Montelukast is only partially effective in inhibiting aspirin responses in aspirin-sensitive asthmatics

Montelukast is only partially effective in inhibiting aspirin responses in aspirin-sensitive asthmatics Donald D Stevenson, MD; Ronald A Simon, MD; David A Mathison, MD; and Sandra C Christiansen, MD

Background: Leukotrienes have been implicated as major mediators of ASAinduced respiratory reactions. In several prior studies, pretreatment of ASA-sensitive respiratory disease (ASRD) patients with leukotriene modifiers have sometimes allowed subjects to tolerate previously established provoking doses of oral ASA or inhalation ASA-lysine, without respiratory reactions. Objective: The purpose of this study was to examine whether ASA-provoked respiratory reactions would be blocked or attenuated by pretreatment with a cystLT1 receptor antagonist, montelukast, particularly if ASA doses were increased above their threshold doses. Methods: Baseline ASA oral challenges were performed. Eight to 12 days later, following pretreatment with montelukast 10 mg daily, threshold and then escalating doses of ASA were used during repeat oral ASA challenges. The differences in responses between baseline and montelukast protected ASA oral challenges were then compared. Results: Nine of 10 patients, despite pretreatment with montelukast, experienced at least naso-ocular reactions during their second oral ASA challenges. In four of nine patients, asthmatic reactions also occurred. In comparing baseline and montelukast protected ASA challenges, there were no statistically significant differences in their responses. Conclusions: Pretreatment with montelukast allowed only one patient to proceed through all challenge doses of ASA without any reactions. The remaining nine patients enjoyed only partial protection from respiratory reactions. Montelukast pretreatment was generally not effective in altering upper airway reactions and only partly effective in altering lower airway reactions. Ann Allergy Asthma Immunol 2000;85:477– 482.

INTRODUCTION Aspirin (ASA)-sensitive respiratory disease (ASRD) is an acquired disease characterized by aggressive respiratory mucosal inflammation and bronchospasm.1 In an affected individual, inges-

Division of Allergy, Asthma & Immunology, Scripps Clinic and The Scripps Research Institute, La Jolla, California. Funding sources: Intramural Grant from the Division of Allergy, Asthma and Immunology, Scripps Clinic; Medical Schools Grant from Merck and Co.; and an NIH grant for the GCRC of Scripps Green Hospital and The Scripps Research Institute (Grant #M01RR00833). Received for publication January 10, 2000. Accepted for publication in revised form April 3, 2000.

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tion of ASA or non-steroidal anti-inflammatory drugs (NSAIDs), which preferentially inhibit COX-1, induce a spectrum of respiratory reactions, ranging from isolated upper airway reactions or lower airway bronchospasm versus a combination of these target organ responses and rarely systemic symptoms.2 Interestingly, withholding ASA does not improve the course of the disease. In the USA, oral ASA challenges are the only available testing method for accurately identifying patients with ASRD. Such challenges have been successfully performed at our institution, with a standard protocol, since the early 1970s.1– 4 Eightyfive percent of reactions, induced dur-

ing oral ASA challenges, involve both the upper and lower respiratory tracts and reactions usually last 2 to 6 hours.2 Leukotrienes are potent pro-inflammatory lipid derived mediators.5 They play an important pathophysiologic role in asthma, including stimulation of airway smooth muscle contraction, increased microvascular permeability, mucus secretion, and eosinophil recruitment.6 It is not surprising, therefore, that a number of leukotriene modifiers have been developed by the pharmaceutical industry. These compounds consist of cysLT1 receptor antagonists or inhibitors of leukotriene synthesis at the 5-lipoxygenase step. Significant improvement in asthma control has been reported after the use of these drugs.7–13 Leukotrienes (LTs) appear to be crucial mediators of ASA-induced respiratory reactions.14,15 In prior studies, elevated concentrations of leukotriene E4 appeared in the urine at the time of ASA-induced bronchospasm and disappeared as the respiratory reactions subsided.14,15 It was therefore logical to propose that an inhibitor of 5-lipoxygenase or antagonists of the cysLT1 receptor might prevent ASA-induced respiratory reactions. The role of antileukotriene drugs in preventing ASAinduced asthma has been previously investigated, using threshold doses of ASA given after protection with several cysLT1 receptor antagonists and the 5-L0 inhibitors ZD2138 and zileuton.16 –20 Under these challenge conditions, inhibition of the respiratory reactions, after challenges with the same doses of ASA, which had induced the baseline reaction, occurred rather frequently.

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Table 1. Individual Clinical Characteristics and Corticosteroid Medications of the 10 Study Subjects Patients

Age, yr

Sex, Male/ Female

Atopy, Positive Skin Test

Sinusitis Episodes, per/yr

No. of Prior ASA Reactions

Nasal Steroids, Puffs/d

Inhaled Steroids, puffs/d

Systemic steroids in mg/d

1 2 3 4 5 6 7 8 9 10 Average

55 44 38 58 54 53 55 72 70 41 54

F M F F F F M F F F 2/10

0 0 0 0 0 Y 0 0 0 Y 2/10

1 0 2 12 10 8 0 3 3 6 4.5

1 2 2 NSAID 2 NSAID 1 2 3 3 4 3 2.3

Flu 4 Bec 2 BecDS 4 0 BecDS 8 BecDS 8 0 Momet 4 Flu 4 Flu 8 4.2

0 Triam 4 0 Flu44 8 0 Flu220 4 BecDS 6 Flu220 4 Flu110 8 Triam 6 4.0

0 0 10 0 0 10 10 20 10 0 6 mg/d

Abbreviations: NSAIDs ⫽ non-steroidal anti-inflammatory drugs; Flu ⫽ fluticasone; Bec ⫽ beclomethasone, 42 ug; BecDS ⫽ beclomethasone double strength, 84 ug; Momet ⫽ mometasone; Triam ⫽ triamcinolone acetonide; and Flu 44, 110 or 220 ⫽ fluticasone 44, 110 or 220 ug.

Our current study was designed to answer two questions: first, to determine whether respiratory reactions would occur after oral challenges with threshold doses of ASA in the presence of montelukast blockade; and second, using the standard ASA desensitization protocol21 to determine whether escalating doses of ASA would override the protective effect of montelukast and induce reactions in ASRD patients. In other words, could ASRD patients undergo “silent” desensitization to ASA, with doses of ASA all the way up to 650 mg, if they were pretreated with 10 mg of montelukast, or would the drug partially or ineffectively alter these reactions? METHODS Patients Approval from the Human Subjects Committee and the General Clinical Research Center (GCRC) Advisory Committee was obtained and all subjects gave their informed consents. Ten

otherwise healthy asthmatic volunteers with documented ASRD were selected as the study population. All demonstrated the typical triad of chronic asthma, nasal polyposis, recurrent or chronic sinusitis, as well as histories of ASA or NSAID-induced respiratory reactions. On average they had been afflicted with ASRD for 11.7 years before this study was performed in 1998 to 1999. It should be noted that all 10 patients gave a prior history of severe asthmatic reactions, usually requiring Emergency Room treatment, after ingesting full therapeutic doses of ASA (650 mg.) or NSAIDs. Table 1 contains detailed information about their clinical characteristics and corticosteroid medications. Six patients underwent oral ASA challenges in our GCRC 1 to 14 years previously and then were treated with ASA, during ASA desensitization, for an average of 6.4 years. All patients, however, had been avoiding ASA/NSAIDs, montelukast, and any other leukotriene mod-

Table 2. Single-Blind Three-Day Oral ASA Challenge Protocol* Time

Day 1

Day 2

Day 3

7:00 AM 10:00 AM 1:00 PM

Placebo Placebo Placebo

aspirin, 30 mg aspirin, 45–60 mg aspirin, 60–100 mg

aspirin, 100–150 mg aspirin, 150–325 mg aspirin, 325–650 mg

* Schedule may be altered by the doctor. FEV1 values obtained at least every hour and observation of naso-ocular reaction, flush, etc made at least every hour. On day 1, placebo challenges should be associated with changes in FEV1 values, which vary by ⬍10% from early AM baseline values.

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ifier, for a minimum of 1 month before the initiation of these studies. Study Design Baseline oral aspirin challenges. Patients were admitted to the GCRC on the day before their first placebo challenge day. FEV1 values (best of three expiratory efforts) were measured every hour during the challenge periods (Table 2). On the day after admission, placebos were given every 3 hours for 9 hours, in order to establish stability of airways. From AM baseline, change in FEV1 values, varied between 0% to 10%. On day 2, oral ASA challenges were performed (Table 2). Aspirin respiratory reactions were defined as a decline of 20% or more in FEV1 values and/or naso-ocular reactions within 3 hours after incremental oral ASA challenges. If FEV1 values declined by 20% or greater, we considered this to be evidence of bronchospasm. Declines in FEV1 values between 15% and 20% were considered evidence of lower airway reactions, if accompanied by a naso-ocular reaction. Nasoocular reactions were defined as, “a positive response consisting of rhinorrhea plus any of the following: ocular chemosis, injection and periorbital swelling, nasal congestion, and paranasal sinus pain.” The scores were recorded as 0 ⫽ absence of any reactions, 1 ⫽ nasal congestion alone, 2 ⫽ partial nasal obstruction with ocular injection, 3 ⫽ complete nasal obstruc-

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tion with ocular injection and paranasal headache, and 4 ⫽ severe reactions with periorbital edema and severe manifestations of all other naso-ocular signs and symptoms. Laryngeal reactions were defined as crowing sounds over the upper chest and trachea, combined with a flattened and notched inspiratory curve in the flow/volume loop. The threshold dose of ASA, which had induced the reaction, was recorded and the elapse time (from ASA ingestion to first onset of respiratory symptoms/signs) was also recorded. The total time of the reaction, from onset to disappearance of all signs and symptoms was referred to as the reaction time. After ASA-induced respiratory reactions were treated and cleared, patients were discharged from the GCRC. ASA desensitization was not attempted during the first admission to GCRC where baseline data were collected. Montelukast treatment phase. After discharge from the GCRC, all study subjects continued their same medications (Table 1) plus the addition of

montelukast 10 mg each night. The importance of daily ingestion of montelukast and all controller medications was emphasized to the patients and pill counts of dispensed montelukast were conducted. To the best of our knowledge, all patients conformed to the medication protocol during this out patient phase. Second admission to GCRC with montelukast pre-treatment. Eight of the 10 patients were readmitted to GCRC on the 6th day, after their first ASA-induced reaction, and the other two patients were admitted on the 8th and 10th days after discharge (patients #3 and 10). All medications were then dispensed by research RNs and montelukast was given at 10 PM each night. On the day after re-admission, during placebo challenges, their FEV1 values again varied by ⬍ 10% from baseline. On the following day (8th day after last ASA reaction for eight patients and the 10th and 12th days for two patients), all patients underwent the same oral ASA challenge sequence that was used during baseline challenges (starting

with 30 mg of ASA). Doses of ASA were advanced until a respiratory reaction occurred or a dose of 650 mg of ASA was ingested without reactions. For each patient, the types and degrees of reactions, the threshold doses of ASA responsible for the reactions, elapse, and reaction times were recorded. Doses of ASA were then escalated over several days until desensitization was completed (650 mg ASA without reactions).21 The results of the two oral ASA challenges were compared. Statistical Analysis Statistical analysis was accomplished using non-parametric rank-sum analysis, Stat View 4.01 for Mac (Abacus Concepts, Inc, Berkeley, Ca). RESULTS In Table 3, data comparing baseline to montelukast-protected oral ASA challenges are presented. At baseline, all 10 patients experienced naso-ocular reactions to ASA with a mean naso-ocular score of 2.6. After montelukast

Table 3. Comparison of Oral Challenge Results Before and After Pretreatment with Montelukast ASA Oral Challenges at Baseline

ASA Oral Challenges with Montelukast

Patients

Naso-ocular scores

FEV1 Changes in %

ASA doses, mg

Elapse times, hr

Reaction times, hr

Naso-ocular scores

FEV1 Changes in %

ASA doses, mg

Elapse times, hr

Reaction times, hr

1 2 3 4 5 6 7 8 9 10 Mean St. Dev. SEM

3 3 2 4 1 2 1 3 4 3 2.6 1.08 0.34

3 15 26 21 20 26 21 24 18 21 19.5 6.72 2.12

60 30 100 60 60 60 100 30 60 45 60.5 24.08 7.62

0.75 3 1 1 3 2.5 2.25 2 1.5 2.5 1.9 0.84 0.27

2 3 3 1 2 2 3 5 0.5 2.5 2.4 1.24 0.39

3 3 2 2 1 2 0 2 4 3 2.4 0.88 0.29

13 14 30 18 24 13 13 23 2 13 16.3 7.80 2.47

100 45 100 60 325 60 * 30 30 60 90.0 91.75 30.58

1.5 1.75 1 3 1.1 3 * 2 1 2 1.8 0.78 0.26

2 2 3 5 5 3.75 * 6 3 2 3.5 1.50 0.50

FEV1 values ⬍15% do not represent significant changes, nor do they document bronchospasm. * Patient 7 did not react to any dose of ASA, up to 650 mg of ASA, and therefore there were no elapse or reaction times. Statistical differences between challenges: Naso-ocular reactions Decline in FEV1 values ASA threshold doses Elapse time Reaction time

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P P P P P

⫽ .18 ⫽ .28 ⫽ .22 ⫽ .87 ⫽ .08

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pretreatment, nine of ten patients experienced naso-ocular reactions with a mean score of 2.4 (P ⫽ .18). At baseline, after ASA challenges, seven of ten patients experienced a ⱖ20% decline in FEV1 values and two patients had declines of 15% and 18%. Patient #1 only had naso-ocular reactions during both challenges. For all 10 patients, the mean decline in FEV1 values was 19.5% during baseline challenges. By contrast, only three of ten patients experienced a ⬎20% decline in FEV1 values during ASA challenges with montelukast pretreatment. Patient 4 had an 18% decline in FEV1 value but the remaining six patients experienced ⬍15% reduction in FEV1 values. At the baseline challenge, patient #7 experienced a typical upper and lower respiratory reaction with an FEV1 drop of 21%. In addition to his nasal symptoms, he also complained of chest tightness, breathlessness and audible wheezing. He required three inhalation treatments with albuterol to remain comfortable during his 3-hour recovery from the baseline ASA-induced reaction. In striking contrast, with montelukast protection, he did not experience any respiratory tract symptoms during the second ASA challenge. He was truly “silently” desensitized to ASA. All of the other nine patients had some respiratory tract symptoms during both baseline and montelukast protected ASA challenges. For this small sample size, however, n ⫽ 10, there were no statistically significant differences in the changes in FEV1 values (P ⫽ .28). For the initial or baseline challenges, the mean threshold dose of ASA was 60.5 mg, although individual responses varied between 30 and 100 mg. By contrast, the mean provoking dose of ASA with montelukast pretreatment was 90 mg (range 30 to 325 mg., with one patient not reacting up to a dose of ASA, 650 mg. Calculation of the mean threshold ASA dose was limited to the nine patients who reacted to ASA). Despite a difference of 30 mg between the two threshold doses, there was no statistically significant difference in this small sample (P ⫽ .22). Even so, there was clearly a trend for higher

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provoking doses of ASA to be needed for initiating respiratory reactions in four patients, while protected by montelukast (#1, 2, 5, and 10). Of the four patients who experienced bronchospastic responses to ASA during both challenges, three patients (#3, 4, and 8) reacted to the same provoking doses of ASA (100, 60, and 30 mg), whereas for patient #5, the provoking doses of ASA progressed from 60 to 325 mg. The mean elapse time to naso-ocular reactions with initial ASA challenges, following provoking doses of ASA, was 1.9 hours. By contrast, the mean elapse time to naso-ocular responses, with montelukast pretreatment, was 1.8 hours (P ⫽ .87). Differences between the reaction times for both challenges also did not reach statistical significance (2.4 and 3.5 hours, P ⫽ .08). DISCUSSION Montelukast in doses of 10 mg/24 hours efficiently blocks cysLT1 receptors; therefore, pretreatment with montelukast represents an excellent model for studying the importance of these mediators in the induction of upper and lower respiratory reactions. Our study showed that only one of ten patients was completely protected from the adverse effects of full therapeutic doses of oral ASA by pretreatment with montelukast. In the remaining nine patients, montelukast pretreatment did not protect any patients from naso-ocular reactions to ASA but did prevent bronchospasm in half the patients, during their second oral challenges. A strong trend toward higher threshold doses of ASA being required to initiate respiratory reactions, in the presence of montelukast, was also noted in this study. A prior study using the selective LTD4 receptor antagonist SK&F 104353 by inhalation, prevented oral ASA-induced bronchospasm in four of five ASA-sensitive asthmatics when comparing the same provoking doses (ranging from 30 to 120 mg of ASA given orally).16 Even in the four subjects, where repeat ASA-provoking doses did not induce bronchospasm, the protection ranged from marginal

(16% decrease in FEV1 with the patient requesting albuterol bronchodilation) to complete prevention of reactions to ASA in three patients. Larger challenge doses of ASA, beyond the threshold dose, were not a part of this study protocol. Dahlen et al20 reported a study where MK-0679 (a potent leukotriene receptor antagonist), given as a single 750-mg oral dose prior to ASA-lysine inhalation challenges, was contrasted with placebo protection in a double blind protocol. In eight ASA-sensitive asthmatic subjects, pretreatment with MK-0679 substantially shifted the dose response to inhaled ASA-lysine to the right. Three of the eight patients were protected from bronchospasm after receiving the highest doses of ASA-lysine (600 and 720 umol). In the other five subjects, the shift was definite but more modest, ranging from a pre of 3 umol (lowest) to a post of 68 umol (highest). In summary, five of eight patients receiving a LTD4 receptor antagonist continued to experience bronchospasm after inhaled ASA-lysine, when the dose of ASA-lysine by inhalation was advanced to the highest concentration available for inhalation. Accurate comparisons between our study, where oral challenges with ASA were employed and the doses of ASA were advanced well beyond those given by inhalation, and the Dahlen study20 cannot be made. In a study by Israel et al,19 eight ASA-sensitive asthmatic patients, previously shown to react to threshold provoking doses of oral ASA (20 to 300 mg range, 90 mg mean), were shown to be protected from the same threshold doses of ASA after pretreatment with a 5-lipoxygenase inhibitor (zileuton). Furthermore, during the zileuton-protected ASA challenges, there was a concomitant blunting of the expected increases in urinary LTE4. The ASA-sensitive patients recruited in the Israel study19 generally had mild-to-moderate ASA respiratory disease. None of their patients required maintenance systemic corticosteroids. The capability of zileuton to block respiratory reactions, following larger

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escalating doses of ASA above the threshold challenge doses, were not a part of this study. In a recent study by Pauls et al,22 however, doses of ASA were escalated beyond the threshold doses during the second challenge with zileuton protection. In this study, following ingestion of ASA, all six patients experienced at least a naso-ocular reaction and four of six had asthmatic reactions despite concomitant ingestion of zileuton. Simultaneous increases in urinary LTE4 confirmed the fact that zileuton, in usual therapeutic doses, did not prevent formation of leukotrienes, during ASAinduced asthmatic reactions in these four patients. Because of these blocking studies, we can draw some inferences about the mechanisms by which ASA induces respiratory reactions. Either montelukast does not effectively block all cysLT1 receptors, or there are other currently undiscovered cysLT receptors that sometimes participate in the ASA-induced respiratory reactions. Alternatively, other mediators, such as histamine,23 are excellent candidates to stimulate upper airways and would not be blocked by pretreatment with montelukast. In this current study, our original goal of providing patients with “silent” ASA desensitization could only be achieved in one patient. The fact that six patients had only naso-ocular reactions, without significant lower respiratory reactions, during pretreatment with montelukast, eliminated the discomfort of bronchospasm. In four patients, however, there was virtually no modification of the ASA-induced reactions. It seems therefore likely that montelukast will enjoy a position similar to systemic corticosteroids in the preparation of some ASRD patients for oral ASA challenges. Corticosteroids stabilize irritable airways and modify the severity of the lower respiratory reactions with reasonable regularity.4 In occasional patients, systemic corticosteroids actually block all ASA-induced respiratory reactions.1,4 Nevertheless, the greater risk of instability of the bronchial airways during oral ASA

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challenges makes it prudent to use systemic corticosteroids in some ASRD patients, during their preparation for oral ASA challenges. With further experience in the use of montelukast, this drug may in some cases replace or be used as an adjunct to systemic corticosteroids, for providing stability of the airways, slightly modifying the severity of the ASA-induced reactions and only rarely blocking both upper and lower respiratory reactions. It has been established that ASAinduced respiratory reactions become more severe as ASA doses are increased.1 Most ASRD patients, who are taking montelukast daily for the control of asthma, will therefore continue to be vulnerable to respiratory reactions, following ingestion of full therapeutic doses of ASA (325 or 650 mg) or equivalent doses of NSAIDs, which preferentially inhibit COX-1. In fact, as shown in the challenge studies in this paper, ASA doses in the equivalency range of children’s aspirin (81 mg) can induce significant respiratory reactions despite the simultaneous ingestion of montelukast. It is important for physicians to counsel their patients about this potential problem. ACKNOWLEDGEMENTS We are indebted to the GCRC research nurses, without whose dedicated efforts, this project could not have been conducted. Special appreciation goes to Mrs. Aliene Duvalian, RN, nurse coordinator for the GCRC Aspirin Project. REFERENCES 1. Stevenson DD, Simon RA. Sensitivity to aspirin and nonsteroidal antiinflammatory drugs. In: Middleton EJ, Reed CE, Ellis EF, et al, eds. Allergy: principles and practice. 5 ed. St. Louis, Mo: Mosby and Co., 1998:1225–1234. 2. Pleskow WW, Stevenson DD, Mathison DA et al. Aspirin-sensitive rhinosinusitis/asthma: Spectrum of adverse reactions to aspirin. J Allergy Clin Immunol 1983;71:574 –579. 3. McDonald J, Mathison DA, Stevenson DD. Aspirin tolerance in asthmadetection by challenge. J Allergy Clin Immunol 1972;50:198 –207.

4. Stevenson DD. Oral challenges to detect aspirin and sulfite sensitivity in asthma. N E Reg Allergy Proc 1988; 9:135–142. 5. Samuelsson B. Leukotrienes: mediators of immediate hypersensitivity reactions and inflammation. Science 1983;220:568 –575. 6. Busse W. The role and contribution of leukotrienes in asthma. Ann Allergy Asthma Immunol 1998;81:17–26. 7. Drazen J, Israel E, O’Byrne PM. Treatment of asthma with drugs modifying the leukotriene pathway. N Engl J Med 1999;340:197–206. 8. Holgate ST, Bradding P, Sampson AP. Leukotriene antagonists and synthesis inhibitors: new directions in asthma therapy. J Allergy Clin Immunol 1996; 98:1–13. 9. Horwitz RJ, McGill KA, Busse WW. The role of leukotriene modifiers in the treatment of asthma. Am J Respir Crit Care Med 1998;157:1363–1371. 10. O’Byrne PM, Israel E, Drazen JM. Antileukotrienes in the treatment of asthma. Ann Intern Med 1997;127: 472– 480. 11. Spector SL. Leukotriene inhibitors and antagonists in asthma. Ann Allergy Asthma Immunol 1995;75:463– 470. 12. Dahlen B, Nizankowska E, Szczeklik A, et al. Benefits from adding the 5-lipoxygenase inhibitor zileuton to conventional therapy in aspirin-intolerant asthmatics. Am J Respir Crit Care Med 1998;157:1187–1194. 13. Dahlen B, Margolskee DJ, Zetterstrom O, et al. SE. Effect of the leukotriene receptor antagonist MK-0679 on baseline pulmonary function in aspirin sensitive asthmatic subjects. Thorax 1993; 48:1205–1210. 14. Christie PE, Tagari P, Ford-Hutchinson AW, et al. Urinary leukotriene E4 concentrations increase after aspirin challenge in aspirin-sensitive asthmatic subjects. Am Rev Respir Dis 1991;143:1025–1029. 15. Kumlin M, Dahlen B, Bjorck T, et al. Urinary excretion of leukotriene E4 and 11-dehydro-thromboxane B2 in response to bronchial provocations with allergen, aspirin, leukotriene D4, and histamine in asthmatics. Am Rev Respir Dis 1992;146:96 –103. 16. Christie PE, Smith CM, Lee TH. The potent and selective sulfidopeptide leukotriene antagonist SK&F 104353, inhibits aspirin-induced asthma. Am Rev Respir Dis 1991;144:957–962.

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17. Yamamoto H, Nagata M, Kuramitsu K, et al. Inhibition of analgesicinduced asthma by leukotriene receptor antagonist ONO-1078. Am J Respir Crit Care Med 1994;150:254 –257. 18. Nasser SM, Bell GS, Foster S, et al. Effect of the 5-lipoxygenase inhibitor ZD2138 on aspirin-induced asthma. Thorax 1994;49:749 –756. 19. Israel E, Fischer AR, Rosenberg MA, et al. The pivotal role of 5-lipoxygenase products in the reaction of aspirinsensitive asthmatics to aspirin. Am Rev Respir Dis 1993;148:1447–1451. 20. Dahlen BJ, Kumlin M, Margolskee D,

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et al. The leukotriene receptor antagonist MK-0679 blocks airway obstruction induced by bronchial provocation with lysine-aspirin in aspirin-sensitive asthmatics. Eur Respir J 1993;6: 1018 –1026. 21. Pleskow WW, Stevenson DD, Mathison DA, et al. Aspirin desensitization in aspirin sensitive asthmatic patients: clinical manifestations and characterization of the refractory period. J Allergy Clin Immunol 1982;69:11–19. 22. Pauls JD, Simon RA, Daffern PJ, et al. Lack of effect of the 5-lipoxygenase inhibitor zileuton in blocking oral as-

pirin challenges in aspirin sensitive asthmatics. Ann Allergy Asthma Immunol 2000;85:40 – 45. 23. Ferreri NR, Howland WC, Stevenson DD, et al. Release of leukotrienes, prostaglandins and histamine into nasal secretions of aspirin-sensitive asthmatic during reaction to aspirin. Am Rev Respir Dis 1988;137:847– 854. Donald D Stevenson, MD Scripps Clinic 10666 N Torrey Pines Rd La Jolla, CA 92037

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