ReviewNew asthma targets: recent clinical and preclinical advances
Introduction
Asthma is a complex disease characterized by chronic inflammation of the airways, hyper-responsiveness of airway smooth muscle to various spasmogens and periodic airway obstruction resulting in decreased lung function (as measured by the forced expiratory volume in one second [FEV1]) [1]. The underlying causal agents of each of these characteristics has been the subject of research efforts for many years. Research of biochemical and animal model-systems have resulted in a large number of potential targets with diverse functions and potential roles in the pathophysiology of asthma. More recently, genetic analysis of asthma susceptibility in humans has begun to elucidate potential new targets.
The chronic inflammatory component of asthma is largely made up of eosinophils with a smaller contribution from neutrophils and phagocytic cells. Studies have indicated that agents released from activated eosinophils, such as major basic protein, eosinophil cationic protein and various enzymes, have the ability to cause tissue damage [2]. It is held by some that the tissue damage resulting from the chronic inflammatory state is the genesis of the other pathophysiological changes that take place in the asthmatic airway. However, studies indicate that increased airway hyper-responsiveness can be obtained in the absence of inflammation 3., 4., 5.. As a result, it has been very difficult to determine whether asthma is indeed a disease that progresses in a serial manner, with one pathophysiology being the direct effect of a prior one, or whether asthma is a series of more or less parallel changes in the airways that ultimately coalesce into what physicians define as asthma.
Current effective treatment of asthma has approached the disease from the objective of treating symptoms. The most prescribed agents to date are corticosteroids, which have been shown to inhibit infiltrating cells, cytokine production and the production of a number of other neurogenic and growth factors associated with asthma. These have limitations in that long-term administration of oral and high-dose inhaled steroids is still considered undesirable, particularly in the growing pediatric asthma population. Short-acting and long-acting beta agonists are drugs that target the decreased airway function aspect of the disease by acting as potent bronchodilators. Short-acting beta agonists are used to ameliorate acute exacerbations. These work with a quick onset of action but lose effectiveness if used on a chronic basis [6]. Long-acting beta agonists are used to prevent exacerbations and provide a partial bronchodilation compared with those of the short-acting forms. Leukotriene synthesis inhibitors and receptor antagonists provide a reduction in inflammation as well as lessening the frequency of exacerbations. Leukotriene antagonists are not as effective anti-inflammatory agents as corticosteroids, but the combined effect of these agents makes them attractive therapies. New therapies either directed at existing targets or at new targets will have to offer benefits over existing therapies such as decreased side-effect liability, multi-symptom treatment or treatment of underlying causal pathology. This review summarizes recent clinical and preclinical research over the past year and attempts to shed light on new targets that are likely to emerge as new asthma therapies.
Section snippets
Recent clinical advances
Current clinical data regarding asthma treatments have examined only a few new therapies while the majority of clinical investigation has been focused on the efficacy of combining existing therapies. The combination of long-acting beta-agonists and corticosteroids has been the most extensively tested to date. Several reports demonstrate the efficacy of this treatment in reducing inflammation and reversing poor airway function 6., 7., 8.. This combination is approved for use in asthma and is
Glucocorticoids
Recent preclinical studies into the detailed molecular mechanisms by which glucocorticoids effect gene transcription are revealing previously unknown activities and potential new targets for asthma treatment. In addition to effects on various transcription factors, such as NFκB and AP-1, it now appears that glucocorticoids may modulate the histone acetylation state of target genes. Two recent studies indicate that corticosteroids inhibit the histone acetylase activity inherent to certain
Conclusions
Short-term advances in asthma therapy will come with the combination of existing therapies that together enhance the efficacy of treating acute symptoms. Beyond this, major targets for new therapies will seek to be disease-modifying. Several preclinical and early clinical therapies are focused in this direction. The remodeling of airways in asthma is still a poorly understood pathophysiology. It still is not clear whether this remodeling is a direct effect of chronic airway inflammation or if
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
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10H-Phenothiazines: A new class of enzyme inhibitors for inflammatory diseases
2009, European Journal of Medicinal ChemistryCitation Excerpt :The pathophysiological functions of acute and chronic inflammatory diseases such as asthma, arthritis, autoimmuno disorders are due to production of a variety of chemical mediators such as leukotrienes, cytokines and prostaglandins released from biosynthetic cascade of arachidonic acid catalyzed via phospholipase A2 (PLA2), lipoxygenase and cycloxygenase enzymes [1–3]. These regulatory enzymes are believed to play an important role in initiating and amplifying the inflammatory disorders in the body, contributing to diseases such as asthma (bronco contraction), autoimmune disorders, etc. [4–6]. Phenothiazines form an important class of heterocyclic compounds possessing wide spectrum diverse biological activities like antitumor, antimalarial, antipsychotic, anti-inflammatory, etc. [7–9].
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