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

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 (Modgill et al, 2010).

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 (Lipworth, 1999).

There are two different LT inhibitors/modifiers:


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 al, 2007).

## **4.1 Montelukast**

92 Otolaryngology

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

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,

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

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

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

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

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

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

treatment of conjunctivitis associated with AR (Nielsen & Dahl, 2003).

when quick symptom relief is needed.

safety profile.

children aged 2 to 5 years with AR.

symptoms specific to rhinitis.

monitoring adrenal function (Patel et al, 2004).

budesonide and dexamethasone (Waddell et al, 2003).

antihistamines or topical eye drops (De Wester, 2003).

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

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).

Treatment of Allergic Rhinitis: Anticholinergics, Glucocorticotherapy,

**5. Omalizumab (anti-IgE monoclonal antibody)** 

with allergic diseases. (Shiung et al, 2001).

**4.2 Zafirlukast** 

mg (Donnelly et al, 1995)

Leukotriene Antagonists, Omalizumab and Specific-Allergen Immunotherapy 95


Donnelly et al performed a study with 164 patients who were administered increasing doses of oral Zafirlukast (10, 20, 40, 100 mg and placebo). They found a significant decrease in nasal obstruction, sneezing and rhinorrhoea in patients who received doses starting from 20

Several therapeutic anti-IgE antibodies, able to reduce free IgE levels and to block the binding of IgE to FcRI without cross-linking IgE and triggering degranulation of IgEsensitized cells have been developed. At present omalizumab is the only monoclonal antibody (mAb) - based drug approved for the treatment of asthma. A new mAb specific for human IgE has been shown to possess a unique set of binding specificities. This mAb, 8D6, binds to a conformational epitope on the CH3 domain of human IgE and can compete with omalizumab for binding to IgE. Like omalizumab, it does not bind to IgE already bound to the high-affinity IgE Fc receptor (FcɛRI) on basophils and mast cells. It also does not cause activation and degranulation of IgE-pulsed, human FcɛRI-expressing rat basophilic leukemic cells (RBL SX-38). This mAb can inhibit IgE binding to recombinant α chain of human FcɛRI in ELISA and to human FcɛRI-expressing RBL SX38 cells in fluorescence flow cytometric analysis. However, unlike omalizumab, 8D6 can bind to IgE already bound by the low-affinity IgE Fc receptors (FcɛRII, or CD23). Since earlier investigators have shown that anti-CD23 mAbs can inhibit the synthesis of IgE in lymphocyte culture in vitro and can down-regulate IgE production in treated patients, 8D6 may offer pharmacological mechanisms in addition to those mediated by omalizumab, for controlling IgE in patients

Chu et al, have explored the effects of IgE sequestration versus IgE suppression by comparing omalizumab to FcγRIIb-optimized anti-IgE antibodies in humanized mouse models of immunoglobulin production. By using a murine anti-IgE antibody as a template, the authors humanized, increased IgE binding, and modified its Fc domain to increase affinity for FcγRIIb. Relative to omalizumab, this new mab, XmAb7195, has a 5-fold higher affinity for human IgE and more than 400-fold higher affinity for FcγRIIb. In addition to sequestering soluble IgE, XmAb7195 inhibited plasma cell differentiation and consequent human IgE production through coengagement of IgE B-cell receptor with FcγRIIb. In peripheral blood mononuclear cells-engrafted mice, XmAb7195 reduced total human IgE

(but not IgG or IgM) levels by up to 40-fold relative to omalizumab (Chu et al, 2012).

Omalizumab represents an important clinical advance in the management of allergic diseases and can be considered to be safe in children with seasonal allergic rhinitis

(P=0.003 and P≤0.001, respectively, versus placebo) (Philip et al, 2002).

of-life parameters for patients with seasonal AR (van Adelsberg et al, 2003).

emotions) also improved significantly in the montelukast and loratadine groups

Safety and effectiveness in pediatric patients younger than 2 years of age with seasonal AR have not been established. The following doses for the treatment of symptoms of perennial allergic rhinitis 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; 5 mg for pediatric patients 2 to 5 years of age; 4 mg for pediatric patients 6 to 23 months of age. Safety and effectiveness in pediatric patients younger than 6 months of age with perennial AR have not been established.

Montelukast is an orally active compound that binds with high affinity and selectivity to the CysLT1 receptor (in preference to other pharmacologically important airway receptors, such as the prostanoid, cholinergic, or β-adrenergic receptor). Montelukast inhibits physiologic actions of LTD4 at the CysLT1 receptor without any agonist activity.

The efficacy of montelukast for the treatment of persistent and seasonal AR was investigated in different studies and clinical trials.

*Evidence in persistent AR:* 


*Evidence in persistent AR:* 


emotions) also improved significantly in the montelukast and loratadine groups (P=0.003 and P≤0.001, respectively, versus placebo) (Philip et al, 2002).

