Treatment heterogeneity in asthma: genetics of response to leukotriene modifiers

Despite advances in treatment, asthma continues to be a significant health and economic burden. Although asthma cannot be cured, several drugs, including beta2 agonists, corticosteroids, and leukotriene (LT) modifiers, are well tolerated and effective in minimizing symptoms, improving lung function, and preventing exacerbations. However, inter-patient variability in response to asthma drugs limits their effectiveness. It has been estimated that 60-80% of this inter-patient variability may be attributable to genetic variation. LT modifiers, in particular, have been associated with heterogeneity in response. These drugs exert their action by inhibiting the activity of cysteinyl leukotrienes (CysLTs), which are potent bronchoconstrictors and pro-inflammatory agents. Two classes of LT modifiers are 5-lipoxygenase (ALOX5) inhibitors (zileuton) and leukotriene receptor antagonists (LTRAs) [montelukast, pranlukast, and zarfirlukast]. LT modifiers can be used as alternatives to low-dose inhaled corticosteroids (ICS) in mild persistent asthma, as add-on therapy to low- to medium-dose ICS in moderate persistent asthma, and as add-on to high-dose ICS and a long-acting ss2 agonist in severe persistent asthma. At least six genes encode key proteins in the LT pathway: arachidonate 5-lipoxygenase (ALOX5), ALOX5 activating protein (ALOX5AP [FLAP]), leukotriene A4 hydrolase (LTA4H), LTC4 synthase (LTC4S), the ATP-binding cassette family member ABCC1 (multidrug resistance protein 1 [MRP1]), and cysteinyl leukotriene receptor 1 (CYSLTR1). Studies have reported that genetic variation in ALOX5, LTA4H, LTC4S, and ABCC1 influences response to LT modifiers. Plasma concentrations of LTRAs vary considerably among patients. Physio-chemical characteristics make it likely that membrane efflux and uptake transporters mediate the absorption of LTRAs into the systemic circulation following oral administration. Genes that encode efflux and uptake transport proteins harbor many variants that could influence the pharmacokinetics, and particularly the bioavailability, of LTRAs, and could contribute to heterogeneity in response. In the future, large, well designed clinical trials studying the pharmacogenetics of LT modifiers in diverse populations are warranted to determine whether a genetic signature can be developed that will accurately predict which patients will respond.     

Guidelines for the emergency management of asthma in adults. CAEP/CTS Asthma Advisory Committee. Canadian Association of Emergency Physicians and the Canadian Thoracic Society.

OBJECTIVE: To develop a set of comprehensive, standardized evidence-based guidelines for the assessment and treatment of acute asthma in adults in the emergency setting. OPTIONS: The use of medications was evaluated by class, dose, route, onset of action and optimal mode of delivery. The use of objective measurements and clinical features to assess response to therapy were evaluated in relation to the decision to admit or discharge the patient or arrange for follow-up care. OUTCOMES: Control of symptoms and disease reflected in hospital admission rates, frequency of treatment failures following discharge, resolution of symptoms and improvement of spirometric test results. EVIDENCE: Previous guidelines, articles retrieved through a search of MEDLINE, emergency medical abstracts and information from members of the expert panel were reviewed by members of the Canadian Association of Emergency Physicians (CAEP) and the Canadian Thoracic Society. Where evidence was not available, consensus was reached by the expert panel. The resulting guidelines were reviewed by members of the parent organizations. VALUES: The evidence-based methods and values of the Canadian Task Force on the Periodic Health Examination were used. BENEFITS, HARMS AND COSTS: As many as 80% of the approximate 400 deaths from asthma each year in Canada are felt to be preventable. The use of guidelines, aggressive emergency management and consistent use of available options at discharge are expected to decrease the rates of unnecessary hospital admissions and return visits to emergency departments because of treatment failures. Substantial decreases in costs are expected from the use of less expensive drugs, or drug delivery systems, fewer hospital admissions and earlier return to full activity after discharge. RECOMMENDATIONS: Beta2-agonists are the first-line therapy for the management of acute asthma in the emergency department (grade A recommendation). Bronchodilators should be administered by the inhaled route and titrated using objective and clinical measures of airflow limitation (grade A). Metered-dose inhalers are preferred to wet nebulizers, and a chamber (spacer device) is recommended for severe asthma (grade A). Anticholinergic therapy should be added to beta 2 agonist therapy in severe and life-threatening cases and may be considered in cases of mild to moderate asthma (grade A). Aminophylline is not recommended for use in the first 4 hours of therapy (grade A). Ketamine and succinylcholine are recommended for rapid sequence intubation in life-threatening cases (grade B). Adrenaline (administered subcutaneously or intravenously), salbutamol (administered intravenously) and anesthetics (inhaled) are recommended as alternatives to conventional therapy in unresponsive life-threatening cases (grade B). Severity of airflow limitation should be determined according to the forced expiratory volume at 1 second or the peak expiratory flow rate, or both, before and after treatment and at discharge (grade A). Consideration for discharge should be based on both spirometric test results and assessment of clinical risk factors for relapse (grade A). All patients should be considered candidates for systemic corticosteroid therapy at discharge (grade A). Those requiring corticosteroid therapy should be given 30 to 60 mg of prednisone orally (or equivalent) per day for 7 to 14 days; no tapering is required (grade A). Inhaled corticosteroids are an integral component of therapy and should be prescribed for all patients receiving oral corticosteroid therapy at discharge (grade A). Patients should be given a discharge treatment plan and clear instructions for follow-up care (grade C). VALIDATION: The guidelines share the same principles of those from the British Thoracic Society and the National Institutes of Health. Two specific validation initiatives have been undertaken: (a) several Canadian centres have been involved in the collection of comprehensive administrative data to assess compliance and outcome measures and (b) a survey of Canadian emergency physicians conducted to gather baseline informaton of treatment patterns, was conducted before development of the guidelines and will be repeated to re-evaluate emergency management of asthma.     

New therapies for asthma

Asthma is an increasing global health problem, and many patients continue to suffer from chronic symptoms. However, current therapy with inhaled corticosteroids and a long-acting inhaled beta(2)-agonist is highly effective, safe and inexpensive. This poses a major hurdle to the development of new therapies that aim to improve on current treatments. An important unmet need is the treatment of severe asthma, which has different characteristics to mild and moderate asthma and is more similar to chronic obstructive pulmonary disease. Several new treatments are now under development but many of them are too specific, targeting a single receptor, enzyme or mediator, and are unlikely to have a major clinical impact. Another unmet need is the development of an effective oral therapy for mild and moderate asthma, but it is unlikely that such a treatment will be discovered because side effects might be a major problem. Prospects for a cure are currently remote but might arise from the development of vaccines that target the aberrant immune function in asthma.     

Antileukotriene agents in asthma: The dart that kills the elephant?

THE PERSISTENCE OF AIRWAY INFLAMMATION is believed to cause the mechanical changes and symptoms of asthma. After decades of research, a new class of medication has emerged that focuses on leukotrienes, mediators of inflammation. These substances are potent inducers of bronchoconstriction, increased vascular permeability and mucus production, and they potentiate the influx of inflammatory cells in the airways of patients with asthma. In this article the author reviews the development, mechanism of action, and clinical and toxic effects of the leukotriene synthesis inhibitors and receptor antagonists that are entering the North American market. These agents can decrease airway response to antigen, airway hyperresponsiveness and exercise-induced asthma. They are also effective inhibitors of ASA-induced symptoms. Although few published studies are available, the antileukotrienes seem almost as effective in the management of chronic asthma as low-dose inhaled corticosteroids, and their use permits a decrease in the frequency of use or dose of corticosteroids. Further evaluation and clinical experience will determine the position of targeted inhibition of the leukotriene pathway in the treatment of asthma.     

The analysis of the factors influencing the development of glucocorticoid resistance in the etiopathogenesis of severe bronchial asthma

Bronchial asthma is a disease of multi - factored etiology. Current data show that multiple genes may be involved in the pathogenesis of asthma. Corticosteroids (GCS) are the most effective anti-inflammatory therapy for inflammatory disease such as bronchial asthma. There are 2 major types of GCS-resistant asthma to treatment of high doses of inhaled and oral glucocorticoids. Type I GCS-resistant asthma is cytokine-induced or acquired. Type II GCS resistance involves generalized primary cortisol resistance, which affects all tissues and is likely associated with a mutation in the GCR gene or in genes that modulate GCR function. There are clear examples of glucocorticoid gene h-GCR/NR3C1 polymorphisms that can influence responses and sensitivity to glucocorticosteroids. This article may lead to holistic the development analysis of the factors determining the progress of the glucocorticoid resistance in the severe bronchial asthma with special acknowledgement of the influence of polymorphisms of the glucocorticoid receptor gene h-GCR/NR3C1 to formation GCS resistance.     

Risk factors for asthma and allergy associated with urban migration: background and methodology of a cross-sectional study in Afro-Ecuadorian school children in Northeastern Ecuador (Esmeraldas-SCAALA Study)

Background

This study examined the attitudes and actions of 3415 physician-recruited adults aged ≥ 16 years with asthma in eleven countries who were prescribed regular maintenance therapy with inhaled corticosteroids or inhaled corticosteroids plus long-acting β₂-agonists.

Methods

Structured interviews were conducted to assess medication use, asthma control, and patients' ability to recognise and self-manage worsening asthma.

Results

Despite being prescribed regular maintenance therapy, 74% of patients used short-acting β₂-agonists daily and 51% were classified by the Asthma Control Questionnaire as having uncontrolled asthma. Even patients with well-controlled asthma reported an average of 6 worsenings/year. The mean period from the onset to the peak symptoms of a worsening was 5.1 days. Although most patients recognised the early signs of worsenings, the most common response was to increase short-acting β₂-agonist use; inhaled corticosteroids were increased to a lesser extent at the peak of a worsening.

Conclusion

Previous studies of this nature have also reported considerable patient morbidity, but in those studies approximately three-quarters of patients were not receiving regular maintenance therapy and not all had a physician-confirmed diagnosis of asthma. This study shows that patients with asthma receiving regular maintenance therapy still have high levels of inadequately controlled asthma. The study also shows that patients recognise deteriorating asthma control and adjust their medication during episodes of worsening. However, they often adjust treatment in an inappropriate manner, which represents a window of missed opportunity.     

Acute asthma: emergency department management and prospective evaluation of outcome.

To determine the current management of acute asthma in the emergency department and to evaluate outcome we reviewed the charts of 99 patients aged 15 to 55 years who presented to the emergency department of a tertiary referral, university-affiliated hospital and were subsequently discharged with a diagnosis of acute asthma. Outcome was evaluated prospectively, with a structured questionnaire, by telephone. During the visit pulsus paradoxus was documented in four patients. Spirometry was done in 63 patients; postbronchodilator values ranged from 0.9 to 4.1 L. A total of 92 patients received inhaled bronchodilator therapy, most by wet nebulization. Sixteen patients received anticholinergic agents and three received theophylline. Ingested corticosteroids were given to 27 patients. Of the 71 patients contacted, a mean of 12 days after the visit, 26 (37%) had sought further medical attention, 19 at the emergency department; 9 had required admission. Forty-six patients reported that their condition had improved, but over 60% continued to have cough, sputum production, nocturnal waking and early-morning chest tightness. The results indicate that asthma continues to be undertreated in the emergency department and highlight the importance of routine spirometry in all patients and the need for systemic corticosteroid therapy.     

Increased oxidative stress and severe arterial remodeling induced by permanent high-flow challenge in experimental pulmonary hypertension

Atopic asthma is a chronic inflammatory pulmonary disease characterised by recurrent episodes of wheezy, laboured breathing with an underlying Th2 cell-mediated inflammatory response in the airways. It is currently treated and, more or less, controlled depending on severity, with bronchodilators e.g. long-acting beta agonists and long-acting muscarinic antagonists or anti-inflammatory drugs such as corticosteroids (inhaled or oral), leukotriene modifiers, theophyline and anti-IgE therapy. Unfortunately, none of these treatments are curative and some asthmatic patients do not respond to intense anti-inflammatory therapies. Additionally, the use of long-term oral steroids has many undesired side effects. For this reason, novel and more effective drugs are needed. In this review, we focus on the CD4+ Th2 cells and their products as targets for the development of new drugs to add to the current armamentarium as adjuncts or as potential stand-alone treatments for allergic asthma. We argue that in early disease, the reduction or elimination of allergen-specific Th2 cells will reduce the consequences of repeated allergic inflammatory responses such as lung remodelling without causing generalised immunosuppression.     

Treatment of allergic asthma: Modulation of Th2 cells and their responses

Atopic asthma is a chronic inflammatory pulmonary disease characterised by recurrent episodes of wheezy, laboured breathing with an underlying Th2 cell-mediated inflammatory response in the airways. It is currently treated and, more or less, controlled depending on severity, with bronchodilators e.g. long-acting beta agonists and long-acting muscarinic antagonists or anti-inflammatory drugs such as corticosteroids (inhaled or oral), leukotriene modifiers, theophyline and anti-IgE therapy. Unfortunately, none of these treatments are curative and some asthmatic patients do not respond to intense anti-inflammatory therapies. Additionally, the use of long-term oral steroids has many undesired side effects. For this reason, novel and more effective drugs are needed. In this review, we focus on the CD4+ Th2 cells and their products as targets for the development of new drugs to add to the current armamentarium as adjuncts or as potential stand-alone treatments for allergic asthma. We argue that in early disease, the reduction or elimination of allergen-specific Th2 cells will reduce the consequences of repeated allergic inflammatory responses such as lung remodelling without causing generalised immunosuppression.     

The role of leukotrienes in asthma

Leukotrienes (LT), both the cysteinyl LTs, LTC(4), LTD(4) and LTE(4), as well as LTB(4) have been implicated in the clinical course, physiologic changes, and pathogenesis of asthma. The cysteinyl LTs are potent bronchoconstrictors, which have additional effects on blood vessels, mucociliary clearance and eosinophilic inflammation. In addition, the cysteinyl LTs are formed from cells commonly associated with asthma, including eosinophils and mast cells. LTB(4), whose role is less well defined in asthma, is a potent chemoattractant (and cell activator) for both neutrophils and eosinophils. In the last 5 years, drugs have been developed which block the actions or formation of these mediators. Clinical and physiologic studies have demonstrated that they are modest short-acting bronchodilators, with sustained improvement in FEV(1) occurring in double-blind, placebo-controlled clinical trials for up to 6 months. These drugs have demonstrated efficacy in preventing bronchoconstriction caused by LTs, allergen, exercise and other agents. Additionally, there are multiple published studies which have demonstrated improvement in asthma symptoms, beta agonist use and, importantly, exacerbations of asthma in both adults and children. Comparison studies with inhaled corticosteroids (ICS) suggest that ICS are superior to leukotriene modifying drugs in moderate persistent asthma. However, several published studies now suggest that leukotriene modifying drugs are effective when added to ongoing therapy with ICS, either to improve current symptoms or to decrease the dose of ICS required to maintain control. While an anti-inflammatory effect is suggested, longer-term, earlier intervention, studies are needed to determine whether these compounds will have any effect on the natural history of the disease.     

NONSPECIFIC ANTI-INFLAMMATORY AGENTS—Some Notes on Their Practical Application,Especially in Rheumatic Disorders

A number of acute and chronic inflammatory disorders are amenable to varying degrees of therapeutic control with the administration of nonspecific anti-inflammatory drugs. An evaluation of these suppressive agents in the field of rheumatic diseases and practical suggestions regarding their administration are presented.Eight synthetically modified corticosteroid compounds are available commercially. Each of them exhibits qualitative differences in one or several physiologic actions, each has certain advantages and disadvantages in therapy, and each shares the major deterrent features of corticosteroids. Prednisone, prednisolone, methylprednisolone, fluprednisolone and paramethasone have similar therapeutic indices, and there is little choice between them for the usual rheumatoid patient requiring steroid therapy. Conversely, the therapeutic indices of dexamethasone, betamethasone and triamcinolone are lower than that of prednisolone; they are less desirable for routine use and should be reserved for specially selected cases.Salicylates are preferred to adrenocortical steroids in the treatment of the ordinary patient with acute rheumatic fever. Steroid therapy should be reserved for resistant cases and for those with significant carditis. Salicylates are mainstays for pain relief in rheumatoid arthritis, but with the analgesic doses usually employed their anti-inflammatory action is slight.Phenylbutazone is a highly useful anti-inflammatory agent, especially in management of acute gouty arthritis and ankylosing (rheumatoid) spondylitis; its metabolite, oxyphenylbutazone, does not exhibit clear-cut advantages.Colchicine specifically suppresses acute gouty arthritis. Its analogues, desacetylcolchicine and desacetylthiocolchicine, produce fewer unpleasant gastrointestinal symptoms, but may promote agranulocytosis and alopecia.A number of indole preparations with anti-inflammatory activity have been tested clinically. One of them, indomethacin, has received extensive therapeutic trial; with dosages that can be tolerated the drug is fairly effective in the symptomatic control of ankylosing (rheumatoid) spondylitis but it is of questionable value in peripheral rheumatoid arthritis.     

Corticosteroids and Leukotrienes: Chronobiology and Chronotherapy

Corticosteroids and leukotrienes play opposite roles in asthma. Corticosteroids, both endogenously secreted and exogenously administered, are antiinflammatory and are very effective in the treatment of asthma. They have also been evaluated chronotherapeutically and have been found to be very effective in reducing the enhanced airway inflammation and decrement in lung function associated with nocturnal worsening of asthma. Leukotrienes are potent proinflammatory and spasmogenic mediators that have been shown to be increased at night in patients with nocturnal asthma (NA). Leu-kotriene modifiers, a new class of medications to treat asthma, improve, but do not abolish, the symptoms and decrement in lung function associated with nocturnal asthma. However, they have not been evaluated chronotherapeutically. This article addresses the roles of corticosteroids and leukotrienes in nocturnal asthma and their position as therapeutic agents or targets for therapy.     

Corticosteroids and Leukotrienes: Chronobiology and Chronotherapy

Corticosteroids and leukotrienes play opposite roles in asthma. Corticosteroids, both endogenously secreted and exogenously administered, are antiinflammatory and are very effective in the treatment of asthma. They have also been evaluated chronotherapeutically and have been found to be very effective in reducing the enhanced airway inflammation and decrement in lung function associated with nocturnal worsening of asthma. Leukotrienes are potent proinflammatory and spasmogenic mediators that have been shown to be increased at night in patients with nocturnal asthma (NA). Leu-kotriene modifiers, a new class of medications to treat asthma, improve, but do not abolish, the symptoms and decrement in lung function associated with nocturnal asthma. However, they have not been evaluated chronotherapeutically. This article addresses the roles of corticosteroids and leukotrienes in nocturnal asthma and their position as therapeutic agents or targets for therapy.     

Cell surface antigen expression by peripheral blood monocytes in allergic asthma: results of 2.5 years therapy with inhaled beclomethasone dipropionate

At present, inhaled glucocorticoids are widely accepted as the therapy of choice in chronic asthma. Treatment with inhaled glucocorticoids significantly suppresses local airway inflammation in asthmatics, but may also have systemic effects, e.g. a reduction of the number of circulating hypodense eosinophils or a down-modulation of HLA-DR antigen (Ag) expression by T lymphocytes in peripheral blood. However, the effect of long-term therapy with inhaled glucocorticoids on peripheral blood monocytes (PBM), which are the precursors of the most numerous cell type in the lung, the alveolar macrophage, have not yet been evaluated. We therefore investigated the expression of various cell surface Ag on PBM from non-smoking patients with allergic asthma who were treated for 2.5 years with a beta(2)-receptor agonist plus either an inhaled glucocorticoid (beclomethasone dipropionate, BDP) (n = 4) or an anticholinergic or placebo (n = 8). We compared the results with healthy volunteers (n = 7). Long-term treatment of allergic asthmatics with inhaled BDP, but not anticholinergic or placebo therapy, was associated with a significantly lower CDllb Ag expression (p < 0.04) and higher expression of CD13, CD14 and CD18 Ag (p < 0.05, p < 0.02 and p < 0.04, respectively) when compared with the healthy control subjects (n = 7). Most interestingly, PBM of asthmatics treated with inhaled BDP expressed an almost two-fold higher level of CD14 Ag on their cell surface than PBM of patients treated with anticholinergic or placebo (p < 0.03). No significant differences in the expression of CD16, CD23, CD25, CD32 and CD64 Ag or HLA-DR were observed between PBM from the different patient groups or healthy controls. Taken together, this study shows that long-term local therapy with inhaled BDP coincides with an altered expression of at least one cell surface Ag on PBM from allergic asthmatics.     

Inflammatory bowel disease.

An increasing number of options are available for the treatment of inflammatory bowel disease; the selection depends on the extent and severity of the disease. Experience with sulfasalazine and corticosteroids has led to a proliferation of 5-aminosalicylic acid (5-ASA) compounds and experimentation with alternative corticosteroid preparations. Given rectally 5-ASA is particularly effective in the treatment of distal ulcerative colitis, and experience is accumulating with several oral formulations. Metronidazole is useful in some cases, and immunosuppressive agents have a role in some patients with chronic refractory disease. A variety of measures, such as nutritional therapy, surgery and psychosocial support, are important elements of therapy. Further therapeutic innovations are expected as the etiology and pathogenesis are clarified.     

Targeting drug delivery to the lungs by inhalation

Most drugs targeted to the respiratory tract are used for their local action. For example, ephidrine for nasal decongestion, beta-2 agonists for bronchodilatation, and inhaled steroids to suppress the inflammation seen in asthmatic airways. Since the drug is delivered directly to its required site, only a small quantity is needed for an adequate therapeutic response, and consequently there is a low incidence of systemic side effects compared with oral or intravenous administration. More recently, it has become apparent that the lining of the respiratory tract, from nasal mucosa to airways and alveoli, may be used for the absorption of a drug for its systemic effect. This route of administration may be particularly attractive if it avoids the metabolic destruction encountered when some drugs are administered by alternative routes (for instance, peptides and proteins are rapidly destroyed by peptidases when Oven by the oral route). If there is a lack ofclinical response to an aerosolized drug, it is important to question whether the drug has failed or whether delivery to the site of action is inadequate. To deliver therapeutic agents by inhalation to the lower respiratory tract, inhaled drug particles must have appropriate aerodynamic characteristics. In addition, the anatomy and pathophysiology of the patient's respiratory tract, mode of inhalation through the inhaler, and the characteristics of the inhalational device itself, may significantly affect drug deposition.     

Airway remodeling in asthma: mechanisms and therapeutic perspectives

Although asthma is classically defined as reversible airflow obstruction and often remits in younger subjects with milder disease, a proportion of asthmatics experience chronic symptoms, episodic exacerbations and persistent airway obstruction, despite the continuous use of beta 2-agonists, associated with high doses of inhaled/oral corticosteroids. These patients contribute to the majority of asthma costs through hospitalization, emergency visits, absence from work or school and use of medication. Although the mechanisms behind irreversible airflow obstruction in asthma are unclear, a prominent role has been attributed to persistent structural changes of the bronchial wall, defined as airway remodeling. Studies conducted on endobronchial biopsy samples have led to the histopathological characterization of these tissue alterations, which include chronic mucosal inflammation, extensive epithelial damage, collagen deposition, subepithelial fibrosis, increased mucous glands and airway smooth muscle hypertrophy and/or hyperplasia. Several factors, such as polypeptide growth factors and their receptors, matrix metalloproteases, intracellular molecules controlling cell death and survival, adhesion molecules and their ligands, as well a large variety of cytotoxic pro-inflammatory mediators are likely to contribute to the onset and maintenance of these tissue abnormalities. However, to date, the cellular and molecular events driving specifically these phenomena and allowing asthmatics with persistent airflow limitation to be distinguished from patients who normalize their bronchial obstruction upon adequate therapeutic management have not been identified yet. Accordingly, airway remodeling represents a major research challenge, particularly in view of the development of new therapeutic strategies specifically addressed at alleviating persistent bronchial obstruction in these otherwise intractable patients.