inhibiting

the transcription of cyclooxygenase 2, which is

essential for the production of prostaglandin.

The complex formed from binding the molecules

of fluticasone propionate to GR can alter

transcriptional activity (Figure 11), which leads to

decreased expression of proinflammatory molecules

and cells, including Langerhans cells, lymphocytes,

mast cells, basophils, and eosinophils, and inhibits

the arrival of Langerhans cells, macrophages, mast

cells, T-lymphocytes, and eosinophils in the nasal

mucosa (Holm et al 2001). At the same time, it

increases anti-inflammatory molecules and β-

expression of adrenergic receptors (Mygind et al.

2001).

Figure 11: Actions of glucocorticoid (GC) molecule in the inflammatory process (Mygind et al. 2001).

ICBEB 2022 - The International Conference on Biomedical Engineering and Bioinformatics

922

c) Compare azelastine hydrochloride and

fluticasone propionate

Table 1: The differences between azelastine hydrochloride and fluticasone propionate.

azelastine hydrochloride fluticasone propionate

Targets of

drug

H1 histamine receptors on the

target cell.

The glucocorticoid receptors on the target cell.

Functions Compete with histamine for H1

histamine receptors.

Effects of stabilizing mast cells,

anti-leukotrienes, and anti-

inflammatory.

Bind to and activates glucocorticoid receptors, thereby activating lipocortins

and reducing the production of inflammatory mediators.

Alter transcriptional activity, that leads to decreased expression of

proinflammatory molecules and cells, an increase in expression of anti-

inflammatory molecules, and β-expression of adrenergic receptors.

The different pharmacology of the two drugs has

led to different therapeutic effects (see Table 1). Most

patients with allergic rhinitis who present to a

primary care physician have moderate to severe

symptoms, the use of fluticasone propionate is a

better option (Bousquet et al. 2003) because

fluticasone propionate is a potent inhibitor of

anaphylaxis in the late phase of allergic rhinitis. They

are more effective to control the symptoms of allergic

rhinitis, including nasal congestion, and rhinorrhea

than leukotriene receptor antagonists than H1

receptor antagonists (Weiner, Abramson, Puy 1998).

However, it is important to note that intranasal

corticosteroids are best initiated before exposure to

relevant allergens, as their peak effects may take

several days to develop, necessitating their regular

use to achieve better outcomes (Lee, Mace 2009).

4 CONCLUSION

This article has summarized the pathology of allergic

rhinitis and its symptoms, its significance in China

and other countries, and the current three classes of

drugs to treat it. At the same time, azelastine

hydrochloride and fluticasone propionate were used

as an example to explain the targets and

pharmacological effects of these two classes of drugs.

Typically, the effects of intranasal corticosteroids are

more obvious than those of second-generation

antihistamines. It is worth noting that current

medications only alleviate symptoms of allergic

rhinitis. Finding any approach to the thorough

treatment of allergic rhinitis is the direction of

research in the future.

REFERENCES

Aaronson D. Comparative efficacy of H1 antihistamines.

Annals of allergy. 1991;67(5):541-7.

Ali Habibi ETR. Antihistamines: H1- and H2-Blockers. in

Complications in Anesthesia (Second Edition). 2007.

Ansotegui IJ, Melioli G, Canonica GW, Caraballo L, Villa

E, Ebisawa M, et al. IgE allergy diagnostics and other

relevant tests in allergy, a World Allergy Organization

position paper. World allergy organization journal.

2020;13(2):100080.

Bachert C, Borchard U, Wedi B, Klimek L, Rasp G,

Riechelmann H, et al. Allergic rhinoconjunctivitis.

Guidelines of the DGAI in association with the DDG.

Journal der Deutschen Dermatologischen

Gesellschaft= Journal of the German Society of

Dermatology: JDDG. 2006;4(3):264-75.

Bauchau V, Durham S. Prevalence and rate of diagnosis of

allergic rhinitis in Europe. European respiratory

journal. 2004; 24(5):758-64.

Berdy GJ, ABELSON MB, GEORGE MA, SMITH LM,

GIOVANONI RL. Allergic conjunctivitis: a survey of

new antihistamines. Journal of Ocular Pharmacology

and Therapeutics. 1991;7(4):313-24.

Bjermer L, Westman M, Holmström M, Wickman MC. The

complex pathophysiology of allergic rhinitis: scientific

rationale for the development of an alternative

treatment option. Allergy, Asthma & Clinical

Immunology. 2019;15(1):1-15.

Bousquet J, Khaltaev N, Cruz AA, Denburg J, Fokkens W,

Togias A, et al. Allergic rhinitis and its impact on

asthma (ARIA) 2008. Allergy. 2008;63:8-160.

Bousquet J, Lund V, Van Cauwenberge P, Bremard‐Oury

C, Mounedji N, Stevens M, et al. Implementation of

guidelines for seasonal allergic rhinitis: a randomized

controlled trial. Allergy. 2003;58(8):733-41.

Canonica G, Bousquet J, Mullol J, Scadding G, Virchow J.

A survey of the burden of allergic rhinitis in Europe.

Allergy. 2007;62:17-25.

Cardell L-O, Olsson P, Andersson M, Welin K-O,

Svensson J, Tennvall GR, et al. TOTALL: high cost of

Azelastine Hydrochloride and Fluticasone Propionate in the Alleviation of Allergic Rhinitis

923

allergic rhinitis—a national Swedish population-based

questionnaire study. NPJ primary care respiratory

medicine. 2016;26(1):1-5.

Dykewicz MS, Hamilos DL. Rhinitis and sinusitis. Journal

of Allergy and Clinical Immunology. 2010;

125(2):S103-S15.

Group IRMW. International consensus report on the

diagnosis and management of allergic rhinitis. Allergy.

1994;49:5-34.

Hamasaki Y, Shafigeh M, Yamamoto S, Sato R, Zaitu M,

Muro E, et al. Inhibition of leukotriene synthesis by

azelastine. Annals of Allergy, Asthma & Immunology.

1996;76(5):469-75.

Holm A, Dijkstra M, Kleinjan A, Severijnena L-a, Boksa S,

Mulder P, et al. Fluticasone propionate aqueous nasal

spray reduces inflammatory cells in unchallenged

allergic nasal mucosa: effects of single allergen

challenge. Journal of allergy and clinical immunology.

2001;107(4):627-33.

Horak F, Zieglmayer UP. Azelastine nasal spray for the

treatment of allergic and nonallergic rhinitis. Expert

Review of Clinical Immunology. 2009;5(6):659-69.

Kalpaklioglu F, Baccioglu A. Efficacy and safety of H1-

antihistamines: an update. Anti-Inflammatory & Anti-

Allergy Agents in Medicinal Chemistry (Formerly

Current Medicinal Chemistry-Anti-Inflammatory and

Anti-Allergy Agents). 2012;11(3):230-7.

Kay GG. The effects of antihistamines on cognition and

performance. Journal of Allergy and Clinical

Immunology. 2000;105(6):S622-S7.

Kempuraj D, Huang M, Kandere-Grzybowska K, Basu S,

Boucher W, Letourneau R, et al. Azelastine inhibits

secretion of IL-6, TNF-α and IL-8 as well as NF-κB

activation and intracellular calcium ion levels in normal

human mast cells. International archives of allergy and

immunology. 2003;132(3):231-9.

Lee P, Mace S. An approach to allergic rhinitis. Allergy

Rounds. 2009;1:1.

Lu NZ, Wardell SE, Burnstein KL, Defranco D, Fuller PJ,

Giguere V, et al. International Union of Pharmacology.

LXV. The pharmacology and classification of the

nuclear receptor superfamily: glucocorticoid,

mineralocorticoid, progesterone, and androgen

receptors. Pharmacological reviews. 2006;58(4):782-

97.

Lytinas M, Kempuraj D, Huang M, Kandere K, Boucher

W, Letourneau R, et al., editors. Azelastine's inhibition

of histamine and tryptase release from human umbilical

cord blood-derived cultured mast cells as well as rat

skin mast cell-induced vascular permeability:

comparison with olopatadine. Allergy and asthma

proceedings; 2002: OceanSide Publications.

Meltzer EO, Blaiss MS, Derebery MJ, Mahr TA, Gordon

BR, Sheth KK, et al. Burden of allergic rhinitis: results

from the Pediatric Allergies in America survey. Journal

of Allergy and Clinical Immunology. 2009;124(3):S43-

S70.

Meltzer EO, Blaiss MS, Naclerio RM, Stoloff SW,

Derebery MJ, Nelson HS, et al., editors. Burden of

allergic rhinitis: allergies in America, Latin America,

and Asia-Pacific adult surveys. Allergy and Asthma

Proceedings; 2012: OceanSide Publications, Inc.

Meltzer EO. Quality of life in adults and children with

allergic rhinitis. Journal of allergy and clinical

immunology. 2001;108(1):S45-S53.

Min Y-G. The pathophysiology, diagnosis and treatment of

allergic rhinitis. Allergy, asthma & immunology

research. 2010;2(2):65-76.

Molimard M, Diquet B, Benedetti MS. Comparison of

pharmacokinetics and metabolism of desloratadine,

fexofenadine, levocetirizine and mizolastine in

humans. Fundamental & clinical pharmacology. 2004;

18(4):399-411.

Moon TC, Befus AD, Kulka M. Mast cell mediators: their

differential release and the secretory pathways

involved. Frontiers in immunology. 2014;5:569.

Muñoz-Cano R, Ribó P, Araujo G, Giralt E, Sanchez-Lopez

J, Valero A. Severity of allergic rhinitis impacts sleep

and anxiety: results from a large Spanish cohort.

Clinical and translational allergy. 2018;8(1):1-9.

Mygind N, Nielsen LP, Hoffmann H-J, Shukla A,

Blumberga G, Dahl R, et al. Mode of action of

intranasal corticosteroids. Journal of allergy and

clinical immunology. 2001;108(1):S16-S25.

Nathan RA, Meltzer EO, Derebery J, Campbell UB, Stang

PE, Corrao MA, et al., editors. The prevalence of nasal

symptoms attributed to allergies in the United States:

findings from the burden of rhinitis in an America

survey. Allergy and asthma proceedings; 2008:

OceanSide Publications.

Peters-Golden M, Henderson Jr WR. The role of

leukotrienes in allergic rhinitis. Annals of Allergy,

Asthma & Immunology. 2005;94(6):609-18.

Pichler W, Klint T, Blaser M, Graf W, Sauter K, Weiss S,

et al. Clinical comparison of systemic

methylprednisolone acetate versus topical budesonide

in patients with seasonal allergic rhinitis. Allergy.

1988;43(2):87-92.

Rhen T, Cidlowski JA. Antiinflammatory action of

glucocorticoids—new mechanisms for old drugs. New

England Journal of Medicine. 2005;353(16):1711-23.

Schatz M. A survey of the burden of allergic rhinitis in the

USA. Allergy. 2007;62:9-16.

Simoens S, Laekeman G. Pharmacotherapy of allergic

rhinitis: a pharmaco‐economic approach. Allergy.

2009;64(1):85-95.

Simons FER, Simons KJ. The pharmacology and use of

H1-receptor-antagonist drugs. New England Journal of

Medicine. 1994;330(23):1663-70.

Sin B, Togias A. Pathophysiology of allergic and

nonallergic rhinitis. Proceedings of the American

Thoracic Society. 2011;8(1):106-14.

Singh RK, Tandon R, Dastidar SG, Ray A. A review on

leukotrienes and their receptors with reference to

asthma. Journal of Asthma. 2013;50(9):922-31.

Siraganian RP. Mast cell signal transduction from the high-

affinity IgE receptor. Current opinion in immunology.

2003;15(6):639-46.

Strachan D, Sibbald B, Weiland S, Ait‐Khaled N,

Anabwani G, Anderson HR, et al. Worldwide

ICBEB 2022 - The International Conference on Biomedical Engineering and Bioinformatics

924

variations in prevalence of symptoms of allergic

rhinoconjunctivitis in children: the International Study

of Asthma and Allergies in Childhood (ISAAC).

Pediatric allergy and immunology. 1997;8(4):161-8.

Szefler SJ. Pharmacokinetics of intranasal corticosteroids.

Journal of allergy and clinical immunology.

2001;108(1):S26-S31.

Tamaoki J, Yamawaki I, Tagaya E, Kondo M, Aoshiba K,

Nakata J, et al. Effect of azelastine on platelet-

activating factor-induced microvascular leakage in rat

airways. American Journal of Physiology-Lung

Cellular and Molecular Physiology. 1999;276(2):L351-

L7.

Thau L, Gandhi J, Sharma S. Physiology, cortisol. 2019.

Trangsrud AJ, Whitaker AL, Small RE. Intranasal

corticosteroids for allergic rhinitis. Pharmacotherapy:

The Journal of Human Pharmacology and Drug

Therapy. 2002;22(11):1458-67.

Turner H, Kinet J-P. Signalling through the high-affinity

IgE receptor FcεRI. Nature. 1999;402(6760):24-30.

Urien S, Tillement J, Ganem B, Kuch M. A

pharmacokinetic-pharmacodynamic modelling of the

antihistaminic (H1) effects of cetirizine. International

Journal of clinical pharmacology and therapeutics.

1999;37(10):499-502.

Vaillant AAJ, Vashisht R, Zito PM. Immediate

Hypersensitivity Reactions. StatPearls [Internet]. 2020.

Van Hoecke H, Vandenbulcke L, Van Cauwenberge P.

Histamine and Leukotriene Receptor Antagonism in

the Treatment of Allergic Rhinitis. Drugs.

2007;67(18):2717-26.

Wang Z, Lin W, Li S, Zhao S, Wang L, Yang Z, et al.

Analysis of the correlation of prevalence in allergic

rhinitis and other allergic diseases. Zhonghua er bi yan

hou tou jing wai ke za zhi= Chinese journal of

otorhinolaryngology head and neck surgery.

2012;47(5):379-82.

Wang Z, Lin W, Li S, Zhao S, Wang L, Yang Z, et al.

Research on prevalence and related factors in allergic

rhinitis. Zhonghua er bi yan hou tou jing wai ke za zhi=

Chinese journal of otorhinolaryngology head and neck

surgery. 2011;46(3):225-31.

Weiner JM, Abramson MJ, Puy RM. Intranasal

corticosteroids versus oral H1 receptor antagonists in

allergic rhinitis: systematic review of randomised

controlled trials. Bmj. 1998;317(7173):1624-9.

Welch MJ, Meltzer EO, Simons FER. H1-antihistamines

and the central nervous system. Histamine and H1-

antihistamines in allergic disease. 2002:353-404.

Zhang Y, Zhang L. Prevalence of allergic rhinitis in china.

Allergy, asthma & immunology research. 2014;

6(2):105-13.

Azelastine Hydrochloride and Fluticasone Propionate in the Alleviation of Allergic Rhinitis

925