Postgrad Med J 2000;76:767–773 767 Postgrad Med J: first published as 10.1136/pgmj.76.902.767 on 1 December 2000. Downloaded from antagonist therapy

O J Dempsey

Abstract antagonists (LTRA) Box 1: Biological eVects of cysteinyl are a new class of for treat- ment, available in tablet form. Their x (100–10000 times unique results in a more potent than ). combination of both bronchodilator and x Bronchial smooth muscle anti-inflammatory eVects. While their hyperresponsiveness, for example to optimal place in asthma management is allergen. still under review, LTRA represent an x Inflammatory cell recruitment, for important advance in asthma pharmaco- example eosinophils. therapy. Vascular permeability (leading to tissue (Postgrad Med J 2000;76:767–773) x oedema and airflow obstruction). Keywords: leukotriene ; asthma; x Mucus formation (leading to further ; zafirlukast airflow obstruction).

Asthma and Leukotriene receptor antagonists (LTRA) are a Research Group, new class of drugs for asthma treatment, avail- Department of Clinical able in tablet form.12Their unique mechanism Methods and of action results in a combination of both Fully published papers and review articles Therapeutics, between 1966 and January 2000 were sought Ninewells Hospital and bronchodilator and anti-inflammatory eVects. While their optimal place in asthma manage- using appropriate index terms and the National Medical School, Library of ’s computerised search University of Dundee, ment is still under review, LTRA represent an Dundee DD1 9SY, UK important advance in asthma pharmaco- service (providing access to Medline, Pre- Medline, and other related databases). Studies O J Dempsey therapy. In this article I provide a brief published only in abstract form (and thus sub- overview of evidence supporting their use in Correspondence to: ject to less rigorous peer review) are not Dr Dempsey patients with chronic asthma, focusing on two discussed. [email protected] leukotriene receptor antagonists, montelukast and zafirlukast, currently licensed for use in the Submitted 6 March 2000 Background Accepted 19 April 2000 United Kingdom. The term “slow reacting substance of anaphy- laxis” (SRS-A), coined by Brocklehurst in Phospholipids in cell 1960, is still familiar to many physicians.3 The http://pmj.bmj.com/ membrane chemical structure of SRS-A, however, was not A 2 identified until 1979 by Samuelsson and colleagues, who discovered that it consisted of a family of biologically active fatty acids Cyclo-oxygenase 5-/FLAP derived from arachidonic acid metabolism in many cells, including eosinophils, mast cells, 45 and lymphocytes (fig 1). The term “leuko- on September 28, 2021 by guest. Protected copyright. 5-HPETE triene” is apt, given their synthesis in leucocytes 5-Lipoxygenase/FLAP and their chemical structure (containing three conjugated double bonds, that is, a triene). Of LTB4 LTA4 particular importance in the patient with LTA4 hydrolase LTC synthase asthma are leukotrienes C4,D4, and E4.As 4 these contain the residue cysteine,

LTC4 they are sometimes referred to collectively as the cysteinyl leukotrienes. γ-Glutamyl transpeptidase Cysteinyl leukotrienes are important biologi- CYSTEINYL cal mediators in asthma, interacting with at LTD LEUKOTRIENE 4 least one specific receptor in the lungs, which 67 RECEPTOR has now been fully identified, leading to vari- Dipeptidase ous important biological eVects (box 1). Of these, potent bronchoconstriction is well rec- LTE4 ognised, but they also have a variety of eVects that are proinflammatory.8 Thus leukotrienes MONTELUKAST are capable of inducing several key features of asthma. Furthermore, studies have shown that leukotrienes are produced in excessive quanti- Figure 1 Arachidonic acid metabolism. Cysteinyl leukotrienes (LTC4,LTD4,LTE4) ties in patients with asthma, reinforcing the interact with a specific receptor, which is blocked by antagonists such as montelukast or zafirlukast. FLAP,5-lipoxygenase activating ; HPETE, view that they are important biological 5-hydroxyperoxyeicosatetraenoic acid. mediators.9

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bile. The terminal half lives of the two drugs are Zafirlukast CH3 N five and 10 hours, respectively. O Zafirlukast can inhibit the hepatic micro- CH 3 somal cytochrome P450 isoenzymes CYP2C9 O N O H and CYP3A at therapeutic concentrations, N which clinically may result in interactions H with other drugs using these . Simi- S CH larly, as montelukast is metabolised by CYP O OO3 3A4, caution should be exercised, particularly Montelukast COONa in children when montelukast is co- administered with inducers of this , as listed in table 1. OH Another clinically relevant point is that S co-administration of food with zafirlukast can reduce oral by approximately N Cl 40%, which means that patients should avoid taking this preparation soon before or after Figure 2 Structure of zafirlukast (top) and montelukast food (see table 1). This may have implications (bottom). for patient compliance. Interestingly, inhaled or oral corticosteroids have not been shown to attenuate leukotriene CLINICAL IN ASTHMA production significantly in vivo. This led to The optimal place of LTRA in asthma interest in the development of specific leuko- management is still under review. This reflects triene modifying asthma drugs, which might their recent introduction and the relative confer additional benefits even in patients paucity of fully published comparative studies, already receiving an optimal dose of inhaled 10 particularly compared with existing asthma corticosteroid. Several drug classes were treatments. For simplicity, in this article I will developed, aVecting various sites in the leuko- describe as their use in stud- triene biosynthetic cascade, of which the most first line treatment ies in conjunction with “as required” short act- successful have been receptor antagonists. ing â2 . Their use in patients already Leukotriene receptor antagonists receiving inhaled corticosteroids and “as re- quired” short acting agonists will be STRUCTURE â2 Montelukast and zafirlukast are two of the described as second line treatment. most commonly prescribed LTRA available worldwide. Their structures are shown in fig 2. First line treatment studies—chronic asthma PRESCRIBING INFORMATION LTRA v PLACEBO 13–22 Prescribing information is given in table 1.11 12 These studies are summarised in table 2. http://pmj.bmj.com/ Montelukast and zafirlukast share some phar- Most of the patients in these studies were ster- macokinetic properties including rapid oral oid naive, and hence the description “first line absorption (three hours to peak plasma con- treatment studies”; however, some did include centrations), near maximal (99%) plasma pro- a minority of patients receiving low dose tein binding, and, after extensive hepatic inhaled corticosteroids or oral theophyllines, or biotransformation, principally in the both.13–16 20

Table 1 Prescribing information on September 28, 2021 by guest. Protected copyright.

Generic name Montelukast11 Zafirlukast12 Trade name SingulairTM AccolateTM Indications (UK) 1. Add on treatment in patients with mild to moderate persistent Treatment of asthma asthma, inadequately controlled on inhaled corticosteroids and short

acting â2 agonists alone 2. Exercise induced bronchoconstriction Contraindications Acute asthma Acute asthma Pregnancy / lactation Pregnancy / lactation Severe hepatic impairment Hepatic impairment Moderate to severe renal impairment Age group > 6 years old > 12 years old No dose adjustment in the elderly No dose adjustment in the elderly Formulation Tablet (paediatric tablet chewable and cherry flavoured) Tablet Dose 5mg (if aged 6–14 years) 20 mg 10 mg (if > 14 years) Frequency Once daily Twice daily Special instructions Adult dose can be taken with food Avoid1hbeforeand2hafter meals Paediatricdose:avoid1hbeforeand2hafter meals Drug interactions None with oral contraceptive pill, warfarin, , theophylline, or Patients on warfarin may have ⇑ prothrombin times (monitor INR) Coadministration with CYP 3A4 hepatic enzyme inducers (eg Aspirin may ⇑ zafirlukast levels , phenobarbitone, rifampicin) may ⇓ montelukast levels ⇓ Zafirlukast levels with erythromycin, terfenadine, theophylline

www.postgradmedj.com ektin eetrantagonists receptor Leukotriene

Table 2 First line treatment—leukotriene receptor antagonists v placebo: randomised, placebo controlled, parallel group studies

Treatment Age range duration FEV1 Inclusion criteria‡ and Study n (years) (weeks) (% predicted) intercurrent treatment Treatment(s) Primary endpoint(s) Results Montelukast 13 Altman 343 18–65 6 40–80 â2 use > 1puV/day; 36% on M 10 mg, 100 mg, or 200 mg od; FEV1 Mall doses*>P ⇑ ICS, 15% on theo M10mgor50mgbd;P For M10mg, mean % in FEV1 = 11.4% No dose (or dosage interval) relation with eYcacy 14 Knorr 336 6–14 8 50–85 36% on ICS M 5 mg od; P FEV1 M** > P ⇑ For M5mg, mean % in FEV1 = 8.2% Also significant ⇑ in quality of life 15 www.postgradmedj.com Noonan 281 18–65 3 40–80 â2 use > 1puV/day; 24% on M 2 mg, 10 mg, or 50 mg od; P FEV1 Mall doses*>P ⇑ ICS, 19% on theo For M10mg, mean % in FEV1 = 13.5% No added eYcacy with doses > M10mg Also significant ⇑ in quality of life Improvement regardless of whether treated with inhaled steroids or oral theophyllines 16 Reiss 681 > 15 12 50–85 23% on ICS M 10 mg od; P FEV1, daytime symptoms M** > P for both endpoints ⇑ Mean in FEV1 = 13.1% Improvement regardless of whether treated with inhaled steroids or not On withdrawal of M, no rebound worsening Zafirlukast 17 Fish 762 > 12 13 > 55 BHR, â2 reversibility Z 20 mg bd; P FEV1, daytime symptoms Z* > P ⇑ Mean in FEV1 = 6.3% Symptoms ⇓ by 26% 18 Kemp 261† > 12 in 3 trials 13 > 55 in 3 trials Z 20 mg bd; P FEV1, morning PEF Z* > P ⇑ benefit in those with more severe disease > 18 in 1 trial 45–80 in 1 trial Nathan19 454 > 12 13 45–<80 Z 20 mg bd; P Morning PEF, daytime Z** > P symptoms ⇓ symptoms 23% and ⇑ PEF (25 l/min) Also ⇑ quality of life, Z* > P 20 Spector 276 18–65 6 40–70 BHR; could be on theo Z 5 mg, 10 mg, or 20 mg bd; P PEF, symptoms Z20mg bd* > P for symptoms and evening PEF (withdrawn during study) Symptoms ⇓ 27% ⇑ Mean in FEV1 = 11% Suissas21 146 > 12 13 > 55 BHR Z 20 mg bd; P Clinical/economic Z* > P eYcacy Several endpoints, incl significant ⇓ in health contacts and days oV school/work 22 ⇑ ⇑ Tashkin 1484† > 12 in 3 trials 13 > 55 in 3 trials BHR Z 20 mg bd; P Exploratory subset Z* > P, benefit in those with more severe disease, ie â2 analysis requirement, peak flow variability (> 20%), or FEV1 < 70% > 18 in 1 trial 45–80 in 1 trial predicted

†Retrospective analysis of four studies.

‡In addition to inclusion criteria shown, all studies required asthmatics to be symptomatic (minimum predefined symptom score) and demonstrate reversible airflow obstruction (following challenge with a short acting â2 ). >, Significantly greater eVect than placebo. *p<0.05;**p<0.01.

bd, twice daily; BHR, bronchial hyperresponsiveness; FEV1, forced expiratory volume in 1 second (litres); ICS, inhaled steroid; M, montelukast; od, once daily; P, placebo; PEF, peak expiratory flow rate (l/min); theo, theophylline; Z, zafirlukast. 769

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The primary endpoint in most of the studies LTRA v OTHER ASTHMA TREATMENTS was pulmonary function, usually forced expira- There is only one published study comparing 26 tory volume in one second (FEV1). Improve- an LTRA with sodium cromoglycate. This 13

ments in mean FEV1 were typically modest, for week, randomised, parallel group study re- example 10%, with much interindividual cruited 287 patients with mild to moderate variation. Commonly used secondary end- asthma, comparing zafirlukast, sodium cromo- points included symptoms and quality of life glycate aerosol (1.6 mg four times daily), and scores, other measures of pulmonary function placebo. No significant diVerence was detected such as peak expiratory flow rates, the need for between either of the active treatments, al- though both were better than placebo in terms other drugs (short acting â2 agonist or inhaled/ oral corticosteroid use), and eVects on daily of symptom improvement and reduced â2 ago- living (days oV school or work). Improvement nist use. Subset analysis suggested greatest improvement in patients with > 10% peak flow in these secondary outcomes was typically 26 more impressive, for example 25%. The variability. majority of these studies concluded that the use of an LTRA in patients with mild asthma was Second line treatment studies—chronic superior to placebo, using these subjective and asthma objective measures. LTRA v PLACEBO Subgroup analysis of several studies mentioned Only one of these studies examined use of earlier (table 2) suggested that montelukast LTRA in patients with more severe airflow 18 could provide additional clinical benefit for obstruction. In this retrospective pooled sub- patients using concomitant inhaled group analysis, data were reviewed from four corticosteroids.13–16 This has now been con- clinical trials in which zafirlukast 20 mg twice firmed prospectively in an important study by daily or placebo was given over a 13 week 27 Laviolette et al. In that study, 642 patients period to 261 steroid naive patients identified with chronic asthma incompletely controlled as having severe persistent asthma. Compared by inhaled beclomethasone 200 µg twice daily with placebo, patients receiving zafirlukast had with a spacer were randomised to one of four significantly (p < 0.05) greater improvements treatment groups: (1) montelukast 10 mg once in spirometry, peak expiratory flow, symptoms, daily + continuing beclomethasone; (2) pla- and â2 agonist requirement. However, these cebo tablet + continuing beclomethasone; (3) changes—although statistically significant— montelukast + inhaled placebo (after blind were small. Furthermore, given that current beclomethasone removal); and (4) placebo United Kingdom and American asthma man- tablet and inhaler. The use of montelukast, in agement guidelines advise early use of an opti- conjunction with 400 µg/day beclomethasone mal dose of inhaled corticosteroids in patients dipropionate, provided significant additional with asthma of this severity,23 24 this study is of benefit in terms of improving FEV1, daytime limited clinical relevance. asthma scores, and nocturnal awakenings.

LTRA v LONG ACTING â2 AGONISTS LTRA INHALED CORTICOSTEROID http://pmj.bmj.com/ v There is only one published study comparing There is only one fully published study directly these drug classes in chronic asthma.28 Salm- comparing use of an LTRA with low dose eterol and zafirlukast were compared in a four inhaled corticosteroid in patients with mild week, randomised, double blind, parallel group asthma.25 multicentre study. Over 80% of the patients In this randomised, double bind, parallel were having concomitant inhaled cortico- group, multicentre study, 895 patients with steroid treatment, and received either inhaled mild to moderate asthma received montelukast

salmeterol 42 µg twice daily by metered dose on September 28, 2021 by guest. Protected copyright. 10 mg once daily, 200 µg of beclomethasone inhaler or oral zafirlukast 20 mg twice daily. twice daily with a spacer, or placebo for three The primary outcome measure was morning months. Both montelukast and beclometha- peak expiratory flow (PEF) rates. Both active sone were more eVective than placebo, primary treatments were associated with improvements endpoints being daytime asthma symptoms from baseline in pulmonary function, asthma and FEV1; montelukast had a faster onset of symptoms, and short acting â2 agonist use. Sal- action (day 1) compared with beclomethasone meterol treatment resulted in significantly (day 8). Nevertheless, patients receiving beclo- greater improvements from baseline compared methasone achieved a significantly better mean with zafirlukast for most eYcacy measures, eVect in terms of increased FEV1 and symptom including morning PEF (29.6 l/min v 13.0 reduction. For example, the average percentage l/min; p < 0.01), percentage of symptom-free change from baseline in FEV1 over three days (22.4% v 8.8%; p < 0.01), and percent- months was 13.1% with beclomethasone, 7.4% age of days and nights with no supplemental with montelukast, and 0.7% with placebo short acting â2 agonist use (30.5% v 11.3%; (p < 0.001 for each active treatment compared p < 0.01).28 with placebo; p < 0.01 for beclomethasone These results, while in favour of salmeterol, compared with montelukast). It is interesting are perhaps not surprising, as LTRA are recog- to note that both active treatment groups had a nised as being less potent bronchodilators than

similar (normal) distribution of response, so it long acting â2 agonists. The endpoint chosen in is incorrect to assume that patients are easily this short study is therefore very relevant when categorised into “responders” or “non- comparing these two drug classes. It may be responders” to either treatment.25 that the presumed additional anti-

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inflammatory eVects conferred by LTRA use all, patients with mild stable asthma. An (which may take several months to see) may be advantage of LTRA in these patients is their equally as important as improvements in spiro- duration of action. For example, protection metry. against exercise induced bronchoconstriction is evident with montelukast even 20 to 24 LTRA v OTHER ASTHMA TREATMENTS hours after dosing. Furthermore, unlike long

There are few fully published studies compar- acting â2 agonists, chronic dosing with LTRA is ing the use of alternative second line treatments not associated with tolerance to their 40–42 such as theophyllines, long acting â2 agonists, eVects. or cromones with LTRA. One study has suggested that combination treatment with Aspirin induced asthma montelukast and salmeterol confers additive Aspirin induced asthma aVects approximately benefits to patients who are suboptimally con- 10% of adult patients with asthma.43 In these trolled on inhaled corticosteroids, in terms of patients, exposure to aspirin and other cyclo- bronchoprotection to challenge and oxygenase inhibitors, for example non- bronchodilatation.29 steroidal anti-inflammatory agents, is associ- ated with excessive leukotriene release. LTRA AS STEROID SPARING AGENTS Interestingly, bronchial biopsies from these

Although not currently licensed for use in this patients show overexpression of way, two studies have addressed the potential synthase in eosinophils and mast cells (fig 1).44 role of LTRA as steroid sparing agents in This may be secondary to a common polymor- 45 patients requiring high maintenance doses of phism of the LTC4 gene. Intuitively therefore, inhaled corticosteroids.30 31 This is an impor- LTRA are a logical treatment choice in this tant issue, particularly given concerns about type of asthma patient. Clinical eYcacy has the potential risk of systemic adverse eVects been demonstrated compared with placebo, associated with prolonged use of high dose even in patients already receiving inhaled inhaled corticosteroids. corticosteroid treatment.11 It should be empha- In a randomised, double blind, placebo con- sised, however, that patients should still avoid

trolled study, 79 asthma patients (mean FEV1 ingestion of aspirin and related drugs, even if 81% of predicted) requiring a mean daily dose taking an LTRA, as protection is not of approximately 1900 µg of beclomethasone complete.46 47 dipropionate were studied.30 Following a two week run in phase, each patient’s dose of Premenstrual asthma beclomethasone was halved for six weeks. Dur- Many women describe an increase in asthma ing this time, patients received additional treat- symptoms just before and during ment, either as placebo or as an LTRA menstruation.48 While the mechanism remains (, in a standard adult dose of 450 mg unclear, one theory is that systemic twice daily). After six weeks, those receiving occurs in response to altered female placebo had a significant deterioration in levels, resulting in release of potent symptoms and lung function, combined with mediators including leukotrienes. Interestingly, http://pmj.bmj.com/

increased â2 agonist requirement. Further- a recent study supports this hypothesis, sug- more, this was mirrored by a rise in non- gesting that use of an LTRA may be beneficial invasive markers of airway inflammation, in- in these patients.49 cluding exhaled breath nitric oxide and blood eosinophil cationic protein. Interestingly, in the Safety pranlukast group this subjective and objective Montelukast and zafirlukast were first mar- deterioration was not seen, suggesting that use keted in the United Kingdom in February and

of an LTRA may facilitate dose reduction in July 1998, respectively. Up to the end of April on September 28, 2021 by guest. Protected copyright. patients dependent on high doses of inhaled 1999, 233 000 prescriptions had been issued corticosteroid, but not necessarily at the cost of for montelukast and 17 000 for zafirlukast. an increase in airway inflammation.30 Both drugs remain under close observation, In another study of diVerent design, the use but appear to be generally well tolerated. Most of montelukast was also shown to facilitate a side eVects are mild, for example gastro- significant reduction in maintenance inhaled intestinal disturbance, rashes, and fatigue corticosteroid dose compared with placebo, (box 2).50 over a period of 12 weeks.31 Studies longer than Some isolated cases of Churg–Strauss syn- 12 weeks will obviously be necessary to see drome, a rare systemic vasculitis associated whether this is indeed a true steroid sparing with asthma, have been reported, but it seems eVect. unlikely that LTRA are directly implicated.51 A more likely explanation is that inhaled (high Exercise induced asthma dose) or oral corticosteroid treatment in these Exercise induced bronchoconstriction is com- patients may mask the underlying vasculitis. If mon in asthmatic patients, although the steroid doses are reduced inappropriately, mechanisms underlying this are still poorly facilitated by use of LTRA, the underlying vas- understood.32 Leukotrienes are recognised as culitis may be revealed. It should be empha- important mediators associated with the reduc- sised that LTRA are not currently licensed in tion in airway calibre. Studies in both chil- order to allow dose reduction of either inhaled dren33 34 and adults35–39 have shown that LTRA or oral corticosteroids. Clinicians should be aVord substantial protection against exercise suspicious if patients with asthma in these cir- induced bronchoconstriction in many, but not cumstances develop worsening asthma symp-

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Box 2: Safety of leukotriene receptor Box 3: Leukotriene receptor antagonists antagonists: summary x Generally well tolerated, side eVect x Novel class of chronic asthma treatment, profile similar to placebo. available in tablet form. x Common side eVects reported include x In UK, montelukast and zafirlukast are gastrointestinal disturbance, rashes, available for prescription. fatigue. x Combination of bronchodilator and x Report any side eVects to Committee of anti-inflammatory properties. Safety of using yellow card x Rapid eVects (days) and ease of scheme. administration may aid compliance. x Rare cases of Churg–Strauss syndrome x Useful in exercise induced and (see text)—caution if reducing aspirin/NSAID induced asthma in maintenance inhaled or oral particular. corticosteroid. x May be useful in other conditions, eg allergic rhinitis, atopic dermatitis. toms in association with marked serum eosi- nophilia (> 1.5 × 109/l) and signs of a systemic vasculitis such as non-blanching rash, cardiac patients who are still suboptimally controlled. complications, and peripheral neuropathy.52 New guidelines may also suggest that, in selected patients, monotherapy with an LTRA Clinical eYcacy in conditions other than is still appropriate, particularly in patients with asthma extremely mild disease reluctant to take Leukotriene receptor antagonists have been inhaled corticosteroids, or in patients with used successfully in a variety of other condi- aspirin induced or exercise induced symptoms. tions, notably rhinitis, which often coexists in Acute asthma management guidelines are asthma patients.53–55 Other conditions have unlikely to advise the use of an LTRA, as there included atopic dermatitis56 and eosinophilic is no evidence to support their use in these gastroenteritis.57 There is no evidence that the patients. current cysteinyl leukotriene receptor antago- 1 Lipworth BJ. Leukotriene-receptor antagonists. Lancet nists will be useful in patients with chronic 1999;353:57–62. obstructive pulmonary disease. 2 Drazen JM, Israel E, O’Byrne PM. Treatment of asthma with drugs modifying the leukotriene pathway.N Engl J Med 1999;340:197–206. Predictors of response to LTRA 3 Brocklehurst WE. The release of histamine and the forma- Currently, it is not possible to predict who will tion of a slow reacting substance (SRS–A) during anaphy- lactic shock. J Physiol (Lond) 1960;151:416–35. respond well to an LTRA and, as described 4 Murphy RC, Hammarstrom S, Samuelsson B. Leukotriene earlier, this response is normally distributed, so C. A slow reacting substance from murine mastocytoma cells. Proc Natl Acad Sci USA 1979;76:4275–79. some patients (perhaps as many as 50%) may 5 Dahlen SE, Hedqvist P, Hammarstrom S, et al. Leukot- rienes are potent constrictors of human bronchi. Nature http://pmj.bmj.com/ have a disappointing response. Thus many clin- 1980;288:484–6. icians opt for a four to eight week therapeutic 6 Lynch KR, O’Neill GP, Liu Q, et al. Characterization of the human cysteinyl leukotriene CysLT1 receptor. Nature 1999; trial of an LTRA, although longer trials may be 399:789–93. necessary to detect beneficial eVects in terms of 7 Sarau HM, Ames RS, Chambers J, et al. Identification, attenuating airway inflammation. Recently, molecular cloning, expression, and characterization of a cysteinyl leukotriene receptor. Mol Pharmacol 1999;56:657– genetic polymorphisms of the enzymes control- 63. ling biosynthesis of leukotrienes have been 8 Busse WW. Leukotrienes and inflammation. Am J Respir Crit Care Med 1998;157:S210–13.

described and may be important predictors of 9 Wardlaw AJ, Hay H, Cromwell O, et al. Leukotrienes, LTC4 on September 28, 2021 by guest. Protected copyright. response.44 45 58 59 and LTB4 in bronchoalveolar lavage in bronchial asthma and other respiratory diseases. J Allergy Clin Immunol 1989; 84:19–26. 10 Dworski R, Fitzgerald GA, Oates JA, et al.EVect of oral Place of LTRA in asthma management prednisone on airway inflammatory mediators in atopic guidelines asthma. Am J Respir Crit Care Med 1994;149:953–9. 11 Summary of product characteristics. Singulair. Hertfordshire, The current British Thoracic Society asthma UK: Merck Sharp & Dohme Ltd, January 1998. management guidelines, published in 1997, are 12 Summary of product characteristics. Accolate. Cheshire, UK: in need of updating, as leukotriene receptor Zeneca Ltd, July 1998. 13 Altman LC, Munk Z, Seltzer J, et al. A placebo-controlled, antagonists only became available for prescrip- dose-ranging study of montelukast, a cysteinyl leukotriene tion after that date. The current American receptor antagonist. Montelukast Asthma Study Group. J Allergy Clin Immunol 1998;102:50–6. guidelines, similarly published in 1997, do 14 Knorr B, Matz J, Bernstein JA, et al. Montelukast for mention the LTRA zafirlukast and suggest that chronic asthma in 6- to 14-year-old children: a randomized, double-blind trial. JAMA 1998;279:1181–6. it may be an option as monotherapy in patients 15 Noonan MJ, Chervinsky P, Brandon M et al. Montelukast, a potent leukotriene receptor antagonist, causes dose-related aged > 12 years or older with mild persistent improvements in chronic asthma. Montelukast Asthma asthma. Both guidelines acknowledge that the Study Group. Eur Respir J 1998;11:1232–9. 16 Reiss TF, Chervinsky P, Dockhorn RJ, et al. Montelukast, a position of leukotriene receptor antagonists in once-daily leukotriene receptor antagonist, in the treatment current practice “is not fully established.” of chronic asthma : a multicentre, randomized, double-blind It seems likely that forthcoming United trial. Montelukast Clinical Research Study Group. Arch Intern Med 1998;158:1213–20. Kingdom guidelines will continue to advise 17 Fish JE, Kemp JP, Lockey RF, et al. Zafirlukast for sympto- early use of anti-inflammatory treatment in the matic mild-to-moderate asthma: a 13-week multicenter study. The Zafirlukast Trialists Group. Clin Ther 1997;19: form of low dose inhaled corticosteroid (< 800 675–90. 18 Kemp JP, Minkwitz MC, Bonuccelli CM, et al. Therapeutic µg/day of beclomethasone or equivalent), with eVect of zafirlukast as monotherapy in steroid-naive patients LTRA reserved for second line use in those with severe persistent asthma. Chest 1999;115:336–42.

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19 Nathan RA, Bernstein JA, Bielory L, et al. Zafirlukast 38 Bronsky EA, Kemp JP, Zhang J, et al. Dose-related improves asthma symptoms and quality of life in patients protection of exercise bronchoconstriction by montelukast, with moderate reversible airflow obstruction. J Allergy Clin a cysteinyl leukotriene-receptor antagonist, at the end of a Immunol 1998;102:935–42. once-daily dosing interval Clin Pharmacol Ther 1997;62: 20 Spector SL, Smith LJ, Glass M. EVects of 6 weeks of 556–61. therapy with oral doses of ICI 204,219, a 39 Dessanges JF, Prefaut C, Taytard A, et al. The eVect of receptor antagonist, in subjects with bronchial asthma. zafirlukast on repetitive exercise-induced bronchoconstric- ACCOLATE Asthma Trialists Group. Am J Respir Crit Care tion : The possible role of leukotrienes in exercise-induced Med 1994;150:618–23. refractoriness. 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induced bronchospasm by montelukast, a cysteinyl leukot- modify transcription factor binding and reporter gene tran- on September 28, 2021 by guest. Protected copyright. riene receptor antagonist. Thorax 1997;52:1030–5. scription. J Clin Invest 1997;99:1130–7.

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