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New asthma treatments: recent advances and current objectives
REVUE FRAN~AISE D'ALLERGOLOGIE
ET D'IMMUNOLOGIE CLINIQUE
New asthma treatments: recent advances and current objectives K.E CHUNG
KEY-WORDS: Asthma - Treatment - Inhaled corticosteroids - ~2-agonists - Theophylline - Leukotriene inhibitors.
MOTS-CLI~S: Asthme - Traitement - Corticost~roides inhalfis - ~2-agonistes - Th6ophylline - Inhibiteurs du Leucotri6ne.
INTRODUCTION
hyperresponsiveness and airway narrowing, a n d to r e m o d e l l i n g o f the airways has increasingly led to the use o f anti-inflammatory agents as first-line t r e a t m e n t o f asthma, leaving the use o f shorta c t i n g [3-agonists f o r r e l i e f o f b r e a k t h r o u g h symptoms. T h e initial r e c o m m e n d a t i o n has b e e n to use either non-steroidal ,~anti-inflammatory,, a g e n t s s u c h as s o d i u m c r o m o g l y c a t e o r n e d o c r o m i l s o d i u m , p a r t i c u l a r l y in p e d i a t r i c asthma or low-dose i n h a l e d corticosteroid therapy. However, e x p e r i e n c e with these agents indicates that low-dose inhaled steroid therapy is m o r e predictably effective [4,5] a n d that the antii n f l a m m a t o r y a g e n t o f c h o i c e is i n h a l e d corticosteroids even at low doses. T h e r e are also doubts as to w h e t h e r n e d o c r o m i l s o d i u m has antii n f l a m m a t o r y effects such as r e d u c i n g eosinophil infiltration in the airways s u b m u c o s a [6]. By contrast, m o r e r e c e n t studies c o n f i r m the effect o f topical corticosteroid t r e a t m e n t in r e d u c i n g the n u m b e r o f i n f l a m m a t o r y cells in the airways
In o r d e r to u n d e r s t a n d t h e r o l e o f n e w treatments in asthma, it is necessary to review first the r e c e n t changes that have taken place and to survey the c u r r e n t clinical u n m e t n e e d s for asthma such that particular areas o f n e e d could be specifically targeted. Over the last eight years or so since t h e i n t r o d u c t i o n o f n a t i o n a l a s t h m a guidelines in m a n y countries [1-3], there has b e e n several advances in the t r e a t m e n t o f asthma. T h e s e advances relate to i m p r o v e d u n d e r s t a n d i n g o f existing drugs such as the p h a r m a c o l o g y and m o l e c u l a r mechanisms o f corticosteroid actions, the positioning o f the new class o f long-acting ~agonists o n the basis o f new studies a n d the i n t r o d u c t i o n o f a new class o f drugs for asthma, the l e u k o t r i e n e inhibitors. T h e recognition that c h r o n i c i n f l a m m a t o r y processes are p r e s e n t in the airways o f patients with even mild asthma and that such p r o c e s s e s m a y c o n t r i b u t e to b r o n c h i a l
National Heart & Lung Institute, Imperial College School of Medicine, & Royal Brompton Hospital, LONDON, (United Kingdom). Correspondence : Pr. K.E Chung, National Heart & Lung Institute, Dovehouse St, LONDON SW3 6LY, (United Kingdom). Interasma Marrakeeh' 98.
CHUNG K.E - New asthma treatments: recent a d v a n c e s and current objectives. Rev. fr. Allergol., 1998, 38 (7S), $214-$221.
© Expansion Scientifique Publications, 1998
/ NEWASTHMA TREATMENTS: RECENT ADVANCES AND CURRENT OBJECTIVES •
submucosa, such as eosinophils, activated T-cells and mast cells, together with the restoration of epithelial integrity [7-9]. O t h e r i m p o r t a n t observations have also been made over the past decade, namely the benefits of early introduction of inhaled corticosteroid therapy, the introduction of more potent topical steroids and the plateauing dose-response to inhaled corticosteroids.
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Long-acting B-agonists were introduced in several countries at the time when there was concern regarding the possible contribution of short-acting 6-agonist to increasing asthma deaths and to loss of asthma control [10, 11]. The use of long-acting 6-agonists in the management of asthma has been clarified in the initial pioneering clinical trials of salmeterol, in which salmeterol was added to inhaled steroid therapy in patients whose asthma was not adequately controlled at a given dose of inhaled steroids (400 p g / d a y or 800 pg/day). Addition of salmeterol provided better control of asthma in terms of peak flow measurements and day-to-day control of asthma compared to the option of increasing the dose of inhaled steroids in these short-term studies of 3 months' duration [12,13]. These studies also indicated that the dose-response benefits from inhaled steroids do plateau at the doses studied. More recently, the additive effects of another long-acting [3-agonist, eformoterol, to inhaled steroid therapy (budesonide inhaled via turbohaler R, 200 and 800 pg/day) has also been demonstrated to be persistent up to one year of therapy; more importantly, the addition of eformoterol to inhaled corticosteroids at either dose provides additive protection against mild to severe attacks of asthma [14]. Long-acting 6-agonists do not appear to possess antiinflammatory effects on their own, but the effects observed in combination with corticosteroids may reflect more than a bronchodilator effect, perhaps other antiinflammatory effects such as anti-edema effects [15]. It would be unwise to initiate long-acting [3-agonist therapy without corticosteroid therapy. A study in children showed that salmeterol treatment alone for one year caused a trend toward a decrease in lung function and a worsening of bronchial hyperresponsiveness [16]. Whether there are any potential significant differences between the two longRe~frAllergoL, 1998, 3& 7S
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acting ~-agonists, salmeterol, a partial agonist, and eformoterol, a full agonist, is not known, but perhaps unlikely. Because both inhaled steroids and long-acting [3-agonists are usually administered twice daily, it would make sense to combine both in the same inhaler. This may improve patient compliance. These combinations should allow 2 to 3 different doses of inhaled steroids with a fixed dose of long-acting-beta agonist. Such combinations will be available soon. Addition of slow-release theophylline to inhaled corticosteroid therapy also provided better control of asthma than increasing the dose of inhaled corticosteroid therapy [17]. The mechanism of action of theophylline in this response is not clear but theophylline particularly at the doses used which do not achieve the so-called ~
A NEW CLASS OF ANTIASTHMA DRUGS: LEUKOTRIENE INHIBITORS
A new class of drugs has been introduced over the last couple of years in many countries around the world, including Japan. Inhibitors of cysteinyl leukotriene synthesis or leukotriene receptor antagonists such as zileuton, zafirlukast, pranlukast and montelukast are available for prescription [22], but their exact place in asthma management has not been determined in many countries. R e g a r d i n g the d e v e l o p m e n t of mediator antagonists in asthma, it is of interest to note that other mediator antagonist apart from leukotriene antagonists have not been shown to be clinically effective in asthma, such as plateletactivating factor, thromboxane and bradykinin receptor antagonists. Cysteinyl-leukotrienes are important mediators of asthma, participating in bronchoconstriction, airway m i c r o v a s c u l a r leakage and probably in eosinophil recruitment in asthma. Leukotriene receptor antagonists are also effective in preventing exercise-induced asthma and allergen-induced early and late-phase responses [23, 24]. When leukotriene inhibitors are administered to patients with moderately-
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severe asthma, there is a bronchodilator response as m e a s u r e d e i t h e r by p e a k flow or FEV1 measurements, together with an improvement in symptoms, a reduction in the amount of daily 6agonist therapy n e e d e d for controlling asthma symptoms [25, 27]. This effect is observed even in patients already on inhaled corticosteroid therapy [28,29]. Such additive effects of leukotriene receptor antagonists can also be observed in patients with severe a s t h m a n e e d i n g oral c o r t i c o s t e r o i d t h e r a p y [30]. C o r t i c o s t e r o i d therapy indeed does not appear to modulate leukotriene metabolism. Leukotriene receptor antagonists can be used to reduce the amount of inhaled steroids n e e d e d to control asthma [31]. Patients with aspirin-induced asthma respond particularly well to this therapy, as this condition is associated with i n c r e a s e d l e u k o t r i e n e p r o d u c t i o n t h r o u g h an upregulation of the leukotriene C4 synthase enzyme [32]. These compounds can be used as an addition to both oral or i n h a l e d steroid t h e r a p y to provide additional control of asthma in moderately severe to severe asthmatics. It has been r e c o m m e n d e d as a first-line anti-inflammatory agent for asthma, as an alternative to using inhaled steroid therapy by the US National Heart Lung & Blood Institution Expert Panel Report, although it is less potent than low-dose inhaled steroid in controlling asthma. Long-term studies are n e e d e d in this area, b u t the leukotriene blockers have the advantage of being an oral therapy, with greater patient compliance to therapy. The response to these compounds is variable and at present there are no ways of predicting those who will respond to the treatment. In a recent study of responses to the 5-1ipoxygenase inhibitor, zileuton, the b r o n c h o d i l a t o r r e s p o n s e was r e l a t e d to a p o l y m o r p h i s m of the 5-1ipoxygenase g e n e promoter that modifies transcription factor and the activity of the enzyme [33].
U N M E T CLINICAL N E E D S IN A S T H M A : WHERE S H O U L D NEW THERAPIES BE T A R G E T E D TO?
It can be argued that the treatment for mild to moderately severe asthma is effective with the use of inhaled steroid therapy and the addition of other therapies such as long-acting 6-agonists, slow-release t h e o p h y l l i n e and l e u k o t r i e n e inhibitors, and that new treatments should be targeted for patients whose asthma is not well-
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controlled by existing therapies. One approach to determining the role of new treatments in asthma would be to look for current u n m e t clinical needs and target new treatments to these needs. One group of patients that particularly need new effective treatments are those with ~difficult therapy-resistant,, asthma, who appear to have uncontrolled asthma despite on inhaled and often on oral corticosteroid therapy [34, 35]. While much n e e d e d data should be collected from such patients, difficult asthma may comprise of several distinct clinical phenotypes such as brittle asthma with recurrent sometimes rapid onset of life-threatening asthma exacerbations, fixed asthma with chronic obstructive c o m p o n e n t and rapid loss of lung function, and those on high dose oral corticosteroid therapy for control of their a s t h m a ( c o r t i c o s t e r o i d d e p e n d e n t ) . Research in these patients is difficult because of the difficulty in obtaining a sufficient n u m b e r of these patients for detailed study. However, development of protocols to define these patients in cooperative multi-centers may provide a d a t a b a s e for collecting such patients. T h e question is what are the characteristics of these difficult asthmatics that make them different from the asthmatic whose disease is controlled by low to middle doses of inhaled corticosteroids alone. A recent study of proximal mucosal airway biopsies and of transbronchial lung biopsies from such difficult asthmatics taking at least 20 mg of prednisolone per day showed that these patients had a predominance of neutrophil influx in their proximal as well as distal airways [36]. However, it is unclear whether this could have resulted from the oral corticosteroid treatment itself. Part of the problem is that we may not have the efficacious i n t e r v e n t i o n s to deal with the specific inflammatory responses in these patients. One particular difference between the difficult and the mild asthmatic is the difference in responsiveness to corticosteroids. What determines this responsiveness remains unclear but restoring corticosteroid responsiveness could be an important therapeutic exercise. Much has been learnt from the rare corticosteroid-resistant asthmatic p a t i e n t who are patients w h o demonstrate a bronchodilator response to 6agonists but not to two weeks' treatment with 40 mg of prednisolone per day [37]. One proposed mechanism of primary steroid resistance is that there is increased activation of the transcription factor activator protein-1 resulting in complexing of glucocorticoid receptors, thus preventing the anti-inflammatory actions of steroids, either through binding to glucocorticoid elements or Rev.fr. AllergoL, 1998, 38, 7S
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through the inhibition of another transcription factor, nuclear factor-KB [38]. Other mechanisms of g l u c o c o r t i c o i d d o w n - r e g u l a t i o n are also possible. D o w n - r e g u l a t i o n of g l u c o c o r t i c o i d r e c e p t o r s has b e e n shown in circulating lymphocytes after oral prednisolone in normal individuals [39], but it is not known whether this occurs in the airway epithelium exposed to high concentrations of topical steroids. Worsening of a s t h m a s y m p t o m s e i t h e r t h r o u g h allergen e x p o s u r e or d u r i n g s p o n t a n e o u s attacks is accompanied by a decreased affinity of the steroid receptors on circulating mononuclear cells [40, 41], and patients with severe steroid-dependent asthma also demonstrate similar reduction in receptor affinity [42]. This reduction in receptor affinity can be demonstrated by incubation of mononuclear cells in vitro by the combination of cytokines, IL-2 and IL-4 [43], and recent evidence indicates that this can be p r e v e n t e d by an inhibitor of the intracellular signalling p38 kinase [44]. W h e t h e r these m e a s u r e m e n t s are also reflected in airway cells as a result of exposures to these cytokines released in the airways is not known, but prevention or restoration of steroid r e c e p t o r affinity may p r o v i d e o n e way of improving the therapy of asthma.
drugs often lead to remission of the cancer for many months. This possibility may exist from our c u r r e n t u n d e r s t a n d i n g o f the i n f l a m m a t o r y process in asthma. This may also helps us to determine the potential effects of certain classes of drugs in the treatment of asthma.
WHAT SHOULD WE BE STRIVING FOR AS IDEAL ASTHMA TREATMENTS?
Strategies for inhibition of eosinophil activation and recruitment
Although the term antiinflammatory treatments have b e e n a p p l i e d to the drugs such as corticosteroids and sodium cromoglycate, another term has been used that is more relevant to the concept behind the use of such drugs, namely ~
RECENT NEW APPROACHES TO THE THERAPY OF ASTHMA
Although there are specific areas of u n m e t clinical needs in asthma, research into new drugs for asthma have not necessarily focused on these areas. Often new treatments with potentially important side-effects have been reserved for patients with difficult severe asthma. The last 10 years has seen m u c h research into the development of receptor antagonists such as leukotriene, platelet-activating factor and bradykinin B2-receptor antagonists. Only leukotriene antagonists have been shown to have beneficial effects. Phosphodiesterase 4 (PDE4) is the p r e d o m i n a n t PDE in inflammatory cells including mast cells, eosinophils, T-lymphocytes, macrophages and epithelial cells. Inhibitors of PDE4 have been the subject of clinical trials recently but no full analysis has been published yet.
Eosinophils have long been implicated in the pathogenesis of asthma, being present in the airways submucosa with evidence of activation as indicated by the presence of release of eosinophil proteins such as eosinophil cationic protein and m a j o r basic p r o t e i n . Eosinophils are also important sources of cysteinyl-leukotrienes. Much has been learnt about the kinetics of eosinophil traffic between the bone marrow and the the airways. Eosinophilopoiesis in the bone marrow is u n d e r the control of IL-5 which regulates terminal differentiation of these cells [45]. Release of chemokines such as eotaxin in the airways may be the event that causes chemoattraction of eosinophils to the airways, through the upregulation of adhesion molecules such as ICAM-1 and VCAM-1 on the vascular endothelium and the integrins VLA4 on the eosinophil [46]. Therefore, several strategies for inhibiting eosinophit activation and recruitment have been put in place including inhibition of IL5 effects by using a neutralising antibody or an IL5 receptor antagonist, inhibition of chemokine
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effects through an antagonist or antibody to chemokine receptor CCR3 and blocking the effects of adhesion molecules with an antMCAM1 or anti-VLA4 antibody. Studies in animal models indicate that anti-IL-5 antibodies can inhibit eosinophil influx into the airways of sensitised guinea-pigs or m o n k e y s following allergen exposure and can also inhibit the increase in bronchial hyperresponsiveness [47-49]. In one study, the effect of a single administration of antiIL-5 a n t i b o d y p r o v i d e d p r o t e c t i o n up to 3 months, suggestion that ,remission,, may be obtained. An anti-VLA4 antibody in the sheep and rat inhibited bronchial hyperresponsiveness but not the eosinophil influx [50]. This t r e a t m e n t c o u l d be used to reverse established disease and could be particularly tried in patients with severe asthma. The idea of inducing remission of disease would also be an exciting prospect. It could also be administered for prophylaxis of asthma. I n h e r e n t in this approach is the concept that inhibiting a single target may be sufficient. However, studies in animals indicate that IL-5 and chemokines such as RANTES and eotaxin cooperate in eosinophil recruitment and activation [51,52]. These would suggest that a combined inhibition of IL-5 and chemokine effects may be more effective.
Modulation of TH-1/TH2 T-cell activation The concept of interfering with the imbalance of the Th-1 and Th-2 T-cell activities derives from the observations that Th-2 derived cytokines such as IL-4 and IL-5 are over-expressed in asthma, and that Th-2 T-cells may be suppressed by enhancing Th-1 responses. Cytokines from Th-1 cells, notably IFNy and IL-12, can prevent or reverse Th-2 responses. There is an inverse association between a positive tuberculin test indicating a Th-1mediated response and the development of atopy [53]. Apart from inhibiting the Th-2 response, it would be possible to enhance Th-1 T-cell function. Interleukin-12 and IFN~, are b o t h potential candidates for use as treatment in asthma, and can inhibit allergic e o s i n o p h i l i a a n d b r o n c h i a l hyperresponsiveness in the ovalbumin-sensitised mouse [54-57]. A reduction in IL-12 expression in airway biopsies of patients with allergic asthma has been reported, supporting a reduction in Th-1 response [58]. Other approaches would include the use of vaccination to induce a Th-1 response. Approaches aimed at restoring the Th-1/Th-2 imbalance (eg BCG vaccination) may be aimed early in the disease process, perhaps towards those
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at risk of developing asthma. However, ways of identifying such people at risk are needed. More classical i m m u n o m o d u l a t o r s such as cyclosporin A has been tried in asthma and found to possess oral steroid-sparing effects in severe asthma [59]. It is likely that such T-cell inhibitors inhibit both Th-1 and Th-2 cells and therefore do not reset the imbalance in T-helper subsets. The mechanisms by which Th-2 cells are selectively activated involves the co-stimulatory molecule B7.2 which is expressed on antigen-presenting cells that interacts with CD28 on T-cells [60]. Blocking this co-stimulatory molecule may yield novel therapies.
Targetting IgE receptors with an anti-IgE approach IgE is an important mediator of allergic airways disease and a relationship between IgE levels and airway h y p e r r e s p o n s i v e n e s s , and asthma symptoms have been reported [61, 62]. Allergen exposure of sensitised asthmatics may cause both early and late b r o n c h o c o n s t r i c t o r responses which are both considred to be IgE- and mast cell dependent. The late response is associated with airway inflammation characterised by eosinophil influx, airway oedema and activation of adhesion molecules. A recombinant humanised monoclonal antibody that binds to IgE recognised by the highaffinity IgE receptor FceR1 has been developed. This antibody blocks the binding of IgE to mast cells and inhibits mediator release [63]. This antibody (rhuMAb-E25) reduces free IgE levels in serum [64], and inhibits both the early and late responses to allergen exposure [65, 66]. Which categories of patients should such a potential treatment be targetting? From its properties, this novel a p p r o a c h should be m o r e preventive (similar to the use for sodium cromoglycate) such as prophylaxis for seasonal rhinitis or asthma, or preventing the onset of symptoms in allergic patients. In the latter group, however, we have no diagnostic m e t h o d s for p r e d i c t i n g allergic patients at risk of developing asthma. This approach is now being tested in symptomatic patients with allergic asthma.
Anti-hfflammatory cytokines and inhibition of pro-inflammatory cytokines A number of cytokines expressed in asthma appear to have antiinflammatory properties such as interleukin-10 (IL-10) and interleukin-1 r e c e p t o r antagonist (IL-lra). IL-10 which is produced by CD4+ and CD8+ T-cells and activated Rev. fr. AllergoL, 1998, 38, 7S
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monocytes is a potent inhibitor of m o n o c y t e / macrophage function, of IL-4 and IL-5 production by Th2 T-cells, of eosinophil survival and IL-4 induced IgE synthesis. There is a reduced capacity for alveolar macrophages to produce IL-10 in asthma, a defect which is reversed by inhaled corticosteroid t h e r a p y [67]. IL-10 inhibits eosinophilia induced by ovalbumin in immunised mice [68, 69]. IL-10 has been administered to normal volunteers inducing a fall in circulating Tcells with suppression of T-cell proliferation and a reduction of TNFcz and IL-113 production by mononuclear cells [70]. IL-lra can block the proliferation of Th-2 cell clones but not of Th-1 cell clones [71], and in ovalbumin-sensitised model, there is an inhibition of allergen-induced b r o n c h i a l hyperreactivity and p u l m o n a r y eosinophilia [72]. Other approaches include the inhibition of effects of proinflammatory cytokines such as TNFct a n d IL-I[3 which may be overexpressed in chronic severe asthma. These cytokines may play a role as amplifying mechanisms, through the activation of NF-KB and other transcription factors. Blocking antibodies may be used or soluble TNF receptors or IL-lra respectively. These approaches should probably be directed towards established disease, particularly not responding to currently-available therapies. Potential for n e w corticosteroids
While currently-available inhaled corticosteroids are highly effective and have a good margin of safety, there is still r o o m for improvements. Development of even more potent corticosteroids with lesser potential for systemic side-effects continues. However, this raises several issues as to whether more potent steroids will provide more clinical benefits particularly for the more difficult asthmatic patients. In addition, some contribution of systemic effects of inhaled corticosteroids in suppressing eosinophilopoiesis in the bone m a r r o w has b e e n raised. The potential
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p r o l o n g a t i o n of effects of topical steroids delivered by liposomes in the airways may be useful. These improvements may lead to the use of a once daily inhaled steroid dosage. Corticosteroids may control airway inflammation t h r o u g h suppression of transcription factors largely through a direct interaction of the activated glucocorticoid receptor with transcription factors such as AP-1 and NF•B (trans-repression) [73]. It seems likely that the side effects of corticosteroids are mostly the result of trans-activation of genes through binding of glucocorticoid receptors to DNA. Some steroids may have greater potency against trans-repression than Fans-activation [74], which may translate in less side-effect profile, while increasing anti-inflammatory potency. O t h e r a p p r o a c h e s would be to develop specific transcription factor blockers.
CONCLUSIONS
Although there have been new advances in the treatment of asthma, the effort to search for new targets to aim at with the hope of developing novel asthma treatments continues so long as research into the i n f l a m m a t o r y a n d i m m u n o l o g i c a l mechanisms of asthma progresses. However, such search must be combined with the clinical needs of patients with asthma, and of the particular needs of certain subgroups. Novel drugs by their properties should be considered as whether they should be used as preventors, i n d u c e r s of remission, controllers or relievers. The long-term aim of new asthma treatments is to prevent the disease f r o m o c c u r i n g which would m e a n targetting susceptible persons, and to provide better controllers or drugs that cause remission in those at the more severe spectrum of the disease. Current treatments for asthma are very effective for those with mild-to-moderate disease severity.
REFERENCES
1. British Thoracic Society. Guidelines for management of asthma in adults: I - chronic persistent asthma. Br. Med.J., 1990, 301, 651653.
4. Price J.E, Weller P.H. - Comparison of fluticasone propionate and sodium cromoglycate for the treatment of childhood asthma (an open parallel group study). Respir. Med., 1995, 89, 363-368.
2. Woolcock A , Rubinfeld A.R., Seale J:R, et al. - Asthma Management Plan, 1989. Med. J. Austr., 1989, 151, 650-652.
5. Price'J.F. - Inhaled corticosteroids: clinical relevance of safety measures. Pediatr. PulmonoL Suppl., 1997, 15, 4045.
3. Global Initiative for Asthma. Global strategyfor asthma management and prevention: NHLBI/WHO workshop ~port. National Institutes of health, 1995.
6. ManolitsasN.D.,wangJ. D~,/aliaJ. TriggCJ McAulayA.E. DaviesR.J. - Regular albuterol, ned6cromil sodium, and bronchial inflammation in asthma. A m!J. Resl)i~ Crit. CareMed., 1995, 151, 1925-2002.
Rev. fr. Allergol., 1998, 38, 7S
$220 7. Trigg CJ., Manolitsas N.D., Wang J., et al. - Placebo-controlled immunopathologic study of four months of inhaled corticosteroids in asthma. Am. J. Respir. Crit. Care Med., 1994, 150, 17-22. 8. Laitinen L.A., Laitinen A., Haahtele T. - A comparative study of the effects of an inhaled corticosteroid, budesomide, and of a !32agonist, terbutaline, on a!rway inflammation in newly diagnosed asthma. J. Allergy Clin. Immunol., 1992, 90, 32-42. 9. Djukanovic R., Wilson J.W., Britten K.M., et al. - The effect of an inhaled corticosteroid on airway inflammation and symptoms in asthma. Am. Rev. Respi~: Dis., 1992, 145, 669-674. 10. Spitzer W.O., Suissa S., Ernst P., et al. - The use of 13-agonists and the risk of death and near death from asthma. N. Engt. J. Med., 1992, 326, 501-506. 11. Sears M.R., Taylor R.D., Print C.G., et al. - Regular inhaled betaagonist treatment in bronchial asthma. Lancet, 1990, 336, 13911396. 12. Greening A.E, Ind P.W., Northfield M., Shaw G. - Added salmeterol versus higher-dose corticosteroid in asthma patients with symptoms on existing inhaled corticosteroid in asthma patients with symptoms on existing inhaled corticosteroid. Lancet, 1994, 344, 219-224. 13. Woolcock A., Lnndback B., Ringdal N., Jacques L.A. Comparison of addition of salmeterol to inhaled steroids with doubling of the dose of inhaled steroids. Am. J. Respir. Crit. Care Med., 1996, 153, 1481-1488.
• K.E C H U N G / 27. Reiss T.E, Sorkness C.A., Stricker W., et aL - Effects of montelukast (MK-0476), a potent cysteinyl leukotriene receptor antagonist, on bronchodilation in asthmatic subjects treated with and without inhaled corticosteroids. Thorax, 1997, 52, 4548. 28. VirchowJ., Hassall S.M., Summerton L. - Improved asthma control over 6 weeks with Accolate (zafirlukast) in patients on high dose corticosteroids. Allergy, 1997, 52, 183(Abstract). 29. O'Shaughnessy K.M., Wellings R., Gillies B., Fuller R.W. Differential effects of fluticasone propionate on allergen-evoked bronchoconstriction and increased urinary leukotriene E4 excretion [see comments]. Am. Rev. Respir. Dis., 1993, 147, 14721476. 30. Dworski R., Fitzgerald G.A., OatesJ.A., ShellerJ.R. - Effect of oral prednisone on airway inflammatory mediators in atopic asthma. Am. J. Respir. Crit. Care Med., 1994, 149, 953-959. 31. Tamaoki J., Kondo M., Sakai N., et al. - Leukotriene antagonist prevents exacerbation of asthma during reduction of high-dose inhaled corticosteroid. The Tokyo Joshi-Idai Asthma Research Group. Am. J. Respir. Crit. Care Med., 1997, 155, 1235-1240. 32. Cowburn A.S., Sladek K-, Soja J., et aL - Overexpression of leukotriene C4 synthase in bronchial biopsies from patients with aspirin-intolerant asthma, f Clin. Invest., 1998, 101, 834-846. 33. In K.H., Asano K., Beier D., et al. - Naturally occurring mutations in the human 5-1ipoxygenase gene promoter that modify transcription factor binding and reporter gene transcription. f Clin. Invest., 1997, 99, 1130-1137.
14. Pauwels R.A., Lofdahl C., Postma D., et al. - Effect of inhaled formoterol and budesonide on exacerbations of asthma. N. Engl. J. Med., 1997, 337, 1405-1411.
34. Chung K.E - Management of difficult asthma [editorial]. Br. f Hosp. Med., 1994, 51, 80-81.
15. Chung K.E - The complementary role of glucocorticosteroids and long-acting 13-adrenergic agonists. Allergy, 1998, In press.
35. Barnes PJ., Chung K-E - Difficult asthma: cause for concern. Br Med.J., 1989, 299, 695-698.
16. Verberne AAPH, Frost C., Roorda R.J., Laag H., Kerrebijn K-E One year treatment with salmeterol compared with beclomethasone in children with asthma. Am. J. Respir. Crit. Care Med., 1997, 156, 688-695.
36. Wenzel S.E., Szefler SJ., Leung DYM, Sloan S.h, Rex M.D., Martin R.J. - Bronchoscopic evaluation of severe asthma: persistent inflammation associated with high dose glucocorticoids. Am. f Respi~: Crit. Care Med., 1997, 156, 737-743.
17. Evans DJ., Taylor D.A., Zetterstrom O., Chung ICE, O'Connor B.J., Barnes P.J. - Theophylline plus low dose inhaled steroid is as effective as high dose inhaled steroid in the control of asthma. N. Engl.J. Med., 1997, 337, 1412-1418.
37. Woolcock AJ. - Corticosteroid-resistant asthma. Definitions. Am. J. Respir. Crit. Care Med., 1996, 154, $4548.
18. Kidney J., Dominguez M., Taylor EM., Rose M., Chung K.E, Barnes PJ. Immunomodulation by theophylline in asthma. Demonstration by withdrawal of therapy. Am. J. Respir. Crit. Care Med., 1995, 151, 1907-1914.
39. Rosewicz S., McDonald A.R., Maddux B.A., Goldfine I.D., Miesfeld R.L., Logsdon C.D. - Mechanism of glucocorticoid receptor down-regulation by glucocorticoids, f Biol. Chem., 1988, 263, 2581-2584.
19. Sullivan R, Bekir S.,Jaffar Z., Page C.,Jeffrey E, CostelloJ. - Antiinflammatory effects of low-dose oral theophylline in atopic asthma. Lancet, 1994, 343, 1006-1008.
40. Spahn J.D., Leung D.Y., Surs W., Harbeck R.J., Nimmagadda S., Szefler s.J. - Reduced glucocorticoid binding affinity in asthma is related to ongoing allergic inflammation. Am. J. Respi~: Crit. Care Med., 1995, 151, 1709-1714.
20. Tinkelman D.G., Reed C.E., Nelson H.S., Offord K.E - Aerosol beclomethasone dipropionate compared with theophylline as primary treatment of chronic, mild to moderate severe asthma in children. Pediatrics, 1993, 92, 64-77. 21. Meltzer E.O., Orgel H.A., Ellis E.E, Eigen H.N., Hemstreet M.E Long-term comparison of three combinations of albuterol, theophylline, and beclomethasone in children with chronic asthma. J. Allergy Clin. ImmunoL, 1992, 90, 2-11. 22. Chung K-E - Leukotriene receptor antagonists and biosynthesis inhibitors: potential breakthrough in asthma therapy. Eur. Respir. Ji, 1995, 8, 1203-1213. 23. Taylor I.K., O'Shaughnessy K.M., Fuller R.W., Dollery C.T. - Effect of cysteinyl-leukotrieue receptor antagonist ICI 204-219 on allergen-induced bronchoconstriction and airway hyperreactivitiy in atopic subjects. Lancet, 1991, 337, 690-694. 24. Manning P.J., Watson R.M., Margolskee D.J., Williams V.C., Schwartz J.I., O'Byrne EM. - Inhibition of exercise-induced bronchoconstriction by MK-751, a potent leukotriene-D4 receptor antagonist. N. Engl. J. Med., 1990, 323, 1736-1739. 25. Spector S.L., Smith L.J., Glass M. - Effects of six weeks of therapy with oral doses of ICI 204,219, a leukotriene D4 receptor antagonist, in subjects with bronchial asthma. Am. J. Respir. Crit. Care Med., 1994, 150, 618-623. (Abstract) 26. Hui K.E, Barnes N.C. - Lung function improvement in asthma with a cystemyl-leukotriene receptor antagonist. Lancet, 1991, 337, 1062-1063.
38. Barnes PJ., Adcock I.M. - Steroid resistance in asthma. Q.J. Med., 1995, 88, 455-468.
41. Nimmagadda S.R., Szefler SJ., SpahnJ.D., Surs W., Leung D.Y. Allergen exposure decreases glucocorticoid receptor binding affinity and steroid responsiveness in atopic asthmatics. Am. J. Respir. Crit. Care Med., 1997, 155, 87-93. 42. Irusen E., Barnes PJ., Adcock I.M., Chung ILE - Altered affinity of dexamethasone for the glucocorticoid receptor (GR) in oral steroiddependent asthmatics. Eur. Respir.J., 1998, in press, (Abstract) 43. Kam J.C., Szefler s.J., Surs W., Sher E.R., Leung D.Y. Combination IL-2 and IL-4 reduces glucocorticoid receptorbinding affinity and T cell response to glucocorticoids. a~ Immunol., 1993, 151, 3460-3466. 44. Irusen E., Chung K.E, Barnes P.J., Adcock I.M. - p38 mitogenactivated protein kinase mediates IL-2 and 4 changes in glucocorticoid receptor (GR) affinity. Eu~: Respir.J., 1998, in press, (Abstract). 45. Sanderson cJ., Warren D.J., Strath M. - Identification of a lymphokine that stimulates eosinophil differentiation in vitro. Its relationship to interleukin 3, and functional properties of eosinophils produced in cultures.J. Exp. Med., 1985, 162, 60-74. 46. Burke Gaffney A., Hellewell EG. - Eotaxin stimulates eosinophil adhesion to human lung microvascular endothelial cells. Biochem. Biophys. Res. Commun., 1996, 227, 35-40. 47. Mauser PJ., Pitman A.M., Fernandez X., et al. - Effects of an antibody to interleukin-5 in a monkey model of asthma. Am. J. Respir. Crit. Care Med., 1995, 152, 467-472.
Rev. fr. AllergoL, 1998, 38, 7S
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48. Mauser P.J., Pitman A., Witt A., et al. - Inhibitory effect of the TRFK-5 anti-IL-5 antibody in a guinea pig model of asthma. Am. Rev. Respir. Dis., 1993, 148, 1623-1627.
62. Sunyer J., Anto J.M., Sabria J., et al. - Relationship between serum IgE and airway responsiveness in adults with asthma, a( Allergy Clin. [mmunol., 1995, 95, 699-706.
49. Van Oosterhout A.J.M., Rudolf A., Ladenius C., et aL - Effect of anti-IL-5 and IL-5 in airway hyperreactivity and eosinophils in guinea pigs. Am. Rev. Respir Dis., 1993, 14Z 548-552.
63. Saban R., Haak Frendscho M., Zine M., et al. - H u m a n FcERI-IgG and humanized anti-IgE monoclonal antibody MaE11 block passive sensitization of h u m a n and rhesus monkey lung.j~ Allergy Clin. Immunol., 1994, 94, 836-843.
50. Abraham W.M., Sielczak M.W., A h m e d A., et al. - Alpha 4integrins mediate antigen-induced late bronchial responses and prolonged airway hyperresponsiveness in sheep, j( Clin. Invest., 1994, 93, 776-787.
64. Haak Frendscho M., Robbins g,., Lyon R., et al. - Administration of an anti-IgE antibody in~bits CD23 expression and IgE production in vivo. Immunology, 1994, 82, 306-313.
51. Collins ED., Griffiths-Johnson D.A., Jose P.J., Williams TJ, Marleau S. - Co-operation between interleukin-5 and the chemokine,eotaxin, to induce eosinophil accumulation in vivo. a( Exp. Med., 1995, 182, 1169-1174.
65. FahyJ.V., Fleming H.E., Wong H.H., et al. - The effect of an antiIgE monoclonal antibody on the early- and late-phase responses to allergen inhalation in asthmatic subjects [see comments]. Am. a( Respir. Crit. Care Med., 1997, 155, 1828-1834.
52. Hisada rE, Hellewell P., Teixeira M.M., Malta M.G.K., Chung K.E Cooperative effects between eotaxin and interleukin-5 on airway hyperresponsiveness and eosinophil accumulation in the airways in mice. Am. J. Respir Crit. Care Med., 1998, 157, A700 (Abstract).
66. Boulet L..P, Chapman K.R., CoteJ., et al. - Inhibitory effects of an anti-IgE antibody E25 on allergen-induced early asthmatic response [see comments]. Am.a( Respir. Crit. Care Med., 1997, 155, 1835-1840.
-
53. Shirakawa T., Enomoto T., Shimazu S., Hopkin J.M. - The inverse association between tuberculin responses and atopic disorder [see comments]. Science, 1997, 275, 77-79. 54. Gavett S.H., O ' H e a r n D.J., Li X., Huang S.K., Finkelman ED., Wills Karp M. - Interleukin 12 inhibits antigen-induced airway hyperresponsiveness, i n f l a m m a t i o n , a n d Th2 cytokine expression in mice.a( Exp. Med., 1995, 182, 1527-1536. 55. Kips J.C., Brusselle G.j.,joos G.E, et aL - Interleukin-12 inhibits antigen-induced airway hyperresponsiveness in mice. Am. a( Respir Crit. Care Med., 1996, 153, 535-539. 56. Lack G., Bradley K.L., Hamelmann E., et al. - Nebulized IFNg a m m a inhibits the development of secondary allergic responses in mice.a( Immunol., 1996, 157, 1432-1439. 57. Zuany Amorim C., Leduc D., Vargaftig B.B., Pretolani M. Modulation by rm interferon-gamma and CD4+ T-lymphocytes of allergic eosinophil accumulation in the mice peritoneal cavity. Ann. N. E Acad. Sci., 1994, 725, 34-43. 58. Naseer T., Minshall E.M., Leung D.Y., et al. - Expression of IL-12 and IL-13 mRNA in asthma and their modulation in response to steroid therapy. Am.a( Respir. Crit. Care Med., 1997, 155, 845-851. 59. Alexander A:G., Barnes N.C., Kay A.B. - Cyclosporin A in corticosteroid-dependent chronic severe asthma. Lancet, 1992, 339, 324-327. 60. Kuchroo V.K., Das M.E, Brown J.A., et al. - B7-1 and B7-2 costimulatory molecules activate differentially the T h l / T h 2 developmental pathways: application to autoimmune disease therapy. Cell, 1995, 80, 707-718. 61. Burrows B., Martinez ED., Halonen M. - Association of asthma with serum IgE levels and skin-test reactivity to allergens. N. Engl. a( Med., 1989, 320, 271-272.
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Rev. f~ Allergol., 1998, 38, 7S
67. John M., Lim S., Seybold J., et al. - Inhaled corticosteroids increase interleukin-10 but reduce macrophage inflammatory protein-la, granulocyte-macrophage colony-stimulating factor and interferon. (release from alveotar macrophages in asthma. Am.a( Respi~: Crit. Care Med., 1998, 157, 256-263. 68. Zuany Amorim C., Creminon C., Nevers M.C., Nahori M.A., Vargaftig B.B., Pretolani M. - Modulation by IL-10 of antigeni n d u c e d IL-5 g e n e r a t i o n , a n d CD4+ T lymphocyte a n d eosinophil infiltration into the mouse peritoneal cavity. J. ImmunoL, 1996, 157, 377-384. 69. Zuany Amorim C., Haile S., Leduc D., et al. - Interleukin-10 inhibits antigen-induced cellular recruitment into the airways of sensitized mice.a( Clin. Invest., 1995, 95, 2644-2651. 70. ChernoffA.E., Granowitz E.V., Shapiro L., et al. - A randomized, controlled trial of IL-10 in humans. Inhibition of inflammatory cytokine production and immune responses, j( Immunol., 1995, 154, 5492-5499. 71. Abbas A.K., Williams M.E., Burstein H.J., Chang T.L., Bossu E, Lichtman A.H. - Activation and functions of CD4+ T-cell subsets. Immunol. Rev., 1991, 123, 5-22. 72. Watson M.L., Smith D, Bourne A.D., Thompson R.C., WestwickJ. - Cytokines contribute to airway dysfunction in mltigen-challenged gumea pigs, inhibition of airway hyperreactivity, pulmonary eosinophil accumulation, and tumor necrosis factor generation by pretreatment with an interleukin-1 receptor antagonist. Am. a( Respi~: Cell MoL Biol., 1993, 8, 365-369. 73. Barnes P.J., Adcock I.M. - Anti-inflammatory actions of steroids: molecular mechanisms. Trends Pharmacol. Sci., 1993, 14, 436-441. 74. Heck S., Kullmann M., Gast A., et al. - A distinct modulating domain in glucocorticoid receptor monomers in the repression of activity of the transcription factor AP-1. EMBO. J., 1994, 13, 4087-4095.
ET D'IMMUNOLOGIE CLINIQUE
New asthma treatments: recent advances and current objectives K.E CHUNG
KEY-WORDS: Asthma - Treatment - Inhaled corticosteroids - ~2-agonists - Theophylline - Leukotriene inhibitors.
MOTS-CLI~S: Asthme - Traitement - Corticost~roides inhalfis - ~2-agonistes - Th6ophylline - Inhibiteurs du Leucotri6ne.
INTRODUCTION
hyperresponsiveness and airway narrowing, a n d to r e m o d e l l i n g o f the airways has increasingly led to the use o f anti-inflammatory agents as first-line t r e a t m e n t o f asthma, leaving the use o f shorta c t i n g [3-agonists f o r r e l i e f o f b r e a k t h r o u g h symptoms. T h e initial r e c o m m e n d a t i o n has b e e n to use either non-steroidal ,~anti-inflammatory,, a g e n t s s u c h as s o d i u m c r o m o g l y c a t e o r n e d o c r o m i l s o d i u m , p a r t i c u l a r l y in p e d i a t r i c asthma or low-dose i n h a l e d corticosteroid therapy. However, e x p e r i e n c e with these agents indicates that low-dose inhaled steroid therapy is m o r e predictably effective [4,5] a n d that the antii n f l a m m a t o r y a g e n t o f c h o i c e is i n h a l e d corticosteroids even at low doses. T h e r e are also doubts as to w h e t h e r n e d o c r o m i l s o d i u m has antii n f l a m m a t o r y effects such as r e d u c i n g eosinophil infiltration in the airways s u b m u c o s a [6]. By contrast, m o r e r e c e n t studies c o n f i r m the effect o f topical corticosteroid t r e a t m e n t in r e d u c i n g the n u m b e r o f i n f l a m m a t o r y cells in the airways
In o r d e r to u n d e r s t a n d t h e r o l e o f n e w treatments in asthma, it is necessary to review first the r e c e n t changes that have taken place and to survey the c u r r e n t clinical u n m e t n e e d s for asthma such that particular areas o f n e e d could be specifically targeted. Over the last eight years or so since t h e i n t r o d u c t i o n o f n a t i o n a l a s t h m a guidelines in m a n y countries [1-3], there has b e e n several advances in the t r e a t m e n t o f asthma. T h e s e advances relate to i m p r o v e d u n d e r s t a n d i n g o f existing drugs such as the p h a r m a c o l o g y and m o l e c u l a r mechanisms o f corticosteroid actions, the positioning o f the new class o f long-acting ~agonists o n the basis o f new studies a n d the i n t r o d u c t i o n o f a new class o f drugs for asthma, the l e u k o t r i e n e inhibitors. T h e recognition that c h r o n i c i n f l a m m a t o r y processes are p r e s e n t in the airways o f patients with even mild asthma and that such p r o c e s s e s m a y c o n t r i b u t e to b r o n c h i a l
National Heart & Lung Institute, Imperial College School of Medicine, & Royal Brompton Hospital, LONDON, (United Kingdom). Correspondence : Pr. K.E Chung, National Heart & Lung Institute, Dovehouse St, LONDON SW3 6LY, (United Kingdom). Interasma Marrakeeh' 98.
CHUNG K.E - New asthma treatments: recent a d v a n c e s and current objectives. Rev. fr. Allergol., 1998, 38 (7S), $214-$221.
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submucosa, such as eosinophils, activated T-cells and mast cells, together with the restoration of epithelial integrity [7-9]. O t h e r i m p o r t a n t observations have also been made over the past decade, namely the benefits of early introduction of inhaled corticosteroid therapy, the introduction of more potent topical steroids and the plateauing dose-response to inhaled corticosteroids.
,
Long-acting B-agonists were introduced in several countries at the time when there was concern regarding the possible contribution of short-acting 6-agonist to increasing asthma deaths and to loss of asthma control [10, 11]. The use of long-acting 6-agonists in the management of asthma has been clarified in the initial pioneering clinical trials of salmeterol, in which salmeterol was added to inhaled steroid therapy in patients whose asthma was not adequately controlled at a given dose of inhaled steroids (400 p g / d a y or 800 pg/day). Addition of salmeterol provided better control of asthma in terms of peak flow measurements and day-to-day control of asthma compared to the option of increasing the dose of inhaled steroids in these short-term studies of 3 months' duration [12,13]. These studies also indicated that the dose-response benefits from inhaled steroids do plateau at the doses studied. More recently, the additive effects of another long-acting [3-agonist, eformoterol, to inhaled steroid therapy (budesonide inhaled via turbohaler R, 200 and 800 pg/day) has also been demonstrated to be persistent up to one year of therapy; more importantly, the addition of eformoterol to inhaled corticosteroids at either dose provides additive protection against mild to severe attacks of asthma [14]. Long-acting 6-agonists do not appear to possess antiinflammatory effects on their own, but the effects observed in combination with corticosteroids may reflect more than a bronchodilator effect, perhaps other antiinflammatory effects such as anti-edema effects [15]. It would be unwise to initiate long-acting [3-agonist therapy without corticosteroid therapy. A study in children showed that salmeterol treatment alone for one year caused a trend toward a decrease in lung function and a worsening of bronchial hyperresponsiveness [16]. Whether there are any potential significant differences between the two longRe~frAllergoL, 1998, 3& 7S
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acting ~-agonists, salmeterol, a partial agonist, and eformoterol, a full agonist, is not known, but perhaps unlikely. Because both inhaled steroids and long-acting [3-agonists are usually administered twice daily, it would make sense to combine both in the same inhaler. This may improve patient compliance. These combinations should allow 2 to 3 different doses of inhaled steroids with a fixed dose of long-acting-beta agonist. Such combinations will be available soon. Addition of slow-release theophylline to inhaled corticosteroid therapy also provided better control of asthma than increasing the dose of inhaled corticosteroid therapy [17]. The mechanism of action of theophylline in this response is not clear but theophylline particularly at the doses used which do not achieve the so-called ~
A NEW CLASS OF ANTIASTHMA DRUGS: LEUKOTRIENE INHIBITORS
A new class of drugs has been introduced over the last couple of years in many countries around the world, including Japan. Inhibitors of cysteinyl leukotriene synthesis or leukotriene receptor antagonists such as zileuton, zafirlukast, pranlukast and montelukast are available for prescription [22], but their exact place in asthma management has not been determined in many countries. R e g a r d i n g the d e v e l o p m e n t of mediator antagonists in asthma, it is of interest to note that other mediator antagonist apart from leukotriene antagonists have not been shown to be clinically effective in asthma, such as plateletactivating factor, thromboxane and bradykinin receptor antagonists. Cysteinyl-leukotrienes are important mediators of asthma, participating in bronchoconstriction, airway m i c r o v a s c u l a r leakage and probably in eosinophil recruitment in asthma. Leukotriene receptor antagonists are also effective in preventing exercise-induced asthma and allergen-induced early and late-phase responses [23, 24]. When leukotriene inhibitors are administered to patients with moderately-
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severe asthma, there is a bronchodilator response as m e a s u r e d e i t h e r by p e a k flow or FEV1 measurements, together with an improvement in symptoms, a reduction in the amount of daily 6agonist therapy n e e d e d for controlling asthma symptoms [25, 27]. This effect is observed even in patients already on inhaled corticosteroid therapy [28,29]. Such additive effects of leukotriene receptor antagonists can also be observed in patients with severe a s t h m a n e e d i n g oral c o r t i c o s t e r o i d t h e r a p y [30]. C o r t i c o s t e r o i d therapy indeed does not appear to modulate leukotriene metabolism. Leukotriene receptor antagonists can be used to reduce the amount of inhaled steroids n e e d e d to control asthma [31]. Patients with aspirin-induced asthma respond particularly well to this therapy, as this condition is associated with i n c r e a s e d l e u k o t r i e n e p r o d u c t i o n t h r o u g h an upregulation of the leukotriene C4 synthase enzyme [32]. These compounds can be used as an addition to both oral or i n h a l e d steroid t h e r a p y to provide additional control of asthma in moderately severe to severe asthmatics. It has been r e c o m m e n d e d as a first-line anti-inflammatory agent for asthma, as an alternative to using inhaled steroid therapy by the US National Heart Lung & Blood Institution Expert Panel Report, although it is less potent than low-dose inhaled steroid in controlling asthma. Long-term studies are n e e d e d in this area, b u t the leukotriene blockers have the advantage of being an oral therapy, with greater patient compliance to therapy. The response to these compounds is variable and at present there are no ways of predicting those who will respond to the treatment. In a recent study of responses to the 5-1ipoxygenase inhibitor, zileuton, the b r o n c h o d i l a t o r r e s p o n s e was r e l a t e d to a p o l y m o r p h i s m of the 5-1ipoxygenase g e n e promoter that modifies transcription factor and the activity of the enzyme [33].
U N M E T CLINICAL N E E D S IN A S T H M A : WHERE S H O U L D NEW THERAPIES BE T A R G E T E D TO?
It can be argued that the treatment for mild to moderately severe asthma is effective with the use of inhaled steroid therapy and the addition of other therapies such as long-acting 6-agonists, slow-release t h e o p h y l l i n e and l e u k o t r i e n e inhibitors, and that new treatments should be targeted for patients whose asthma is not well-
• K.E C H U N G /
controlled by existing therapies. One approach to determining the role of new treatments in asthma would be to look for current u n m e t clinical needs and target new treatments to these needs. One group of patients that particularly need new effective treatments are those with ~difficult therapy-resistant,, asthma, who appear to have uncontrolled asthma despite on inhaled and often on oral corticosteroid therapy [34, 35]. While much n e e d e d data should be collected from such patients, difficult asthma may comprise of several distinct clinical phenotypes such as brittle asthma with recurrent sometimes rapid onset of life-threatening asthma exacerbations, fixed asthma with chronic obstructive c o m p o n e n t and rapid loss of lung function, and those on high dose oral corticosteroid therapy for control of their a s t h m a ( c o r t i c o s t e r o i d d e p e n d e n t ) . Research in these patients is difficult because of the difficulty in obtaining a sufficient n u m b e r of these patients for detailed study. However, development of protocols to define these patients in cooperative multi-centers may provide a d a t a b a s e for collecting such patients. T h e question is what are the characteristics of these difficult asthmatics that make them different from the asthmatic whose disease is controlled by low to middle doses of inhaled corticosteroids alone. A recent study of proximal mucosal airway biopsies and of transbronchial lung biopsies from such difficult asthmatics taking at least 20 mg of prednisolone per day showed that these patients had a predominance of neutrophil influx in their proximal as well as distal airways [36]. However, it is unclear whether this could have resulted from the oral corticosteroid treatment itself. Part of the problem is that we may not have the efficacious i n t e r v e n t i o n s to deal with the specific inflammatory responses in these patients. One particular difference between the difficult and the mild asthmatic is the difference in responsiveness to corticosteroids. What determines this responsiveness remains unclear but restoring corticosteroid responsiveness could be an important therapeutic exercise. Much has been learnt from the rare corticosteroid-resistant asthmatic p a t i e n t who are patients w h o demonstrate a bronchodilator response to 6agonists but not to two weeks' treatment with 40 mg of prednisolone per day [37]. One proposed mechanism of primary steroid resistance is that there is increased activation of the transcription factor activator protein-1 resulting in complexing of glucocorticoid receptors, thus preventing the anti-inflammatory actions of steroids, either through binding to glucocorticoid elements or Rev.fr. AllergoL, 1998, 38, 7S
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through the inhibition of another transcription factor, nuclear factor-KB [38]. Other mechanisms of g l u c o c o r t i c o i d d o w n - r e g u l a t i o n are also possible. D o w n - r e g u l a t i o n of g l u c o c o r t i c o i d r e c e p t o r s has b e e n shown in circulating lymphocytes after oral prednisolone in normal individuals [39], but it is not known whether this occurs in the airway epithelium exposed to high concentrations of topical steroids. Worsening of a s t h m a s y m p t o m s e i t h e r t h r o u g h allergen e x p o s u r e or d u r i n g s p o n t a n e o u s attacks is accompanied by a decreased affinity of the steroid receptors on circulating mononuclear cells [40, 41], and patients with severe steroid-dependent asthma also demonstrate similar reduction in receptor affinity [42]. This reduction in receptor affinity can be demonstrated by incubation of mononuclear cells in vitro by the combination of cytokines, IL-2 and IL-4 [43], and recent evidence indicates that this can be p r e v e n t e d by an inhibitor of the intracellular signalling p38 kinase [44]. W h e t h e r these m e a s u r e m e n t s are also reflected in airway cells as a result of exposures to these cytokines released in the airways is not known, but prevention or restoration of steroid r e c e p t o r affinity may p r o v i d e o n e way of improving the therapy of asthma.
drugs often lead to remission of the cancer for many months. This possibility may exist from our c u r r e n t u n d e r s t a n d i n g o f the i n f l a m m a t o r y process in asthma. This may also helps us to determine the potential effects of certain classes of drugs in the treatment of asthma.
WHAT SHOULD WE BE STRIVING FOR AS IDEAL ASTHMA TREATMENTS?
Strategies for inhibition of eosinophil activation and recruitment
Although the term antiinflammatory treatments have b e e n a p p l i e d to the drugs such as corticosteroids and sodium cromoglycate, another term has been used that is more relevant to the concept behind the use of such drugs, namely ~
RECENT NEW APPROACHES TO THE THERAPY OF ASTHMA
Although there are specific areas of u n m e t clinical needs in asthma, research into new drugs for asthma have not necessarily focused on these areas. Often new treatments with potentially important side-effects have been reserved for patients with difficult severe asthma. The last 10 years has seen m u c h research into the development of receptor antagonists such as leukotriene, platelet-activating factor and bradykinin B2-receptor antagonists. Only leukotriene antagonists have been shown to have beneficial effects. Phosphodiesterase 4 (PDE4) is the p r e d o m i n a n t PDE in inflammatory cells including mast cells, eosinophils, T-lymphocytes, macrophages and epithelial cells. Inhibitors of PDE4 have been the subject of clinical trials recently but no full analysis has been published yet.
Eosinophils have long been implicated in the pathogenesis of asthma, being present in the airways submucosa with evidence of activation as indicated by the presence of release of eosinophil proteins such as eosinophil cationic protein and m a j o r basic p r o t e i n . Eosinophils are also important sources of cysteinyl-leukotrienes. Much has been learnt about the kinetics of eosinophil traffic between the bone marrow and the the airways. Eosinophilopoiesis in the bone marrow is u n d e r the control of IL-5 which regulates terminal differentiation of these cells [45]. Release of chemokines such as eotaxin in the airways may be the event that causes chemoattraction of eosinophils to the airways, through the upregulation of adhesion molecules such as ICAM-1 and VCAM-1 on the vascular endothelium and the integrins VLA4 on the eosinophil [46]. Therefore, several strategies for inhibiting eosinophit activation and recruitment have been put in place including inhibition of IL5 effects by using a neutralising antibody or an IL5 receptor antagonist, inhibition of chemokine
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effects through an antagonist or antibody to chemokine receptor CCR3 and blocking the effects of adhesion molecules with an antMCAM1 or anti-VLA4 antibody. Studies in animal models indicate that anti-IL-5 antibodies can inhibit eosinophil influx into the airways of sensitised guinea-pigs or m o n k e y s following allergen exposure and can also inhibit the increase in bronchial hyperresponsiveness [47-49]. In one study, the effect of a single administration of antiIL-5 a n t i b o d y p r o v i d e d p r o t e c t i o n up to 3 months, suggestion that ,remission,, may be obtained. An anti-VLA4 antibody in the sheep and rat inhibited bronchial hyperresponsiveness but not the eosinophil influx [50]. This t r e a t m e n t c o u l d be used to reverse established disease and could be particularly tried in patients with severe asthma. The idea of inducing remission of disease would also be an exciting prospect. It could also be administered for prophylaxis of asthma. I n h e r e n t in this approach is the concept that inhibiting a single target may be sufficient. However, studies in animals indicate that IL-5 and chemokines such as RANTES and eotaxin cooperate in eosinophil recruitment and activation [51,52]. These would suggest that a combined inhibition of IL-5 and chemokine effects may be more effective.
Modulation of TH-1/TH2 T-cell activation The concept of interfering with the imbalance of the Th-1 and Th-2 T-cell activities derives from the observations that Th-2 derived cytokines such as IL-4 and IL-5 are over-expressed in asthma, and that Th-2 T-cells may be suppressed by enhancing Th-1 responses. Cytokines from Th-1 cells, notably IFNy and IL-12, can prevent or reverse Th-2 responses. There is an inverse association between a positive tuberculin test indicating a Th-1mediated response and the development of atopy [53]. Apart from inhibiting the Th-2 response, it would be possible to enhance Th-1 T-cell function. Interleukin-12 and IFN~, are b o t h potential candidates for use as treatment in asthma, and can inhibit allergic e o s i n o p h i l i a a n d b r o n c h i a l hyperresponsiveness in the ovalbumin-sensitised mouse [54-57]. A reduction in IL-12 expression in airway biopsies of patients with allergic asthma has been reported, supporting a reduction in Th-1 response [58]. Other approaches would include the use of vaccination to induce a Th-1 response. Approaches aimed at restoring the Th-1/Th-2 imbalance (eg BCG vaccination) may be aimed early in the disease process, perhaps towards those
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at risk of developing asthma. However, ways of identifying such people at risk are needed. More classical i m m u n o m o d u l a t o r s such as cyclosporin A has been tried in asthma and found to possess oral steroid-sparing effects in severe asthma [59]. It is likely that such T-cell inhibitors inhibit both Th-1 and Th-2 cells and therefore do not reset the imbalance in T-helper subsets. The mechanisms by which Th-2 cells are selectively activated involves the co-stimulatory molecule B7.2 which is expressed on antigen-presenting cells that interacts with CD28 on T-cells [60]. Blocking this co-stimulatory molecule may yield novel therapies.
Targetting IgE receptors with an anti-IgE approach IgE is an important mediator of allergic airways disease and a relationship between IgE levels and airway h y p e r r e s p o n s i v e n e s s , and asthma symptoms have been reported [61, 62]. Allergen exposure of sensitised asthmatics may cause both early and late b r o n c h o c o n s t r i c t o r responses which are both considred to be IgE- and mast cell dependent. The late response is associated with airway inflammation characterised by eosinophil influx, airway oedema and activation of adhesion molecules. A recombinant humanised monoclonal antibody that binds to IgE recognised by the highaffinity IgE receptor FceR1 has been developed. This antibody blocks the binding of IgE to mast cells and inhibits mediator release [63]. This antibody (rhuMAb-E25) reduces free IgE levels in serum [64], and inhibits both the early and late responses to allergen exposure [65, 66]. Which categories of patients should such a potential treatment be targetting? From its properties, this novel a p p r o a c h should be m o r e preventive (similar to the use for sodium cromoglycate) such as prophylaxis for seasonal rhinitis or asthma, or preventing the onset of symptoms in allergic patients. In the latter group, however, we have no diagnostic m e t h o d s for p r e d i c t i n g allergic patients at risk of developing asthma. This approach is now being tested in symptomatic patients with allergic asthma.
Anti-hfflammatory cytokines and inhibition of pro-inflammatory cytokines A number of cytokines expressed in asthma appear to have antiinflammatory properties such as interleukin-10 (IL-10) and interleukin-1 r e c e p t o r antagonist (IL-lra). IL-10 which is produced by CD4+ and CD8+ T-cells and activated Rev. fr. AllergoL, 1998, 38, 7S
/ N E W ASTHMA TREATMENTS: RECENT ADVANCES AND C U R t ~ N T OBJECTIVES •
monocytes is a potent inhibitor of m o n o c y t e / macrophage function, of IL-4 and IL-5 production by Th2 T-cells, of eosinophil survival and IL-4 induced IgE synthesis. There is a reduced capacity for alveolar macrophages to produce IL-10 in asthma, a defect which is reversed by inhaled corticosteroid t h e r a p y [67]. IL-10 inhibits eosinophilia induced by ovalbumin in immunised mice [68, 69]. IL-10 has been administered to normal volunteers inducing a fall in circulating Tcells with suppression of T-cell proliferation and a reduction of TNFcz and IL-113 production by mononuclear cells [70]. IL-lra can block the proliferation of Th-2 cell clones but not of Th-1 cell clones [71], and in ovalbumin-sensitised model, there is an inhibition of allergen-induced b r o n c h i a l hyperreactivity and p u l m o n a r y eosinophilia [72]. Other approaches include the inhibition of effects of proinflammatory cytokines such as TNFct a n d IL-I[3 which may be overexpressed in chronic severe asthma. These cytokines may play a role as amplifying mechanisms, through the activation of NF-KB and other transcription factors. Blocking antibodies may be used or soluble TNF receptors or IL-lra respectively. These approaches should probably be directed towards established disease, particularly not responding to currently-available therapies. Potential for n e w corticosteroids
While currently-available inhaled corticosteroids are highly effective and have a good margin of safety, there is still r o o m for improvements. Development of even more potent corticosteroids with lesser potential for systemic side-effects continues. However, this raises several issues as to whether more potent steroids will provide more clinical benefits particularly for the more difficult asthmatic patients. In addition, some contribution of systemic effects of inhaled corticosteroids in suppressing eosinophilopoiesis in the bone m a r r o w has b e e n raised. The potential
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p r o l o n g a t i o n of effects of topical steroids delivered by liposomes in the airways may be useful. These improvements may lead to the use of a once daily inhaled steroid dosage. Corticosteroids may control airway inflammation t h r o u g h suppression of transcription factors largely through a direct interaction of the activated glucocorticoid receptor with transcription factors such as AP-1 and NF•B (trans-repression) [73]. It seems likely that the side effects of corticosteroids are mostly the result of trans-activation of genes through binding of glucocorticoid receptors to DNA. Some steroids may have greater potency against trans-repression than Fans-activation [74], which may translate in less side-effect profile, while increasing anti-inflammatory potency. O t h e r a p p r o a c h e s would be to develop specific transcription factor blockers.
CONCLUSIONS
Although there have been new advances in the treatment of asthma, the effort to search for new targets to aim at with the hope of developing novel asthma treatments continues so long as research into the i n f l a m m a t o r y a n d i m m u n o l o g i c a l mechanisms of asthma progresses. However, such search must be combined with the clinical needs of patients with asthma, and of the particular needs of certain subgroups. Novel drugs by their properties should be considered as whether they should be used as preventors, i n d u c e r s of remission, controllers or relievers. The long-term aim of new asthma treatments is to prevent the disease f r o m o c c u r i n g which would m e a n targetting susceptible persons, and to provide better controllers or drugs that cause remission in those at the more severe spectrum of the disease. Current treatments for asthma are very effective for those with mild-to-moderate disease severity.
REFERENCES
1. British Thoracic Society. Guidelines for management of asthma in adults: I - chronic persistent asthma. Br. Med.J., 1990, 301, 651653.
4. Price J.E, Weller P.H. - Comparison of fluticasone propionate and sodium cromoglycate for the treatment of childhood asthma (an open parallel group study). Respir. Med., 1995, 89, 363-368.
2. Woolcock A , Rubinfeld A.R., Seale J:R, et al. - Asthma Management Plan, 1989. Med. J. Austr., 1989, 151, 650-652.
5. Price'J.F. - Inhaled corticosteroids: clinical relevance of safety measures. Pediatr. PulmonoL Suppl., 1997, 15, 4045.
3. Global Initiative for Asthma. Global strategyfor asthma management and prevention: NHLBI/WHO workshop ~port. National Institutes of health, 1995.
6. ManolitsasN.D.,wangJ. D~,/aliaJ. TriggCJ McAulayA.E. DaviesR.J. - Regular albuterol, ned6cromil sodium, and bronchial inflammation in asthma. A m!J. Resl)i~ Crit. CareMed., 1995, 151, 1925-2002.
Rev. fr. Allergol., 1998, 38, 7S
$220 7. Trigg CJ., Manolitsas N.D., Wang J., et al. - Placebo-controlled immunopathologic study of four months of inhaled corticosteroids in asthma. Am. J. Respir. Crit. Care Med., 1994, 150, 17-22. 8. Laitinen L.A., Laitinen A., Haahtele T. - A comparative study of the effects of an inhaled corticosteroid, budesomide, and of a !32agonist, terbutaline, on a!rway inflammation in newly diagnosed asthma. J. Allergy Clin. Immunol., 1992, 90, 32-42. 9. Djukanovic R., Wilson J.W., Britten K.M., et al. - The effect of an inhaled corticosteroid on airway inflammation and symptoms in asthma. Am. Rev. Respi~: Dis., 1992, 145, 669-674. 10. Spitzer W.O., Suissa S., Ernst P., et al. - The use of 13-agonists and the risk of death and near death from asthma. N. Engt. J. Med., 1992, 326, 501-506. 11. Sears M.R., Taylor R.D., Print C.G., et al. - Regular inhaled betaagonist treatment in bronchial asthma. Lancet, 1990, 336, 13911396. 12. Greening A.E, Ind P.W., Northfield M., Shaw G. - Added salmeterol versus higher-dose corticosteroid in asthma patients with symptoms on existing inhaled corticosteroid in asthma patients with symptoms on existing inhaled corticosteroid. Lancet, 1994, 344, 219-224. 13. Woolcock A., Lnndback B., Ringdal N., Jacques L.A. Comparison of addition of salmeterol to inhaled steroids with doubling of the dose of inhaled steroids. Am. J. Respir. Crit. Care Med., 1996, 153, 1481-1488.
• K.E C H U N G / 27. Reiss T.E, Sorkness C.A., Stricker W., et aL - Effects of montelukast (MK-0476), a potent cysteinyl leukotriene receptor antagonist, on bronchodilation in asthmatic subjects treated with and without inhaled corticosteroids. Thorax, 1997, 52, 4548. 28. VirchowJ., Hassall S.M., Summerton L. - Improved asthma control over 6 weeks with Accolate (zafirlukast) in patients on high dose corticosteroids. Allergy, 1997, 52, 183(Abstract). 29. O'Shaughnessy K.M., Wellings R., Gillies B., Fuller R.W. Differential effects of fluticasone propionate on allergen-evoked bronchoconstriction and increased urinary leukotriene E4 excretion [see comments]. Am. Rev. Respir. Dis., 1993, 147, 14721476. 30. Dworski R., Fitzgerald G.A., OatesJ.A., ShellerJ.R. - Effect of oral prednisone on airway inflammatory mediators in atopic asthma. Am. J. Respir. Crit. Care Med., 1994, 149, 953-959. 31. Tamaoki J., Kondo M., Sakai N., et al. - Leukotriene antagonist prevents exacerbation of asthma during reduction of high-dose inhaled corticosteroid. The Tokyo Joshi-Idai Asthma Research Group. Am. J. Respir. Crit. Care Med., 1997, 155, 1235-1240. 32. Cowburn A.S., Sladek K-, Soja J., et aL - Overexpression of leukotriene C4 synthase in bronchial biopsies from patients with aspirin-intolerant asthma, f Clin. Invest., 1998, 101, 834-846. 33. In K.H., Asano K., Beier D., et al. - Naturally occurring mutations in the human 5-1ipoxygenase gene promoter that modify transcription factor binding and reporter gene transcription. f Clin. Invest., 1997, 99, 1130-1137.
14. Pauwels R.A., Lofdahl C., Postma D., et al. - Effect of inhaled formoterol and budesonide on exacerbations of asthma. N. Engl. J. Med., 1997, 337, 1405-1411.
34. Chung K.E - Management of difficult asthma [editorial]. Br. f Hosp. Med., 1994, 51, 80-81.
15. Chung K.E - The complementary role of glucocorticosteroids and long-acting 13-adrenergic agonists. Allergy, 1998, In press.
35. Barnes PJ., Chung K-E - Difficult asthma: cause for concern. Br Med.J., 1989, 299, 695-698.
16. Verberne AAPH, Frost C., Roorda R.J., Laag H., Kerrebijn K-E One year treatment with salmeterol compared with beclomethasone in children with asthma. Am. J. Respir. Crit. Care Med., 1997, 156, 688-695.
36. Wenzel S.E., Szefler SJ., Leung DYM, Sloan S.h, Rex M.D., Martin R.J. - Bronchoscopic evaluation of severe asthma: persistent inflammation associated with high dose glucocorticoids. Am. f Respi~: Crit. Care Med., 1997, 156, 737-743.
17. Evans DJ., Taylor D.A., Zetterstrom O., Chung ICE, O'Connor B.J., Barnes P.J. - Theophylline plus low dose inhaled steroid is as effective as high dose inhaled steroid in the control of asthma. N. Engl.J. Med., 1997, 337, 1412-1418.
37. Woolcock AJ. - Corticosteroid-resistant asthma. Definitions. Am. J. Respir. Crit. Care Med., 1996, 154, $4548.
18. Kidney J., Dominguez M., Taylor EM., Rose M., Chung K.E, Barnes PJ. Immunomodulation by theophylline in asthma. Demonstration by withdrawal of therapy. Am. J. Respir. Crit. Care Med., 1995, 151, 1907-1914.
39. Rosewicz S., McDonald A.R., Maddux B.A., Goldfine I.D., Miesfeld R.L., Logsdon C.D. - Mechanism of glucocorticoid receptor down-regulation by glucocorticoids, f Biol. Chem., 1988, 263, 2581-2584.
19. Sullivan R, Bekir S.,Jaffar Z., Page C.,Jeffrey E, CostelloJ. - Antiinflammatory effects of low-dose oral theophylline in atopic asthma. Lancet, 1994, 343, 1006-1008.
40. Spahn J.D., Leung D.Y., Surs W., Harbeck R.J., Nimmagadda S., Szefler s.J. - Reduced glucocorticoid binding affinity in asthma is related to ongoing allergic inflammation. Am. J. Respi~: Crit. Care Med., 1995, 151, 1709-1714.
20. Tinkelman D.G., Reed C.E., Nelson H.S., Offord K.E - Aerosol beclomethasone dipropionate compared with theophylline as primary treatment of chronic, mild to moderate severe asthma in children. Pediatrics, 1993, 92, 64-77. 21. Meltzer E.O., Orgel H.A., Ellis E.E, Eigen H.N., Hemstreet M.E Long-term comparison of three combinations of albuterol, theophylline, and beclomethasone in children with chronic asthma. J. Allergy Clin. ImmunoL, 1992, 90, 2-11. 22. Chung K-E - Leukotriene receptor antagonists and biosynthesis inhibitors: potential breakthrough in asthma therapy. Eur. Respir. Ji, 1995, 8, 1203-1213. 23. Taylor I.K., O'Shaughnessy K.M., Fuller R.W., Dollery C.T. - Effect of cysteinyl-leukotrieue receptor antagonist ICI 204-219 on allergen-induced bronchoconstriction and airway hyperreactivitiy in atopic subjects. Lancet, 1991, 337, 690-694. 24. Manning P.J., Watson R.M., Margolskee D.J., Williams V.C., Schwartz J.I., O'Byrne EM. - Inhibition of exercise-induced bronchoconstriction by MK-751, a potent leukotriene-D4 receptor antagonist. N. Engl. J. Med., 1990, 323, 1736-1739. 25. Spector S.L., Smith L.J., Glass M. - Effects of six weeks of therapy with oral doses of ICI 204,219, a leukotriene D4 receptor antagonist, in subjects with bronchial asthma. Am. J. Respir. Crit. Care Med., 1994, 150, 618-623. (Abstract) 26. Hui K.E, Barnes N.C. - Lung function improvement in asthma with a cystemyl-leukotriene receptor antagonist. Lancet, 1991, 337, 1062-1063.
38. Barnes PJ., Adcock I.M. - Steroid resistance in asthma. Q.J. Med., 1995, 88, 455-468.
41. Nimmagadda S.R., Szefler SJ., SpahnJ.D., Surs W., Leung D.Y. Allergen exposure decreases glucocorticoid receptor binding affinity and steroid responsiveness in atopic asthmatics. Am. J. Respir. Crit. Care Med., 1997, 155, 87-93. 42. Irusen E., Barnes PJ., Adcock I.M., Chung ILE - Altered affinity of dexamethasone for the glucocorticoid receptor (GR) in oral steroiddependent asthmatics. Eur. Respir.J., 1998, in press, (Abstract) 43. Kam J.C., Szefler s.J., Surs W., Sher E.R., Leung D.Y. Combination IL-2 and IL-4 reduces glucocorticoid receptorbinding affinity and T cell response to glucocorticoids. a~ Immunol., 1993, 151, 3460-3466. 44. Irusen E., Chung K.E, Barnes P.J., Adcock I.M. - p38 mitogenactivated protein kinase mediates IL-2 and 4 changes in glucocorticoid receptor (GR) affinity. Eu~: Respir.J., 1998, in press, (Abstract). 45. Sanderson cJ., Warren D.J., Strath M. - Identification of a lymphokine that stimulates eosinophil differentiation in vitro. Its relationship to interleukin 3, and functional properties of eosinophils produced in cultures.J. Exp. Med., 1985, 162, 60-74. 46. Burke Gaffney A., Hellewell EG. - Eotaxin stimulates eosinophil adhesion to human lung microvascular endothelial cells. Biochem. Biophys. Res. Commun., 1996, 227, 35-40. 47. Mauser PJ., Pitman A.M., Fernandez X., et al. - Effects of an antibody to interleukin-5 in a monkey model of asthma. Am. J. Respir. Crit. Care Med., 1995, 152, 467-472.
Rev. fr. AllergoL, 1998, 38, 7S
/ NEWASTHMA
T R E A T M E N T S : R E C E N T ADVANCES A N D C U R R E N T OBJECTIVES *
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48. Mauser P.J., Pitman A., Witt A., et al. - Inhibitory effect of the TRFK-5 anti-IL-5 antibody in a guinea pig model of asthma. Am. Rev. Respir. Dis., 1993, 148, 1623-1627.
62. Sunyer J., Anto J.M., Sabria J., et al. - Relationship between serum IgE and airway responsiveness in adults with asthma, a( Allergy Clin. [mmunol., 1995, 95, 699-706.
49. Van Oosterhout A.J.M., Rudolf A., Ladenius C., et aL - Effect of anti-IL-5 and IL-5 in airway hyperreactivity and eosinophils in guinea pigs. Am. Rev. Respir Dis., 1993, 14Z 548-552.
63. Saban R., Haak Frendscho M., Zine M., et al. - H u m a n FcERI-IgG and humanized anti-IgE monoclonal antibody MaE11 block passive sensitization of h u m a n and rhesus monkey lung.j~ Allergy Clin. Immunol., 1994, 94, 836-843.
50. Abraham W.M., Sielczak M.W., A h m e d A., et al. - Alpha 4integrins mediate antigen-induced late bronchial responses and prolonged airway hyperresponsiveness in sheep, j( Clin. Invest., 1994, 93, 776-787.
64. Haak Frendscho M., Robbins g,., Lyon R., et al. - Administration of an anti-IgE antibody in~bits CD23 expression and IgE production in vivo. Immunology, 1994, 82, 306-313.
51. Collins ED., Griffiths-Johnson D.A., Jose P.J., Williams TJ, Marleau S. - Co-operation between interleukin-5 and the chemokine,eotaxin, to induce eosinophil accumulation in vivo. a( Exp. Med., 1995, 182, 1169-1174.
65. FahyJ.V., Fleming H.E., Wong H.H., et al. - The effect of an antiIgE monoclonal antibody on the early- and late-phase responses to allergen inhalation in asthmatic subjects [see comments]. Am. a( Respir. Crit. Care Med., 1997, 155, 1828-1834.
52. Hisada rE, Hellewell P., Teixeira M.M., Malta M.G.K., Chung K.E Cooperative effects between eotaxin and interleukin-5 on airway hyperresponsiveness and eosinophil accumulation in the airways in mice. Am. J. Respir Crit. Care Med., 1998, 157, A700 (Abstract).
66. Boulet L..P, Chapman K.R., CoteJ., et al. - Inhibitory effects of an anti-IgE antibody E25 on allergen-induced early asthmatic response [see comments]. Am.a( Respir. Crit. Care Med., 1997, 155, 1835-1840.
-
53. Shirakawa T., Enomoto T., Shimazu S., Hopkin J.M. - The inverse association between tuberculin responses and atopic disorder [see comments]. Science, 1997, 275, 77-79. 54. Gavett S.H., O ' H e a r n D.J., Li X., Huang S.K., Finkelman ED., Wills Karp M. - Interleukin 12 inhibits antigen-induced airway hyperresponsiveness, i n f l a m m a t i o n , a n d Th2 cytokine expression in mice.a( Exp. Med., 1995, 182, 1527-1536. 55. Kips J.C., Brusselle G.j.,joos G.E, et aL - Interleukin-12 inhibits antigen-induced airway hyperresponsiveness in mice. Am. a( Respir Crit. Care Med., 1996, 153, 535-539. 56. Lack G., Bradley K.L., Hamelmann E., et al. - Nebulized IFNg a m m a inhibits the development of secondary allergic responses in mice.a( Immunol., 1996, 157, 1432-1439. 57. Zuany Amorim C., Leduc D., Vargaftig B.B., Pretolani M. Modulation by rm interferon-gamma and CD4+ T-lymphocytes of allergic eosinophil accumulation in the mice peritoneal cavity. Ann. N. E Acad. Sci., 1994, 725, 34-43. 58. Naseer T., Minshall E.M., Leung D.Y., et al. - Expression of IL-12 and IL-13 mRNA in asthma and their modulation in response to steroid therapy. Am.a( Respir. Crit. Care Med., 1997, 155, 845-851. 59. Alexander A:G., Barnes N.C., Kay A.B. - Cyclosporin A in corticosteroid-dependent chronic severe asthma. Lancet, 1992, 339, 324-327. 60. Kuchroo V.K., Das M.E, Brown J.A., et al. - B7-1 and B7-2 costimulatory molecules activate differentially the T h l / T h 2 developmental pathways: application to autoimmune disease therapy. Cell, 1995, 80, 707-718. 61. Burrows B., Martinez ED., Halonen M. - Association of asthma with serum IgE levels and skin-test reactivity to allergens. N. Engl. a( Med., 1989, 320, 271-272.
nmm
Rev. f~ Allergol., 1998, 38, 7S
67. John M., Lim S., Seybold J., et al. - Inhaled corticosteroids increase interleukin-10 but reduce macrophage inflammatory protein-la, granulocyte-macrophage colony-stimulating factor and interferon. (release from alveotar macrophages in asthma. Am.a( Respi~: Crit. Care Med., 1998, 157, 256-263. 68. Zuany Amorim C., Creminon C., Nevers M.C., Nahori M.A., Vargaftig B.B., Pretolani M. - Modulation by IL-10 of antigeni n d u c e d IL-5 g e n e r a t i o n , a n d CD4+ T lymphocyte a n d eosinophil infiltration into the mouse peritoneal cavity. J. ImmunoL, 1996, 157, 377-384. 69. Zuany Amorim C., Haile S., Leduc D., et al. - Interleukin-10 inhibits antigen-induced cellular recruitment into the airways of sensitized mice.a( Clin. Invest., 1995, 95, 2644-2651. 70. ChernoffA.E., Granowitz E.V., Shapiro L., et al. - A randomized, controlled trial of IL-10 in humans. Inhibition of inflammatory cytokine production and immune responses, j( Immunol., 1995, 154, 5492-5499. 71. Abbas A.K., Williams M.E., Burstein H.J., Chang T.L., Bossu E, Lichtman A.H. - Activation and functions of CD4+ T-cell subsets. Immunol. Rev., 1991, 123, 5-22. 72. Watson M.L., Smith D, Bourne A.D., Thompson R.C., WestwickJ. - Cytokines contribute to airway dysfunction in mltigen-challenged gumea pigs, inhibition of airway hyperreactivity, pulmonary eosinophil accumulation, and tumor necrosis factor generation by pretreatment with an interleukin-1 receptor antagonist. Am. a( Respi~: Cell MoL Biol., 1993, 8, 365-369. 73. Barnes P.J., Adcock I.M. - Anti-inflammatory actions of steroids: molecular mechanisms. Trends Pharmacol. Sci., 1993, 14, 436-441. 74. Heck S., Kullmann M., Gast A., et al. - A distinct modulating domain in glucocorticoid receptor monomers in the repression of activity of the transcription factor AP-1. EMBO. J., 1994, 13, 4087-4095.