Montelukast is only partially effective ininhibiting aspirin responses in aspirin-sensitiveasthmaticsDonald 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 ASA-induced respiratory reactions. In several prior studies, pretreatment of ASA-sensi-tive respiratory disease (ASRD) patients with leukotriene modifiers have sometimesallowed subjects to tolerate previously established provoking doses of oral ASA orinhalation 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 cystLT1receptor antagonist, montelukast, particularly if ASA doses were increased abovetheir threshold doses.Methods: Baseline ASA oral challenges were performed. Eight to 12 days later,

following pretreatment with montelukast 10 mg daily, threshold and then escalatingdoses of ASA were used during repeat oral ASA challenges. The differences inresponses between baseline and montelukast protected ASA oral challenges werethen compared.Results: Nine of 10 patients, despite pretreatment with montelukast, experienced

at least naso-ocular reactions during their second oral ASA challenges. In four ofnine patients, asthmatic reactions also occurred. In comparing baseline and monte-lukast protected ASA challenges, there were no statistically significant differencesin their responses.Conclusions: Pretreatment with montelukast allowed only one patient to proceed

through all challenge doses of ASA without any reactions. The remaining ninepatients enjoyed only partial protection from respiratory reactions. Montelukastpretreatment was generally not effective in altering upper airway reactions and onlypartly effective in altering lower airway reactions.

Ann Allergy Asthma Immunol 2000;85:477–482.

INTRODUCTIONAspirin (ASA)-sensitive respiratorydisease (ASRD) is an acquired diseasecharacterized by aggressive respiratorymucosal inflammation and bronchos-pasm.1 In an affected individual, inges-

tion of ASA or non-steroidal anti-in-flammatory drugs (NSAIDs), whichpreferentially inhibit COX-1, induce aspectrum of respiratory reactions,ranging from isolated upper airway re-actions or lower airway bronchospasmversus a combination of these targetorgan responses and rarely systemicsymptoms.2 Interestingly, withholdingASA does not improve the course ofthe disease. In the USA, oral ASAchallenges are the only available test-ing method for accurately identifyingpatients with ASRD. Such challengeshave been successfully performed atour institution, with a standard proto-col, since the early 1970s.1–4 Eighty-five percent of reactions, induced dur-

ing oral ASA challenges, involve boththe upper and lower respiratory tractsand reactions usually last 2 to 6 hours.2Leukotrienes are potent pro-inflam-

matory lipid derived mediators.5 Theyplay an important pathophysiologicrole in asthma, including stimulationof airway smooth muscle contraction,increased microvascular permeability,mucus secretion, and eosinophil re-cruitment.6 It is not surprising, there-fore, that a number of leukotrienemodifiers have been developed by thepharmaceutical industry. These com-pounds consist of cysLT1 receptor an-tagonists or inhibitors of leukotrienesynthesis at the 5-lipoxygenase step.Significant improvement in asthmacontrol has been reported after the useof these drugs.7–13Leukotrienes (LTs) appear to be cru-

cial mediators of ASA-induced respi-ratory reactions.14,15 In prior studies,elevated concentrations of leukotrieneE4 appeared in the urine at the time ofASA-induced bronchospasm and dis-appeared as the respiratory reactionssubsided.14,15 It was therefore logical topropose that an inhibitor of 5-lipoxy-genase or antagonists of the cysLT1receptor might prevent ASA-inducedrespiratory reactions. The role of anti-leukotriene drugs in preventing ASA-induced asthma has been previouslyinvestigated, using threshold doses ofASA given after protection with sev-eral cysLT1 receptor antagonists andthe 5-L0 inhibitors ZD2138 and zileu-ton.16–20 Under these challenge condi-tions, inhibition of the respiratory re-actions, after challenges with the samedoses of ASA, which had induced thebaseline reaction, occurred rather fre-quently.

Division of Allergy, Asthma & Immunology,Scripps Clinic and The Scripps Research Insti-tute, La Jolla, California.Funding sources: Intramural Grant from the

Division of Allergy, Asthma and Immunology,Scripps Clinic; Medical Schools Grant fromMerck and Co.; and an NIH grant for the GCRCof Scripps Green Hospital and The Scripps Re-search Institute (Grant #M01RR00833).Received for publication January 10, 2000.Accepted for publication in revised form

April 3, 2000.

VOLUME 85, DECEMBER, 2000 477

Our current study was designed toanswer two questions: first, to deter-mine whether respiratory reactionswould occur after oral challenges withthreshold doses of ASA in the presenceof montelukast blockade; and second,using the standard ASA desensitizationprotocol21 to determine whether esca-lating doses of ASA would overridethe protective effect of montelukastand induce reactions in ASRD pa-tients. In other words, could ASRDpatients undergo “silent” desensitiza-tion to ASA, with doses of ASA all theway up to 650 mg, if they were pre-treated with 10 mg of montelukast, orwould the drug partially or ineffec-tively alter these reactions?

METHODSPatientsApproval from the Human SubjectsCommittee and the General ClinicalResearch Center (GCRC) AdvisoryCommittee was obtained and all sub-jects gave their informed consents. Ten

otherwise healthy asthmatic volunteerswith documented ASRD were selectedas the study population. All demon-strated the typical triad of chronicasthma, nasal polyposis, recurrent orchronic sinusitis, as well as histories ofASA or NSAID-induced respiratoryreactions. On average they had beenafflicted with ASRD for 11.7 yearsbefore this study was performed in1998 to 1999. It should be noted thatall 10 patients gave a prior history ofsevere asthmatic reactions, usually re-quiring Emergency Room treatment,after ingesting full therapeutic doses ofASA (650 mg.) or NSAIDs. Table 1contains detailed information abouttheir clinical characteristics and corti-costeroid medications. Six patients un-derwent oral ASA challenges in ourGCRC 1 to 14 years previously andthen were treated with ASA, duringASA desensitization, for an average of6.4 years. All patients, however, hadbeen avoiding ASA/NSAIDs, monte-lukast, and any other leukotriene mod-

ifier, for a minimum of 1 month beforethe initiation of these studies.Study DesignBaseline oral aspirin challenges. Pa-tients were admitted to the GCRC onthe day before their first placebo chal-lenge day. FEV1 values (best of threeexpiratory efforts) were measured ev-ery hour during the challenge periods(Table 2). On the day after admission,placebos were given every 3 hours for9 hours, in order to establish stabilityof airways. From AM baseline, changein FEV1 values, varied between 0% to10%. On day 2, oral ASA challengeswere performed (Table 2). Aspirin re-spiratory reactions were defined as adecline of 20% or more in FEV1 valuesand/or naso-ocular reactions within 3hours after incremental oral ASA chal-lenges. If FEV1 values declined by20% or greater, we considered this tobe evidence of bronchospasm. De-clines in FEV1 values between 15%and 20% were considered evidence oflower airway reactions, if accompa-nied by a naso-ocular reaction. Naso-ocular reactions were defined as, “apositive response consisting of rhinor-rhea plus any of the following: ocularchemosis, injection and periorbitalswelling, nasal congestion, and parana-sal sinus pain.” The scores were re-corded as 0 � absence of any reac-tions, 1 � nasal congestion alone, 2 �partial nasal obstruction with ocularinjection, 3 � complete nasal obstruc-

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

PatientsAge,

yr

Sex,Male/

Female

Atopy,Positive

Skin Test

SinusitisEpisodes,

per/yr

No. of PriorASA

Reactions

NasalSteroids,Puffs/d

InhaledSteroids,puffs/d

Systemicsteroidsin mg/d

1 55 F 0 1 1 Flu 4 0 02 44 M 0 0 2 Bec 2 Triam 4 03 38 F 0 2 2 BecDS 4 0 104 58 F 0 12 NSAID 2 0 Flu44 8 05 54 F 0 10 NSAID 1 BecDS 8 0 06 53 F Y 8 2 BecDS 8 Flu220 4 107 55 M 0 0 3 0 BecDS 6 108 72 F 0 3 3 Momet 4 Flu220 4 209 70 F 0 3 4 Flu 4 Flu110 8 10

10 41 F Y 6 3 Flu 8 Triam 6 0Average 54 2/10 2/10 4.5 2.3 4.2 4.0 6 mg/d

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

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

Time Day 1 Day 2 Day 3

7:00 AM Placebo aspirin, 30 mg aspirin, 100–150 mg10:00 AM Placebo aspirin, 45–60 mg aspirin, 150–325 mg1:00 PM Placebo aspirin, 60–100 mg aspirin, 325–650 mg

* Schedule may be altered by the doctor. FEV1 values obtained at least every hour andobservation of naso-ocular reaction, flush, etc made at least every hour. On day 1, placebochallenges should be associated with changes in FEV1 values, which vary by �10% from earlyAM baseline values.

478 ANNALS OF ALLERGY, ASTHMA, & IMMUNOLOGY

tion with ocular injection and parana-sal headache, and 4 � severe reactionswith periorbital edema and severemanifestations of all other naso-ocularsigns and symptoms. Laryngeal reac-tions were defined as crowing soundsover the upper chest and trachea, com-bined with a flattened and notched in-spiratory curve in the flow/volumeloop. The threshold dose of ASA,which had induced the reaction, wasrecorded and the elapse time (fromASA ingestion to first onset of respi-ratory symptoms/signs) was also re-corded. The total time of the reaction,from onset to disappearance of allsigns and symptoms was referred to asthe reaction time. After ASA-inducedrespiratory reactions were treated andcleared, patients were discharged fromthe GCRC. ASA desensitization wasnot attempted during the first admis-sion to GCRC where baseline datawere collected.Montelukast treatment phase. After

discharge from the GCRC, all studysubjects continued their same medica-tions (Table 1) plus the addition of

montelukast 10 mg each night. Theimportance of daily ingestion of mon-telukast and all controller medicationswas emphasized to the patients and pillcounts of dispensed montelukast wereconducted. To the best of our knowl-edge, all patients conformed to themedication protocol during this out pa-tient phase.Second admission to GCRC with

montelukast pre-treatment. Eight ofthe 10 patients were readmitted toGCRC on the 6th day, after their firstASA-induced reaction, and the othertwo patients were admitted on the 8thand 10th days after discharge (patients#3 and 10). All medications were thendispensed by research RNs and mon-telukast was given at 10 PM each night.On the day after re-admission, duringplacebo challenges, their FEV1 valuesagain varied by � 10% from baseline.On the following day (8th day after lastASA reaction for eight patients and the10th and 12th days for two patients),all patients underwent the same oralASA challenge sequence that was usedduring baseline challenges (starting

with 30 mg of ASA). Doses of ASAwere advanced until a respiratory reac-tion occurred or a dose of 650 mg ofASA was ingested without reactions.For each patient, the types and degreesof reactions, the threshold doses ofASA responsible for the reactions,elapse, and reaction times were re-corded. Doses of ASA were then esca-lated over several days until desensiti-zation was completed (650 mg ASAwithout reactions).21 The results of thetwo oral ASA challenges were com-pared.Statistical AnalysisStatistical analysis was accomplishedusing non-parametric rank-sum analy-sis, Stat View 4.01 for Mac (AbacusConcepts, Inc, Berkeley, Ca).

RESULTSIn Table 3, data comparing baseline tomontelukast-protected oral ASA chal-lenges are presented. At baseline, all10 patients experienced naso-ocular re-actions to ASA with a mean naso-oc-ular score of 2.6. After montelukast

Table 3. Comparison of Oral Challenge Results Before and After Pretreatment with Montelukast

Patients

ASA Oral Challenges at Baseline ASA Oral Challenges with Montelukast

Naso-ocularscores

FEV1

Changesin %

ASAdoses,

mg

Elapsetimes,

hr

Reactiontimes, hr

Naso-ocularscores

FEV1

Changesin %

ASAdoses,

mg

Elapsetimes,

hr

Reactiontimes, hr

1 3 3 60 0.75 2 3 13 100 1.5 22 3 15 30 3 3 3 14 45 1.75 23 2 26 100 1 3 2 30 100 1 34 4 21 60 1 1 2 18 60 3 55 1 20 60 3 2 1 24 325 1.1 56 2 26 60 2.5 2 2 13 60 3 3.757 1 21 100 2.25 3 0 13 * * *8 3 24 30 2 5 2 23 30 2 69 4 18 60 1.5 0.5 4 2 30 1 3

10 3 21 45 2.5 2.5 3 13 60 2 2Mean 2.6 19.5 60.5 1.9 2.4 2.4 16.3 90.0 1.8 3.5St. Dev. 1.08 6.72 24.08 0.84 1.24 0.88 7.80 91.75 0.78 1.50SEM 0.34 2.12 7.62 0.27 0.39 0.29 2.47 30.58 0.26 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 P � .18Decline in FEV1 values P � .28ASA threshold doses P � .22Elapse time P � .87Reaction time P � .08

VOLUME 85, DECEMBER, 2000 479

pretreatment, nine of ten patients ex-perienced naso-ocular reactions with amean score of 2.4 (P � .18). At base-line, after ASA challenges, seven often patients experienced a �20% de-cline in FEV1 values and two patientshad declines of 15% and 18%. Patient#1 only had naso-ocular reactions dur-ing both challenges. For all 10 patients,the mean decline in FEV1 values was19.5% during baseline challenges. Bycontrast, only three of ten patients ex-perienced a �20% decline in FEV1values during ASA challenges withmontelukast pretreatment. Patient 4had an 18% decline in FEV1 value butthe remaining six patients experienced�15% reduction in FEV1 values. Atthe baseline challenge, patient #7 ex-perienced a typical upper and lowerrespiratory reaction with an FEV1 dropof 21%. In addition to his nasal symp-toms, he also complained of chesttightness, breathlessness and audiblewheezing. He required three inhalationtreatments with albuterol to remaincomfortable during his 3-hour recov-ery from the baseline ASA-inducedreaction. In striking contrast, withmontelukast protection, he did not expe-rience any respiratory tract symptomsduring the second ASA challenge. Hewas truly “silently” desensitized to ASA.All of the other nine patients had somerespiratory tract symptoms during bothbaseline and montelukast protectedASA challenges. For this small samplesize, however, n � 10, there were nostatistically significant differences inthe changes in FEV1 values (P � .28).For the initial or baseline challenges,the mean threshold dose of ASA was60.5 mg, although individual responsesvaried between 30 and 100 mg. Bycontrast, the mean provoking dose ofASA with montelukast pretreatmentwas 90 mg (range 30 to 325 mg., withone patient not reacting up to a dose ofASA, 650 mg. Calculation of the meanthreshold ASA dose was limited to thenine patients who reacted to ASA).Despite a difference of 30 mg betweenthe two threshold doses, there was nostatistically significant difference inthis small sample (P � .22). Even so,there was clearly a trend for higher

provoking doses of ASA to be neededfor initiating respiratory reactions infour patients, while protected by mon-telukast (#1, 2, 5, and 10). Of the fourpatients who experienced bronchos-pastic responses to ASA during bothchallenges, three patients (#3, 4, and 8)reacted to the same provoking doses ofASA (100, 60, and 30 mg), whereasfor patient #5, the provoking doses ofASA progressed from 60 to 325 mg.The mean elapse time to naso-ocularreactions with initial ASA challenges,following provoking doses of ASA,was 1.9 hours. By contrast, the meanelapse time to naso-ocular responses,with montelukast pretreatment, was1.8 hours (P � .87). Differences be-tween the reaction times for both chal-lenges also did not reach statistical sig-nificance (2.4 and 3.5 hours, P � .08).

DISCUSSIONMontelukast in doses of 10 mg/24hours efficiently blocks cysLT1 recep-tors; therefore, pretreatment with mon-telukast represents an excellent modelfor studying the importance of thesemediators in the induction of upper andlower respiratory reactions. Our studyshowed that only one of ten patientswas completely protected from the ad-verse effects of full therapeutic dosesof oral ASA by pretreatment withmontelukast. In the remaining nine pa-tients, montelukast pretreatment didnot protect any patients from naso-oc-ular reactions to ASA but did preventbronchospasm in half the patients, dur-ing their second oral challenges. Astrong trend toward higher thresholddoses of ASA being required to initiaterespiratory reactions, in the presenceof montelukast, was also noted in thisstudy.A prior study using the selective

LTD4 receptor antagonist SK&F104353 by inhalation, prevented oralASA-induced bronchospasm in four offive ASA-sensitive asthmatics whencomparing the same provoking doses(ranging from 30 to 120 mg of ASAgiven orally).16 Even in the four sub-jects, where repeat ASA-provokingdoses did not induce bronchospasm,the protection ranged from marginal

(16% decrease in FEV1 with the pa-tient requesting albuterol bronchodila-tion) to complete prevention of reac-tions to ASA in three patients. Largerchallenge doses of ASA, beyond thethreshold dose, were not a part of thisstudy protocol.Dahlen et al20 reported a study

where MK-0679 (a potent leukotrienereceptor antagonist), given as a single750-mg oral dose prior to ASA-lysineinhalation challenges, was contrastedwith placebo protection in a doubleblind protocol. In eight ASA-sensitiveasthmatic subjects, pretreatment withMK-0679 substantially shifted the doseresponse to inhaled ASA-lysine to theright. Three of the eight patients wereprotected from bronchospasm after re-ceiving the highest doses of ASA-ly-sine (600 and 720 umol). In the otherfive subjects, the shift was definite butmore modest, ranging from a pre of 3umol (lowest) to a post of 68 umol(highest). In summary, five of eightpatients receiving a LTD4 receptor an-tagonist continued to experience bron-chospasm after inhaled ASA-lysine,when the dose of ASA-lysine by inha-lation was advanced to the highest con-centration available for inhalation. Ac-curate comparisons between our study,where oral challenges with ASA wereemployed and the doses of ASA wereadvanced well beyond those given byinhalation, and the Dahlen study20 can-not be made.In a study by Israel et al,19 eight

ASA-sensitive asthmatic patients, pre-viously shown to react to thresholdprovoking doses of oral ASA (20 to300 mg range, 90 mg mean), wereshown to be protected from the samethreshold doses of ASA after pretreat-ment with a 5-lipoxygenase inhibitor(zileuton). Furthermore, during thezileuton-protected ASA challenges,there was a concomitant blunting ofthe expected increases in urinary LTE4.The ASA-sensitive patients recruitedin the Israel study19 generally hadmild-to-moderate ASA respiratory dis-ease. None of their patients requiredmaintenance systemic corticosteroids.The capability of zileuton to block re-spiratory reactions, following larger

480 ANNALS OF ALLERGY, ASTHMA, & IMMUNOLOGY

escalating doses of ASA above thethreshold challenge doses, were not apart of this study. In a recent study byPauls et al,22 however, doses of ASAwere escalated beyond the thresholddoses during the second challenge withzileuton protection. In this study, fol-lowing ingestion of ASA, all six pa-tients experienced at least a naso-ocu-lar reaction and four of six hadasthmatic reactions despite concomi-tant ingestion of zileuton. Simulta-neous increases in urinary LTE4 con-firmed the fact that zileuton, in usualtherapeutic doses, did not prevent for-mation of leukotrienes, during ASA-induced asthmatic reactions in thesefour patients.Because of these blocking studies,

we can draw some inferences about themechanisms by which ASA inducesrespiratory reactions. Either monte-lukast does not effectively block allcysLT1 receptors, or there are othercurrently undiscovered cysLT recep-tors that sometimes participate in theASA-induced respiratory reactions.Alternatively, other mediators, such ashistamine,23 are excellent candidates tostimulate upper airways and would notbe blocked by pretreatment with mon-telukast.In this current study, our original

goal of providing patients with “silent”ASA desensitization could only beachieved in one patient. The fact thatsix patients had only naso-ocular reac-tions, without significant lower respi-ratory reactions, during pretreatmentwith montelukast, eliminated the dis-comfort of bronchospasm. In four pa-tients, however, there was virtually nomodification of the ASA-induced reac-tions. It seems therefore likely thatmontelukast will enjoy a position sim-ilar to systemic corticosteroids in thepreparation of some ASRD patients fororal ASA challenges. Corticosteroidsstabilize irritable airways and modifythe severity of the lower respiratoryreactions with reasonable regularity.4In occasional patients, systemic corti-costeroids actually block all ASA-in-duced respiratory reactions.1,4 Never-theless, the greater risk of instability ofthe bronchial airways during oral ASA

challenges makes it prudent to use sys-temic corticosteroids in some ASRDpatients, during their preparation fororal ASA challenges. With further ex-perience in the use of montelukast, thisdrug may in some cases replace or beused as an adjunct to systemic cortico-steroids, for providing stability of theairways, slightly modifying the sever-ity of the ASA-induced reactions andonly rarely blocking both upper andlower respiratory reactions.It has been established that ASA-

induced respiratory reactions becomemore severe as ASA doses are in-creased.1 Most ASRD patients, whoare taking montelukast daily for thecontrol of asthma, will therefore con-tinue to be vulnerable to respiratoryreactions, following ingestion of fulltherapeutic doses of ASA (325 or 650mg) or equivalent doses of NSAIDs,which preferentially inhibit COX-1. Infact, as shown in the challenge studiesin this paper, ASA doses in the equiv-alency range of children’s aspirin (81mg) can induce significant respiratoryreactions despite the simultaneous in-gestion of montelukast. It is importantfor physicians to counsel their patientsabout this potential problem.

ACKNOWLEDGEMENTSWe are indebted to the GCRC researchnurses, without whose dedicated ef-forts, this project could not have beenconducted. Special appreciation goesto Mrs. Aliene Duvalian, RN, nursecoordinator for the GCRC AspirinProject.

REFERENCES1. Stevenson DD, Simon RA. Sensitivityto aspirin and nonsteroidal antiinflam-matory drugs. In: Middleton EJ, ReedCE, Ellis EF, et al, eds. Allergy: prin-ciples and practice. 5 ed. St. Louis,Mo: Mosby and Co., 1998:1225–1234.

2. Pleskow WW, Stevenson DD, Mathi-son DA et al. Aspirin-sensitiverhinosinusitis/asthma: Spectrum of ad-verse reactions to aspirin. J AllergyClin Immunol 1983;71:574–579.

3. McDonald J, Mathison DA, StevensonDD. Aspirin tolerance in asthma-detection by challenge. J Allergy ClinImmunol 1972;50:198–207.

4. Stevenson DD. Oral challenges to de-tect aspirin and sulfite sensitivity inasthma. N E Reg Allergy Proc 1988;9:135–142.

5. Samuelsson B. Leukotrienes: media-tors of immediate hypersensitivity re-actions and inflammation. Science1983;220:568–575.

6. Busse W. The role and contribution ofleukotrienes in asthma. Ann AllergyAsthma Immunol 1998;81:17–26.

7. Drazen J, Israel E, O’Byrne PM. Treat-ment of asthma with drugs modifyingthe leukotriene pathway. N Engl J Med1999;340:197–206.

8. Holgate ST, Bradding P, Sampson AP.Leukotriene antagonists and synthesisinhibitors: new directions in asthmatherapy. J Allergy Clin Immunol 1996;98:1–13.

9. Horwitz RJ, McGill KA, Busse WW.The role of leukotriene modifiers inthe treatment of asthma. Am J RespirCrit Care Med 1998;157:1363–1371.

10. O’Byrne PM, Israel E, Drazen JM. An-tileukotrienes in the treatment ofasthma. Ann Intern Med 1997;127:472–480.

11. Spector SL. Leukotriene inhibitors andantagonists in asthma. Ann AllergyAsthma Immunol 1995;75:463–470.

12. Dahlen B, Nizankowska E, SzczeklikA, et al. Benefits from adding the 5-li-poxygenase inhibitor zileuton to con-ventional therapy in aspirin-intolerantasthmatics. Am J Respir Crit Care Med1998;157:1187–1194.

13. Dahlen B, Margolskee DJ, ZetterstromO, et al. SE. Effect of the leukotrienereceptor antagonist MK-0679 on base-line pulmonary function in aspirin sen-sitive asthmatic subjects. Thorax 1993;48:1205–1210.

14. Christie PE, Tagari P, Ford-Hutchin-son AW, et al. Urinary leukotriene E4concentrations increase after aspirinchallenge in aspirin-sensitive asth-matic subjects. Am Rev Respir Dis1991;143:1025–1029.

15. Kumlin M, Dahlen B, Bjorck T, et al.Urinary excretion of leukotriene E4and 11-dehydro-thromboxane B2 inresponse to bronchial provocationswith allergen, aspirin, leukotriene D4,and histamine in asthmatics. Am RevRespir Dis 1992;146:96–103.

16. Christie PE, Smith CM, Lee TH. Thepotent and selective sulfidopeptideleukotriene antagonist SK&F 104353,inhibits aspirin-induced asthma. AmRev Respir Dis 1991;144:957–962.

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17. Yamamoto H, Nagata M, KuramitsuK, et al. Inhibition of analgesic-induced asthma by leukotriene recep-tor antagonist ONO-1078. Am J RespirCrit Care Med 1994;150:254–257.

18. Nasser SM, Bell GS, Foster S, et al.Effect of the 5-lipoxygenase inhibitorZD2138 on aspirin-induced asthma.Thorax 1994;49:749–756.

19. Israel E, Fischer AR, Rosenberg MA,et al. The pivotal role of 5-lipoxygen-ase products in the reaction of aspirin-sensitive asthmatics to aspirin. AmRev Respir Dis 1993;148:1447–1451.

20. Dahlen BJ, Kumlin M, Margolskee D,

et al. The leukotriene receptor antago-nist MK-0679 blocks airway obstruc-tion induced by bronchial provocationwith lysine-aspirin in aspirin-sensitiveasthmatics. Eur Respir J 1993;6:1018–1026.

21. Pleskow WW, Stevenson DD, Mathi-son DA, et al. Aspirin desensitizationin aspirin sensitive asthmatic patients:clinical manifestations and character-ization of the refractory period. J Al-lergy Clin Immunol 1982;69:11–19.

22. Pauls JD, Simon RA, Daffern PJ, et al.Lack of effect of the 5-lipoxygenaseinhibitor zileuton in blocking oral as-

pirin challenges in aspirin sensitiveasthmatics. Ann Allergy Asthma Im-munol 2000;85:40–45.

23. Ferreri NR, Howland WC, StevensonDD, et al. Release of leukotrienes,prostaglandins and histamine into na-sal secretions of aspirin-sensitive asth-matic during reaction to aspirin. AmRev Respir Dis 1988;137:847–854.

Donald D Stevenson, MDScripps Clinic10666 N Torrey Pines RdLa Jolla, CA 92037

482 ANNALS OF ALLERGY, ASTHMA, & IMMUNOLOGY