Theodore F Reiss, James B Hill, Eloise Harman, Ji Zhang, Wesley K Tanaka, Edwin Bronsky, Debra Guerreiro, Leslie Hendeles

Transcription

1 1030 Thorax 1997;52: Increased urinary excretion of LTE 4 after exercise and attenuation of exercise-induced bronchospasm by montelukast, a cysteinyl leukotriene receptor antagonist Theodore F Reiss, James B Hill, Eloise Harman, Ji Zhang, Wesley K Tanaka, Edwin Bronsky, Debra Guerreiro, Leslie Hendeles Abstract leukotriene receptor antagonist provide Background A study was undertaken to further evidence of the role of leukotrienes determine whether montelukast, a new in the pathogenesis of exercise-induced potent cysteinyl leukotriene receptor bronchoconstriction. antagonist, attenuates exercise-induced (Thorax 1997;52: ) bronchoconstriction. The relationship between the urinary excretion of LTE Keywords: leukotriene receptor antagonist, exercise- 4 and induced bronchoconstriction, montelukast. exercise-induced bronchoconstriction was also investigated. Methods Nineteen non-smoking asth- Cysteinyl leukotrienes, synthesised from matic patients with a forced expiratory arachidonic acid through the 5-lipoxygenase volume in one second (FEV 1 )of[65% of pathway, have an important role in asthma. 1 the predicted value and a reproducible fall Leukotriene C 4 (LTC 4 ) is the dominant metain FEV 1 after exercise of at least 20% were bolite of arachidonic acid released in lung tissue enrolled. Subjects received placebo and but it is very unstable and quickly converted montelukast 100 mg once daily in the even- to leukotriene D 4 (LTD 4 ). In turn, LTD 4 is ing or 50 mg twice daily, each for two days, converted to a less potent metabolite, leukoin a three-period, randomised, double Department of triene E 4 (LTE 4 ), which is excreted in the blind, crossover design. In the evening, Pulmonary/ urine. 2 These leukotrienes are released from Immunology and approximately hours after the once eosinophils, mast cells, and other inflammatory Biostatistics, daily dose or 12 hours after the twice daily cells in the airways of patients with asthma Merck Research dose, a standardised exercise challenge Laboratories, Rahway, and are highly potent constrictors of bronchial New Jersey, USA was performed. Data from 14 patients were smooth muscle. 3 Observations in experimental T F Reiss available for complete analysis. animal models also suggest that they stimulate J Zhang Results The mean (SD) maximal per- W K Tanaka airway mucus secretion, impair mucociliary D Guerreiro centage decrease in FEV 1 after exercise clearance, and increase vascular permeability. 3 was 29.6 (16.0), 17.1 (8.2), and 14.0 (9.4) There is increasing evidence of the import- School of Medicine for placebo, once daily, and twice daily J B Hill ance of the cysteinyl leukotrienes as mediators regimens, respectively. The mean (95% of exercise-induced bronchoconstriction. Al- Pulmonary Division, CI) percentage protection was 37 (15 to 59) though the mechanism of exercise-induced Department of for the group who received 50 mg twice Medicine bronchoconstriction is controversial, one E Harman daily and 50 (31 to 69) for those who re- theory suggests that loss of heat and water from ceived 100 mg once daily. Active treat- the respiratory mucosa during exercise results College of Pharmacy ments were not different from each other. and Pulmonary in a hyperosmolar stimulus of mast cell de- Division The mean (SD) plasma concentrations of granulation releasing bronchospastic mediators L Hendeles montelukast were higher after the twice such as leukotrienes. 4 Previous studies have daily regimen (1.27 (0.81) μg/ml) than after shown that cysteinyl leukotriene receptor ant- Department of Pediatrics, University the once daily regimen (0.12 (0.09) μg/ml); agonists attenuate airway responsiveness to exof Florida, Gainesville, there was no correlation between the ercise, suggesting that the pathogenesis of Florida, USA percentage protection against exercise- exercise-induced bronchoconstriction, at least AAAA Medical induced bronchoconstriction and plasma in part, involves the release of leukotrienes. 56 Research, concentrations. After exercise urinary ex- If leukotrienes are involved in exercise-induced Salt Lake City, cretion of LTE 4 increased significantly bronchoconstriction, then urinary excretion of Utah, USA E Bronsky during placebo treatment (from 34.3 to LTE 4 should increase after exercise. However, 73.7 pg/mg creatinine; p<0.05) but did not the evidence is conflicting 78 and increases have Correspondence to: correlate with the extent of exercise- Dr T F Reiss, Merck only been seen in children with more severe Research Laboratories, induced bronchoconstriction. asthma. 8 P.O. Box 2000-RY , Conclusions Montelukast protects sim- Rahway, New Jersey 07065, Montelukast (MK-0476) is an orally bio- USA. ilarly against exercise-induced broncho- available, selective, and potent cysteinyl leukoconstriction Received 5 March 1997 between plasma concentra- triene receptor antagonist capable of significant Returned to authors tions of 0.12 and 1.27 μg/ml. The increase in 28 April 1997 blockade of airway cysteinyl leukotriene re- Revised version received the urinary excretion of LTE 4 after exercise ceptors over a 24 hour dosing interval. 9 7 July 1997 and the protection from exercise-induced Accepted for publication Since cysteinyl leukotriene receptor ant- 31 July 1997 bronchoconstriction with a cysteinyl agonists differ in potency, the present study was

2 Montelukast and exercise 1031 conducted to determine whether montelukast and plasma concentrations of montelukast. The attenuates exercise-induced bronchoconstriction interval between treatment periods was at least and whether there is a relationship between four days. plasma concentration and effect by testing two dosage regimens producing different plasma concentrations. In addition, it was the aim of EXERCISE CHALLENGE this study to determine whether a sensitive For each subject exercise was performed on a assay could detect an increase in the urinary treadmill for six minutes. The gradient and excretion of LTE 4 after exercise. speed of the treadmill was adjusted to achieve a work load of more than 80% of that subject s age-predicted maximum heart rate. Minor adjustments Methods in work load were allowed in order to SUBJECTS achieve the heart rate obtained in the prestudy Nineteen men aged years with exerciseinduced visits. Pre-exercise spirometric values were bronchoconstriction were selected for measured in accordance with ATS guidelines 10 study. Each subject had at least a one year 20 and five minutes before the challenge. The history of typical recurring symptoms of asthma best of three attempts at each time point were including dyspnoea, wheezing, and cough. Furthermore, recorded and had to be at least 65% of the during the prestudy evaluation each predicted value five minutes before exercise for subject had a forced expiratory volume in one the challenge to proceed. During the exercise second (FEV 1 ) of at least 65% of the predicted the subject wore a nose clip and breathed value for age, height, and sex. A 20% decrease room air (constant ambient environment in air in FEV 1 in response to standardised exercise conditioned laboratories). FEV 1 was measured bronchoprovocation was required on two prestudy immediately after exercise and at five, 10, 15, (qualifying) visits. All of the subjects were 30, 45, 60, 75 and 90 minutes. After exercise non-smokers for at least a year, with a smoking a β agonist was administered to the patient if history of no more than one pack per day for the FEV 1 fell by 40% of the predicted value, five years. Subjects were excluded if they had if it was requested by the patient, or if the other illnesses based upon history, physical or investigator thought it was clinically indicated. laboratory examination, or had a respiratory infection within six weeks of the prestudy visit. Asthma medications were limited to rapidly MONTELUKAST PLASMA CONCENTRATION acting inhaled β agonists and inhaled corticosteroids For the analysis of plasma drug concentration (maintained at a constant dose be- blood samples were collected from all subjects ginning four weeks before and throughout the on the second prestudy visit and three minutes study). All inhaled β agonists were withheld before exercise on day 3 (study day) of each for at least six hours and inhaled corticosteroids treatment period. The plasma specimens were for at least one hour before the exercise chal- analysed for montelukast by high performance lenges. None of the subjects were taking antihistamines liquid chromatography (HPLC). The limit of or salmeterol prior to the study. detection was 30 ng/ml. The intraday precision The protocol was approved by the institutional values (percentage Relative Standard Dereview board and written informed consent was viation, %RSD) were in the range of 0 5.7% obtained from each subject. and the interday precision values (%RSD) at concentrations of 51 and 2040 ng/ml were 10% and 3%, respectively. STUDY DESIGN The study was a double blind, randomised, three period, crossover trial. Treatments con- URINE LTE 4 AND CREATININE sisted of either 100 mg of montelukast with the A separate objective of this study was to deter- evening meal and placebo with breakfast, 50 mg mine whether exercise challenge in asthmatic of montelukast with the evening meal and patients with exercise-induced bronchocon- breakfast, or placebo twice daily for two days striction is associated with increases in urinary (to achieve steady state plasma concentration). concentrations of LTE 4. Urine was collected Thus, all subjects received a total of 100 mg/ one hour before and one and two hours after day of montelukast or placebo in the 48 hour exercise. Urinary LTE 4 concentrations (pg/ml) period prior to the test exercise challenge. were expressed as the ratio of creatinine (mg/ All subjects returned to the pulmonary function ml) to correct for differences in urinary volume. laboratory on the third day between Urinary LTE 4 was measured by a modified and hours when the exercise challenge HPLC/radioimmunoassay originally described was performed hours after the last dose by Tagari et al 11 and used clinically to demonstrate of the twice daily regimen or hours after increases in urinary LTE 4 levels after the last dose of the once daily regimen. In antigen challenge in allergic asthmatic addition, routine physical examinations were patients. 12 HPLC separation was carried out performed, vital signs and electrocardiographic as described previously 13 and fractions were changes were measured, and blood and urine assayed in a competitive-binding radio- were collected for laboratory tests of safety and immunoassay using a commercially available measurement of montelukast plasma con- peptidyl leukotriene antibody (Cascade Bio- centration and urine concentration of LTE 4. Adherence was monitored by capsule counts, telephone contact by the study coordinator, chem Ltd, Berkshire, UK). The between day precision of the radioimmunoassay, expressed as coefficient of vari-

3 1032 Reiss, Hill, Harman, Zhang, Tanaka, Bronsky, et al ation (CV), was 6.0%, 8.5%, and 13.6% for 100 minutes minus the time required for the radioimmunoassay samples containing 104.2, maximum decrease in FEV 1 from baseline to 35.1, and 10.0 pg LTE 4, respectively. Overall occur. recovery of 3 H-LTE 4 used as internal standard was 63%. Interday assay precision determined from analysis of pooled urine from healthy Area under the curve (AUC) subjects was 13.3% and 11.4% for urine The area under the post-exercise FEV 1 per- samples containing 54.5 and 20.2 pg LTE 4 /mg centage decrease through 60 minutes (AUC 0 60 ) creatinine, respectively. The limit of reliable was also determined. This parameter provides quantitation (LLRQ) was 5.24 pg LTE 4 /mg a single number that summarises the extent creatinine (based on a creatinine concentration and duration of bronchoconstriction. The tra- of mg/dl). LTE 4 values below this were pezoidal method was used to calculate the reported as 2.5 pg LTE 4 /mg creatinine. AUC Only areas below the pre-exercise The urine creatinine assay is based on a baseline were included when computing the modified Jaffe reaction as described by Chasson. AUC The between day precision at 150.1, 70.5, and 13.8 mg/dl were 5.6%, 3.4%, and 5.6%, respectively. URINARY LTE 4 The ability of exercise to increase urinary LTE 4 levels (pg/mg creatinine) was determined by DATA ANALYSIS analysing the change between the pre-exercise Exercise end points: general baseline and the value two hours after exercise The ability of montelukast to attenuate exsigned during the placebo period using the Wilcoxon ercise-induced bronchoconstriction was determined rank test. by comparing three study end points among treatments: the maximum percentage decrease in FEV 1 after exercise, the time re- STATISTICAL ANALYSIS quired after maximal decrease for FEV 1 to The analysis of variance (ANOVA) model for return to within 5% of the pre-exercise baseline a crossover study 15 was used to compare treat- value (recovery time), and the area above the ments for the three end points. The model post-exercise FEV 1 /time curve (AUC 0 60 min ). included terms for subject, treatment, and The mean of the 20 minute and five minute period. Carryover effects were assessed by addpre-exercise measurements was used as the pre- ing a carryover factor in the ANOVA model. exercise FEV 1 value. End points were calwere made using linear contrasts. 95% con- Pairwise comparisons of the treatment means culated for each individual and then averaged. If a patient required a bronchodilator during fidence limits on differences or changes from the post-exercise period or the FEV 1 value was baseline were provided when appropriate with not available, the last recorded FEV 1 was used p values of Ζ0.05 (with a two-tailed test) being at all subsequent time points. considered significant. The study was designed to have 80% power (for 12 completing patients) to detect (α= Maximal decrease in FEV , two-sided) a mean difference between The maximum percentage decrease in FEV 1 treatment groups of 8.1 percentage points for after exercise was defined as: maximal percentage decrease in FEV 1. pre-exercise FEV 1 lowest FEV 1 (after exercise) pre-exercise FEV The ability of the two montelukast dosage regimens to attenuate airway responsiveness to exercise relative to placebo was defined as percentage protection from exercise-induced bronchoconstriction and calculated as follows: % protection= maximum % fall on placebo maximum % fall on drug 100 maximum % fall on placebo Results DEMOGRAPHIC DATA Nineteen subjects qualified and received allocation numbers. Three subjects discontinued before completing the three study periods Table 1 Demographic data Subject Age Prestudy FEV 1 Maximal decrease in no. (years) (% predicted) FEV 1 after exercise (%) Time to recovery The time to recovery was defined as the time required after maximum decrease in FEV 1 for the FEV to return to within 5% of the pre exercise baseline value. If the exercise-induced bronchoconstriction was completely blocked (maximal decrease in FEV 1 5%) the time to Median recovery was assigned a value of zero minutes. Range Additionally, if the post-exercise FEV 1 did not return to within 5% of baseline within 90 min- Average of two pre-exercise challenges. utes the recovery time was assigned a value of Patient was using inhaled corticosteroids at a constant dose throughout the study.

4 Montelukast and exercise 1033 Mean FEV 1 (l) BLN Placebo 100 mg montelukast daily 50 mg montelukast b.i.d RESPONSE TO EXERCISE The mean (SD) maximal percentage decrease in FEV 1 from the pre-exercise baseline value was 29.6 (16.0)%, 17.1 (8.2)%, and 14.0 (9.4)% for the placebo, twice daily and once daily regimens, respectively (fig 1, table 2). The decrease in FEV 1 was significantly (p<0.05) attenuated during both montelukast treatment regimens compared with placebo (mean protection of 37% (95% CI 15 to 59) for the group who received 50 mg twice daily and 50% (95% CI 31 to 69) for those who received 100 mg once daily, but there was no significant difference between the active treatments. Monte Minutes after exercise challenge lukast provided a mean protection against Figure 1 Mean forced expiratory volume in one second (FEV 1 ) before and after exercise exercise-induced bronchoconstriction of 37% challenge among 14 subjects with data available from all treatments. Subjects received placebo, montelukast 50 mg twice daily or 100 mg daily for two days. Exercise challenge (95% CI 15 to 59) during the twice daily was performed 12 hours after the last dose on the twice daily regimen or placebo and 24 hours after the last dose of the once daily regimen. At the time of the exercise challenge the mean montelukast trough plasma concentrations were 1.27 μg/ml on the twice daily regimen and 0.12 μg/ml on the once daily regimen. There was no significant correlation between plasma concentration and the extent of protection for exercise-induced bronchoconstriction. Table 2 Response to exercise challenge regimen and 50% (95% CI 31 to 69) during the once daily regimen (p<0.05). The mean time to recovery to within 5% of the pre-exercise baseline FEV 1 value after the maximum decrease in post-exercise challenge was 67.1 (30.1), 20.7 (23.3), 25.7 (33.4) minutes for the placebo, twice daily, and once daily regimens, respectively (table 2). The recovery one because of a urinary tract infection and time was significantly shorter with both active two because of asthma exacerbations unrelated treatments (p<0.001) than with placebo but to the exercise challenge (one each during did not differ between themselves. 50 mg twice daily and placebo periods). Of the The mean AUC 0 60 was 1166 (980)%, subjects who completed the three study (218)%, and 387 (316)% (table 2) for the periods, data from two subjects were un- placebo, twice daily and once daily regimens, available for complete analysis. In one of these respectively. Both active treatments were sigpatients maximal exercise was not achieved due nificantly (p<0.001) smaller than placebo but to chest tightness (thought to be caused by did not differ between themselves. bronchoconstriction) in one period, and in the Beta agonist was administered to five patients second patient a technical problem with the while receiving placebo, three patients while spirometric measurement (moisture on the dia- receiving montelukast 100 mg once daily, but phragm of the pneumotachometer) prevented to no patients receiving montelukast 50 mg appropriate interpretation of the exercise chal- twice daily. lenge. The analysis was therefore based upon data from 14 subjects, only one of whom used concomitant inhaled corticosteroids (table 1). There were no important differences in air- MONTELUKAST PLASMA CONCENTRATIONS way calibre before each exercise challenge for Plasma concentrations from 11 patients were each treatment period with mean pre-exercise available for analysis. The pre-exercise mean baseline FEV 1 values ranging from 3.67 to (SD) plasma concentration of montelukast was 3.83 l. Additionally, there was no significant 1.27 (0.81) μg/ml during the 50 mg twice daily treatment or carryover effect. regimen and 0.12 (0.09) μg/ml for the 100 mg Subject Maximal decrease in FEV 1 Time to recovery (min) AUC 0 60 minutes no. (% change from pre-exercise baseline) (FEV 1 to 5% of pre-exercise baseline) (min %) Placebo Montelukast Montelukast Placebo Montelukast Montelukast Placebo Montelukast Montelukast 50 mg twice daily 100 mg once daily 50 mg twice daily 100 mg once daily 50 mg twice daily 100 mg once daily Mean SD Difference from placebo (6.5 to 18.8) (9.7 to 22.0) (69.5 to 23.8) (65.9 to 20.3) (371 to 1229) (350 to 1208) (95% CI)

5 1034 Reiss, Hill, Harman, Zhang, Tanaka, Bronsky, et al Mean (SE) LTE 4 (pg/mg creatinine) choconstriction. This conclusion is based upon the observation that the concentration of LTE 4 increased after exercise challenge and montelukast, a potent and specific inhibitor of cysteinyl leukotrienes, attenuated the characteristic decrease in FEV 1 following exercise. This study shows that urinary concentrations of LTE 4 increase after exercise in adults with mild asthma. Previous studies have shown an increase in urine concentrations of LTE 4 during severe episodes of worsening asthma and after bronchoprovocation with allergen or aspirin. 16 However, results from exercise studies have been conflicting. Previous adult studies were unable to detect increases in urinary levels of LTE 4 after exercise 17 while others detected increases after exercise in children with asthma but not in normal children. 18 A possible explanation for the differences between studies Preexercise Placebo 1 h after exercise Urine collection times 2 h after exercise Figure 2 Mean (SE) urinary concentration of LTE 4 in the recovery of LTE 4 may be the timing of (pg/mg creatinine) before and one and two hours after exercise in 13 subjects while receiving placebo. Patients sample collection and/or the sensitivity of the received placebo, montelukast 50 mg twice daily or 100 mg assay employed. for two days before exercise in a double blind, randomised, The protection from exercise-induced broncrossover design. There was no significant correlation chospasm was similar 24 hours after montebetween severity of exercise-induced bronchoconstriction and urinary concentration of LTE 4. lukast 100 mg once daily and 12 hours after 50 mg twice daily. On average, the plasma concentrations were almost 10 times higher at the Table 3 Clinical adverse events trough of the twice daily regimen than at the trough of the once daily regimen, yet the pro- Placebo Montelukast Montelukast 100 mg once daily 50 mg twice daily tection was no greater. This indicates that the response after the 100 mg once daily regimen Back pain Asthma Dry mouth Nausea Fatigue Diarrhoea (0.12 μg/ml) is at or near the top of the con- Headache Epistaxis centration-response curve. A subsequent large Upper respiratory Asthma infection clinical trial has shown the clinical benefit of Urinary tract infection montelukast in chronic asthma at a lower dose Each listing represents a single episode. of 10 mg once daily at bedtime. 19 If a β agonist was administered after exercise the last value before its administration was used once daily dose. There was no correlation be- at all subsequent time points. This decision tween the plasma concentration and the extent of protection from exercise-induced bronchoconstriction, as measured by either the AUC or the maximal percentage fall in FEV 1. rule tends to underestimate the true end point values (maximal FEV 1 % fall, time to recovery, and AUC). Because rescue occurs more frequently with placebo, the true difference between active treatment and placebo will also be underestimated. Exercise challenges were generally re- LTE 4 IN URINE The urine concentration of LTE 4 increased producible for example, between prestudy significantly (p<0.05) two hours after exercise and placebo treatments providing internal challenge during placebo treatment from a validation to the conclusions of this study. mean (SD) of 34.3 (6.9) pg/mg creatinine to Using the parameters of the maximal fall 73.7 (20.4) pg/mg creatinine (fig 2). Neither in FEV 1 after exercise, previous studies have the pre-exercise LTE 4 nor the change in LTE 4 shown that β 2 selective sympathomimetics may after exercise correlated with the maximal de- provide about 70% protection from exerciseinduced crease in FEV 1 after exercise. bronchospasm immediately after adcrease ministration which dissipates within six hours with short acting agents and within 12 hours ADVERSE EFFECTS with long acting agents. 20 Cromolyn provides Clinical adverse events were infrequent and about 50% protection within the first two hours there were no significant differences in frequencies after administration. 21 In the present study between the three treatments (table montelukast produced about 50% protection 3). There were no significant changes in 24 hours after dosing. The magnitude of inlaboratory measurements of blood haem- hibition is consistent with similar studies with atology and chemistry or urinalysis with montelukast cysteinyl leukotriene receptor antagonists 22 or treatments. Discussion The results of this study provide further evidence that cysteinyl leukotrienes are involved in the pathogenesis of exercise-induced bron- a 5-lipoxygenase inhibitor. 23 Since leukotriene modifiers (5-lipoxygenase inhibitors or receptor antagonists) incompletely block the response to exercise, it is probable that other mediators released in response to exercise are also involved in the pathogenesis of exercise-induced bronchospasm.

6 Montelukast and exercise 1035 The authors thank Amy Ko for assisting with the statistical phase liquid chromatography and radioimmunoassay. Clin analysis, Stephanie Simon for expert technical assistance in the Chem 1989;35: urinary LTE 4 assay, and Joy Mitchell and Judy Evans for word 12 Diamant Z, Timmers MC, van der Veen H, Friedman BS, processing and editing the typescript. Desmet M, Depre M, et al. The effect of MK-0591, This study was supported by a grant from the Merck Research a novel 5-lipoxygenase activating protein inhibitor, on Laboratories, Rahway, New Jersey, NIH Short Term Research leukotriene biosynthesis and allergen-induced airway re- Training for Minority Students, and NIH General Clinical sponses in asthmatic subjects in vivo. J Allergy Clin Immunol Research Center Grant #M-01-RR ; Muller M, Sorrel T. Quantitation of sulfidopeptide leukotrienes by high-performance liquid chromatography. J 1 Lam S, Chan H, LeRiche JC, Chan-Yeung M, Salari H. Chromatogr 1985;343: Release of leukotrienes in patients with bronchial asthma. 14 Chasson AK, Grady HJ, Stanley MA. Determination of J Allergy Clin Immunol 1988;81: creatinine by means of automatic chemical analysis. Am 2 Kumlin M, Dahlen B, Bjorck T, Zetterstrom O, Granstrom J Clin Pathol 1961;35:83 8. E, Dahlen S-E. Urinary excretion of leukotriene E 4 and 15 Jones B, Kenward MG. Design and analysis of cross-over trials. 11-dehydro-thromboxane B 2 in response to bronchial pro- London: Chapman & Hall, vocations with allergen, aspirin, leukotriene D 4 and hist- 16 Smith CM, Christie PE, Hawksworth RJ, Thien F, Lee TH. amine in asthmatics. Am Rev Respir Dis 1992;146: Urinary leukotriene E 4 levels after allergen and exercise 3 Drazen JM, Austen KF. Leukotrienes and airway responses. challenge in bronchial asthma. Am Rev Respir Dis 1991; Am Rev Respir Dis 1987;136: : Anderson SD, Daviskas E, Smith CM. Exercise-induced 17 Taylor IK, Wellings R, Taylor GW, Fuller RW. Urinary asthma: a difference in opinion regarding the stimulus. leukotriene E 4 excretion in exercise induced asthma. J Allergy Proc 1989;10: Appl Physiol 1992;73: Manning PJ, Watson RM, Margolskee DJ, Williams VC, 18 Kikawa Y, Miyanomae T, Inoue Y, Saito M, Nakai A, Schwartz JI, O Byrne PM. Inhibition of exercise-induced Shigematsu Y, et al. Urinary leukotriene E 4 after exercise bronchoconstriction by MK-571, a potent leukotriene D 4 - challenge in children with asthma. J Allergy Clin Immunol receptor antagonist. N Engl J Med 1990;323: ;89: Finnerty JP, Wood-Baker R, Thomson H, Holgate ST. Role 19 Reiss TF, Chervinsky P, Edwards T, Dockhorn R, Nayak A, of leukotrienes in exercise-induced asthma. Inhibitory Hess J, et al. Montelukast (MK-0476) a CysLT 1 receptor effect of ICI , a potent leukotriene D 4 receptor antagonist improves asthma outcomes over a 3-month antagonist. Am Rev Respir Dis 1992;145: treatment period. Am J Respir Crit Care Med 1997;155: 7 Jarjour NN, Calhoun WJ. Exercise-induced asthma is not A662. associated with mast cell activation or airway in- 20 Anderson SD, Rodwell LT, Du Toit J, Young IH. Duration flammation. J Allergy Clin Immunol 1992;89:60 8. of protection by inhaled salmeterol in exercise-induced 8 Kikawa Y, Miyanoimae T, Inoue YM, Saito M, Nakai A, asthma. Chest 1991;100: Shigematsu Y, et al. Exercise-induced urinary excretion of 21 Patel KR, Berkin KE, Kerr JW. Dose-response study of leukotrienes E 4 in children with atopic asthma. Pediatr Res sodium cromoglycate in exercise-induced asthma. Thorax 1991;29: ;37: DeLepeleire I, Reiss TF, Rochette BS, Botto A, Zhang J, 22 Robuschi M, Riva E, Fuccella LM, et al. Prevention of Kundu S, et al. Montelukast causes prolonged, potent exercise-induced bronchoconstriction by a new leukoleukotriene D 4 -receptor antagonism in the airways of triene antagonist (SK&F ). A double-blind study patients with asthma. Clin Pharmacol Ther 1997;61: versus disodium cromoglycate and placebo. Am Rev Respir 10 Crapo RO, Hankinson J, Irvin C, Macintyre R, Voter KZ, Dis 1992:145: Wise RA. ATS standardization of spirometry, 1994 update. 23 Meltzer SS, Hasday JD, Cohn J, Bleecker ER. Inhibition of Am J Respir Crit Care Med 1995;152: exercise-induced bronchospasm by zileuton: a 5-lip- 11 Tagari P, Ethier D, Carry M, Korley V, Charleson S, Girard oxygenase inhibitor. Am J Respir Crit Care Med 1996;153: Y, et al. Measurement of urinary leukotrienes by reversed Thorax: first published as /thx on 1 December Downloaded from on 11 November 2018 by guest. Protected by copyright.