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      Editorial

      Therapeutics and Clinical Risk Management

      Dove Medical Press

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          Abstract

          Asthma is now one of the most common chronic diseases in westernized countries and is characterized by reversible airway obstruction, bronchial hyperresponsiveness, and airway inflammation. Key pathological features include: infiltration of the airways by activated lymphocytes and eosinophils; damage to, and loss of, the bronchial epithelium; mast cell degranulation; mucous gland hyperplasia; and collagen deposition in the epithelial sub-basement membrane area. Presently, antiinflammatory therapy in asthma is largely reliant on corticosteroids, particularly in their inhaled form, and their use is associated with a striking reduction in the numbers of activated eosinophils, mast cells, and T cells in vivo. For the majority of patients, corticosteroids are effective at suppressing airway inflammation and the associated re-modelling of the airways that leads to progressive and irreversible loss of lung function. In his overview, Olof Selroos (2007) describes the various treatment options for the use of inhaled corticosteroids therapy in asthma with an emphasis on Symbicort SMART® (Symbicort Maintenance and Reliever Therapy). This consists of a budesonide–formoterol combination enabling patients to use one inhaler for both maintenance and reliever therapy. Benefits of the use of a combined corticosteroids–long-acting β2-agonist bronchodilator in the one inhaler include reductions in the rate of asthma exacerbations and maintenance of day-to-day asthma control at a reduced load of corticosteroids when compared with higher fixed maintenance doses of combination inhalers. However, although corticosteroids are usually efficacious, they may not be of benefit to patients with severe asthma who experience virally-induced exacerbations of their disease. Their use also raises concerns regarding side-effects and compliance particularly in children and adolescents. Furthermore, even in cases of good compliance for corticosteroid usage, patients with moderate and severe asthma may experience significant residual symptoms including exacerbations of their disease that in some cases can be life-threatening (Holtzman 2003). There remains an urgent need for the development of more targeted, effective, and safe therapy for asthma. Asthma pathology is associated with the release of myriad pro-inflammatory substances including lipid mediators, inflammatory peptides, chemokines, cytokines, and growth factors. As many mediators contribute to the pathophysiology of asthma, the development of specific antagonists directed at these substances represents an attractive target for inflammation resolution. However, it is unlikely that a single antagonist will have a major clinical effect compared with nonspecific agents such as corticosteroids. Indeed, strategies to block a single mediator such as platelet-activating factor antagonists, thromboxane inhibitors, and bradykinin antagonists have all proved to be disappointing. However some specific inhibitors, notably cysteinyl leukotriene antagonists, have had promising clinical effects (Walsh 2005). The cysteinyl leukotriene receptor antagonists were the first new class of anti-asthma drugs to be introduced in the last 30 years and are now an established part of the asthma armamentarium. Overall, they are less effective than inhaled corticosteroids, but some patients show a striking improvement and a corticosteroid-sparing effect has been demonstrated. It is of interest therefore that Lagos and Marshall (2007) have reviewed the use of the cysteinyl leukotriene antagonist montelukast in the treatment of seasonal allergic rhinitis (SAR). The authors conclude that montelukast confers comparable benefit to that given by antihistamines in SAR and that both drugs are more efficacious when given together. In some cases the efficacy of combined therapy in the treatment of SAR approaches that of nasal steroids. However the author acknowledges that more research is required in order to determine the efficacy of montelukast in treating perennial allergic rhinitis but early indications do indicate a likely favorable profile. Finally, montelukast may be the treatment of choice for SAR in those patients with concomitant asthma.

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          Most cited references 5

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          Drug development for asthma.

          Asthma is characterized by abnormal immune cell accumulation and activation in the airways as well as dysfunction of specialized parenchymal cells. Research strategies to define asthma pathogenesis have focused on the hypothesis that this altered state is a consequence of an excessive allergen-driven response. Drug development for asthma has been directed at improving existing agents and expanding new modalities that target the Th2 allergic cascade. Significant opportunities are being pursued in each of these areas. However, this strategy may not account for some critical aspects of asthma pathogenesis. Alternative considerations include the need for a multidisciplinary approach to dissect the complexity of the asthma phenotype as well as a better understanding of nonallergic factors (especially viral reprogramming of airway behavior) in the development of the phenotype. Each of these considerations may provide an alternative strategy for further drug development for asthma and other complex diseases.
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            A smarter way to manage asthma with a combination of a long-acting β2-agonist and inhaled corticosteroid

            Symbicort SMART® (Symbicort Maintenance and Reliever Therapy) represents a new and unique way of treating patients with moderate-to-severe asthma, ie, those patients who require combination treatment with an inhaled corticosteroid and a long-acting inhaled β2-agonist. Symbicort SMART enables patients to use only one inhaler, the budesonide-formoterol combination inhaler, for both maintenance and reliever therapy. The maintenance dose is adjustable, but should be a minimum of two doses per day which can be administered as two doses once daily or as one dose twice daily. It is important that the temporary reliever medication includes not only a bronchodilator but also an antiinflammatory drug because worsening of asthma includes not only more airway narrowing, but also an increase in airway inflammation. The Symbicort SMART concept therefore ensures that the patient gets an antiinflammatory drug at the time of the first signs of asthma worsening. Clinical results show that Symbicort SMART prolongs the time to the first severe asthma exacerbation, reduces the rate of exacerbations, and maintains day-to-day asthma control at a reduced load of corticosteroids (inhaled plus systemic) when compared with higher fixed maintenance doses of combination inhalers. Symbicort SMART consequently offers a more effective and simple approach to asthma management for physicians and patients. Symbicort SMART is also easier for the patient as only one inhaler is required. The positive results with Symbicort SMART can be explained by the early as-needed use on the inhaled corticosteroid component, which puts out the early flames of inflammation, together with the interaction between the β2-agonist, formoterol, and the inhaled corticosteroid, budesonide.
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              Novel therapies for asthma--advances and problems.

               Markus Walsh (2004)
              It is now widely accepted that airway inflammation is the key factor underlying the pathogenesis of asthma. While corticosteroids remain the most important anti-inflammatory treatment for asthma they are rather non-specific in their actions. Their use also raises concerns over side effects and compliance issues, particularly in children and adolescents. There is therefore much effort being made to develop novel more specific and safer therapy for asthma. Efforts are being made to improve existing drugs together with the use of combination therapy with anti-histamines and leukotriene antagonists. An important area for potential advances in glucocorticoid (GC) development include the elucidation of the crystal structure of the GC receptor ligand-binding domain that may provide vital information in dissociating the anti-inflammatory effects of GCs from unwanted side-effects. Other areas include the development of humanised monoclonal antibodies for asthma therapy including those against IgE, IL-4 and IL-5 together with the inhibition of adhesion pathways and/or chemokines responsible for inflammatory cell accumulation in the asthmatic lung. The potential for immunotherapy using T cell peptide epitopes or DNA-based vaccines and the use of anti-inflammatory cytokines such as IL-10 or IFN-gamma are discussed. Several avenues of research are currently underway in an attempt to define mechanisms by which pro-inflammatory cells such as eosinophils can be safely removed from the asthmatic lung through apoptosis induction and their subsequent ingestion by phagocytes. Novel strategies include elucidation of the intracellular pathways controlling granulocyte apoptosis and the receptor mediated events employed by macrophages and bronchial epithelial cells in the recognition and removal of apoptotic cellular corpses. This paper will provide an overview of both the potential and shortcomings of these diverse approaches to drug development for asthma.
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                Author and article information

                Journal
                Ther Clin Risk Manag
                Therapeutics and Clinical Risk Management
                Therapeutics and Clinical Risk Management
                Dove Medical Press
                1176-6336
                1178-203X
                June 2007
                June 2007
                : 3
                : 2
                : 211-212
                Affiliations
                Asthmatic and Allergy Inflammation Group, School of Medicine, University of Aberdeen UK
                Article
                1936302
                18360629
                © 2007 Dove Medical Press Limited. All rights reserved
                Categories
                Editorial Foreword

                Medicine

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