Drugs for asthma

Current drug therapy for asthma is highly effective and has evolved from naturally occurring substances through logical pharmaceutical developments. Pharmacology has played a critical role in asthma drug development and several key experimental observations have been published in this journal. Understanding the pharmacology of effective drug therapies has also taught us much about the underlying mechanisms of asthma. beta(2)-Adrenoceptor agonists are the most effective bronchodilators and evolved from catecholamines from the adrenal medulla, whereas corticosteroids, from the adrenal cortex, are by far the most effective controllers of the underlying inflammatory process in the airways. The current 'gold standard' of asthma therapy is a combination inhaler containing a long-acting beta(2)-agonist with a corticosteroid - an improved form of adrenal gland extract. Cromoglycate, derived from a plant product and theophylline, a dietary methyl xanthine, have also been extensively used in the therapy of asthma, but we still do not understand their molecular mechanisms. Pharmacology has played an important role in improving natural products to make effective long lasting and safe asthma therapies, but has so far been challenged to produce new classes of antiasthma therapy. The only novel class of antiasthma therapy introduced in the last 30 years are leukotriene antagonists, which are less effective than existing treatments. New, more specific, therapies targeted at specific cytokines are less effective than corticosteroids, whereas more effective therapies carry a risk of side effects that may not be acceptable. It seems likely that pharmacology, rather than molecular genetics, will remain the main approach to the further improvement of treatment for asthma.     

TNF-alpha in asthma

Although only 5-10% of patients with asthma are relatively unresponsive to treatment with inhaled corticosteroids, refractory asthma represents an important condition, as these patients suffer considerable morbidity and mortality and consume a disproportionately large amount of health resource. Treatment options are limited and there is a large unmet clinical need for additional therapies. Tumour necrosis factor (TNF)-alpha is a pro-inflammatory cytokine that has been implicated in many aspects of the airway pathology in asthma, and which has recently been highlighted as potentially important in refractory asthma. The development of neutralising biological agents against TNF-alpha has allowed us to test the role of this cytokine in vivo. Preliminary studies have demonstrated an improvement in lung function, airway hyperresponsiveness and asthma quality-of-life, together with a reduction in exacerbation frequency, in patients treated with anti-TNF-alpha therapy.     

Emerging drugs for asthma

INTRODUCTION: Current drug treatments for asthma relieve bronchospasm and airway inflammation but do not offer a cure, and symptoms return when treatment is stopped. Asthma management guidelines emphasize the importance of effective asthma treatment to achieve and maintain asthma control. However, despite widely available and effective treatments, achieving asthma control is still an unmet need for many patients. AREAS COVERED: Remarkable efforts have been made to identify the characteristic features of difficult-to-control (usually severe) asthma that are different from those described for mild-to-moderate asthma, setting the stage for the development of new and even individualized therapies. The most fascinating options of the new asthma treatments are biologic therapies, in particular monoclonal antibodies. In addition, some novel once-daily combinations of long-acting β(2)-agonist and inhaled corticosteroids are under development. EXPERT OPINION: Asthma is a complex syndrome made up of a number of disease variants or asthma phenotypes, with different underlying pathophysiology. As different drugs target different pathways, it is necessary to determine the individual profile of pathophysiological abnormalities for each patient. Several cytokines have been implicated in the inflammatory cascades leading to the different asthma phenotypes, and the most relevant ones are discussed. The challenge in treating asthma resides precisely in its heterogeneity.     

Asthma. Anti-inflammatory therapies.

It is likely that airway inflammation has an central role in the development and maintenance of the structural and functional abnormalities that characterise asthma. The recognition that asthma is a chronic inflammatory disorder of the airways has resulted in an increased emphasis on the use of anti-inflammatory drugs. The principal anti-inflammatory drugs are corticosteroids and to a lesser extent sodium cromoglycate and nedocromil sodium. Several other drugs and therapies may also have anti-inflammatory effects in asthma. The early use of prophylactic anti-inflammatory agents is advocated in the treatment of chronic asthma. It is hoped that this treatment scheme will result in a reduction in the morbidity and mortality from this common chronic condition.     

Treating asthma in the older patient: is there a place for leukotriene modifiers?

Asthma is a common airway disease found in people of all ages, although most studies of asthma therapies are focused on adolescent and young adults. Little information exists on the use of asthma therapeutics in the older patient (>65 years of age). The newest therapeutic class to be released in the US for the treatment of asthma is the leukotriene modifiers. These medications (either receptor antagonists or enzyme inhibitors) have been found to be beneficial in younger patients with asthma, but their potential role in older patients is less clear. In this review, the data regarding the use of these medications in older patients are examined, as are the epidemiological and pathophysiological issues regarding asthma in this growing patient population. On the basis of the two published reports of leukotriene modifiers in the older patient, we conclude that leukotriene modifiers are useful in this population, but like other controller therapies for asthma, they are less effective in the older population.     

Leukotriene inhibitors and non-steroidal therapies in the treatment of asthma

Asthma is the most common chronic disease of childhood whose morbidity and mortality continues to rise [1]. Drugs used in the treatment of asthma must be targeted at reversing three principle pathophysiologic features: bronchoconstriction, mucus plugging/hypersecretion and inflammation. In the past two decades, the contribution of airway inflammation to the development and progression of asthma symptoms and airway pathology has become a critical focus. Chronic airway inflammation can lead to the progressive decline and irreversible loss of lung function and airway remodelling [2]. In recent years, therapies aimed at diminishing airway inflammation have been at the forefront of asthma management. Steroids have been extensively studied and used as primary anti-inflammatory agents in the management of the asthmatic patient with persistent symptoms of varying severity. Within the last decade, however, several additional non-steroidal classes of drugs have begun to emerge as anti-inflammatory agents for the treatment of asthma. This article will focus on these non-steroidal drugs which have been developed and investigated within the last 5 years. Particular emphasis will be placed on leukotriene receptor antagonists, but anti-IgE and anti-IL-4 therapies, as well as phosphodiesterase inhibitors will also be discussed. Of these new therapies, only two leukotriene receptor antagonists, montelukast (Singulair?, Merck) and zafirlukast (Accolate?, AstraZeneca) and the 5-lipoxygenase inhibitor, zileuton (Zyflo?, Abbott Laboratories), have been recommended, approved and are currently available for use in the treatment of paediatric patients with asthma in the United States.     

Leukotriene inhibitors and non-steroidal therapies in the treatment of asthma

Asthma is the most common chronic disease of childhood whose morbidity and mortality continues to rise [1]. Drugs used in the treatment of asthma must be targeted at reversing three principle pathophysiologic features: bronchoconstriction, mucus plugging/hypersecretion and inflammation. In the past two decades, the contribution of airway inflammation to the development and progression of asthma symptoms and airway pathology has become a critical focus. Chronic airway inflammation can lead to the progressive decline and irreversible loss of lung function and airway remodelling [2]. In recent years, therapies aimed at diminishing airway inflammation have been at the forefront of asthma management. Steroids have been extensively studied and used as primary anti-inflammatory agents in the management of the asthmatic patient with persistent symptoms of varying severity. Within the last decade, however, several additional non-steroidal classes of drugs have begun to emerge as anti-inflammatory agents for the treatment of asthma. This article will focus on these non-steroidal drugs which have been developed and investigated within the last 5 years. Particular emphasis will be placed on leukotriene receptor antagonists, but anti-IgE and anti-IL-4 therapies, as well as phosphodiesterase inhibitors will also be discussed. Of these new therapies, only two leukotriene receptor antagonists, montelukast (Singulairtrade mark, Merck) and zafirlukast (Accolatetrade mark, AstraZeneca) and the 5-lipoxygenase inhibitor, zileuton (Zyflotrade mark, Abbott Laboratories), have been recommended, approved and are currently available for use in the treatment of paediatric patients with asthma in the United States.     

Montelukast for the treatment of asthma in the adult population

INTRODUCTION: Asthma is a complex process that results from airway inflammation and manifests as bronchoconstriction. Infiltration of the airway mucosa and lumen by activated inflammatory cells, along with release of mediators, can occur extensively. Chemical mediators known as leukotrienes are believed to play a major role in this process. At present, inhaled corticosteroids (ICS) are the pharmacologic cornerstone of asthma management. However, asthma control may remain suboptimal when relying on ICS because of problems with compliance, poor inhaler technique and concerns about the side effects of steroids; additional agents are often required to control symptoms. Leukotriene receptor antagonists (LTRA), namely montelukast, provide a safe and effective additional anti-inflammatory treatment option. There is particular benefit for patients with asthma and concomitant allergic rhinitis. AREAS COVERED: Montelukast has been well studied through rigorous clinical trials. A thorough review of the literature has been undertaken to assess the evidence supporting the use of LTRAs. This review focuses on the role of montelukast not only as monotherapy but also as add-on therapy to ICS in the adult asthma population, as well as adult asthmatics with concomitant allergic rhinitis. In addition, there is often some discrepancy between the evidence generated in the idealized asthma patients recruited into randomized clinical trials and results obtained in the real-life setting. This review assesses recent clinical trials evaluating the real-life evaluation of montelukast, achieved mainly through open-label observational studies. EXPERT OPINION: Oral LTRA bring remarkable ease of anti-inflammatory treatment administration and symptom improvement with minimal side effects to the management of adult asthma. Basic asthma mechanisms and much-valued scientific groundwork has been identified by exploring target asthma treatment with anti-leukotriene therapy. This will have a significant impact in the future development of targeted asthma therapies as well as the current management of asthma and other inflammatory medical conditions.     

Herbal remedies for asthma treatment: between myth and reality

Asthma is one of the most common chronic diseases worldwide. To treat this widespread disease there is a high prevalence of usage of herbal medicine. The use of plants is as old as humankind and it has been steadily increasing over the past 10 years. Plant-based remedies are now one of the most popular complementary treatments. Herbal supplements are receiving increasing exposure through media, including the Internet, in lay journals and more recently in the scientific press. Interest in herbal medicine has been facilitated by multiple factors, including the perception that pharmaceutical medications are expensive, overprescribed and may often be dangerous. Alternatively, herbal medicine is often perceived as being "natural" and therefore is considered safe. However, the scientific literature supporting the efficacy of herbal therapies is incomplete. There are few well-controlled studies that support the efficacy of herbal remedies in the treatment and clinical improvement of patients with asthma. Available scientific evidence has not yet confirmed the validity of their popular role in the treatment of asthma. The present review evaluates herbs and their efficacy in asthma to provide a balanced and objective view for the reader seeking information on herbal therapy     

Drug therapy in asthma bronchiale in the new millennium

Asthma bronchiale represents a major health issue in industrialized countries and will likely remain so for decades. The drug treatment of asthma demonstrates certain peculiarities: revolutionary new drug introductions happen almost each quarter century. With improved understanding of asthma pathogenesis and drug metabolism, the potential for specific targeted and constructed therapies has become evident. Monoclonal antibodies to IgE and certain cytokines such IL-4 and IL-5 are being investigated as possible treatments for asthma. Similarly, preliminary studies of selective phosphodiesterase inhibitors in asthmatic patients have been encouraging. Other potential therapies include for example inhibitors of cytokine synthesis, promoters of Th2-Th1 switch, adenosine receptor agonists or antagonists, etc.. A new way is represented by a modified retrometabolic drug design resulting in so-called soft drugs. The first representative of this new drug class is loteprednol etabote (LE), a non-fluorinated glucocorticoid approved for the allergic ophthalmological indications and now in clinical trial for the treatment of allergic airway diseases. Today's intensive search for new treatments should ensure a greater diversity of therapeutic possibilities for the management of asthma in the new millennium.     

Novel therapy for asthma

The health burden of asthma is increasing globally at an alarming rate, providing a strong impetus for the development of new therapeutics. Currently available inhaled bronchodilators and anti-inflammatory drugs are effective in most asthmatics, but this palliative therapy requires long-term daily administration. Despite considerable efforts by the pharmaceutical industry, it has been difficult to develop novel therapeutic agents; the leukotriene antagonists and synthesis inhibitors being the only new class of asthma treatments to have been licensed in the last 30 years. It is clearly important to understand more about the underlying mechanisms of asthma and about how current drugs work before rational improvements in therapy can be expected. There are numerous therapies in clinical development that combat the inflammation found in asthma, specifically targeting eosinophils, IgE, adhesion molecules, cytokines and chemokines, inflammatory mediators and cell signalling. In particular, there is the obvious need for new therapy for severe asthma that is poorly controlled by high doses of corticosteroids, as well as agents to counter acute emergency asthma. A long-term goal is to develop disease-modifying immunotherapy, that could be introduced in childhood to alter the natural history of asthma. Thanks to the extensive efforts of the pharmaceutical industry, in the near future we can expect the introduction of a range of novel therapies for asthma.     

Anti-IgE monoclonal antibody,omalizumab: a new treatment for allergic asthma

Omalizumab (Xolair^?; Genentech, USA/Tanox, Inc., USA/Novartis Pharma AG, Switzerland) – a humanised antibody to IgE that reduces circulating free IgE – has been developed for the treatment of allergic asthma. It inhibits the early- and late-phase response to allergens, suppresses eosinophilic and T cell inflammation in asthmatic airways and reduces the levels of high-affinity IgE receptors on basophils. In clinical trials of moderate-to-severe asthma, omalizumab allowed a reduction in inhaled corticosteroid dosage while improving peak flows and reducing exacerbations, particularly in patients at high-risk of serious asthma-related morbidity and improved quality of life scores. When added to existing therapies of patients with more severe asthma, omalizumab also improved asthma control. Additionally, in asthma patients with concomitant perennial allergic rhinitis, omalizumab provides improvement in these comorbid conditions. Omalizumab is well-tolerated by asthma patients and represents a new approach to the treatment of the moderate-to-severe asthmatic patient. It is likely that it will first be used at the more severe end of the asthmatic diathesis.     

Emerging drugs for asthma

Background: Current therapies for asthma are aimed at controlling disease symptoms and for the majority of asthmatics inhaled corticosteroid anti-inflammatory therapy is effective. However, this approach requires life-time therapy while a subset of patients remains symptomatic despite optimal treatment creating a clear unmet medical need. Objectives: It is recognised that airway inflammation is key to asthma pathogenesis. Biopharmaceutical approaches may identify new therapies that target key cells and mediators that drive the inflammatory responses in the asthmatic lung. Such an approach may provide disease-modifying treatments. Results: Significant areas of drug development include humanised monoclonal antibodies (mAb) for asthma therapy including those against IgE, IL-4 and IL-5. Asthma-relevant cytokines or chemokines have been targeted in a number of other ways. These include the use of humanised receptor blocking mAb or the removal of cytokines or chemokines via their binding to soluble receptor constructs. Small-molecule receptor antagonists also target receptors or the cellular signal transduction pathways that are activated following cytokine or chemokine receptor ligation. Another approach is to target asthma relevant mediators or the pathways controlling pro-inflammatory leukocyte accumulation within the asthmatic lung. Conclusions: This review will discuss the current status, therapeutic potential and potential problems of these novel drug developments in asthma therapy. Current therapies for asthma are aimed at controlling disease symptoms, and for the majority of asthmatics inhaled corticosteroid anti-inflammatory therapy is effective. However, this approach requires lifetime therapy; and a subset of patients remains symptomatic despite optimal treatment, creating a clear unmet medical need. It is recognised that airway inflammation is key to asthma pathogenesis. Biopharmaceutical approaches may identify new therapies that target key cells and mediators that drive the inflammatory responses in the asthmatic lung. Such an approach may provide disease-modifying treatments. Significant areas of drug development include humanised mAb for asthma therapy, including those against IgE, IL-4 and IL-5. Asthma-relevant cytokines or chemokines have been targeted in a number of other ways. These include the use of humanised receptor blocking mAb or the removal of cytokines or chemokines via their binding to soluble receptor constructs. Small-molecule receptor antagonists also target receptors or the cellular signal transduction pathways that are activated following cytokine or chemokine receptor ligation. Another approach is to target asthma-relevant mediators, or the pathways controlling pro-inflammatory leukocyte accumulation within the asthmatic lung. This review will discuss the current status, therapeutic potential and potential problems of these novel drug developments in asthma therapy.     

Combining inhaled glucocorticoids and long acting beta(2)-adrenoceptor agonists in asthma and COPD

Inhaled long-acting beta(2)-adrenoceptor agonists and glucocorticoids form the mainstay of maintenance treatment of asthma and chronic obstructive pulmonary disease (COPD), usually given as a combination inhaler. Most patients will have good asthma control if they comply with this therapy, although it is generally less effective in COPD. The traditional dogma has been that these agents act on distinct components of disease pathophysiology with beta(2) agonists acting on the bronchospastic component and glucocorticoids acting on the inflammatory component. Considerable evidence has emerged recently, however, to suggest that these two classes of agents interact at a molecular level. Understanding the mechanisms of these interactions may enable the development of new therapies for asthma and COPD.     

Targeting Th2 cells in asthmatic airways

The most effective anti-asthmatic drugs currently available include inhaled beta2-agonists and glucocorticoids and control asthma in about 95% of patients. The current asthma therapies are not cures and symptoms return soon after the treatment is stopped even after long-term therapy. In addition, severe glucocorticoid-dependent and -resistant asthma still represents a great clinical burden accounting for approximately 50% of the health care costs of asthma and reducing the side-effects of glucocorticoids using novel dissociated steroids, soft steroids or with steroid-sparing agents will prove beneficial. Furthermore, the mechanisms involved in the persistence of inflammation are poorly understood and the reasons why some patients have severe life threatening asthma and others have very mild disease are still unknown. Hopefully, it will soon be possible to identify and manipulate the molecular switches that result in asthmatic inflammation. This may lead to the treatment of susceptible individuals at birth or in the early years and thus prevent the disease from becoming established. Drug development for asthma has been directed at improving currently available drugs and finding new compounds that usually target the Th2-driven airway inflammatory response. Several new drugs have been developed to target specific components of the Th2-driven inflammatory process in asthma (e.g. IgE antibodies, cytokines and/or chemokines, immunomodulators, antagonists of adhesion molecules), although they have not yet been proven to be particularly effective. Some of these new Th2-oriented strategies may in the future not only control symptoms, but also potentially prevent or cure the disease.     

Dual role of Toll-like receptors in asthma and chronic obstructive pulmonary disease

During the last decade, significant research has been focused on Toll-like receptors (TLRs) in the pathogenesis of airway diseases. TLRs are pattern recognition receptors that play pivotal roles in the detection of and response to pathogens. Because of the involvement of TLRs in innate and adaptive immunity, these receptors are currently being exploited as possible targets for drug development. Asthma and chronic obstructive pulmonary disease (COPD) are chronic inflammatory airway diseases in which innate and adaptive immunity play an important role. To date, asthma is the most common chronic disease in children aged 5 years and older. COPD is prevalent amongst the elderly and is currently the fifth-leading cause of death worldwide with still-growing prevalence. Both of these inflammatory diseases result in shortness of breath, which is treated, often ineffectively, with bronchodilators and glucocorticosteroids. Symptomatic treatment approaches are similar for both diseases; however, the underlying immunological mechanisms differ greatly. There is a clear need for improved treatment specific for asthma and for COPD. This review provides an update on the role of TLRs in asthma and in COPD and discusses the merits and difficulties of targeting these proteins as novel treatment strategies for airway diseases. TLR agonist, TLR adjuvant, and TLR antagonist therapies could all be argued to be effective in airway disease management. Because of a possible dual role of TLRs in airway diseases with shared symptoms and risk factors but different immunological mechanisms, caution should be taken while designing pulmonary TLR-based therapies.     

Oxidants in asthma and in chronic obstructive pulmonary disease (COPD)

Experimental and clinical evidences suggest that oxidants play a role in the pathogenesis of respiratory disorders characterised by chronic airway inflammation such as asthma and chronic obstructive pulmonary disease (COPD). The respiratory system is chronically exposed to environmental pollutants, including oxidants. Exogenous sources of oxidants are particularly relevant to the pathogenesis of COPD, being cigarette smoke an extremely rich source of oxidants. In addition, the inflammatory cells recruited to the airways of patients with asthma and COPD, have an exceptional capacity to produce oxidants. Many decades of research have produced a significant amount of data indicating pro-oxidative molecular mechanisms putatively relevant in the pathogenesis of the oxidative stress which characterises these diseases, both locally and systemically. As a consequence, a drug therapy able to restore the redox imbalance in asthma and COPD would probably exert clinical and functional benefits. Indeed, currently available therapies for asthma and COPD can exert an inhibitory effect on oxidant production in the airways. However, it is unknown whether the efficacy of the treatment is somehow linked to the pharmacological modulation of the oxidant/antioxidant balance. So far, it appears that the potential role of antioxidant compounds in the treatment of asthma and COPD has not been fully explored.     

New anti-inflammatory therapies and targets for asthma and chronic obstructive pulmonary disease

Asthma and chronic obstructive pulmonary disease (COPD) are diseases of the airways with an underlying inflammatory component. The prevalence and healthcare burden of asthma and COPD is still rising and is predicted to continue to rise in the foreseeable future. β-agonists and corticosteroids form the basis of the therapies available to treat asthma. However, the treatments available for COPD, corticosteroids and anticholinergics, reduce the number and severity of exacerbations, but have a limited effect on slowing the progression of the disease. The inflammatory processes underlying the pathology of asthma have received a great deal of attention and more recently, those underlying COPD have begun to be elucidated. This has resulted in the identification of new targets that will allow the development of novel approaches by the pharmaceutical industry, which will be able to focus its efforts in an attempt to provide new and improved therapies to treat these debilitating diseases. The resultant therapies should impinge on the underlying development of these diseases rather than providing symptomatic relief or palliative treatment alone. This review will outline new targets and novel approaches currently under investigation, which may provide opportunities for novel anti-inflammatory therapeutic interventions that slow or halt disease progression in asthma and COPD.     

New anti-inflammatory therapies and targets for asthma and chronic obstructive pulmonary disease

Asthma and chronic obstructive pulmonary disease (COPD) are diseases of the airways with an underlying inflammatory component. The prevalence and healthcare burden of asthma and COPD is still rising and is predicted to continue to rise in the foreseeable future. Beta-agonists and corticosteroids form the basis of the therapies available to treat asthma. However, the treatments available for COPD, corticosteroids and anticholinergics, reduce the number and severity of exacerbations, but have a limited effect on slowing the progression of the disease. The inflammatory processes underlying the pathology of asthma have received a great deal of attention and more recently, those underlying COPD have begun to be elucidated. This has resulted in the identification of new targets that will allow the development of novel approaches by the pharmaceutical industry, which will be able to focus its efforts in an attempt to provide new and improved therapies to treat these debilitating diseases. The resultant therapies should impinge on the underlying development of these diseases rather than providing symptomatic relief or palliative treatment alone. This review will outline new targets and novel approaches currently under investigation, which may provide opportunities for novel anti-inflammatory therapeutic interventions that slow or halt disease progression in asthma and COPD.