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Copyright #ERS Journals Ltd 2001 Eur Respir J 2001; 18: Suppl. 34, 34s–40s European Respiratory Journal DOI: 10.1183/09031936.01.00252501 ISSN 0904-1850 Printed in UK – all rights reserved ISBN 1-904097-20-0

Pharmacological treatment of today

K.F. Rabe, D.T. Schmidt

Pharmacological treatment of asthma today. K.F. Rabe, D.T. Schmidt. #ERS Leiden University Medical Centre, Journals Ltd 2001. Dept of , Leiden, the ABSTRACT: The current concept of asthma therapy is based on a stepwise approach, Netherlands. depending on disease severity, and the aim is to reduce the symptoms that result from Correspondence: K.F. Rabe airway obstruction and inflammation, to prevent exacerbations and to maintain normal Leiden University Medical Centre lung function. Dept of Pulmonology b2-Adrenoceptor agonists and are at present the most effective C3-P drugs for the treatment of airway obstruction and inflammation, with , P.O. Box 9600 NL-2300 RC Leiden antagonists and as second- or third-line therapy. The Netherlands There are, to date, no additional or newly developed drugs available that add Fax: 31 715266927 substantially to the current strategies or even replace b2-adrenoceptor agonists or glucocorticoids. New approaches in asthma therapy recommend drug combinations of Keywords: Asthma b2-agonist inhaled steroids, primarily with long-acting b2-adrenoceptor agonists, based on their improved efficacy and the potential for a steroid-sparing effect. leukotriene antagonists Although existing drug entities are able to control the vast majority of patients pharmacology with mild and moderate asthma, patients9 (and doctors9) adherence to guidelines and treatment strategies falls well short of the desired standards. Received: June 14 2001 Treatment choices, however, differ between countries and should take into account Accepted June 20 2001 convenience to the patient and the occurrence of side-effects. Additionally, the cost of therapy and reimbursement policies also influences therapeutic strategies. Eur Respir J 2001; 18: Suppl. 34, 34s–40s.

Bronchial asthma is an inflammatory disease of the to result from airway hyperresponsiveness and inflam- airways, characterized by bronchial hyperrespon- mation irrespective of whether the origin of the siveness and variable airway obstruction. Current disease is allergic or nonallergic. The underlying pharmacotherapy aims primarily at symptomatic mechanisms of airway hyperresponsiveness are still improvement through the use of far from being completely understood. and suppression of airway inflammation and decrease In allergic asthma, it is assumed that the early-phase of bronchial hyperresponsiveness through the use of reaction is based on an immunoglobulin (Ig)-E anti-inflammatory therapy. mediated reaction with antigen cross-linking of Ig-E The goal of the current and established treatment of molecules bound to specific receptors on mast cells. asthma is minimization of symptoms, maintenance of Subsequent activation of Ig-E (FceRI receptors) normal lung function and prevention of irreversible leads to the release of bronchoconstricting mediators changes within the airways. In future, it will be including and histamine. In contrast, the important to develop preventive and, possibly, cura- allergic late-phase reaction is believed to result from tive therapeutic approaches, which are based on infiltration of the airway wall by inflammatory cells an improved understanding of the pathogenesis and such as and lymphocytes, especially pathophysiology of asthma. CD4-positive T-cells. The mediators, which are released Current treatment strategies advocate a stepwise by these cells, are implicated in not only causing approach to treatment, which depends on the severity but also increasing bronchial of the disease [1]. This classification requires a stand- responsiveness after exposure. Repeated aller- ardized clinical assessment as well as measurement gen exposure might lead to chronic changes within of lung function. Current pharmacotherapy should the airways and the well-described pathological aspects provide adequate control for the majority of patients; of airways from asthmatic patients, i.e. epithelial however, implementation of current guidelines, includ- damage, hyperplasia of mucous glands, subepithelial ing lung function measurement and rational therapy, fibrosis, collagen deposition, inflammatory cell infil- still falls well short of the desired standards [2]. trates and increase in mass through hyperplasia and hypertrophy. General considerations To date, asthma severity has been classified according to the frequency of symptoms in combina- Asthma symptoms are mainly caused by recurrent tion with lung function parameters such as forced episodes of acute airway narrowing that are believed expiratory volume in one second and peak expiratory PHARMACOLOGICAL TREATMENT OF ASTHMA TODAY 35s

flow; this classification forms the basis of a stepwise of long-acting drugs in combination with steroids on approach to asthma therapy. Although parameters the frequency of exacerbations might support an addi- that are assumed to reflect changes in airway inflam- tional effect of this class of drug on airway inflammation mation have been used successfully to characterize [5, 6]. patients and evaluate therapeutic effects within At present, clinical and experimental experience clinical studies, these parameters have not been with short- and long-acting b2-adrenoceptor agonists taken into account in the current guidelines for the seems to suggest that it is rather unlikely that novel treatment of asthma. These indicators of airway bronchodilators, in the foreseeable future, that are inflammation, believed to be directly involved in the better tolerated and more effective, will be developed. pathophysiology of asthma, are inflammatory cells Since b2-adrenoceptor agonists are believed to cause (eosinophils, lymphocytes and mast cells) in induced airway smooth muscle to relax primarily by increasing sputum and bronchoalveolar lavage (BAL) fluid, intracellular levels of cyclic adenosine monophosphate inflammatory mediators (cytokines, chemokines, and opening potassium channels, attempts have been immunoglobulins, leukotrienes and prostanoids) in made to imitate these effects with other substances, serum, urine, sputum and BAL fluid, and tissues such as nonselective phosphodiesterase inhibitors and obtained from the airways via biopsy (structure, potassium channel openers. These drugs were shown adhesion molecules and receptors). Improved under- to be far less effective as bronchodilators compared to standing of the relationship between symptoms b-adrenoceptor agonists, and their application at on the one hand, and lung function and inflam- higher doses was limited by marked side-effects. matory parameters on the other, forms the basis of Therefore, current drug research focuses primarily new concepts and approaches in the treatment of on the development of new substances that interfere asthma. with pathways of inflammation and those that might provide preventive approaches for the treatment of asthma. Established therapy and its further development Anticholinergics. Relaxation of airway smooth muscle The established treatment of asthma primarily can be effected by stimulation of the adrenergic comprises two classes of drug, bronchodilators and nervous system through b2-adrenoceptor agonists, anti-inflammatory/immunosuppressive drugs. By far on the one hand, and, on the other, by inhibition of the most effective bronchodilators in asthma are the cholinergic nervous system by b2-adrenoceptoragonists. Inhaled short-acting b2- drugs. However, antagonists of muscarinic receptors, adrenoceptoragonists or, less frequently, anticholi- such as the short-acting , which nergic drugs are used either on an as required basis, nonselectively inhibit the effect of acetylcholine on prophylactically, i.e. prior to exercise, or as rescue muscarinic receptors, play only a minor role in . Anti-inflammatory glucocorticoids are the treatment of asthma. Ipratropium bromide is primarily long-term and are aimed at the administered by inhalation and is primarily used as an treatment of airway inflammation and responsiveness "as-needed medication" in cases of intolerance of [3]. In very selected cases, disodium cromoglycate b-agonists. Since newly developed long-acting anti- and are available as alternatives to treat- cholinergics are primarily used in the treatment of ment with very low doses of inhaled steroids. Because chronic obstructive pulmonary disease [7, 8] they will of their significant side-effects, systemic steroids are not be discussed further here. used exclusively for the treatment of severe asthma or asthma exacerbations against which other therapies exhibit insufficient effects. Anti-inflammatory therapy

Mediators such as prostanoids, histamine, leuko- Bronchodilators trienes, cytokines, chemokines and immunoglobulins are believed to play a central role in the pathogenesis b2-Adrenoceptor agonists. For decades, b2-adreno- and maintenance of airway inflammation in asthma. ceptor agonists have been among the most important Their individual contributions, effects and origins are drug classes for the treatment of bronchial asthma. currently under intense investigation. Better under- In the meanwhile, short- and long-acting inhaled standing of these pathways could contribute to b2-adrenoceptor agonists have become available. It is unravelling the mode of action of the currently used recommended that short-acting preparations (e.g. and effective classes of drugs (e.g. glucocorticoids) , and ) be used on an and might identify new targets for asthma therapy. as needed basis, whereas the long-acting preparations Anti-inflammatory or immunosuppressive therapy ( and ) should be used in can intervene at the levels of synthesis, release and combination with inhaled glucocorticoids within the effects of inflammatory mediators. Conceptually, framework of the long-term treatment. Both short- and improved understanding of the regulatory mechan- long-acting preparations possess reliable isms should lead to a more specific and hence more effects. Moreover, there is some evidence that short- effective form of therapy. However, whether such acting b2-adrenoceptor agonists also exhibit anti- specific approaches will lead to the expected effects inflammatory effects [4], although direct proof in vivo in vivo must be evaluated in clinical studies. The has been difficult to obtain. In this context, the effect development of such "tailor-made" interventions will 36s K.F. RABE, D.T. SCHMIDT be complicated by differences between species, since years, their mode of action remains unknown. Clinical results from animal studies, in general, are only of studies have shown that they exert almost no limited predictive value in the clinical setting; this is bronchodilatory effect, while reducing both the early even more evident from data from recent clinical and the late allergic response [9]. These drugs are safe trials, reviewed later. and, in selected patients with mild asthma, might be used as an alternative anti-inflammatory therapy [17], Glucocorticoids. Glucocorticoids are the most effective although low doses of inhaled steroids are preferred at anti-inflammatory drugs used in the treatment of present. asthma. Clinical studies have shown that steroids primarily affect the allergic late-phase reaction [9]. Although asthma can be controlled with high doses of Methylxanthines systemic steroids (prednisone, prednisolone, methyl- prednisolone, fluocortolone and ) in Nonselective inhibitors of cyclic nucleotide phos- almost every patient, the use of systemic steroids phodiesterase, such as theophylline, have been used in over a longer period of time is limited by marked side- the treatment of bronchial asthma for several decades effects. [18] and are still included in current guidelines [1, 19]. Inhaled steroids (, dipro- Alongside a moderate bronchodilatory effect [20, pionate (BDP), flunisolide and fluticasone), which in 21], phosphodiesterase inhibitors have been shown to low doses have hardly any unwanted effects, although reduce airway inflammation [22, 23] and to be effec- side-effects have been described at high doses, have tive against early- and late-phase allergic responses. been available since the early 1970s. Inhaled cortico- The mechanisms by which methylxanthines exert these steroids are currently the drugs of first choice in the effects appear to involve adenosine receptor antago- long-term treatment of asthma, and are the only drugs nism [24–26] and, through elevation of intracellular for the treatment of this condition that have a cyclic adenosine monophosphate concentrations [27, documented effect on mortality [10]. 28], a direct relaxant effect on smooth muscle, as well The effect of glucocorticoids is mediated via a as inhibition of mediator release from inflammatory cytoplasmic receptor. Bound to this cells [29]. receptor, steroids enter the nucleus, where they regu- Clinical studies have shown that the effect of late gene transcription; synthesis of proinflammatory theophylline on the early- and late-phase allergic cytokines is increased and that of anti-inflammatory response cannot be explained by its mild broncho- cytokines enhanced [11]. It has been speculated that dilatory effect [20, 30], which, if at all, can be demon- the anti-inflammatory effects of steroids are medi- strated only in response to very high doses that ated mainly by inactivation of transcription factors, are frequently accompanied by side-effects. It is whereas the unwanted effects result primarily from more likely that the effects on allergic response that binding of steroids to deoxyribonucleic acid [12]. On can be observed even after low doses of theophyl- this basis, drug development has been aimed at line result from a direct effect on inflammatory cells developing steroids with an improved ratio of desired [22, 31]. to unwanted effects, e.g. transactivation/transrepres- Use of theophylline is frequently limited by its side- sion ratio. Whether this concept holds true in clinical effects, which probably result from nonselective practice remains to be evaluated. inhibition of phosphodiesterase isoenzymes. There- Additionally, glucocorticoids with novel pharmaco- fore, in recent years, drug research has aimed at kinetic profiles are currently being tested [13]. Even developing selective phosphodiesterase inhibitors with modern inhaled glucocorticoids, such as fluticasone, reduced side-effects. with high lipophilicity, are absorbed via the lung after topical application and may, therefore, still exert side- effects despite a high degree of first-pass metabolism antagonists and synthase [13, 14]. Therefore, efforts are being made to develop inhibitors steroids, which are metabolized locally in the lung or in the plasma and/or are not absorbed at mucous Leukotrienes and histamine are the most important membranes, e.g. [15]. mediators in allergic asthma [32], and are released Furthermore, the increasing avoidance of chloro- after contact with allergen from mast cells, eosinophils fluorocarbon (CFC)-containing products has led to and basophils. Although have no the development of novel metered-dose inhalers. proven and documented effect in asthma, "antileuko- CFC-free hydroflouralkane-containing BDP was trienes" have been developed that inhibit either the shown to have an improved deposition profile synthesis of leukotrienes (5-lipoxygenase inhibitors) or compared to CFC-BDP reaching the small airways the interaction of leukotrienes with their receptors. To [16]. This might have consequences for the dosage and date, three drugs from this class of anti-leukotrienes the treatment of patients with inflammation of that have been approved for the combination with primarily the small airways. inhaled steroids in different parts of the world, the leukotriene receptor antagonists, , Cromones zafirlukast and [33]. In clinical studies, montelukast was shown to reduce allergen- and Although disodium cromoglycate and nedocromil exercise-induced bronchoconstriction. Other studies have been used in the treatment of asthma for many demonstrated that inhibition of the leukotriene PHARMACOLOGICAL TREATMENT OF ASTHMA TODAY 37s pathway might decrease asthma symptoms, increase Clinical approach lung function and reduce the use of rescue medication [34]. However, only a certain subgroup of patients, According to guidelines, asthma severity can be including some patients with severe asthma, appear to classified as intermittent, mild persistent, moderate respond to treatment with . Although persistent or severe persistent based on a standardized it has been indicated that patients with aspirin- assessment of asthma symptoms and lung function in induced asthma might benefit from this treatment combination with the current medication [1, 17, 45]. [35], it is, unfortunately, not possible to identify the Although these classification criteria were published subgroup in advance. in 1995, the categories are still valid and are likely to be retained in the next Global Initiative for Asthma Combination therapy guidelines, which will be published in the near future. The clinical classification of asthma severity forms the Inhaled steroid preparations, alone or in combination basis of the stepwise approach to asthma pharmaco- with long-acting b2-adrenoceptor agonists [36], form therapy. However, in addition to and regardless of the the basis of the long-term treatment of asthma. severity or "step", an important goal should always Dependent on asthma severity, this combination of be the avoidance or control of asthma triggers. The drugs can be supplemented with the phosphodie- "step" approach is represented in table 1. sterase inhibitor, theophylline, not only because of its In general, asthma medication can be divided into mild bronchodilating effects but also because of its two groups: 1) controllers, such as corticosteroids, suggested steroid-sparing effects [37]. that are taken daily on a long-term basis to get and keep persistent asthma under control; and 2) relievers, e.g. b2-adrenoceptor agonists, that act quickly to Combining glucocorticoids and b2-adrenoceptor agonists relieve bronchoconstriction and its accompanying acute symptoms such as cough, chest tightness and Combination inhalers that contain a long-acting wheezing, and which can also be used on an as needed basis, i.e. as rescue medication. b2-adrenoceptor agonist and an inhaled steroid, i.e. salmeterol/fluticasone-dipropionate [36, 38–40] and In the treatment of patients with intermittent asthma formoterol/budesonide [6, 41] have very recently been (Step 1), short-acting b2-adrenoceptor agonists should approved for the treatment of asthma and chronic be used on an as needed basis to relieve symptoms and obstructive pulmonary disease. The fixed combina- to prevent those which are provoked by exercise or tion is at least as effective as both of its components exposure to . If control is not achieved and are individually and has the advantage that only symptoms require use of b2-adrenoceptor agonists one inhaler has to be used by the patient, which is more than once a week, a stepping up should be expected, although not proven, to increase adherence considered. to therapy [38]. Furthermore, it has been indicated Patients with mild persistent asthma (Step 2) should, in the first instance, be treated daily with that addition of a long-acting b2-adreoceptor agonist to an inhaled steroid provides greater clinical advan- inhaled steroids, 200–500 mg, or, alternatively, with tage than doubling the dose of inhaled steroids in cromones (see earlier comments) or sustained-release patients with symptomatic asthma [36, 42]. The combi- theophylline. For the relief of acute symptoms, nation of both drugs in one inhaler influences neither inhaled b2-adrenoceptor agonists should be used at the pharmacodynamic and pharmacokinetic charac- levels not exceeding three or four applications in a teristics nor the side-effect profiles of the individual day. If the asthma is insufficiently controlled, the dose substances [40]. of the inhaled steroid can be increased (up to 800 mg) and/or a long-acting b2-adrenoceptor agonist added, especially for persistent night-time symptoms. Combining glucocorticoids and theophylline Treatment of moderate persistent asthma (Step 3) involves inhaled corticosteroids at 800–2,000 mg and the Similar to findings with long-acting b2-adrenoceptor use of long-acting b2-adrenoceptor agonists. Espe- agonists, theophylline can have a steroid-sparing effect, cially for night-time symptoms, sustained-release theo- i.e. addition of theophylline might result in similar or phylline or long-acting oral b2-adrenoceptor agonists even greater clinical benefit than doubling the dose of can be added, and for the treatment of acute symp- inhaled steroid [37, 43]. toms, short-acting bronchodilators should be used as needed up to three or four times a day. The addition of a Combining glucocorticoids and antileukotrienes long-acting b2-adrenoceptor agonist or low-dose theo- phylline might have the same or even a better effect than Like long-acting b2-adrenoceptor agonists and doubling the dose of inhaled steroid. Treatment with an theophylline, leukotriene receptor antagonists have can be a further option. been demonstrated in a recently published clinical Patients with severe persistent asthma (Step 4) trial, to have a steroid-sparing effect. Addition of should be treated with inhaled corticosteroids at the leukotriene receptor agonist montelukast to the ¢800–2,000 mg and long-acting b2-adrenoceptor current treatment reduced the need for inhaled corti- agonists and/or sustained-release theophylline as costeroids among patients requiring moderate-to-high well as long-term oral corticosteroids. Short-acting doses of to maintain asthma control b2-adrenoceptor agonists should be used for the [44]. relief of symptoms. During exacerbations, an oral 38s K.F. RABE, D.T. SCHMIDT

Table 1. – Summary of the stepwise approach to asthma therapy* Step and asthma severity

1: intermittent 2: mild persistent 3: moderate persistent 4: severe persistent

Clinical Intermittent Symptoms w1?week-1 Symptoms daily Continuous features symptoms but v1?day-1 Exacerbations symptoms before v1?week-1 Exacerbations affect activity Frequent treatment Night-time may affect and sleep exacerbations symptoms activity Night-time Frequent v2?month-1 and sleep symptoms night-time Brief Night-time w1?week-1 symptoms exacerbations symptoms Daily use Physical (hours to days) w2?month-1 of inhaled activities limited Asymptomatic PEF or FEV1 short-acting by symptoms and normal ¢80% pred; b2-agonist PEF or FEV1 lung function variability PEF or FEV1 w60– v60% pred; between v20–30% v80% pred; variability w30% exacerbations variability w30% PEF or FEV1 w80% pred; variability v20% Controller Low dose Conventional approach High-dose inhaled treatment inhaled steroid High-dose steroids (0.8–2 mg) (400 mg) inhaled steroid Oral corticosteroid (doubling of low long-term dose up to 2 mg) plus long-acting New approach bronchodilator Low-dose (long-acting inhaled steroid b2-agonist plus long-acting inhaled and/or b2-agonist theophylline) (salmeterol or formoterol, Additional also in fixed bronchodilators combination), Anticholinergics plus low dose Oral b2-agonists theophyline or plus Nebulizers anti-leukotriene (montelukast, zafirlucast) Reliever Inhaled b2-agonist Inhaled b2-agonist Inhaled b2-agonist Inhaled b2-agonist treatment v1 dose?week-1 v3–4 doses?week-1 v3–4 doses?week-1 as needed for symptoms

*: according to current guidelines [1]; Note the treatment choices at Step 3. It has recently been shown that the addition of long-acting b2-adrenoceptor agonists, low-dose theophylline or antileukotrienes is equally or even more effective than doubling the dose of inhaled steroid. (Adapted from [1]). corticosteroid may be needed at any time and at any cost of the therapy and reimbursement policies also step. If control is sustained at any of the four steps for influence therapeutic strategies. ¢3 months, the possibility of a gradual stepwise It appears, however, despite all the effort put into reduction in treatment should be evaluated. developing new strategies for the treatment of asthma, established drug entities such as b2-adrenoceptor agonists with a long duration of action and inhaled Treatment options corticosteroids remain the first-line therapy recom- mended by current guidelines. In general, today9s The established therapeutic strategies, as recom- combinations of drugs that primarily relieve airway mended by current guidelines and based on an understanding of the pathophysiological and immu- smooth muscle tone with those having a controller nological mechanisms of asthma have been discussed effect on airway inflammation will remain tomorrow9s above. There are many more approaches and new treatment for the foreseeable future. developments such as specific immunotherapy and cytokine, chemokine or adhesion molecule agonists/ antagonists as well as monoclonal antibodies, which References are partly reviewed in other articles in this supple- ment. Treatment choices differ between countries and 1. Global Initiative for Asthma. Global Strategy for must take into account the convenience to the patient Asthma Management and Prevention. NHLBI/WHO and the occurrence of side-effects. Additionally, the Workshop report. Publication No. 95-3659. 1995. PHARMACOLOGICAL TREATMENT OF ASTHMA TODAY 39s

2. Rabe KF, Vermeire PA, Soriano JB, Maier WC. 18. Weinberger M, Hendeles L. Theophylline in asthma. Clinical management of asthma in 1999: the Asthma N Engl J Med 1996; 334: 1380–1388. Insights and Reality in Europe (AIRE) study. Eur 19. Guidelines for the Diagnosis and Management of Respir J 2000; 16: 802–807. Asthma. Expert Panel Report 2. Publication No. 1997 3. Sont JK. How do we monitor asthma control? 97-4051. 1997. 1999; 54: 68–73. 20. Pauwels R, van Renterghem D, Van der Straeten M, 4. Butchers PR, Varday CJ, Johnson M. Salmeterol: a Johannesson N, Persson CGA. The effect of theophyl- potent and long-acting inhibitor of inflammatory line and on allergen-induced bronchocon- mediator release from human lung. Br J Pharmacol striction. J Allergy Clin Immunol 1985; 76: 583–590. 1991; 104: 672–676. 21. Ward AJ, McKenniff M, Evans JM, Page CP, 5. Pauwels RA, Lofdahl CG, Postma DS, et al. Effect of Costello JF. Theophylline: an immunomodulatory inhaled formoterol and budesonide on exacerbations role in asthma. Am Rev Respir Dis 1993; 147: 518–523. of asthma. Formoterol and Corticosteroids Establish- 22. Banner KH, Page CP. Anti-inflammatory effects of ing Therapy (FACET) International Study Group. theophylline and selective phosphodiesterase inhibi- N Engl J Med 1997; 337: 1405–1411. tors. Clin Exp Allergy 1996; 26: 2–9. 6. Kips JC, O9Connor BJ, Inman MD, Svensson K, 23. Karlsson J-A. Theophylline: anti-inflammatory effects. Pauwels RA, O9Byrne PM. A long-term study of the In: Leff AR, editor. Pulmonary and Critical Care antiinflammatory effect of low-dose budesonide plus Pharmacology and Therapeutics. USA, McGraw-Hill, formoterol versus high-dose budesonide in asthma. 1996; pp. 609–620. Am J Respir Crit Care Med 2000; 161: 996–1001. 24. Crimi N, Polosa R, Mistretta A. Role of adenosine in 7. Pauwels RA, Buist AS, Calverley PM, Jenkins CR, the pathogenesis of bronchial asthma. Recenti Prog Hurd SS. Global strategy for the diagnosis, manage- Med 1989; 80: 372–376. ment, and prevention of chronic obstructive pulmo- 25. Karlsson J-A. Purines and sensory neuropeptides in nary disease. NHLBI/WHO Global Initiative for human asthma. Bull Eur Physiopathol Respir 1987; 23: Chronic (GOLD) Work- 95s–101s. shop summary. Am J Respir Crit Care Med 2001; 163: 26. Coward W, Sagara H, Church MK. Asthma, adeno- 1256–1276. sine, mast cells and theophylline. Clin Exp Allergy 8. Disse B. Antimuscarinic treatment for lung diseases: 1998; 28: 42–46. from research to clinical practice. Life Sci 2001; 68: 27. Bergstrand H. Phosphodiesterase inhibition and theo- 2557–2564. phylline. Eur J Respir Dis 1980; 109: 37–44. 9. Cockcroft DW, Murdock KY. Comparative effects of 28. Hill GE, Anderson JL, Whitten CW. Ketamine inhaled salbutamol, sodium cromoglycate, and beclo- inhibits agonist-induced cAMP accumulation increase methasone dipropionate on allergen-induced early in human airway smooth muscle cells. Can J Anaesth asthmatic responses, late asthmatic responses, and 1999; 46: 1172–1177. increased bronchial responsiveness to histamine. 29. Louis R, Bury T, Corhay JL, Radermecker M. J Allergy Clin Immunol 1987; 79: 734–740. LY18665, a phosphodiesterase inhibitor, inhibits his- 10. Suissa S, Ernst P, Benayoun S, Baltzan M, Cai B. tamine release from human basophils, lung and skin Low-dose inhaled corticosteroids and the prevention fragments. Int J Immunopharmacol 1992; 14: 191–194. of death from asthma. N Engl J Med 2000; 343: 332– 30. Ward JK, Belvisi MG, Fox AJ, et al. Modulation of 336. cholinergic bronchoconstrictor responses by endo- 11. Barnes PJ, Adcock IM. NF-kB: a pivotal role in genous nitric oxide and vasoactive intestinal peptide asthma and a new target for therapy. Trends in human airways in vitro. J Clin Invest 1993; 92 Pharmacol Sci 1997; 18: 46–50. 736–742. 12. Vayssiere BM, Dupont S, Choquart A, et al. Synthetic 31. Karlsson J-A. Anti-inflammatory effects of phospho- glucocorticoids that dissociate transactivation and diesterase inhibitors. In: Leff AR, ed. Pulmonary and AP-1 transrepression exhibit antiinflammatory activity Critical Care Pharmacology and Therapeutics. USA, in vivo. Mol Endocrinol 1997; 11: 1245–1255. McGraw-Hill, 1996; pp. 621–633. 13. Barnes PJ, Pedersen S, Busse WW. Efficacy and safety 32. Roquet A, Dahlen B, Kumlin M, et al. Combined of inhaled corticosteroids. New developments.Am antagonism of leukotrienes and histamine produces J Respir Crit Care Med 1998; 157: S1–S3. predominant inhibition of allergen-induced early and 14. Lipworth BJ, Jackson CM. Safety of inhaled and late phase airway obstruction in asthmatics.Am intranasal corticosteroids: lessons for the new millen- J Respir Crit Care Med 1997; 155: 1856–1863. nium. Drug Saf 2000; 23: 11–33. 33. Markham A, Faulds D. Montelukast. Drugs 1998; 56: 15. Taylor DA, Jensen MW, Kanabar V, et al. A dose- 251–256. dependent effect of the novel inhaled corticosteroid 34. Drazen JM, Israel E, O9Byrne PM. Treatment of ciclesonide on airway responsiveness to adenosine-59- asthma with drugs modifying the leukotriene pathway. monophosphate in asthmatic patients. Am J Respir N Engl J Med 1999; 340: 197–206. Crit Care Med 1999; 160: 237–243. 35. Dahlen B, Nizankowska E, Szczeklik A, et al. Benefits 16. Leach CL, Davidson PJ, Boudreau RJ. Improved from adding the 5-lipoxygenase inhibitor to airway targeting with the CFC-free HFA-beclometha- conventional therapy in aspirin-intolerant asthmatics. sone metered-dose inhaler compared with CFC- Am J Respir Crit Care Med 1998; 157: 1187–1194. beclomethasone. Eur Respir J 1998; 12: 1346–1353. 36. Shrewsbury S, Pyke S, Britton M. Meta-analysis of 17. Wettengel R, Berdel D, Hofmann D, et al. Asth- increased dose of inhaled steroid or addition of matherapie bei Kindern und Erwachsenen. Empfeh- salmeterol in symptomatic asthma (MIASMA). BMJ lungen der Deutschen Atemwegsliga in der Deutschen 2000; 320: 1368–1373. Gesellschaft fu¨r Pneumologie. Med Klin 1998; 93: 37. Ukena D, Harnest U, Sakalauskas R, et al. Compar- 639–650. ison of addition of theophylline to inhaled steroid with 40s K.F. RABE, D.T. SCHMIDT

doubling of the dose of inhaled steroid in asthma. Eur Addition of salmeterol versus doubling the dose of Respir J 1997; 10: 2754–2760. fluticasone propionate in patients with mild to 38. Bateman ED, Britton M, Carillo T, Almeida J, Wixon moderate asthma. Thorax 1999; 54: 207–212. C. Salmeterol/fluticasone combination inhaler. A new, 43. Evans DJ, Taylor DA, Zetterstro¨m O, Chung KF, effective and well tolerated treatment for asthma. Clin O9Conner BJ, Barnes PJ. A comparison of low-dose Drug Invest 1998; 16: 193–201. inhaled budesonide plus theophylline and high-dose 39. Chapman KR, Ringdal N, Backer V, Palmqvist M, inhaled budesonide for moderate asthma. N Engl Saarelainen S, Briggs M. Salmeterol and fluticasone J Med 1997; 337: 1412–1418. propionate (50/250 mg) administered via combination 44. Lofdahl CG, Reiss TF, Leff JA, et al. Randomised, Diskus inhaler: as effective as when given via separate placebo controlled trial of effect of a leukotriene Diskus inhalers. Can Respir J 1999; 6: 45–51. , montelukast, on tapering inhaled 40. Spencer CM, Jarvis B. Salmeterol/fluticasone propio- corticosteroids in asthmatic patients. BMJ 1999; 319: nate combination. Drugs 1999; 57: 933–940. 87–90. 41. McGavin JK, Goa KL, Jarvis B. Inhaled budesonide/ 45. Britisch Thoracic Society. BTS guidelines for the formoterol combination. Drugs 2001; 61: 71–78. management of chronic obstructive pulmonary dis- 42. van Noord JA, Schreurs AJ, Mol SJ, Mulder PG. ease. Thorax 1997; 52: S1–S28.