- Email: [email protected]
New therapies for asthma
Review
TRENDS in Molecular Medicine
Vol.12 No.11
New therapies for asthma Peter J. Barnes National Heart and Lung Institute, Imperial College, London, SW3 6LY, UK
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 b2-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. Current asthma therapies Asthma has become one of the most-common chronic diseases in industrialised countries and its frequency is predicted to increase throughout the world over the next decade, particularly in developing countries. Twenty years ago, asthma was viewed as a disease of bronchoconstriction and treated predominantly with bronchodilators. However, at present it is considered as an inflammatory disease of the airways, and the mainstay of modern management is treatment with inhaled corticosteroids. It is also recognized that, particularly in more-severe asthma, there are structural changes in the airway that might reduce its reversibility and response to therapy. The inflammation of the airway in asthma is characterised by activation of mast cells, infiltration of eosinophils and an increased number of activated T helper 2 (Th2) cells, which orchestrate allergic inflammation. Inhaled corticosteroids have revolutionised the management of asthma, leading to better control of asthma, reduced hospital admissions and reduced mortality. Corticosteroids and long-acting b2-agonists in fixed-combination inhalers are currently the most-effective therapy for asthma and are increasingly used in patients with persistent symptoms. However, there is still concern about the use of inhaled corticosteroids because patients fear long-term side effects such as osteoporosis and stunting of growth in children. Furthermore, these effective medications have to be taken by inhalation, although oral Corresponding author: Barnes, P.J. ([email protected]). Available online 29 September 2006. www.sciencedirect.com
medications are generally preferred by patients. Although inhaled corticosteroids are effective, compliance with this medication is surprisingly poor. Even when taken regularly, inhaled corticosteroids do not seem to modify the course of the disease significantly and are not curative because asthma symptoms and inflammation rapidly recur when the treatment is discontinued. Also, although this therapy is effective for the majority of patients, there is a small percentage of patients (5%) who are not responsive [1,2]. These patients account for a disproportionate amount of healthcare spending because they are frequently admitted to hospital, take many medications and miss time from work. This has led to the search for novel or improved therapies for asthma, driven by the prospect of large sales for anti-asthma medications globally. It is now recognized that distinct therapeutic approaches might have effects on different aspects of the inflammatory process, resulting in a change in different outcome measurements. For example, some treatments might have a major impact on exacerbation frequency, whereas others might predominantly improve lung function. This means that several outcome measures might need to be assessed in the clinical development of new treatments for asthma. Moreover, better understanding of mechanisms might lead to improved design in clinical trials. Here, we discuss some of the new therapeutic targets and treatments for asthma that are currently under clinical development. The need for new therapies A major problem that new drug development is facing is the fact that existing therapies for asthma, particularly combination inhalers, are highly effective, inexpensive and reasonably safe. There is a strong scientific rationale for this approach to asthma therapy [3]. This poses an enormous hurdle that has to be overcome in providing treatments that improve on existing therapy. Another problem is that animal models of asthma are poorly predictive of efficacy of treatment in asthmatic patients; indeed, most drugs that have proved effective in preclinical models have failed in clinical trials. The types of new drugs that are needed for asthma include: (i) new classes that are effective in severe poorly controlled asthma; (ii) an oral treatment that is as effective as inhaled corticosteroids without any side effects; or (iii) drugs that modify or even cure the disease. Up to date, the approaches that have been taken are to improve existing treatments, such as b2-agonists or corticosteroids, or to find drugs against novel targets that have been identified by better understanding of the disease, such as blockers of cysteinyl-leukotrienes or interleukin(IL)-5. There are
1471-4914/$ – see front matter ß 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.molmed.2006.09.006
516
Review
TRENDS in Molecular Medicine
several new classes of drugs currently under development for asthma [4]. New bronchodilators Bronchodilators are important for preventing and relieving bronchoconstriction. The major advance has been the introduction of the long-acting bronchodilators salmeterol and formoterol, the action of which lasts for >12 hours. These drugs have complementary actions to corticosteroids. Fixed-combination inhalers together with a corticosteroid are now the most-effective available therapy for asthma. There are now several even longer-acting b2-agonists (‘ultra-long acting’ b2-agonists) under development, including indacaterol, carmoterol and GSK-159797, which act for >24 hours and might be suitable for once-daily dosing [5]. A once-daily anticholinergic bronchodilator, tiotropium bromide, is now available but is less effective in asthma than b2-agonists and is used predominantly in chronic obstructive pulmonary disease (COPD). Novel classes of bronchodilators have proved difficult to develop and new drugs, such as analogues of vasoactive intestinal peptide and K+-channel openers, have had side effects due to the fact that they are more-potent vasodilators than bronchodilators. New corticosteroids Inhaled corticosteroids are by far the most-effective anti-inflammatory therapy for asthma and work in almost every patient [6]. However, all currently available inhaled corticosteroids are absorbed by the lungs and, therefore, might have systemic effects. This has led to a concerted effort to find safer corticosteroids that have reduced oral bioavailability, are less absorbed by the lungs or are inactivated in the circulation. Ciclesonide, a newly introduced steroid, is a pro-drug that becomes activated (desciclesonide) by the action of esterases in the lung. This corticosteroid seems to have less systemic effects than currently available corticosteroids; this might be due to long-term retention in the lung, no oral bioavailability and a high degree of binding to circulating proteins [7]. Another approach is to develop dissociated steroids that have separate side-effect mechanisms and anti-inflammatory mechanisms. This is theoretically possible because side effects are largely mediated by genomic effects and binding of glucocorticoid receptors to DNA, whereas anti-inflammatory effects are largely mediated by inhibition of transcription factors through a non-genomic effect [8]. Some novel corticosteroids have a greater effect on the non-genomic than genomic effect (dissociated steroids) and, thus, might have a better therapeutic ratio and might even be suitable for oral administration [9]. Non-steroidal glucocorticoid-receptor activators such as AL-438 have recently been discovered and are under clinical development [10]. Corticosteroids switch off inflammatory genes by recruiting the nuclear enzyme histone deacetylase-2 (HDAC2) to the activated inflammatory gene initiation site so that activators of this enzyme can also have antiinflammatory effects or enhance the anti-inflammatory effects of corticosteroids [8]. There might be additional mechanisms for the anti-inflammatory effects of corticosteroids that might also be targeted in the future. www.sciencedirect.com
Vol.12 No.11
Mediator antagonists Over 100 mediators are involved in the complex inflammatory process that is present in asthma, so blocking the synthesis or the receptor of a single mediator is probably not effective. The only mediator antagonists that are currently used in asthma therapy are the antileukotrienes, which block cysteinyl-leukotriene1 receptors, but these drugs are only weakly effective. Inhibitors of other mediators, including histamine, prostaglandins, platelet-activating factor, bradykinin and tachykinins have all proved to be ineffective in asthma [11]. Cytokine inhibitors There has been particular interest in cytokines as targets for new asthma therapies because of their key role in chronic inflammation [12]. Many cytokines are now implicated in asthmatic inflammation and airway wall remodelling, and some cytokine inhibitors have already been tested in asthma [12]. IL-5 is of crucial importance for eosinophilic inflammation and a blocking antibody to IL-5 depletes eosinophils from the circulation and sputum of asthmatic patients but, disappointingly, has no effect on the response to inhaled allergen, airway hyper-responsiveness symptoms, lung function or exacerbation frequency in asthmatic patients [13,14]. However, it seems that eosinophils are not eradicated from the airway wall and therefore might continue to drive inflammation in this protected site. Another Th2 cytokine, IL-4, has also been inhibited in asthma patients [12]; in this case, inhaled soluble receptors that mop up IL-4 were used. This approach was disappointing and has been discontinued; however, there is continued interest in blocking IL-13, a related cytokine that regulates IgE formation because there are larger amounts of IL-13 compared with IL-4 in asthmatic airways [15]. Another cytokine that is currently targeted in asthma is the tumour necrosis factor-a (TNF-a), which seems to have a role in severe asthma. Etanercept, a soluble receptor that blocks TNF-a, has some efficacy in patients with refractory asthma who are not responsive to maximum conventional therapy [16], but another anti-TNF-a therapy (infliximab) is less effective in less-severe asthmatics than in severe asthmatics [17]. This might reflect the fact that TNF-a levels are increased only in severe asthma. Stem-cell factor (SCF) is a key regulator of mast-cell survival in the airways and acts via the receptor c-kit on mast cells [18]. Blockade of SCF or c-kit is effective in animal models of asthma, suggesting that this pathway might be a good target for new asthma therapies. Imatinib is a potent inhibitor of c-kit and is therefore a potential new asthma therapy. Thymic stromal lymphopoietin (TSLP) is a novel IL-7-like cytokine that is highly expressed in airway epithelial cells of asthmatic patients. It activates dendritic cells to orchestrate an allergic pattern of inflammation through the activation of Th2 cells [19]. There is intense interest in blocking TSLP as a new therapeutic approach to allergic diseases. Anti-inflammatory cytokines Some cytokines are inhibitory to the inflammatory process and therefore might be considered as therapy. For example, IL-10 has a broad spectrum of anti-inflammatory
Review
TRENDS in Molecular Medicine
effects and its secretion is defective in asthma, especially in patients with more-severe symptoms [12]. IL-10 is effective in some animal models of asthma, but its efficacy has not yet been demonstrated in humans. IL-10 needs to be injected on a daily basis and it is likely to have unacceptable side effects; thus, it is probably not useful. IL-12 is a cytokine that regulates the balance between Th1 and Th2 cells by suppressing Th2 cells, thus reducing eosinophilic inflammation and IgE levels. Although repeated IL-12 injections decrease circulating eosinophils in asthmatic patients, they do not reduce the response to inhaled allergen or airway hyper-responsiveness, as with IL-5 inhibitors [20]. In addition, this cytokine has unacceptable side effects, including malaise and occasional dangerous cardiac arrhythmias. Chemokine antagonists Chemokines are small peptides that attract inflammatory cells, including mast cells, eosinophils and Th2 cells into the airways and are therefore appropriate targets for new therapies for asthma, particularly because they signal via G-protein-coupled receptors for which small-molecule inhibitors can be developed [21]. The major focus of interest has been the chemokine (C-C motif) receptor 3 (CCR3), which is predominantly expressed on eosinophils and mediates the chemotactic response to the CC-chemokine eotaxin, which is secreted in asthma [22]. CCR3 is also expressed on mast cells and some Th2 cells. Several small-molecule inhibitors of CCR3 are under clinical development but their effects in asthma have not yet been reported. Other chemokine receptors that are also targeted for asthma therapy are CCR2 on monocytes and T cells and CCR4 on Th2 cells. Novel anti-inflammatory treatments Although corticosteroids are effective in most patients with asthma, they have to be given in high doses in the minority of patients that have a severe form of the disease, and there are still concerns about systemic side effects of inhaled steroids. This has prompted the search for alternative antiinflammatory therapies, particularly treatments that are effective orally because this might also treat associated allergic diseases such as rhinitis and atopic dermatitis. In severe asthma, many patients seem to have reduced responsiveness to corticosteroids so that non-steroidal anti-inflammatory drugs might be indicated. There are several new classes of treatments that are now at various stages of development as asthma therapies; many of them act on signal-transduction mechanisms, such as kinases [23] (Figure 1). Phosphodiesterase inhibitors The most advanced of these anti-inflammatory therapies are phosphodiesterase-4 (PDE4) inhibitors. PDE4 inhibitors have a wide spectrum of anti-inflammatory effects, inhibiting T cells, eosinophils, mast cells, airway smooth muscle, epithelial cells and airway nerves. They have been shown to be highly effective in various animal models of asthma [24]. An oral PDE4 inhibitor, roflumilast, has an inhibitory effect on allergen-induced responses in asthma and also reduces symptoms and lung function in a comparable way to low doses of inhaled steroids [25]. However, a www.sciencedirect.com
Vol.12 No.11
517
Figure 1. Inhibition of signal transduction pathways. Selective inhibitors have been developed for: phosphodieatease-4 (PDE4), which degrades cyclic adenosine monophosphate (cAMP); inhibitor of NF-kB kinase (IKK2), which activates NF-kB; and p39 mitogen-activated protein (MAP) kinase, which activates MAP kinase activated protein kinase 2 (MAPKAPK2). Selective inhibitors have now been developed for these enzyme targets.
major limitation to this class of drugs is the side-effect profile, including nausea, vomiting, headaches and gastrointestinal disturbance, which might restrict the dose. These side effects are also mediated by PDE4; therefore, it has been difficult to avoid them in new PDE4 inhibitors. However, it now seems that the anti-inflammatory effects of PDE4 are mediated by the 4B isoenzyme, whereas nausea and vomiting are mediated by the 4D isoenzyme, suggesting that PDE4B selective inhibitors might be better tolerated [26]. Another approach is to deliver PDE4 inhibitors by inhalation. Transcription-factor blockade Transcription factors have a crucial role in regulating the expression of inflammatory genes in asthma. In particular, there has been interest in the role of nuclear factor-kB (NF-kB), which is activated in asthmatic airways and activates many of the inflammatory genes that are switched on in asthma [27]. Small-molecule inhibitors of the key enzyme inhibitor of NF-kB kinase (IKK2) block inflammation that is induced by NF-kB activation and are now under preclinical testing [28]. P38 mitogen-activated protein (MAP) kinase activates inflammatory genes similar to those activated by NF-kB, and several small-molecule inhibitors are now under clinical development for the treatment of other inflammatory diseases [29]. An antisense molecule that was able to block p38 MAP kinase in a murine model demonstrated marked efficacy in suppressing pulmonary inflammation [30]. One general concern about all these novel kinase inhibitors is that they might have side effects because they target mechanisms that are present in many cell types. It might therefore be necessary to develop inhaled formulations for use in asthma in the future, as for corticosteroids. Another approach to inhibit inflammation is to block the adhesion molecules that are involved in the recruitment of inflammatory cells from the circulation into the airways [31]. Although many different adhesion molecules have been identified, there has been particular interest in very late antigen-4 (VLA-4, a4b1), which is involved in the recruitment of eosinophils and T cells [32]. Small-molecule
518
Review
TRENDS in Molecular Medicine
Vol.12 No.11
Figure 2. Inhibition of eosinophilic inflammation. There are several strategies to inhibit eosinophil inflammation in tissues, including immunomodulators (e.g. cyclosporin), inhibitors of proinflammatory cytokines (e.g. IL-4, IL-5 and IL-13), inhibition of critical adhesion molecules (e.g. very late antigen 4, VLA4), blockade of chemokine receptors on eosinophils (e.g. chemokine (C-C motif) receptor 3, CCR3) and induction of apoptosis (e.g. by corticosteroids and p38 MAP kinase inhibitors).
inhibitors have been effective in animal models and are currently being tested in asthma patients, although there have been concerns about long-term safety. Many new drugs under development, including anti-cytokines, immunomodulators, adhesion molecule blockers and signal transduction inhibitors target eosinophilic inflammation (Figure 2). Anti-allergy treatments Most asthmatic patients are atopic. Therefore, treatments that target the underlying allergic inflammation are a logical approach, particularly because these treatments might also treat associated allergic conditions. Indeed, even in patients with non-atopic asthma the same
inflammatory mechanisms seem to be operative. The most advanced of these approaches is a humanised monoclonal antibody that blocks IgE (omalizumab) (Figure 3). Omalizumab is injected twice or four times per week and is a useful add-on therapy in some patients who are affected by very severe asthma with frequent exacerbations who are not responsive even by high doses of corticosteroids [33]. It is an expensive treatment, so patients must be selected carefully for a trial of therapy. Oral drugs that might inhibit IgE signalling are also of potential value. Inhibitors of the enzyme spleen tyrosine kinase (SYK), which is involved in the activation of mast cells, is currently under development [34]. An antisense inhibitor of SYK is effective in an animal model of asthma [35], and the
Figure 3. Inhibition of mast cells in asthma. Mast-cell activation might be inhibited by blocking IgE binding to the high-affinity IgE receptor (FceRI), by inhibiting c-KIT, which is activated by stem-cell factor (SCF), or by inhibiting spleen tyrosine kinase (SYK). www.sciencedirect.com
Review
TRENDS in Molecular Medicine
small-molecule inhibitor R112 given nasally reduces nasal symptoms in hay fever patients [36]. As with other kinase inhibitors, there might be side effects with systemic administration so that inhalation might be the preferred route of delivery. Allergens bind to a low-affinity IgE receptor (FceRII, also known as CD23) and the high-affinity receptor FceRI on several immune cells, including T and B cells [37]. An anti-CD23 antibody (lumiliximab) was well tolerated and reduced IgE concentrations in patients with mild asthma, but its clinical efficacy has not been reported [38]. Regulatory T cells (Treg) have a key role in orchestrating immunity. There is evidence for a defect in Treg function in patients with asthma that might be linked to increased numbers of Th2 cells. There is convincing evidence that specific immunotherapy increases IL-10 production from Treg cells (Tr-1 cells) [39]. Vaccines that enhance Tr-1-cell function and increase IL-10 release are now under development. T-cell peptides are also under development as a safer form of immunotherapy. A cure for asthma? None of the currently available treatments for asthma have long-term effects on airway inflammation or remodelling and therefore are not disease-modifying or curative. Inhaled corticosteroids are effective, but asthma usually rapidly returns when they are discontinued. The prospects for a cure are remote until the molecular and genetic causes of asthma are better understood. However, there is a possibility that vaccination approaches might reverse the abnormal immune regulation found in asthma, restoring Th1 predominance or Treg function [39,40]. Various approaches, including non-pathogenic bacterial products, such as CpG oligodeoxynucleotides, which target toll-like receptor-9 (TLR-9), are currently being explored as potential therapies for asthma [41]. However, the long-term consequences of these approaches need to be carefully evaluated, particularly as they would probably need to be used in children at the onset of disease. The role of other TLRs in asthma is uncertain, with beneficial and detrimental effects reported in different animal models [42]. Future perspectives It has proved remarkably difficult to discover novel therapies for asthma, despite intense effort and investment. We already have effective therapies that are also safe, placing an additional demand on drug discovery. Despite the availability of highly effective therapies, asthma is often poorly controlled because of poor adherence. Strategies to increase adherence or better ways to monitor compliance with regular therapy should be sought in the future. Asthma is a highly complex disease; therefore, it is unlikely that targeting a single receptor or mediator will be effective. Corticosteroids are effective because they suppress multiple inflammatory mechanisms at the same time. It is possible that a key target that is upstream in the complex inflammatory process might be effective, such as anti-TNF therapy in rheumatoid arthritis. However, these targets are usually only identifiable by trial and error in the disease. More selective targeting of www.sciencedirect.com
Vol.12 No.11
519
drugs to patients with particular subtypes of asthma might be possible in the future with the development of discriminatory biomarkers and genetic profiling. Animal models have proved to be misleading and there is now pressure to do earlier proof-of-concept studies in humans. A major unmet need in asthma is to treat patients with severe asthma who are relatively corticosteroid-resistant more effectively. These patients share several characteristics with patients who have COPD who are also steroidresistant. This means that drugs under discovery for COPD might also be effective in treating severe asthma [43]. The mechanism of corticosteroid-resistance in COPD seems to be defective function of HDAC2 [44] and similar abnormalities might also be found in severe asthma [45]. HDAC2 activity might be restored by low doses of theophylline [46], and identification of the pathways involved might lead to new approaches to restore steroid sensitivity in severe asthma [47]. The other unmet need in asthma is to develop an effective oral therapy for patients with mild and moderate disease. However, this has proved to be a major challenge because it is likely that any therapy that will be effective has side effects and, therefore, is disadvantageous compared with current inhaled therapy. References 1 Heaney, L.G. et al. (2005) Severe asthma treatment: need for characterising patients. Lancet 365, 974–976 2 Wenzel, S. (2005) Severe asthma in adults. Am. J. Respir. Crit. Care Med. 172, 149–160 3 Barnes, P.J. (2002) Scientific rationale for combination inhalers with a long-acting b2-agonists and corticosteroids. Eur. Respir. J. 19, 182–191 4 Barnes, P.J. (2004) New drugs for asthma. Nat. Rev. Drug Discov. 3, 831–844 5 Cazzola, M. et al. (2005) Ultra long-acting b2-agonists in development for asthma and chronic obstructive pulmonary disease. Expert Opin. Investig. Drugs 14, 775–783 6 Barnes, P.J. et al. (2003) How do corticosteroids work in asthma? Ann. Intern. Med. 139, 359–370 7 Reynolds, N.A. et al. (2004) Ciclesonide. Drugs 64, 511–519 8 Barnes, P.J. (2006) How corticosteroids control inflammation. Br. J. Pharmacol. 148, 245–254 9 Schacke, H. et al. (2004) Dissociation of transactivation from transrepression by a selective glucocorticoid receptor agonist leads to separation of therapeutic effects from side effects. Proc. Natl. Acad. Sci. U. S. A. 101, 227–232 10 Rosen, J. et al. (2005) The search for safer glucocorticoid receptor ligands. Endocr. Rev. 26, 452–464 11 Barnes, P.J. et al. (1998) Inflammatory mediators of asthma: an update. Pharmacol. Rev. 50, 515–596 12 Barnes, P.J. (2003) Cytokine-directed therapies for the treatment of chronic airway diseases. Cytokine Growth Factor Rev. 14, 511–522 13 Leckie, M.J. et al. (2000) Effects of an interleukin-5 blocking monoclonal antibody on eosinophils, airway hyperresponsiveness and the late asthmatic response. Lancet 356, 2144–2148 14 Kips, J.C. et al. (2003) Effect of SCH55700, a humanized anti-human interleukin-5 antibody, in severe persistent asthma: a pilot study. Am. J. Respir. Crit. Care Med. 167, 1655–1659 15 Wills-Karp, M. (2004) Interleukin-13 in asthma pathogenesis. Immunol. Rev. 202, 175–190 16 Berry, M.A. et al. (2006) Evidence of a role of tumor necrosis factor alpha in refractory asthma. N. Engl. J. Med. 354, 697–708 17 Erin, E.M. et al. (2006) The effects of a monoclonal antibody directed against tumor necrosis factor-a in asthma. Am. J. Respir. Crit. Care Med. DOI: 10.1164/rccm.200601-072OCv1 18 Reber, L. et al. (2006) Stem cell factor and its receptor c-Kit as targets for inflammatory diseases. Eur. J. Pharmacol. 533, 327–340 19 Liu, Y.J. (2006) Thymic stromal lymphopoietin: master switch for allergic inflammation. J. Exp. Med. 203, 269–273
Review
520
TRENDS in Molecular Medicine
20 Bryan, S. et al. (2000) Effects of recombinant human interleukin-12 on eosinophils, airway hyperreactivity and the late asthmatic response. Lancet 356, 2149–2153 21 Lukacs, N.W. et al. (2005) Chemokines and their receptors in chronic pulmonary disease. Curr. Drug Targets Inflamm. Allergy 4, 313–317 22 Erin, E.M. et al. (2002) Eotaxin receptor (CCR3) antagonism in asthma and allergic disease. Curr. Drug Targets Inflamm. Allergy 1, 201–214 23 Barnes, P.J. (2006) Novel signal transduction modulators for the treatment of airway diseases. Pharmacol. Ther. 109, 238–245 24 Lipworth, B.J. (2005) Phosphodiesterase-4 inhibitors for asthma and chronic obstructive pulmonary disease. Lancet 365, 167–175 25 Bousquet, J. et al. (2006) Comparison of roflumilast, an oral anti-inflammatory, with beclomethasone dipropionate in the treatment of persistent asthma. Allergy 61, 72–78 26 Houslay, M.D. et al. (2005) Keynote review: phosphodiesterase-4 as a therapeutic target. Drug Discov. Today 10, 1503–1519 27 Barnes, P.J. (2006) Transcription factors in airway diseases. Lab. Invest. 86, 867–872 28 Karin, M. et al. (2004) The IKK NF-kB system: a treasure trove for drug development. Nat. Rev. Drug Discov. 3, 17–26 29 Kumar, S. et al. (2003) p38 MAP kinases: key signalling molecules as therapeutic targets for inflammatory diseases. Nat. Rev. Drug Discov. 2, 717–726 30 Duan, W. et al. (2005) Inhaled p38a mitogen-activated protein kinase antisense oligonucleotide attenuates asthma in mice. Am. J. Respir. Crit. Care Med. 171, 571–578 31 Bochner, B.S. (2004) Adhesion molecules as therapeutic targets. Immunol. Allergy Clin. North Am. 24, 615–630 32 Singh, J. et al. (2004) Rational design of potent and selective VLA-4 inhibitors and their utility in the treatment of asthma. Curr. Top. Med. Chem. 4, 1497–1507 33 Strunk, R.C. et al. (2006) Omalizumab for asthma. N. Engl. J. Med. 354, 2689–2695
Vol.12 No.11
34 Wong, B.R. et al. (2004) Targeting Syk as a treatment for allergic and autoimmune disorders. Expert Opin. Investig. Drugs 13, 743–762 35 Stenton, G.R. et al. (2002) Inhibition of allergic inflammation in the airways using aerosolized antisense to Syk kinase. J. Immunol. 169, 1028–1036 36 Meltzer, E.O. et al. (2005) An intranasal Syk-kinase inhibitor (R112) improves the symptoms of seasonal allergic rhinitis in a park environment. J. Allergy Clin. Immunol. 115, 791–796 37 Rosenwasser, L.J. et al. (2005) Anti-CD23. Clin. Rev. Allergy Immunol. 29, 61–72 38 Rosenwasser, L.J. et al. (2003) Allergic asthma and an anti-CD23 mAb (IDEC-152): results of a phase I, single-dose, dose-escalating clinical trial. J. Allergy Clin. Immunol. 112, 563–570 39 Akdis, M. et al. (2005) T regulatory cells in allergy: novel concepts in the pathogenesis, prevention, and treatment of allergic diseases. J. Allergy Clin. Immunol. 116, 961–968 40 Wohlleben, G. et al. (2001) Atopic disorders: a vaccine around the corner? Trends Immunol. 22, 618–626 41 Krieg, A.M. (2006) Therapeutic potential of Toll-like receptor 9 activation. Nat. Rev. Drug Discov. 5, 471–484 42 Feleszko, W. et al. (2006) Toll-like receptors–novel targets in allergic airway disease (probiotics, friends and relatives). Eur. J. Pharmacol. 533, 308–318 43 Barnes, P.J. et al. (2004) Prospects for new drugs for chronic obstructive pulmonary disease. Lancet 364, 985–996 44 Barnes, P.J. (2006) Reduced histone deacetylase in COPD: clinical implications. Chest 129, 151–155 45 Cosio, B.G. et al. (2004) Histone acetylase and deacetylase activity in alveolar macrophages and blood monocytes in asthma. Am. J. Respir. Crit. Care Med. 170, 141–147 46 Cosio, B.G. et al. (2004) Theophylline restores histone deacetylase activity and steroid responses in COPD macrophages. J. Exp. Med. 200, 689–695 47 Barnes, P.J. (2005) Targeting histone deacetylase 2 in chronic obstructive pulmonary disease treatment. Expert Opin. Ther. Targets 9, 1111–1121
Elsevier.com – linking scientists to new research and thinking Designed for scientists’ information needs, Elsevier.com is powered by the latest technology with customer-focused navigation and an intuitive architecture for an improved user experience and greater productivity. The easy-to-use navigational tools and structure connect scientists with vital information – all from one entry point. Users can perform rapid and precise searches with our advanced search functionality, using the FAST technology of Scirus.com, the free science search engine. Users can define their searches by any number of criteria to pinpoint information and resources. Search by a specific author or editor, book publication date, subject area – life sciences, health sciences, physical sciences and social sciences – or by product type. Elsevier’s portfolio includes more than 1800 Elsevier journals, 2200 new books every year and a range of innovative electronic products. In addition, tailored content for authors, editors and librarians provides timely news and updates on new products and services. Elsevier is proud to be a partner with the scientific and medical community. Find out more about our mission and values at Elsevier.com. Discover how we support the scientific, technical and medical communities worldwide through partnerships with libraries and other publishers, and grant awards from The Elsevier Foundation. As a world-leading publisher of scientific, technical and health information, Elsevier is dedicated to linking researchers and professionals to the best thinking in their fields. We offer the widest and deepest coverage in a range of media types to enhance cross-pollination of information, breakthroughs in research and discovery, and the sharing and preservation of knowledge.
Elsevier. Building insights. Breaking boundaries. www.elsevier.com www.sciencedirect.com
TRENDS in Molecular Medicine
Vol.12 No.11
New therapies for asthma Peter J. Barnes National Heart and Lung Institute, Imperial College, London, SW3 6LY, UK
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 b2-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. Current asthma therapies Asthma has become one of the most-common chronic diseases in industrialised countries and its frequency is predicted to increase throughout the world over the next decade, particularly in developing countries. Twenty years ago, asthma was viewed as a disease of bronchoconstriction and treated predominantly with bronchodilators. However, at present it is considered as an inflammatory disease of the airways, and the mainstay of modern management is treatment with inhaled corticosteroids. It is also recognized that, particularly in more-severe asthma, there are structural changes in the airway that might reduce its reversibility and response to therapy. The inflammation of the airway in asthma is characterised by activation of mast cells, infiltration of eosinophils and an increased number of activated T helper 2 (Th2) cells, which orchestrate allergic inflammation. Inhaled corticosteroids have revolutionised the management of asthma, leading to better control of asthma, reduced hospital admissions and reduced mortality. Corticosteroids and long-acting b2-agonists in fixed-combination inhalers are currently the most-effective therapy for asthma and are increasingly used in patients with persistent symptoms. However, there is still concern about the use of inhaled corticosteroids because patients fear long-term side effects such as osteoporosis and stunting of growth in children. Furthermore, these effective medications have to be taken by inhalation, although oral Corresponding author: Barnes, P.J. ([email protected]). Available online 29 September 2006. www.sciencedirect.com
medications are generally preferred by patients. Although inhaled corticosteroids are effective, compliance with this medication is surprisingly poor. Even when taken regularly, inhaled corticosteroids do not seem to modify the course of the disease significantly and are not curative because asthma symptoms and inflammation rapidly recur when the treatment is discontinued. Also, although this therapy is effective for the majority of patients, there is a small percentage of patients (5%) who are not responsive [1,2]. These patients account for a disproportionate amount of healthcare spending because they are frequently admitted to hospital, take many medications and miss time from work. This has led to the search for novel or improved therapies for asthma, driven by the prospect of large sales for anti-asthma medications globally. It is now recognized that distinct therapeutic approaches might have effects on different aspects of the inflammatory process, resulting in a change in different outcome measurements. For example, some treatments might have a major impact on exacerbation frequency, whereas others might predominantly improve lung function. This means that several outcome measures might need to be assessed in the clinical development of new treatments for asthma. Moreover, better understanding of mechanisms might lead to improved design in clinical trials. Here, we discuss some of the new therapeutic targets and treatments for asthma that are currently under clinical development. The need for new therapies A major problem that new drug development is facing is the fact that existing therapies for asthma, particularly combination inhalers, are highly effective, inexpensive and reasonably safe. There is a strong scientific rationale for this approach to asthma therapy [3]. This poses an enormous hurdle that has to be overcome in providing treatments that improve on existing therapy. Another problem is that animal models of asthma are poorly predictive of efficacy of treatment in asthmatic patients; indeed, most drugs that have proved effective in preclinical models have failed in clinical trials. The types of new drugs that are needed for asthma include: (i) new classes that are effective in severe poorly controlled asthma; (ii) an oral treatment that is as effective as inhaled corticosteroids without any side effects; or (iii) drugs that modify or even cure the disease. Up to date, the approaches that have been taken are to improve existing treatments, such as b2-agonists or corticosteroids, or to find drugs against novel targets that have been identified by better understanding of the disease, such as blockers of cysteinyl-leukotrienes or interleukin(IL)-5. There are
1471-4914/$ – see front matter ß 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.molmed.2006.09.006
516
Review
TRENDS in Molecular Medicine
several new classes of drugs currently under development for asthma [4]. New bronchodilators Bronchodilators are important for preventing and relieving bronchoconstriction. The major advance has been the introduction of the long-acting bronchodilators salmeterol and formoterol, the action of which lasts for >12 hours. These drugs have complementary actions to corticosteroids. Fixed-combination inhalers together with a corticosteroid are now the most-effective available therapy for asthma. There are now several even longer-acting b2-agonists (‘ultra-long acting’ b2-agonists) under development, including indacaterol, carmoterol and GSK-159797, which act for >24 hours and might be suitable for once-daily dosing [5]. A once-daily anticholinergic bronchodilator, tiotropium bromide, is now available but is less effective in asthma than b2-agonists and is used predominantly in chronic obstructive pulmonary disease (COPD). Novel classes of bronchodilators have proved difficult to develop and new drugs, such as analogues of vasoactive intestinal peptide and K+-channel openers, have had side effects due to the fact that they are more-potent vasodilators than bronchodilators. New corticosteroids Inhaled corticosteroids are by far the most-effective anti-inflammatory therapy for asthma and work in almost every patient [6]. However, all currently available inhaled corticosteroids are absorbed by the lungs and, therefore, might have systemic effects. This has led to a concerted effort to find safer corticosteroids that have reduced oral bioavailability, are less absorbed by the lungs or are inactivated in the circulation. Ciclesonide, a newly introduced steroid, is a pro-drug that becomes activated (desciclesonide) by the action of esterases in the lung. This corticosteroid seems to have less systemic effects than currently available corticosteroids; this might be due to long-term retention in the lung, no oral bioavailability and a high degree of binding to circulating proteins [7]. Another approach is to develop dissociated steroids that have separate side-effect mechanisms and anti-inflammatory mechanisms. This is theoretically possible because side effects are largely mediated by genomic effects and binding of glucocorticoid receptors to DNA, whereas anti-inflammatory effects are largely mediated by inhibition of transcription factors through a non-genomic effect [8]. Some novel corticosteroids have a greater effect on the non-genomic than genomic effect (dissociated steroids) and, thus, might have a better therapeutic ratio and might even be suitable for oral administration [9]. Non-steroidal glucocorticoid-receptor activators such as AL-438 have recently been discovered and are under clinical development [10]. Corticosteroids switch off inflammatory genes by recruiting the nuclear enzyme histone deacetylase-2 (HDAC2) to the activated inflammatory gene initiation site so that activators of this enzyme can also have antiinflammatory effects or enhance the anti-inflammatory effects of corticosteroids [8]. There might be additional mechanisms for the anti-inflammatory effects of corticosteroids that might also be targeted in the future. www.sciencedirect.com
Vol.12 No.11
Mediator antagonists Over 100 mediators are involved in the complex inflammatory process that is present in asthma, so blocking the synthesis or the receptor of a single mediator is probably not effective. The only mediator antagonists that are currently used in asthma therapy are the antileukotrienes, which block cysteinyl-leukotriene1 receptors, but these drugs are only weakly effective. Inhibitors of other mediators, including histamine, prostaglandins, platelet-activating factor, bradykinin and tachykinins have all proved to be ineffective in asthma [11]. Cytokine inhibitors There has been particular interest in cytokines as targets for new asthma therapies because of their key role in chronic inflammation [12]. Many cytokines are now implicated in asthmatic inflammation and airway wall remodelling, and some cytokine inhibitors have already been tested in asthma [12]. IL-5 is of crucial importance for eosinophilic inflammation and a blocking antibody to IL-5 depletes eosinophils from the circulation and sputum of asthmatic patients but, disappointingly, has no effect on the response to inhaled allergen, airway hyper-responsiveness symptoms, lung function or exacerbation frequency in asthmatic patients [13,14]. However, it seems that eosinophils are not eradicated from the airway wall and therefore might continue to drive inflammation in this protected site. Another Th2 cytokine, IL-4, has also been inhibited in asthma patients [12]; in this case, inhaled soluble receptors that mop up IL-4 were used. This approach was disappointing and has been discontinued; however, there is continued interest in blocking IL-13, a related cytokine that regulates IgE formation because there are larger amounts of IL-13 compared with IL-4 in asthmatic airways [15]. Another cytokine that is currently targeted in asthma is the tumour necrosis factor-a (TNF-a), which seems to have a role in severe asthma. Etanercept, a soluble receptor that blocks TNF-a, has some efficacy in patients with refractory asthma who are not responsive to maximum conventional therapy [16], but another anti-TNF-a therapy (infliximab) is less effective in less-severe asthmatics than in severe asthmatics [17]. This might reflect the fact that TNF-a levels are increased only in severe asthma. Stem-cell factor (SCF) is a key regulator of mast-cell survival in the airways and acts via the receptor c-kit on mast cells [18]. Blockade of SCF or c-kit is effective in animal models of asthma, suggesting that this pathway might be a good target for new asthma therapies. Imatinib is a potent inhibitor of c-kit and is therefore a potential new asthma therapy. Thymic stromal lymphopoietin (TSLP) is a novel IL-7-like cytokine that is highly expressed in airway epithelial cells of asthmatic patients. It activates dendritic cells to orchestrate an allergic pattern of inflammation through the activation of Th2 cells [19]. There is intense interest in blocking TSLP as a new therapeutic approach to allergic diseases. Anti-inflammatory cytokines Some cytokines are inhibitory to the inflammatory process and therefore might be considered as therapy. For example, IL-10 has a broad spectrum of anti-inflammatory
Review
TRENDS in Molecular Medicine
effects and its secretion is defective in asthma, especially in patients with more-severe symptoms [12]. IL-10 is effective in some animal models of asthma, but its efficacy has not yet been demonstrated in humans. IL-10 needs to be injected on a daily basis and it is likely to have unacceptable side effects; thus, it is probably not useful. IL-12 is a cytokine that regulates the balance between Th1 and Th2 cells by suppressing Th2 cells, thus reducing eosinophilic inflammation and IgE levels. Although repeated IL-12 injections decrease circulating eosinophils in asthmatic patients, they do not reduce the response to inhaled allergen or airway hyper-responsiveness, as with IL-5 inhibitors [20]. In addition, this cytokine has unacceptable side effects, including malaise and occasional dangerous cardiac arrhythmias. Chemokine antagonists Chemokines are small peptides that attract inflammatory cells, including mast cells, eosinophils and Th2 cells into the airways and are therefore appropriate targets for new therapies for asthma, particularly because they signal via G-protein-coupled receptors for which small-molecule inhibitors can be developed [21]. The major focus of interest has been the chemokine (C-C motif) receptor 3 (CCR3), which is predominantly expressed on eosinophils and mediates the chemotactic response to the CC-chemokine eotaxin, which is secreted in asthma [22]. CCR3 is also expressed on mast cells and some Th2 cells. Several small-molecule inhibitors of CCR3 are under clinical development but their effects in asthma have not yet been reported. Other chemokine receptors that are also targeted for asthma therapy are CCR2 on monocytes and T cells and CCR4 on Th2 cells. Novel anti-inflammatory treatments Although corticosteroids are effective in most patients with asthma, they have to be given in high doses in the minority of patients that have a severe form of the disease, and there are still concerns about systemic side effects of inhaled steroids. This has prompted the search for alternative antiinflammatory therapies, particularly treatments that are effective orally because this might also treat associated allergic diseases such as rhinitis and atopic dermatitis. In severe asthma, many patients seem to have reduced responsiveness to corticosteroids so that non-steroidal anti-inflammatory drugs might be indicated. There are several new classes of treatments that are now at various stages of development as asthma therapies; many of them act on signal-transduction mechanisms, such as kinases [23] (Figure 1). Phosphodiesterase inhibitors The most advanced of these anti-inflammatory therapies are phosphodiesterase-4 (PDE4) inhibitors. PDE4 inhibitors have a wide spectrum of anti-inflammatory effects, inhibiting T cells, eosinophils, mast cells, airway smooth muscle, epithelial cells and airway nerves. They have been shown to be highly effective in various animal models of asthma [24]. An oral PDE4 inhibitor, roflumilast, has an inhibitory effect on allergen-induced responses in asthma and also reduces symptoms and lung function in a comparable way to low doses of inhaled steroids [25]. However, a www.sciencedirect.com
Vol.12 No.11
517
Figure 1. Inhibition of signal transduction pathways. Selective inhibitors have been developed for: phosphodieatease-4 (PDE4), which degrades cyclic adenosine monophosphate (cAMP); inhibitor of NF-kB kinase (IKK2), which activates NF-kB; and p39 mitogen-activated protein (MAP) kinase, which activates MAP kinase activated protein kinase 2 (MAPKAPK2). Selective inhibitors have now been developed for these enzyme targets.
major limitation to this class of drugs is the side-effect profile, including nausea, vomiting, headaches and gastrointestinal disturbance, which might restrict the dose. These side effects are also mediated by PDE4; therefore, it has been difficult to avoid them in new PDE4 inhibitors. However, it now seems that the anti-inflammatory effects of PDE4 are mediated by the 4B isoenzyme, whereas nausea and vomiting are mediated by the 4D isoenzyme, suggesting that PDE4B selective inhibitors might be better tolerated [26]. Another approach is to deliver PDE4 inhibitors by inhalation. Transcription-factor blockade Transcription factors have a crucial role in regulating the expression of inflammatory genes in asthma. In particular, there has been interest in the role of nuclear factor-kB (NF-kB), which is activated in asthmatic airways and activates many of the inflammatory genes that are switched on in asthma [27]. Small-molecule inhibitors of the key enzyme inhibitor of NF-kB kinase (IKK2) block inflammation that is induced by NF-kB activation and are now under preclinical testing [28]. P38 mitogen-activated protein (MAP) kinase activates inflammatory genes similar to those activated by NF-kB, and several small-molecule inhibitors are now under clinical development for the treatment of other inflammatory diseases [29]. An antisense molecule that was able to block p38 MAP kinase in a murine model demonstrated marked efficacy in suppressing pulmonary inflammation [30]. One general concern about all these novel kinase inhibitors is that they might have side effects because they target mechanisms that are present in many cell types. It might therefore be necessary to develop inhaled formulations for use in asthma in the future, as for corticosteroids. Another approach to inhibit inflammation is to block the adhesion molecules that are involved in the recruitment of inflammatory cells from the circulation into the airways [31]. Although many different adhesion molecules have been identified, there has been particular interest in very late antigen-4 (VLA-4, a4b1), which is involved in the recruitment of eosinophils and T cells [32]. Small-molecule
518
Review
TRENDS in Molecular Medicine
Vol.12 No.11
Figure 2. Inhibition of eosinophilic inflammation. There are several strategies to inhibit eosinophil inflammation in tissues, including immunomodulators (e.g. cyclosporin), inhibitors of proinflammatory cytokines (e.g. IL-4, IL-5 and IL-13), inhibition of critical adhesion molecules (e.g. very late antigen 4, VLA4), blockade of chemokine receptors on eosinophils (e.g. chemokine (C-C motif) receptor 3, CCR3) and induction of apoptosis (e.g. by corticosteroids and p38 MAP kinase inhibitors).
inhibitors have been effective in animal models and are currently being tested in asthma patients, although there have been concerns about long-term safety. Many new drugs under development, including anti-cytokines, immunomodulators, adhesion molecule blockers and signal transduction inhibitors target eosinophilic inflammation (Figure 2). Anti-allergy treatments Most asthmatic patients are atopic. Therefore, treatments that target the underlying allergic inflammation are a logical approach, particularly because these treatments might also treat associated allergic conditions. Indeed, even in patients with non-atopic asthma the same
inflammatory mechanisms seem to be operative. The most advanced of these approaches is a humanised monoclonal antibody that blocks IgE (omalizumab) (Figure 3). Omalizumab is injected twice or four times per week and is a useful add-on therapy in some patients who are affected by very severe asthma with frequent exacerbations who are not responsive even by high doses of corticosteroids [33]. It is an expensive treatment, so patients must be selected carefully for a trial of therapy. Oral drugs that might inhibit IgE signalling are also of potential value. Inhibitors of the enzyme spleen tyrosine kinase (SYK), which is involved in the activation of mast cells, is currently under development [34]. An antisense inhibitor of SYK is effective in an animal model of asthma [35], and the
Figure 3. Inhibition of mast cells in asthma. Mast-cell activation might be inhibited by blocking IgE binding to the high-affinity IgE receptor (FceRI), by inhibiting c-KIT, which is activated by stem-cell factor (SCF), or by inhibiting spleen tyrosine kinase (SYK). www.sciencedirect.com
Review
TRENDS in Molecular Medicine
small-molecule inhibitor R112 given nasally reduces nasal symptoms in hay fever patients [36]. As with other kinase inhibitors, there might be side effects with systemic administration so that inhalation might be the preferred route of delivery. Allergens bind to a low-affinity IgE receptor (FceRII, also known as CD23) and the high-affinity receptor FceRI on several immune cells, including T and B cells [37]. An anti-CD23 antibody (lumiliximab) was well tolerated and reduced IgE concentrations in patients with mild asthma, but its clinical efficacy has not been reported [38]. Regulatory T cells (Treg) have a key role in orchestrating immunity. There is evidence for a defect in Treg function in patients with asthma that might be linked to increased numbers of Th2 cells. There is convincing evidence that specific immunotherapy increases IL-10 production from Treg cells (Tr-1 cells) [39]. Vaccines that enhance Tr-1-cell function and increase IL-10 release are now under development. T-cell peptides are also under development as a safer form of immunotherapy. A cure for asthma? None of the currently available treatments for asthma have long-term effects on airway inflammation or remodelling and therefore are not disease-modifying or curative. Inhaled corticosteroids are effective, but asthma usually rapidly returns when they are discontinued. The prospects for a cure are remote until the molecular and genetic causes of asthma are better understood. However, there is a possibility that vaccination approaches might reverse the abnormal immune regulation found in asthma, restoring Th1 predominance or Treg function [39,40]. Various approaches, including non-pathogenic bacterial products, such as CpG oligodeoxynucleotides, which target toll-like receptor-9 (TLR-9), are currently being explored as potential therapies for asthma [41]. However, the long-term consequences of these approaches need to be carefully evaluated, particularly as they would probably need to be used in children at the onset of disease. The role of other TLRs in asthma is uncertain, with beneficial and detrimental effects reported in different animal models [42]. Future perspectives It has proved remarkably difficult to discover novel therapies for asthma, despite intense effort and investment. We already have effective therapies that are also safe, placing an additional demand on drug discovery. Despite the availability of highly effective therapies, asthma is often poorly controlled because of poor adherence. Strategies to increase adherence or better ways to monitor compliance with regular therapy should be sought in the future. Asthma is a highly complex disease; therefore, it is unlikely that targeting a single receptor or mediator will be effective. Corticosteroids are effective because they suppress multiple inflammatory mechanisms at the same time. It is possible that a key target that is upstream in the complex inflammatory process might be effective, such as anti-TNF therapy in rheumatoid arthritis. However, these targets are usually only identifiable by trial and error in the disease. More selective targeting of www.sciencedirect.com
Vol.12 No.11
519
drugs to patients with particular subtypes of asthma might be possible in the future with the development of discriminatory biomarkers and genetic profiling. Animal models have proved to be misleading and there is now pressure to do earlier proof-of-concept studies in humans. A major unmet need in asthma is to treat patients with severe asthma who are relatively corticosteroid-resistant more effectively. These patients share several characteristics with patients who have COPD who are also steroidresistant. This means that drugs under discovery for COPD might also be effective in treating severe asthma [43]. The mechanism of corticosteroid-resistance in COPD seems to be defective function of HDAC2 [44] and similar abnormalities might also be found in severe asthma [45]. HDAC2 activity might be restored by low doses of theophylline [46], and identification of the pathways involved might lead to new approaches to restore steroid sensitivity in severe asthma [47]. The other unmet need in asthma is to develop an effective oral therapy for patients with mild and moderate disease. However, this has proved to be a major challenge because it is likely that any therapy that will be effective has side effects and, therefore, is disadvantageous compared with current inhaled therapy. References 1 Heaney, L.G. et al. (2005) Severe asthma treatment: need for characterising patients. Lancet 365, 974–976 2 Wenzel, S. (2005) Severe asthma in adults. Am. J. Respir. Crit. Care Med. 172, 149–160 3 Barnes, P.J. (2002) Scientific rationale for combination inhalers with a long-acting b2-agonists and corticosteroids. Eur. Respir. J. 19, 182–191 4 Barnes, P.J. (2004) New drugs for asthma. Nat. Rev. Drug Discov. 3, 831–844 5 Cazzola, M. et al. (2005) Ultra long-acting b2-agonists in development for asthma and chronic obstructive pulmonary disease. Expert Opin. Investig. Drugs 14, 775–783 6 Barnes, P.J. et al. (2003) How do corticosteroids work in asthma? Ann. Intern. Med. 139, 359–370 7 Reynolds, N.A. et al. (2004) Ciclesonide. Drugs 64, 511–519 8 Barnes, P.J. (2006) How corticosteroids control inflammation. Br. J. Pharmacol. 148, 245–254 9 Schacke, H. et al. (2004) Dissociation of transactivation from transrepression by a selective glucocorticoid receptor agonist leads to separation of therapeutic effects from side effects. Proc. Natl. Acad. Sci. U. S. A. 101, 227–232 10 Rosen, J. et al. (2005) The search for safer glucocorticoid receptor ligands. Endocr. Rev. 26, 452–464 11 Barnes, P.J. et al. (1998) Inflammatory mediators of asthma: an update. Pharmacol. Rev. 50, 515–596 12 Barnes, P.J. (2003) Cytokine-directed therapies for the treatment of chronic airway diseases. Cytokine Growth Factor Rev. 14, 511–522 13 Leckie, M.J. et al. (2000) Effects of an interleukin-5 blocking monoclonal antibody on eosinophils, airway hyperresponsiveness and the late asthmatic response. Lancet 356, 2144–2148 14 Kips, J.C. et al. (2003) Effect of SCH55700, a humanized anti-human interleukin-5 antibody, in severe persistent asthma: a pilot study. Am. J. Respir. Crit. Care Med. 167, 1655–1659 15 Wills-Karp, M. (2004) Interleukin-13 in asthma pathogenesis. Immunol. Rev. 202, 175–190 16 Berry, M.A. et al. (2006) Evidence of a role of tumor necrosis factor alpha in refractory asthma. N. Engl. J. Med. 354, 697–708 17 Erin, E.M. et al. (2006) The effects of a monoclonal antibody directed against tumor necrosis factor-a in asthma. Am. J. Respir. Crit. Care Med. DOI: 10.1164/rccm.200601-072OCv1 18 Reber, L. et al. (2006) Stem cell factor and its receptor c-Kit as targets for inflammatory diseases. Eur. J. Pharmacol. 533, 327–340 19 Liu, Y.J. (2006) Thymic stromal lymphopoietin: master switch for allergic inflammation. J. Exp. Med. 203, 269–273
Review
520
TRENDS in Molecular Medicine
20 Bryan, S. et al. (2000) Effects of recombinant human interleukin-12 on eosinophils, airway hyperreactivity and the late asthmatic response. Lancet 356, 2149–2153 21 Lukacs, N.W. et al. (2005) Chemokines and their receptors in chronic pulmonary disease. Curr. Drug Targets Inflamm. Allergy 4, 313–317 22 Erin, E.M. et al. (2002) Eotaxin receptor (CCR3) antagonism in asthma and allergic disease. Curr. Drug Targets Inflamm. Allergy 1, 201–214 23 Barnes, P.J. (2006) Novel signal transduction modulators for the treatment of airway diseases. Pharmacol. Ther. 109, 238–245 24 Lipworth, B.J. (2005) Phosphodiesterase-4 inhibitors for asthma and chronic obstructive pulmonary disease. Lancet 365, 167–175 25 Bousquet, J. et al. (2006) Comparison of roflumilast, an oral anti-inflammatory, with beclomethasone dipropionate in the treatment of persistent asthma. Allergy 61, 72–78 26 Houslay, M.D. et al. (2005) Keynote review: phosphodiesterase-4 as a therapeutic target. Drug Discov. Today 10, 1503–1519 27 Barnes, P.J. (2006) Transcription factors in airway diseases. Lab. Invest. 86, 867–872 28 Karin, M. et al. (2004) The IKK NF-kB system: a treasure trove for drug development. Nat. Rev. Drug Discov. 3, 17–26 29 Kumar, S. et al. (2003) p38 MAP kinases: key signalling molecules as therapeutic targets for inflammatory diseases. Nat. Rev. Drug Discov. 2, 717–726 30 Duan, W. et al. (2005) Inhaled p38a mitogen-activated protein kinase antisense oligonucleotide attenuates asthma in mice. Am. J. Respir. Crit. Care Med. 171, 571–578 31 Bochner, B.S. (2004) Adhesion molecules as therapeutic targets. Immunol. Allergy Clin. North Am. 24, 615–630 32 Singh, J. et al. (2004) Rational design of potent and selective VLA-4 inhibitors and their utility in the treatment of asthma. Curr. Top. Med. Chem. 4, 1497–1507 33 Strunk, R.C. et al. (2006) Omalizumab for asthma. N. Engl. J. Med. 354, 2689–2695
Vol.12 No.11
34 Wong, B.R. et al. (2004) Targeting Syk as a treatment for allergic and autoimmune disorders. Expert Opin. Investig. Drugs 13, 743–762 35 Stenton, G.R. et al. (2002) Inhibition of allergic inflammation in the airways using aerosolized antisense to Syk kinase. J. Immunol. 169, 1028–1036 36 Meltzer, E.O. et al. (2005) An intranasal Syk-kinase inhibitor (R112) improves the symptoms of seasonal allergic rhinitis in a park environment. J. Allergy Clin. Immunol. 115, 791–796 37 Rosenwasser, L.J. et al. (2005) Anti-CD23. Clin. Rev. Allergy Immunol. 29, 61–72 38 Rosenwasser, L.J. et al. (2003) Allergic asthma and an anti-CD23 mAb (IDEC-152): results of a phase I, single-dose, dose-escalating clinical trial. J. Allergy Clin. Immunol. 112, 563–570 39 Akdis, M. et al. (2005) T regulatory cells in allergy: novel concepts in the pathogenesis, prevention, and treatment of allergic diseases. J. Allergy Clin. Immunol. 116, 961–968 40 Wohlleben, G. et al. (2001) Atopic disorders: a vaccine around the corner? Trends Immunol. 22, 618–626 41 Krieg, A.M. (2006) Therapeutic potential of Toll-like receptor 9 activation. Nat. Rev. Drug Discov. 5, 471–484 42 Feleszko, W. et al. (2006) Toll-like receptors–novel targets in allergic airway disease (probiotics, friends and relatives). Eur. J. Pharmacol. 533, 308–318 43 Barnes, P.J. et al. (2004) Prospects for new drugs for chronic obstructive pulmonary disease. Lancet 364, 985–996 44 Barnes, P.J. (2006) Reduced histone deacetylase in COPD: clinical implications. Chest 129, 151–155 45 Cosio, B.G. et al. (2004) Histone acetylase and deacetylase activity in alveolar macrophages and blood monocytes in asthma. Am. J. Respir. Crit. Care Med. 170, 141–147 46 Cosio, B.G. et al. (2004) Theophylline restores histone deacetylase activity and steroid responses in COPD macrophages. J. Exp. Med. 200, 689–695 47 Barnes, P.J. (2005) Targeting histone deacetylase 2 in chronic obstructive pulmonary disease treatment. Expert Opin. Ther. Targets 9, 1111–1121
Elsevier.com – linking scientists to new research and thinking Designed for scientists’ information needs, Elsevier.com is powered by the latest technology with customer-focused navigation and an intuitive architecture for an improved user experience and greater productivity. The easy-to-use navigational tools and structure connect scientists with vital information – all from one entry point. Users can perform rapid and precise searches with our advanced search functionality, using the FAST technology of Scirus.com, the free science search engine. Users can define their searches by any number of criteria to pinpoint information and resources. Search by a specific author or editor, book publication date, subject area – life sciences, health sciences, physical sciences and social sciences – or by product type. Elsevier’s portfolio includes more than 1800 Elsevier journals, 2200 new books every year and a range of innovative electronic products. In addition, tailored content for authors, editors and librarians provides timely news and updates on new products and services. Elsevier is proud to be a partner with the scientific and medical community. Find out more about our mission and values at Elsevier.com. Discover how we support the scientific, technical and medical communities worldwide through partnerships with libraries and other publishers, and grant awards from The Elsevier Foundation. As a world-leading publisher of scientific, technical and health information, Elsevier is dedicated to linking researchers and professionals to the best thinking in their fields. We offer the widest and deepest coverage in a range of media types to enhance cross-pollination of information, breakthroughs in research and discovery, and the sharing and preservation of knowledge.
Elsevier. Building insights. Breaking boundaries. www.elsevier.com www.sciencedirect.com