Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Inflammatory and Anti-Allergy Agents) - Volume 7, Issue 1, 2008

Nitric oxide (NO) is an important biological mediator and the exhaled form is mainly produced by the nose and paranasal sinuses. In the upper airways, NO has been suggested to involve in host defense, regulation of nasal airway flow and aerocrine messenger. It is now clear that many chronic sino-nasal diseases, including allergic rhinitis (AR), may alter the output of exhaled NO levels. AR is a chronic inflammatory disease of the nasal mucosa. Thus AR related symptoms, disease process and medication directly affect the NO production. In this review, it is aimed to reflect the importance of NO in the AR in the light of the current literature.

Allergic rhinitis (AR) is considered to be multifactorial inflammatory diseases involving complex interactions between genetic and environmental influences. Inflammatory reactions in AR are regulated by many cytokines. The impact of genetic factors on the pathogenesis of AR is currently an area of intense investigation. Various loci and candidate genes have been suggested to underlie allergy. Many or all are still controversial. No significant evidence for linkage to AR has been shown so far, although significant evidence for linkage to various allergic diseases. The aim of this review was to investigate whether the genetic polymorphisms were associated with AR in the literature.

Allergic rhinitis (AR) is caused by an immediate type hypersensitivity reaction in sensitized subjects after exposure to airborn allergens. The interaction of the allergen with a specific IgE antibody attached to the nasal mast cells leads to the local release of vasoactive and inflammatory mediators such as histamine, leukotriene C4 and prostaglandin D2. These mediators cause the nasal allergic symptoms complex of rhinorrhea, nasal obstruction, nasal itching and sneezing, which improve spontaneously or with treatment. Cromolyn sodium and nedocromil sodium are often termed ‘antiallergic drugs’, which are defined here as drugs capable of inhibiting both the early-phase response to challenge and chronic allergic inflammation. They act at the cell membrane levels. Intranasal and ocular formulations of cromones, such as cromoglycate, are available without medical prescription in many countries. Sodium cromoglycate or nedocromil have a good safety profile. They reduce the symptoms of AR, and should be used profilactically, but limited efficacy and the need for frequent dosing are disadvantages.

Leukotrienes (LT) are the inflammatory mediators that have an important role in inflammatory diseases such as allergic rhinitis and asthma. The leukotrienes that contain cystein, cysteinyl leukotrienes (Cys LTs), are LTC4, LTD4 and LTE4. They are synthesized from arachidonic acid by 5-lipooxygenase pathway and eosinophils and mast cells can produce large amounts of Cys LTs from an endogenous pool of arachidonic acid. Cys LTs exert their effects by binding to their receptors namely Cys LT1 and Cys LT2 receptors. They contribute the allergic inflammation by promoting inflammatory cell recruitment and activation, enhancing production of certain cytokines that play a role in allergic inflammation, promoting fibrosis and airway remodeling in bronchi, inducing vascular leakage and vasodilatation leading to mucosal edema especially in nasal mucosa, stimulating mucus secretion by goblet cells and decreasing mucociliary clearance. The main symptom of allergic rhinitis related to Cys LTs seems to be nasal congestion. In allergic rhinitis, monotherapy with a Cys LT1 receptor anatagonist is better than placebo and equivalent to oral antihistamine therapy. Combination of LT1 receptor antagonists and oral antihistamines are superior to antihistamines alone. Intranasal corticosteroids alone are more effective than both LT1 receptor antagonists alone and the combination of LT1 eceptor antagonists with antihistamines. Clarification of the actions of Cys LTs mediated by Cys LT2 receptor and other possible receptors and further development of antagonists against those receptors might increase the efficacy of antilekotriene therapy on the symptoms of allergic rhinitis.

The goal of treatment in allergic rhinitis (AR) is to provide effective prevention of or relief from allergic rhinitis symptoms without adversely affecting daily activities or cognitive performance. Effective treatment of allergic rhinitis usually requires an integrated regimen that combines allergen avoidance measures, pharmacotherapy and possible specific- allergen immunotherapy. Oral corticosteroids are very effective but can have unwanted systemic effects. Over the past decade, intranasal corticosteroids have been shown to be the most effective form of pharmacologic treatment for allergic rhinitis. The newer nasal corticosteroids (NCS), offers significant advantages to the patient with AR. They are superior to both antihistamines and cromones and provide topical drug delivery that targets the actions of the drug molecules to the nasal mucosa to minimize the potential for systemic side effects. However, some clinicians remain reluctant to prescribe NCS for children because of their concern for systemic effects, including suppression of growth, of bone metabolism, and of the hypothalamic-pituitary-adrenal (HPA) axis.

Omalizumab is recently developed monoclonal anti-IgE antibody. Clinical trials have demonstrated its efficacy in patients with moderate-to-severe and severe or poorly controlled allergic asthma, in patients with seasonal and perennial allergic disease and in subjects with concomitant asthma and allergic rhinitis. Patients with more severe asthma appear to obtain the greatest benefit from omalizumab therapy. Omalizumab is well tolerated and has a good safety profile. Anti-inflammatory activity has been shown in both allergic asthma and allergic rhinitis [1,2]. Omalizumab is not a firstline therapy in asthmatic patients. FDA (Food and Drug Administration ) approved omalizumab use in June of 2003 for patients satisfying the following criteria (all must be present): 1- total IgE concentration in serum 30-700 klU L. 2- skin test positive for at least one perennial allergen; 3- specific IgE concentration positive for at least one perennial allergen (house dust mite, cat and dog); 4- asthma: moderate to severe persistent asthma; 5- age: > 12 years; 6- inadequate control despite inhaled corticosteroids

Allergic rhinitis is a common immun-mediated inflammatory condition of the nasal mucosa. AR occurs because of the cross linking of IgE by allergens within the upper respiratory tract. Allergy is now understood to be a systemic inflammatory disease. The symptoms caused by this allergic inflammation include sneezing, rhinorrhea, nasal pruritus, and nasal congestion; allergic conjunctivitis often accompanies AR. The interaction of histamine with the histamine H1 receptor, mediates a diversity of classical pathophysiological effects, including nasal blockage, sneezing, itching and rinorrhoea in allergic disease. Antihistamines are very important to the management of allergic disease. They can be classified in three groups. First Generation antihistamines: Promethazine, ketotifen, hydroxyzine, chlorpheniramine, deschlorpheniramine, tripelennamine, oxatomide, cyproheptadine, diphenhydramine. The use of the first-generation antihistamines is considerably limited by their sedative and anticholinergic effects.Second Generation antihistamines: Cetirizine, Loratadine, Mizolastine, ebastine, terfenadine, astemizole, acrivastine, azelastine. The second-generation antihistamines have significantly fewer undesirable CNS and anticholinergic effects than first-generation. New Generation antihistamines: Fexofenadine, levocetirizine, desloratadine, rupatadine. Because of reported cardiac toxicity related to terfenadine and astemizole, new generation antihistamines have been developed. Second and new generation antihistamines are a highly efficacious, fast-acting, and safe therapy for AR in the light of the results of the controlled clinical trials.

Allergic rhinitis is an inflammatory disease of nasal mucosa mediated by IgE-associated response to indoor and outdoor environmental allergens. The treatment of allergic rhinitis involves three main categories: avoidance of allergen, pharmacologic management and immunotherapy. The first therapeutic approach in allergic rhinitis is prevention, which is done by avoidance of causal allergens. This helps reduce the symptoms and the need for medications for allergic rhinitis. But allergen-avoidance measures should be considered before or in association with pharmacologic treatment. The intranasal steroids produce significant relief of all nasal symptoms of allergic rhinitis, including nasal congestion, sneezing, rhinorrhea, and itching. They are the first choice drugs in allergic rhinitis except mild intermittent rhinitis. In mild intermittent allergic rhinitis suggested initial treatment consists of an oral antihistaminic, an intranasal antihistaminic, and/or an oral or intranasal decongestant. Montelukast can be used in children as young as 6 months and it is approved by FDA for treatment of allergic rhinitis, in which it has shown clinical efficacy in both seasonal and perennial AR. Multiple randomized, double-blind, placebo controlled studies have shown efficacy of omalizumab (anti-IgE) in seasonal and perennial allergic rhinitis. However, the application of omalizumab in the treatment of allergic rhinitis in the absence of other atopic diseases will likely be restricted to a narrowly defined set of circumstances due to its cost. Specific immunotherapy should be considered when patients fail to respond to avoidance of allergens and pharmacotherapy or experience side effects, or when it is not cost effective.

Contact hypersensitivity (CHS) is an antigen-specific response elicited by exposure to certain low-molecularweight compounds termed haptens, and is the disease often seen clinically. CHS has also been used as a useful model to assess antigen-specific and T cell-dependent immune response. A wide variety of cells are thought to be involved in the pathogenesis of CHS. Keratinocytes and T cells are regarded as important factors, and besides these cells, mast cells, fibroblasts, B cells, macrophages, neutrophils have been demonstrated to be involved. From the studies of gene knockout experiments, it has been gleaned that IL-1β, IL-2, IL-3, IL-4, IL-6, IL-10, IFN-γ, TNF-α are associated with elicitation of CHS. While the roles of these cytokines in CHS have been well elucidated, recent attention has been directed at members of the superfamily of chemoattractant cytokines that are collectively termed chemokines. Both of mouse and human CHS studies showed chemokine genes were sequentially expressed in the elicitation site, suggesting that chemokine-mediated nonimmunological mechanisms precede and corroborate antigen-specific mechanisms during elicitation of CHS. In a mouse CHS study, topical treatment with a corticosteroid drug suppressed completely the infiltrates as well as the ear swelling response. In addition, the up-regulation of gene expressions for chemokines was suppressed by the corticosteroid drug, indicating that the expression of chemokine genes seems to be essential for orientating non-specific skin response to hapten-specific CHS response through the recruitment of inflammatory cells from the circulation into the tissue site. In this review, we discuss the proposed function of chemokines in the pathogenesis of CHS.

The most common allergic diseases, such as rhinitis, asthma, and atopic dermatitis, are caused by inflammation induced by an immune response to environmental allergens, driven by regulatory cells such as antigen presenting cells and T lymphocytes with their secreted products of multiple activities - cytokines and chemokines - and sustained by effector cells such as mast cells, basophils, and eosinophils. Allergen immunotherapy (AIT) is the only treatment able to modify the natural history of allergy, and a bulk of evidence is available on its effects on allergic inflammation. The antinflammatory effects of AIT rely upon the ability to modify the phenotype of T cells, which recognize in allergic subjects a prevalence of the Th2 type and its cytokine pattern, characterized by production of IL-4, IL-5, IL-13, IL-17, and IL-32. The immunotherapy-induced changes result in a Th1-type response (immune deviation) related to an increased IFN-gamma and IL-2 production or by a Th2 reduced activity, through a mechanism of anergy or tolerance. A number of studies showed that T cell tolerance is characterized by the generation of allergen-specific T regulatory (Treg) cells, which produce cytokines such IL-10 and TGF-beta with immunosuppressant and/or immunoregulatory activity. Recent studies suggest that the antinflammatory mechanism is similar in the two forms of subcutaneous and sublingual immunotherapy, with a particular role in the latter for mucosal dendritic cells. The tolerance pattern induced by Treg accounts for the suppressed or reduced activity of inflammatory cells such as mast cells, basophils and eosinophils and for the isotypic switch of antibody synthesis from IgE to IgG, and especially IgG4, which were early thought to be the major effects of AIT but now must be view in the frame of a general model.