**3.2.6 Mometasone furoate**

A corticosteroid available worldwide in dermatological preparations, mometasone furoate (MF) has been classified as a powerful corticosteroid according to European Union directives. It has few systemic side effects when applied topically to the skin. Solutions of MF in aqueous suspension are prepared for subsequent administration with a nasal nebulizer, and have been marketed for several years now. The absorption rate for MF is 8%, and absolute bioavailability has been estimated at less than 1% of the adjusted dose, due to hepatic metabolism.

MF, a potent, topically active, synthetic, 17-heterocyclic corticosteroid was originally introduced for the treatment of dermatological conditions (Lundbland et al, 2001). MF aqueous nasal spray (Nasonex; Schering-Plough, Inc., Kenilworth, NJ, USA) was shown to be effective in several inflammatory conditions of the upper respiratory tract, including AR (van Drunen et al, 2005) and non-AR (Lundbland et al, 2001), nasal polyps (Small et al, 2005; Stjarne et al, 2006), adenoidal hypertrophy (Berlucchi et al, 2007) and uncomplicated rhinosinusitis (Meltzer et al, 2005). Safety and pharmacokinetic evaluations of MF have shown a lack of systemic activity when applied to the nasal mucosa, even in pediatric patients (Zitt et al, 2007). There is no clinical evidence that MF nasal spray suppresses the function of the hypothalamic–pituitary–adrenal axis when the drug is administered at

Treatment of Allergic Rhinitis: Anticholinergics, Glucocorticotherapy,

making them the ideal drugs for allergic rhinitis (Corren, 1999)

adrenal axis (Lumry, 1999).

corticosteroids (Allen, 2000).

and perennial rhinitis.

(Trangsrud et al, 2002).

(Saengpanich et al, 2003).

Leukotriene Antagonists, Omalizumab and Specific-Allergen Immunotherapy 91

Corren stated that the use of intranasal corticosteroids has been shown to be an effective and safe form of therapy for AR. In terms of side effects, MF and FP seem to be safer and have less potential for systemic effects, even in cases of prolonged use and use in children,

Lumry considered MF and FP as the best drugs for the treatment of AR, although there is lesser systemic involvement with mometasone. A case has been reported of suppression of nocturnal cortisol levels with FP, indicating suppression of the hypothalamic-pituitary-

Other authors tested the superiority of treatment with intranasal FP (200 micrograms once a day) over levocabastine in nasal spray and placebo nasal spray. The antihistamine improved symptoms of nasal blockage and rhinorrhoea. The placebo improved symptoms of sneezing, nasal blockage, rhinorrhoea and pruritus (Di Lorenzo et al, 1999). Furthermore, it is recommended the use of triamcinolone as the intranasal corticosteroid of choice in AR at a

Allen, from his perspective as an endocrinologist, observed that intranasal corticosteroids have been established as the first-line treatment of AR. They are safe and have few reported side effects due to excessive and prolonged doses, or to several concomitant inhaled

However, Szefler warned that topical administration of corticosteroids may reduce the total required dose of corticosteroid for treating patients with minimal side effects (Szefler, 2001). This has prompted the development of intranasal corticosteroids as treatment for allergic

It has been shown that intranasal MF does not cause adverse side effects, and can even be used in children, as it does not affect bone growth. Therefore, we can say that the side effects

Transrud stated that intranasal corticosteroids accepted as first-line treatment of AR are safe and effective. They reduce nasal congestion, pruritus, rhinorrhoea and sneezing that occur in the early and late phases of the allergic response. They join other studies that demonstrated an almost complete prevention of late phase symptoms. Adverse reactions are usually limited to nasal mucosa, along with headache and epistaxis in 5%-10% of patients

Wang reported that there was no difference between the efficacy of anti-Hl and topical corticosteroids in the treatment of AR, with both drugs recommended despite their different pharmacological characteristics. The greater benefit of topical corticosteroids is in its longer lasting anti-inflammatory action, compared with the speed of action of anti-Hl (Wang, 2002). Finally, it is confirmed the greater efficacy of an intranasal treatment with FP over oral loratadine and a leukotriene inhibitor (montelukast) in seasonal AR. The results were significantly better in the fluticasone group in the reduction of nasal symptoms

Other authors showed that both intranasal corticosteroids and intranasal antihistamines were effective topical therapies in the treatment of AR (Salib & Howarth, 2003). Intranasal therapy represents a better form of treatment in AR, with a highly favourable risk/benefit

recommended dose of 220 micrograms once a day (Gawchik & Saccar, 2000).

of intranasal corticosteroids are minimal at the recommended doses.

clinically relevant doses (100-400 µg/day) (Small et al, 2005), and there are no reports of any influence on children´s growth (Schenkel et al, 2000; Meltzer et al, 2005). Histological studies after long-term use of MF nasal spray have shown no signs of atrophy of the nasal mucosa (Minshall et al, 1998).

#### **3.3 Side effects, safety and tolerance of glucocorticosteroids**

We performed a literature review of articles published between 1994 and 2012, and found numerous articles that studied the effectiveness, side effects, safety and tolerance of inhaled corticosteroids, and then compared them with each other and with other drugs. We have summarised these articles below.

Edwards compared BDP with hydrocortisone, prednisolone, dexamethasone and betamethasone, which cause suppression of the hypothalamic-pituitary-adrenal cortex axis and adverse systemic reactions. The undesirable action of the topical corticosteroid is reduced at the application site (Edwards, 1995)

It is metabolised quickly and has longer duration of action. The study concluded by declaring the safety and efficacy of intranasal treatment with BDP as an indicated treatment for patients with AR.

Other authors tested the usefulness and efficacy of topical corticosteroids, with a reduction in the number of Langerhans cells in nasal mucosa, as well as the number of eosinophils. Moreover, they demonstrated the corticosteroids' efficacy, since these reduced three of the major symptoms of AR: sneezing, rhinorrhoea and nasal blockage (Mygind & Dahl, 1996).

Howland tested the advantages of FP in nasal spray over oral antihistamines in the treatment of seasonal AR, in doses of 200 micrograms once a day. After a follow-up of one year, the study found no side effects on bone mineralisation, subcapsular cataracts, glaucoma or the pituitary axis (Howland, 1996).

The same year they published a similar study in another journal: Efficacy of 200 micrograms of FP in aqueous nasal spray once a day. The study observed mild local topical effects and no indirect effects after systemic absorption (Howland et al, 1996).

Other clinicians observed that intranasal FP is an effective treatment for AR, is well tolerated and is indicated over other treatments using intranasal corticosteroids, antihistamines or intranasal cromolyn sodium, when administered once a day. It has better cost-effectiveness than the antihistamines loratadine and terfenadine (Wiseman & Benfield, 1997).

Finally, it confirmed that topical nasal corticosteroids decrease nasal blockage more effectively than antihistamines (Mygind et al, 1977).

The topical corticosteroids, such as triamcinolone, are the most powerful and effective agents in the treatment of AR, and have little systemic absorption (Naclerio, 1998). Oral antihistamines do not always control nasal congestion. Vasoconstrictors can cause druginduced rhinitis, if used for a prolonged period of time, which is typical. Anti-leukotrienes need more studies; cromolyn sodium is effective in AR, but less so than topical corticosteroids.

Storms concluded that the benefits of FP exceed the risk in studies on the treatment of asthma and AR, using intranasal doses of 200 micrograms once a day. There were no cases of adrenal suppression or osteoporosis due to its use (Storms, 1998).

clinically relevant doses (100-400 µg/day) (Small et al, 2005), and there are no reports of any influence on children´s growth (Schenkel et al, 2000; Meltzer et al, 2005). Histological studies after long-term use of MF nasal spray have shown no signs of atrophy of the nasal mucosa

We performed a literature review of articles published between 1994 and 2012, and found numerous articles that studied the effectiveness, side effects, safety and tolerance of inhaled corticosteroids, and then compared them with each other and with other drugs. We have

Edwards compared BDP with hydrocortisone, prednisolone, dexamethasone and betamethasone, which cause suppression of the hypothalamic-pituitary-adrenal cortex axis and adverse systemic reactions. The undesirable action of the topical corticosteroid is

It is metabolised quickly and has longer duration of action. The study concluded by declaring the safety and efficacy of intranasal treatment with BDP as an indicated treatment

Other authors tested the usefulness and efficacy of topical corticosteroids, with a reduction in the number of Langerhans cells in nasal mucosa, as well as the number of eosinophils. Moreover, they demonstrated the corticosteroids' efficacy, since these reduced three of the major symptoms of AR: sneezing, rhinorrhoea and nasal blockage (Mygind & Dahl, 1996). Howland tested the advantages of FP in nasal spray over oral antihistamines in the treatment of seasonal AR, in doses of 200 micrograms once a day. After a follow-up of one year, the study found no side effects on bone mineralisation, subcapsular cataracts,

The same year they published a similar study in another journal: Efficacy of 200 micrograms of FP in aqueous nasal spray once a day. The study observed mild local topical effects and

Other clinicians observed that intranasal FP is an effective treatment for AR, is well tolerated and is indicated over other treatments using intranasal corticosteroids, antihistamines or intranasal cromolyn sodium, when administered once a day. It has better cost-effectiveness

Finally, it confirmed that topical nasal corticosteroids decrease nasal blockage more

The topical corticosteroids, such as triamcinolone, are the most powerful and effective agents in the treatment of AR, and have little systemic absorption (Naclerio, 1998). Oral antihistamines do not always control nasal congestion. Vasoconstrictors can cause druginduced rhinitis, if used for a prolonged period of time, which is typical. Anti-leukotrienes need more studies; cromolyn sodium is effective in AR, but less so than topical corticosteroids. Storms concluded that the benefits of FP exceed the risk in studies on the treatment of asthma and AR, using intranasal doses of 200 micrograms once a day. There were no cases

than the antihistamines loratadine and terfenadine (Wiseman & Benfield, 1997).

**3.3 Side effects, safety and tolerance of glucocorticosteroids** 

(Minshall et al, 1998).

for patients with AR.

summarised these articles below.

reduced at the application site (Edwards, 1995)

glaucoma or the pituitary axis (Howland, 1996).

effectively than antihistamines (Mygind et al, 1977).

no indirect effects after systemic absorption (Howland et al, 1996).

of adrenal suppression or osteoporosis due to its use (Storms, 1998).

Corren stated that the use of intranasal corticosteroids has been shown to be an effective and safe form of therapy for AR. In terms of side effects, MF and FP seem to be safer and have less potential for systemic effects, even in cases of prolonged use and use in children, making them the ideal drugs for allergic rhinitis (Corren, 1999)

Lumry considered MF and FP as the best drugs for the treatment of AR, although there is lesser systemic involvement with mometasone. A case has been reported of suppression of nocturnal cortisol levels with FP, indicating suppression of the hypothalamic-pituitaryadrenal axis (Lumry, 1999).

Other authors tested the superiority of treatment with intranasal FP (200 micrograms once a day) over levocabastine in nasal spray and placebo nasal spray. The antihistamine improved symptoms of nasal blockage and rhinorrhoea. The placebo improved symptoms of sneezing, nasal blockage, rhinorrhoea and pruritus (Di Lorenzo et al, 1999). Furthermore, it is recommended the use of triamcinolone as the intranasal corticosteroid of choice in AR at a recommended dose of 220 micrograms once a day (Gawchik & Saccar, 2000).

Allen, from his perspective as an endocrinologist, observed that intranasal corticosteroids have been established as the first-line treatment of AR. They are safe and have few reported side effects due to excessive and prolonged doses, or to several concomitant inhaled corticosteroids (Allen, 2000).

However, Szefler warned that topical administration of corticosteroids may reduce the total required dose of corticosteroid for treating patients with minimal side effects (Szefler, 2001). This has prompted the development of intranasal corticosteroids as treatment for allergic and perennial rhinitis.

It has been shown that intranasal MF does not cause adverse side effects, and can even be used in children, as it does not affect bone growth. Therefore, we can say that the side effects of intranasal corticosteroids are minimal at the recommended doses.

Transrud stated that intranasal corticosteroids accepted as first-line treatment of AR are safe and effective. They reduce nasal congestion, pruritus, rhinorrhoea and sneezing that occur in the early and late phases of the allergic response. They join other studies that demonstrated an almost complete prevention of late phase symptoms. Adverse reactions are usually limited to nasal mucosa, along with headache and epistaxis in 5%-10% of patients (Trangsrud et al, 2002).

Wang reported that there was no difference between the efficacy of anti-Hl and topical corticosteroids in the treatment of AR, with both drugs recommended despite their different pharmacological characteristics. The greater benefit of topical corticosteroids is in its longer lasting anti-inflammatory action, compared with the speed of action of anti-Hl (Wang, 2002).

Finally, it is confirmed the greater efficacy of an intranasal treatment with FP over oral loratadine and a leukotriene inhibitor (montelukast) in seasonal AR. The results were significantly better in the fluticasone group in the reduction of nasal symptoms (Saengpanich et al, 2003).

Other authors showed that both intranasal corticosteroids and intranasal antihistamines were effective topical therapies in the treatment of AR (Salib & Howarth, 2003). Intranasal therapy represents a better form of treatment in AR, with a highly favourable risk/benefit

Treatment of Allergic Rhinitis: Anticholinergics, Glucocorticotherapy,

(Modgill et al, 2010).

(Lipworth, 1999).

al, 2007).

**4.1 Montelukast** 

Spain) (Merch, Sharp & Dohme, 2011).

There are two different LT inhibitors/modifiers:

pranlukast (Azlaire®, Schering Plough Inc, NJ, USA). - 5-Lypoxigenase inhibitor of LT synthesis [zileuton® (Zyflo®)].

**4. Oral Cys-LT cysteinyl leukotriene receptor-1 antagonist** 

Leukotriene Antagonists, Omalizumab and Specific-Allergen Immunotherapy 93

Allergic rhinitis is a common airways hypersensitivity disease. Histamine and leukotrienes are involved in the pathogenesis of allergic rhinitis. Conventional treatments include topical steroids and antihistamines. Due to the adverse effects of these treatments, new drugs like leukotriene receptor antagonists are being investigated for the treatment of allergic rhinitis

The cysteinyl leukotrienes (LTC4, LTD4, LTE4) are products of arachidonic acid metabolism and are released from various cells, including mast cells and eosinophils. These eicosanoids bind to cysteinyl leukotriene (CysLT) receptors. The CysLT type-1 (CysLT1) receptor is found in the human airway (including airway smooth muscle cells and airway macrophages) and on other pro-inflammatory cells (including eosinophils and certain myeloid stem cells). CysLTs have been correlated with the pathophysiology of asthma and AR. In asthma, leukotriene-mediated effects include airway edema, smooth muscle contraction, and altered cellular activity associated with the inflammatory process. In allergic rhinitis, CysLTs are released from the nasal mucosa after allergen exposure during both early- and late-phase reactions and are associated with symptoms of allergic rhinitis


Montelukast and zafirlukast block binding of cysteinil LTs to the cysLT1 receptor in the extracellular space. Zileuton inhibits 5-lipoxygenase and therefore all LT synthesis within inflammatory cells. By blocking the actions of LTs, it promotes bronchodilation and decreases the inflammatory response. Anti-LTs also have been used successfully by some authors to control allergic diseases such as AR, atopic dermatitis, chronic urticaria and allergic conjunctivitis. The FDA has approved montelukast for the treatment of AR (Scow et

Montelukast is indicated for the prophylaxis and chronic treatment of asthma in adults and pediatric patients 12 months of age and older; for prevention of exercise-induced bronchoconstriction in patients 15 years of age and older; and for the relief of symptoms of seasonal allergic rhinitis in patients 2 years of age and older and perennial allergic rhinitis in patients 6 months of age and older (this last indication is available in the USA but not in

For AR, montelukast should be taken once daily. Efficacy was demonstrated for seasonal AR when montelukast was administered in the morning or the evening without regard to time of food ingestion. The time of administration may be individualized to suit patient needs. The following doses for the treatment of symptoms of seasonal AR are recommended: 10 mg for adults and adolescents 15 years of age and older; 5 mg for pediatric patients 6 to 14 years of age; and one 4 mg for pediatric patients 2 to 5 years of age (Merch, Sharp & Dohme, 2011).

ratio. It is the preferred route of administration of corticosteroids in the treatment of the disease, as well as an important option compared to therapy with antihistamines, especially when quick symptom relief is needed.

Using meta-analysis, Waddell compared the efficacy of intranasal corticosteroids and oral antihistamines in the treatment of AR, and found a clear benefit in favour of intranasal corticosteroids. However, there is no clear evidence that one corticosteroid spray is more effective and safer than another in the treatment of rhinitis. It has not been demonstrated that either FP, MF or triamcinolone are more effective, or they are more expensive than BDP, budesonide and dexamethasone (Waddell et al, 2003).

Conversely, it was demonstrated that intranasal FP, in doses of 200 micrograms once a day, improves ocular symptoms in patients with AR, without the need for adding oral antihistamines or topical eye drops (De Wester, 2003).

Towards the end of 2003, Borish stated that an effective therapy in the treatment of rhinitis is that which is direct and decreases inflammation and its systemic manifestations. Antihistamines quickly resolve nasal symptoms, but not inflammation, at least not significantly. Oral corticosteroids are highly effective, but have significant systemic side effects. Local intranasal corticosteroids act on the level of local inflammatory processes of rhinitis, reducing local inflammatory cells, but without direct involvement of other tissues (Borish, 2003). Anti-leukotrienes have systemic anti-inflammatory effects and an acceptable safety profile.

They compared the efficacy of antihistamines versus intranasal corticosteroids in AR, with the studies favouring corticosteroids. Antihistamines also do not seem to be superior in the treatment of conjunctivitis associated with AR (Nielsen & Dahl, 2003).

Other author warned that it would be best to avoid allergens during pregnancy (Keleç, 2004). If cromolyn is not tolerated or is ineffective, first- or second-generation anti-H1 (cetirizine and loratadine) may be used. Intranasal corticosteroids may be added for treatment of significant nasal obstruction. There are no studies on the use of new intranasal corticosteroids (FP, FF, flunisolide, triamcinolone, MF) during the first trimester of pregnancy. Kim confirmed that intranasal corticosteroids are safe and effective for treating AR in adults (Kim et al, 2004). The administration of budesonide aqueous nasal spray for 6 weeks is well tolerated and safe, with no suppression of the pituitary-adrenal axis, even in children aged 2 to 5 years with AR.

Patel et al stated that the use of betamethasone suppresses the adrenal axis, which does not happen with MF nasal spray. The concentration of cortisol in morning saliva is a tool for monitoring adrenal function (Patel et al, 2004).

Gradually, it has been established that AR and asthma often coexist and represent 2 manifestations of the same disease, which has recently been called CARAS (combined allergic rhinitis and asthma syndrome) (Taramarcaz & Gibson, 2004). The benefit of using intranasal corticosteroids in CARAS has been shown, although there is still a lack of studies. Currently, the best practice is to treat conventional asthma with bronchial corticosteroids (inhaled) with or without ß-agonists and adding intranasal corticosteroids to avoid symptoms specific to rhinitis.
