**3.2.2 Budesonide**

86 Otolaryngology

That same year, other authors found a significant reduction in plasma cortisol 3 weeks after an injection of 80 mg of methylprednisolone, but not during treatment with 200 micrograms of intranasal budesonide. They found no differences between the two therapies in terms of nasal obstruction, but there was a tendency to favour topical treatment with budesonide in

Brooks et al, treated 31 patients with rhinitis for 5 days with placebo or methylprednisolone in daily doses of 6, 12 or 24 mg, divided into 3 daily doses. They achieved significant improvement in nasal obstruction with 6 mg, and with all symptoms except for sneezing

Based on the literature, systemic corticosteroids seem to have a significant effect on nasal obstruction, but less so on sneezing and rhinorrhoea. These studies demonstrated a reduction in cortisol plasma levels after an IM injection of corticosteroids. The effect is

We have not found any published study on whether systemic corticosteroids should be

Several studies have shown the inhibitory efficacy of topical corticosteroids in the delayed response of allergic reactions. Symptoms that occur 2-11 hours after nasal provocation by an allergen are completely eliminated with their administration. Initially, it was thought that topical corticosteroids did not inhibit the early response; however, there is clear evidence that they also act on symptoms immediately. Studies have shown their efficacy in reducing

It has been shown that the effective dose of antihistamines (loratadine oral) can be reduced with the use of fluticasone in nasal spray, in the treatment of seasonal AR. The conclusion is that the efficacy and decreased inflammation is greater with fluticasone (decreases eosinophilic cationic proteins and the number of eosinophils, and improves scores on

A reduction has been shown in the number of subepithelial cells (CD3+, CD4+, CD8+) in patients treated with topical corticosteroids. Recent studies have demonstrated a reduction in the expression of adhesion molecules (ICAM-l) in patients treated over long periods of time. Their anti-inflammatory effects are increased by the decrease in chemotaxis and the activation of eosinophils. In terms of symptoms, this translates into decreased obstruction,

Introduced in 1973 for topical nasal treatment, beclometasone dipropionate (BDP) is a potent local steroid, with absorption at therapeutic doses. It was the first steroid that proved

BDP acts by penetrating the cell membrane and binding with cytoplasmic receptors. The compound formed is transferred to the nucleus, where it binds to the DNA molecule. It seems to act by emptying histamine deposits, reducing the number of mast cells and

pruritus, sneezing and rhinorrhoea. Currently, various compounds are used.

added due to a lack of improvement with topical corticosteroids or other drugs.

terms of sneezing and rhinorrhoea (Pichler et al, 1988).

greatest at 3 days and disappears after 3 weeks.

**3.2 Topical (intranasal) glucocorticosteroids** 

both specific and non-specific nasal hyperreactivity.

with 24 mg (Brooks et al, 1993)

quality-of-life questionnaires).

**3.2.1 Beclometasone dipropionate** 

effective in the topical treatment of hay fever.

A non-halogenated corticosteroid, budesonide is an anti-inflammatory drug 2-3 times more powerful than BDP (Bryson & Faulds, 1992). It has a half-life of 2 hours, and is inactivated in the liver by oxidative metabolism after systemic absorption. It has the same mechanism of action as BDP, and may cause temporary epistaxis, nasal pruritus and sneezing as collateral effects.

The average recommended dose is 100 micrograms every 12 hours in each nostril. Prophylactic administration protects against immediate allergic reactions. Therefore, treatment of seasonal rhinitis should be started before exposure to the allergen.

Cimetidine influences the pharmacokinetics and pharmacodynamics of budesonide after concomitant oral and intravenous administration, although it is of little clinical significance.

#### **3.2.3 Fluticasone propionate**

A fluorinated glucocorticoid with significant topical activity, fluticasone propionate (FP) (Flixonase; GlaxoSmithKline, London, UK) is structurally similar to cortisol, with certain variations that increase its lipophilic properties and its potency of action. It has high selectivity and affinity for glucocorticoid receptors.

FP possesses an anti-inflammatory potency twice than that of BDP which is linked to its effect on various cellular elements and the mediators of the inflammation (Barnes, 1992). It reduces the number of activated eosinophils in the nose during antigenic stimulation in allergic individuals.

FP significantly reduces the number of T lymphocytes, and reduces the number of nonactivated basophils, neutrophils and eosinophils. Meltzer studied nasal eosinophilia in 497 patients treated with fluticasone or placebo, and found a decrease (*P*<.01) in patients treated with fluticasone (Melzer et al, 1990).

The lipolytic character of topical corticosteroids is significant, since it leads to increased drug retention in the tissues. The recommended dose is 200 mg/day (two applications of 50

Treatment of Allergic Rhinitis: Anticholinergics, Glucocorticotherapy,

Leukotriene Antagonists, Omalizumab and Specific-Allergen Immunotherapy 89

improvement in overall relief of associated eye symptoms. Symptomatic relief of allergic rhinitis begins 8 hours after administration and lasts for 24 hours (Máspero et al, 2008;

The efficacy of FF administered for 4 weeks versus placebo has also been assessed in adolescents and adults with perennial allergic rhinitis, with significant improvement in nasal symptoms and extraocular manifestations (such as pharyngeal or palatal itching) and

The recommended dose of FF in Spain for patients older than 12 years is 110 µg, which equals two sprays in each nostril once a day. It may be reduced to one spray in each nostril once symptoms are controlled. For children between 6 and 12 years of age, the recommended dose is one spray in each nostril once daily (55 µg), but can be increased to two sprays if it fails to control the symptoms. In Europe FF is not approved in children less

FF (like the rest of intranasal corticosteroids) has proven effective for controlling nasal symptoms in allergic rhinitis. But unlike other intranasal corticosteroids, which show contradictory effects on ocular symptoms, FF is the only intranasal corticosteroid that demonstrates a consistent positive effect on ocular symptoms in seasonal allergic rhinitis in a large number of patients from different studies, across different pollen seasons and

Introduced in 1978, flunisolide is a poorly water-soluble drug, which is therefore dissolved in propylene glycol and water (Horan & Johnson, 1978; Schulz et al, 1978). Rhinoscopy is

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

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

Nathan RA et al, 2008; Vasar et al, 2008; Baroody et al, 2009; Meltzer et al, 2009).

in the RQLQ scores (Keith & Scadding, 2009; Keith & Scadding, 2010).

geographical locations (Keith & Scadding, 2009; Keith & Scadding, 2010).

than 6 years of age (GlaxoSmithKline, 2011).

recommended once a year for prolonged treatment.

**3.2.5 Flunisolide** 

**3.2.6 Mometasone furoate** 

hepatic metabolism.

µg per nostril, once a day). For children between the ages of 4-11 years, half the dose is recommended. Side effects are similar to those of the other inhaled corticosteroids described above (LaForce et al, 1994).

FP is eliminated from systemic circulation at a rate approximately equal to hepatic blood flow. It is metabolised through hydrolysis with the formation of 17-ß-carboxylic metabolic acid, which has insignificant anti-inflammatory and systemic activity due to incomplete absorption in the gastrointestinal tract and to extensive metabolism during the first hepatic step.

Comparative studies of BDP at similar doses have shown that both steroids have a similar efficacy for controlling nasal symptoms, in all cases superior to that of placebo. The speed of action is greater in fluticasone, as evidenced by the fact that significant improvement in symptoms is seen by the second day of treatment, while the delay in the onset of improvement for those treated with BDP was three days (Scadding et al, 1994).

Same authors found that after nasal provocation with an allergen, treatment with FP decreased obstruction in 45%, sneezing in 73%, pruritus in 78% and hydrorrhoea in 80% (Scadding et al, 1994).

Kaszuba demonstrated the efficacy of antihistamines (loratadine oral) with the use of fluticasone in nasal spray, in the treatment of seasonal AR. The conclusion was that the efficacy and decreased inflammation was greater with FP (decreased ECP, the number of eosinophils and improved scores on quality-of-life questionnaires) (Kaszuba et al, 2001).

#### **3.2.4 Fluticasone furoate**

Fluticasone furoate (FF) (Avamys; GlaxoSmithKline, London, UK) is the most recent intranasal glucocorticosteroid available for the treatment of AR (allergic rhinitis). It possesses a distinctive combination of pharmacodynamic and physico-chemical properties, which confers a high affinity for the glucocorticosteroid receptor and a potent antiinflammatory activity. This allows its effectiveness in treating both nasal and ocular symptoms to be complemented by a favorable safety and tolerance profile. In addition, the new nasal delivery device was designed according to the needs experienced and expressed by patients, which assures an optimal dispensation that promotes its extensive use. (Allen et al, 2007; Rosenblut et al, 2007; Baumann et al, 2009).

The compliance of the patients in treatment with intranasal corticosteroids may be influenced by both the sensorial properties of the drug and the delivery device. FF has been formulated to release a low volume (50 µl) in the form of a fine mist, with a favorable profile of sensory characteristics in terms of reduction in odor, in the posterior aftertaste, and in the retro-nasal dripping down the throat (Mahadevia et al, 2004; Meltzer et al, 2008).

In addition to the greater affinity for the glucocorticosteroid receptor, FF shows a high selectivity for the same as compared to other intranasal glucocorticosteroids; for each FF molecule which binds to the mineralocorticoid receptor, other 800 will bind to the glucocorticosteroid receptor, which considerably limits the potential undesirable side effects.

FF has demonstrated superior efficacy when compared to placebo in the treatment of nasal symptoms of seasonal allergic rhinitis in adults and children, and demonstrated a significant improvement in overall relief of associated eye symptoms. Symptomatic relief of allergic rhinitis begins 8 hours after administration and lasts for 24 hours (Máspero et al, 2008; Nathan RA et al, 2008; Vasar et al, 2008; Baroody et al, 2009; Meltzer et al, 2009).

The efficacy of FF administered for 4 weeks versus placebo has also been assessed in adolescents and adults with perennial allergic rhinitis, with significant improvement in nasal symptoms and extraocular manifestations (such as pharyngeal or palatal itching) and in the RQLQ scores (Keith & Scadding, 2009; Keith & Scadding, 2010).

The recommended dose of FF in Spain for patients older than 12 years is 110 µg, which equals two sprays in each nostril once a day. It may be reduced to one spray in each nostril once symptoms are controlled. For children between 6 and 12 years of age, the recommended dose is one spray in each nostril once daily (55 µg), but can be increased to two sprays if it fails to control the symptoms. In Europe FF is not approved in children less than 6 years of age (GlaxoSmithKline, 2011).

FF (like the rest of intranasal corticosteroids) has proven effective for controlling nasal symptoms in allergic rhinitis. But unlike other intranasal corticosteroids, which show contradictory effects on ocular symptoms, FF is the only intranasal corticosteroid that demonstrates a consistent positive effect on ocular symptoms in seasonal allergic rhinitis in a large number of patients from different studies, across different pollen seasons and geographical locations (Keith & Scadding, 2009; Keith & Scadding, 2010).
