6
Desloratadine reduces allergen challenge-induced mucinous secretion and plasma exudation in allergic rhinitis Lennart Greiff, MD*; Carl GA Persson, PhD†; and Morgan Andersson, MD* Background: Rhinorrhea is a key symptom of allergic rhinitis and this disease feature is reduced by antihistamine treatment. The nasal output of fluid in allergic rhinitis is associated with luminal appearance of bioactive molecules emanating from the microcirculation as well as the secretory apparatus. Objective: In the present study, we examined the effects of antihistamine treatment on nasal symptoms and output of mucinous secretions and plasma. Methods: Desloratadine (5 mg) was administered orally once daily for 5 days in a placebo-controlled, crossover design to 24 patients with allergic rhinitis. Nasal challenges with diluent and allergen (100 to 10,000 SQ-U) were carried out on day 5 of the treatment. The nasal mucosa was lavaged with saline, and symptoms were scored 10 minutes after each allergen challenge and 1 to 4 hours after the challenge series. Nasal lavage fluid levels of fucose and 2 -macroglobulin were determined as indices of mucinous secretion and plasma exudation, respectively. Results: The allergen challenges produced nasal symptoms, including rhinorrhea, and increased nasal output of fucose and 2 -macroglobulin. Desloratadine reduced the nasal symptoms (P 0.05 to 0.001) and output of fucose (P 0.05 at 100 and 1,000 SQ-U) and 2 -macroglobulin (P 0.05 at 1,000 SQ-U). In both treatment groups, symptoms and nasal lavage fluid levels of fucose and 2 -macroglobulin returned toward prechallenge levels 1 to 4 hours after the allergen challenge series. Conclusion: We conclude that the antihistamine desloratadine, in addition to a symptom-reducing effect, also reduces acute allergen challenge-induced mucinous secretion and plasma exudation in allergic rhinitis. Ann Allergy Asthma Immunol 2002;89:413– 418. INTRODUCTION Rhinorrhea is a key symptom of allergic rhinitis and this disease feature is reduced by antihistamine treatment. 1 It has previously been demonstrated that allergen challenge-in- duced acute extravasation and luminal entry of plasma is inhibited by antihistamine treatment, 2,3 suggesting that this action, which reduces the appearance of many multipotent proteins in important airway biophases, 4 is involved in the antirhinorrhea effect of this class of drugs. However, little is known about whether or not antihistamines may also reduce allergen-induced secretion of mucins. Secretion is a mucosal defense mechanism in health and a pathologic factor in airway disease. 5 The study of human nasal secretory activity has typically involved determination of lysozyme and lactoferrin levels, both markers considered to indicate serous secretion. 6 In contrast, the current interest is focused on airway mucinous secretion: mucin genes have been identified, and specific mucins are considered as signif- icant components of airway disease processes. 7 Fucose is one of the most common sugar moieties of the mucin molecule. We have recently demonstrated that the nasal output of fu- cose may be increased by topical challenges. 8 However, ex- cept for a few observations, 9,10 little is known about mucinous secretions in human airways at allergen challenge and during treatment with antihistamines, particularly as reflected by fucose levels. The present study involved patients with seasonal allergic rhinitis examined out of the pollen season. We examined the nasal output of 2 -macroglobulin (as index of bulk plasma exudation) and fucose (as a global marker of mucinous se- cretion) in response to acute allergen challenges. Further, using a placebo-controlled, crossover design, we examined effects on these variables and on nasal symptoms of clinical doses of the antihistamine desloratadine, an active metabolite to loratadine. 11 METHODS Study Design Patients with birch and/or grass pollen allergic rhinitis re- ceived desloratadine treatment (5 mg daily for 5 days) in a double-blind, randomized, placebo-controlled, crossover de- sign out of the pollen season. Nasal diluent and allergen challenges were carried out, and nasal symptoms were mon- itored. Further, nasal lavage was obtained for analysis of 2 -macroglobulin and fucose. Subjects Twenty-four patients, age 18 to 30 years (mean age 23; 19 men and 5 women) participated in the study. The subjects had * Department of Otorhinolaryngology, University Hospital, Lund, Sweden. † Department of Clinical Pharmacology, University Hospital, Lund, Sweden. Received for publication February 27, 2002. Accepted for publication in revised form April 15, 2002. VOLUME 89, OCTOBER, 2002 413

Desloratadine reduces allergen challenge-induced mucinous secretion and plasma exudation in allergic rhinitis

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Page 1: Desloratadine reduces allergen challenge-induced mucinous secretion and plasma exudation in allergic rhinitis

Desloratadine reduces allergen challenge-inducedmucinous secretion and plasma exudationin allergic rhinitisLennart Greiff, MD*; Carl GA Persson, PhD†; and Morgan Andersson, MD*

Background: Rhinorrhea is a key symptom of allergic rhinitis and this disease feature is reduced by antihistamine treatment.The nasal output of fluid in allergic rhinitis is associated with luminal appearance of bioactive molecules emanating from themicrocirculation as well as the secretory apparatus.Objective: In the present study, we examined the effects of antihistamine treatment on nasal symptoms and output of mucinous

secretions and plasma.Methods: Desloratadine (5 mg) was administered orally once daily for 5 days in a placebo-controlled, crossover design to 24

patients with allergic rhinitis. Nasal challenges with diluent and allergen (100 to 10,000 SQ-U) were carried out on day 5 of thetreatment. The nasal mucosa was lavaged with saline, and symptoms were scored 10 minutes after each allergen challenge and1 to 4 hours after the challenge series. Nasal lavage fluid levels of fucose and �

2-macroglobulin were determined as indices of

mucinous secretion and plasma exudation, respectively.Results: The allergen challenges produced nasal symptoms, including rhinorrhea, and increased nasal output of fucose and

�2-macroglobulin. Desloratadine reduced the nasal symptoms (P � 0.05 to 0.001) and output of fucose (P � 0.05 at 100 and1,000 SQ-U) and �2-macroglobulin (P � 0.05 at 1,000 SQ-U). In both treatment groups, symptoms and nasal lavage fluid levelsof fucose and �2-macroglobulin returned toward prechallenge levels 1 to 4 hours after the allergen challenge series.Conclusion: We conclude that the antihistamine desloratadine, in addition to a symptom-reducing effect, also reduces acute

allergen challenge-induced mucinous secretion and plasma exudation in allergic rhinitis.Ann Allergy Asthma Immunol 2002;89:413–418.

INTRODUCTIONRhinorrhea is a key symptom of allergic rhinitis and thisdisease feature is reduced by antihistamine treatment.1 It haspreviously been demonstrated that allergen challenge-in-duced acute extravasation and luminal entry of plasma isinhibited by antihistamine treatment,2,3 suggesting that thisaction, which reduces the appearance of many multipotentproteins in important airway biophases,4 is involved in theantirhinorrhea effect of this class of drugs. However, little isknown about whether or not antihistamines may also reduceallergen-induced secretion of mucins.Secretion is a mucosal defense mechanism in health and a

pathologic factor in airway disease.5 The study of humannasal secretory activity has typically involved determinationof lysozyme and lactoferrin levels, both markers consideredto indicate serous secretion.6 In contrast, the current interest isfocused on airway mucinous secretion: mucin genes havebeen identified, and specific mucins are considered as signif-icant components of airway disease processes.7 Fucose is oneof the most common sugar moieties of the mucin molecule.We have recently demonstrated that the nasal output of fu-cose may be increased by topical challenges.8 However, ex-

cept for a few observations,9,10 little is known about mucinoussecretions in human airways at allergen challenge and duringtreatment with antihistamines, particularly as reflected byfucose levels.The present study involved patients with seasonal allergic

rhinitis examined out of the pollen season. We examined thenasal output of �2-macroglobulin (as index of bulk plasmaexudation) and fucose (as a global marker of mucinous se-cretion) in response to acute allergen challenges. Further,using a placebo-controlled, crossover design, we examinedeffects on these variables and on nasal symptoms of clinicaldoses of the antihistamine desloratadine, an active metaboliteto loratadine.11

METHODSStudy DesignPatients with birch and/or grass pollen allergic rhinitis re-ceived desloratadine treatment (5 mg daily for 5 days) in adouble-blind, randomized, placebo-controlled, crossover de-sign out of the pollen season. Nasal diluent and allergenchallenges were carried out, and nasal symptoms were mon-itored. Further, nasal lavage was obtained for analysis of�2-macroglobulin and fucose.SubjectsTwenty-four patients, age 18 to 30 years (mean age 23; 19men and 5 women) participated in the study. The subjects had

* Department of Otorhinolaryngology, University Hospital, Lund, Sweden.† Department of Clinical Pharmacology, University Hospital, Lund, Sweden.Received for publication February 27, 2002.Accepted for publication in revised form April 15, 2002.

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a history of strictly birch and/or timothy pollen allergic rhi-nitis, which was verified by a positive skin test (Aquagen SQ,ALK, Copenhagen, Denmark). Patients with positive skintests to house-dust mite were excluded, whereas positive teststo cats and dogs were accepted if there was no exposure tothese animals. The patients had no other recent or chronicnasal disorders, and none of the subjects had asthma. None ofthe subjects was on immunotherapy, and no drugs other thanthe study drug were allowed during the course of the study.Further, no drugs were allowed during a period of 4 weeksbefore the start of the study. The study was performed ac-cording to the Helsinki declaration after approval by theregional Ethics Committee and the Swedish Medical ProductsAgency. Informed consent was obtained from the subjects.Study DrugDesloratadine (5 mg; Schering-Plough, Stockholm, Sweden)or placebo (Schering-Plough) was given as one tablet orallyonce daily for 5 days. The subjects were provided with anallocation number, and the order of treatment proceededaccording to a randomization scheme of the allocation num-bers. Blinding was maintained by identical appearance andtaste of the study drug and the placebo preparation. Theduration of treatment was based on our previous experiencewith antihistamines in this model3 and was chosen to estab-lish a steady-state condition.Allergen Challenge and Isotonic Saline LavageNasal challenges and lavages were carried out on day 5 ofeach treatment series approximately 2 hours after the admin-istration of that day’s treatment. Seven nasal isotonic salinelavages were thus carried out at 10-minute intervals using ahead-back lavage technique.2 The first two lavages wereperformed to remove solutes that might have accumulated onthe mucosal surface and to establish a baseline. Accordingly,these lavages were not collected. In addition to the abovelavages, nasal lavages were also performed 1, 2, and 4 hoursafter the last allergen challenge. Taken together, eight lavageswere collected for analysis from each of the two challenge/lavage series.Diluent and allergen (100, 1,000, and 10,000 SQ-U) in

diluent (Aquagen SQ) were administered as single actuations(100 �L) using a pump spray device. The challenges weregiven approximately 1 minute after the preceding lavage,starting after the third lavage, and thus approximately 9minutes before the subsequent lavage. The challenges werecarried out in the right nasal cavity, whereas the lavages (2�5 mL) were carried out in both nasal cavities. The head backlavage technique was used.12 The recovered lavage fluidswere centrifuged (105 � g, 8 minutes), and aliquots wereprepared from the supernatants and frozen (�20° C) for lateranalysis of �2-macroglobulin and fucose. The �2-macroglob-ulin was analyzed in the supernatants as they were, whereasthe fucose was analyzed in homogenized aliquots. In thepresent study, the amount of lavage fluid recovered was not

determined, but it has previously been demonstrated to be�80%.13Oxymetazoline (100 �g) was administered as two actua-

tions (100 �L) using a pump spray, approximately 9 minutesbefore the third lavage procedure to prevent allergen-inducednasal blockage. It has previously been demonstrated thatgiving oxymetazoline in this manner does not affect the nasaloutput of either inflammatory mediators or plasma proteinsinduced by inflammatory challenges.12,14

Nasal Symptom ScoreNasal symptoms of allergic rhinitis were scored by the patientsat baseline and approximately 10 minutes after each diluent andallergen challenge. Thus, sneezes were counted, and rhinorrheaand blockage were scored on a scale from 0 to 3: 0, no symp-toms; 1, mild; 2, moderate; and 3, severe symptoms.AnalysesNasal lavage fluid levels of fucose were measured using aparallel ligand-exchange chromatography in combinationwith postcolumn derivatization and fluorescence detection.8Fucose was released by hydrolysis with 0.5 mol/L sulfuricacid at 100° C for 4 hours. After pH adjustment, remainingproteins were removed by on-line dialysis. The chromato-graphic system comprised two BioRad Aminex HPX-87H300 � 7.8 mm identification columns (BioRad, Hercules,CA) that were separated in a box-car configuration. Theanalytical columns were operated at 50° C and guarded byMicroguard Cation H 30� 4.6 mm i.d. columns. As a mobilephase, 2.5 mmol/L sulfuric acid was run at a flow rate of 0.6mL � min�1. Postcolumn derivatization was carried out in a314-�L reaction coil, which was thermostated at 100° C, byintroducing a 60 mmol/L benzamidine and a 2 mol/L potas-sium hydroxide solution at flow-rates of 0.1 mL � min�1.Fluorescence was monitored at an excitation wavelength of360 nm using an optical cut-off filter of 420 nm. The intraas-say and interassay coefficients of variation were �15 to 25%and �20 to 35%, respectively, at a concentration level of 15�mol/L.The lavage fluid levels of �2-macroglobulin were mea-

sured using a radioimmunoassay sensitive to 7.8 ng/mL.Rabbit antihuman �2-macroglobulin (Dakopatts, Copenha-gen, Denmark) was used as antiserum, and standard humanserum (Behringwerke Diagnostica, Marburg, Germany) asstandard. Human �2-macroglobulin (Cappel-OrganonTeknika, Turnhout, Belgium) was iodinated using the lac-toperoxidase method. Tracer and standard (or sample) weremixed with antiserum before adding goat antirabbit anti-serum. The bound fraction was measured using a gammacounter (Pharmacia, Uppsala, Sweden). The intraassay andinterassay coefficients of variation were between 3.8 and6.0% and 3.1 and 7.2%, respectively.StatisticsFriedman test was used to examine differences in nasal symp-toms and lavage fluid concentrations of fucose and �2-mac-roglobulin in patients receiving placebo and desloratadine

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treatment. If statistically significant differences emerged,Wilcoxon signed rank test was used for further analysis.Wilcoxon signed rank test was also used to compare symp-toms and lavage fluid concentrations of fucose and �2-mac-roglobulin, respectively, between placebo and desloratadinetreatment. P values �0.05 were considered statistically sig-nificant. Data are presented as medians and interquartileranges.

RESULTSAllergen challenge produced dose-dependent increases in na-sal symptoms in subjects receiving placebo treatment (Fried-man; P � 0.0001, all symptoms; Fig 1A-C). These increaseswere significant for the number of sneezes (all challenges;P � 0.01), for nasal secretion (all challenges; P � 0.01), and

for nasal blockage (all challenges; P � 0.01), compared withdiluent. In subjects receiving desloratadine treatment, nasalsymptoms were suppressed (Fig 1A-C). This effect was sta-tistically significant for the number of sneezes (P � 0.01 to0.001), for nasal secretion (P � 0.05 to 0.001), and for nasalblockage (P � 0.01), compared with placebo treatment.Allergen challenge produced dose-dependent increases in

lavage fluid concentrations of fucose in subjects receivingplacebo treatment (Friedman, P � 0.0001; Fig 2). Theseincreases were significant for all allergen-challenges (P �0.001), compared with diluent. In subjects receiving deslora-tadine treatment, lavage fluid concentrations of fucose werereduced (Fig 2). This effect was statistically significant forallergen 100 SQ-U (P � 0.05), 1,000 SQ-U (P � 0.05), butnot for allergen 10,000 SQ-U, compared with placebo. There

Figure 1, A-C. Nasal symptoms (medians and interquartile ranges)in response to diluent and allergen challenges after placebo anddesloratadine treatment. Desloratadine reduced the nasal symptomscompared with placebo. *P � 0.05; **P � 0.01; ***P � 0.001.Pre-Cha denotes prechallenge and Dil denotes diluent.

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were no statistical differences in lavage fluid concentrationsof fucose after the diluent administration compared with theprediluent observation, and there were no differences be-tween placebo and desloratadine at the diluent observation.Allergen challenge produced dose-dependent increases in

lavage fluid concentrations of �2-macroglobulin in subjectsreceiving placebo treatment (Friedman; P � 0.0001; Fig 3).These increases were significant for all allergen challenges(P � 0.01 to 0.0001) compared with diluent. In subjectsreceiving desloratadine treatment, lavage fluid concentrationsof �2-macroglobulin were significantly reduced at allergen1,000 SQ-U (P� 0.05) compared with placebo (Fig 3). Therewere no statistical differences in lavage fluid concentra-tions of �2-macroglobulin after the diluent administrationcompared with the prediluent observation, and there wereno differences between placebo and desloratadine at thediluent observation.In patients receiving placebo, nasal lavage fluid concentra-

tions of fucose were not increased 1 to 4 hours after the chal-lenge series. In patients receiving placebo, nasal lavage fluidconcentrations of �2-macroglobulin remained increased 1 hour(P � 0.001), 2 hours (P � 0.05), and 4 hours (P � 0.05) afterthe challenge series. There were no statistical differences be-tween placebo and desloratadine treatment for any of the ana-lytes 1 to 4 hours after the allergen challenge series.

DISCUSSIONThe present study involving patients with allergic rhinitis hasdemonstrated that acute allergen challenges increase nasaloutput of fucose (reflecting mucinous secretion), and thatdesloratadine treatment significantly reduces this response.The present study has also demonstrated that desloratadine,as is the case with other antihistamines,2,3 reduces allergenchallenge-induced nasal symptoms, including rhinorrhea, andto some degree, decreases nasal output of plasma (�2-macro-globulin). Taken together, the findings suggest that the anti-allergic, antirhinorrhea effect of desloratadine is comple-mented by attenuation of mucosal output of bioactivemolecules emanating from the secretory apparatus as well asfrom the microcirculation.Desloratadine significantly attenuated the allergen chal-

lenge-induced symptoms of allergic rhinitis in the presentchallenge model, in agreement with our previous observa-tions with loratadine in the same model.3 The present studyused the identical allergen challenge series design used in ourprevious study.3 However, because different groups of pa-tients were involved and because proper dose-responsecurves are lacking for loratadine and desloratadine in thepresent challenge model, the two studies can not be used tocompare potency of these antihistamines. Neither would the

Figure 2. Lavage fluid levels of fucose (medians and interquartileranges) in response to diluent and allergen challenges after placebo anddesloratadine treatment. Desloratadine reduced the allergen challenge-induced nasal output of fucose compared with placebo, indicatingdecreased mucinous secretion. *P � 0.05. Pre-Cha denotes prechal-lenge and Dil denotes diluent.

Figure 3. Lavage fluid levels of �2-macroglobulin (medians andinterquartile ranges) in response to diluent and allergen challenges afterplacebo and desloratadine treatment. Desloratadine reduced the aller-gen challenge-induced nasal output of �2-macroglobulin comparedwith placebo, indicating decreased plasma exudation. *P � 0.05.Pre-Cha denotes prechallenge and Dil denotes diluent.

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present acute challenge model be suitable for clinically rele-vant comparisons between antihistamines.In the present study, we have demonstrated that acute

allergen challenges increase nasal mucosal output of fucose,and that the response exhibits a certain degree of interindi-vidual variability. It has previously been demonstrated thatfucose is present in airway goblet cells, as well as in mucosaland submucosal airway glands.15,16 Additionally, and relevantto the present conditions where lavage fluids were obtained atexudative conditions, the concentration of fucose in theplasma compartment is low.17,18 Based on these observations,fucose has been forwarded as a general marker of mucinoussecretions.8,18 It is likely that the presently recorded fucoselevels indicate global mucinous secretion. Thus, the presentfindings would prompt further investigation into the occur-rence of specific mucins7 in allergic rhinitis treated or un-treated with antihistamine drugs. In this context, fucose maybe interesting as a global marker of mucinous secretionneeded to relate changes in specific mucins.The present data on allergen challenge-induced nasal mu-

cosal output of fucose add to our previous observations onluminal entry of this marker after nasal challenge with otherfactors,8,19 supporting the view that mucinous secretion maybe nonspecifically evoked by a range of airway mucosaldisturbances. Also, in agreement with our previous observa-tions, the present findings with allergen suggest that once afull secretory response is evoked acutely, a plateau is reached,and further challenges, even with greater doses of the chal-lenge agent, are not associated with a greater response. Takentogether, the results suggest that mucinous secretion is adepletable defense mechanism. It would be interesting to look atthis tissue response during further repeated allergen challengessuch as during an artificial pollen season20 and during naturaldisease to explore whether frequent exposure of the nasal mu-cosa to allergen is associated with maintained mucinous secre-tory activity or causes this response to be depleted.In the present study, we have for the first time demon-

strated that a treatment for allergic rhinitis reduces the aller-gen challenge-induced nasal output of fucose. Accordingly,the antihistamine desloratadine reduced the allergen chal-lenge-induced output of fucose at 2 of 3 observations. Thissuggests that part of the clinical efficacy of desloratadine (ie,the reduction of rhinorrhea) may be associated with reducedmucinous secretion, possibly involving effects on goblet cellsand mucosal glands, and/or the innervation of the secretoryapparatus. Indirectly, the present observation with deslorata-dine, in combination with our previous observations withexperimental histamine challenges in healthy subjects (Greiffet al, unpublished data), suggest that histamine is an impor-tant mediator in producing mucinous secretion.Extravasation, lamina propria distribution, and luminal en-

try of plasma are important features of inflammatory airwaydiseases. However, these features may be produced acutely inthe healthy airway in response to inflammatory insults.4 Wehave previously demonstrated that acute allergen challengesproduce plasma exudation and that this response is inhibited

by treatment with the antihistamine loratadine.3 In the presentstudy, allergen challenge thus expectedly increased the nasaloutput of �2-macroglobulin, whereas desloratadine reducedthis response at 1 of 3 observation points. We have previouslydemonstrated that histamine challenges produce exudation ofvarious-sized plasma proteins,4 and it is likely that deslora-tadine inhibits the allergen-induced plasma exudation by an-tagonizing the effect of histamine, acutely released from mastcells, at H1-receptors located on the permeability-regulatingendothelial cells of the subepithelial microcirculation. Muco-sal exudation of bulk plasma may reflect the intensity andtime course of epithelial-subepithelial inflammatory pro-cesses in airway diseases including allergic rhinitis.4 How-ever, the most important implication may be that adhesive,leukocyte-activating, growth factor active, complement ac-tive, or otherwise biologically active plasma proteins willoperate not only in the mucosal tissue but also on the surfaceof an insulted but still intact airway mucosa.4 In the presentstudy, desloratadine exerted some degree of antiexudationeffect, verifying this class effect of antihistamines.In the present study, nasal lavage fluid levels of �2-mac-

roglobulin were increased 1 to 4 hours after the allergen-challenge series compared with the observation at diluentchallenge. However, these increases were not of the samemagnitude as the increases observed after each of the allergenchallenges, and the increases were more evident at the 1-hourobservation than later. Our interpretation is that these levelsrepresent a gradual decline of the acute response evoked bythe allergen challenges.

CONCLUSIONThe present study demonstrates that desloratadine inhibitsacute allergen challenge-induced nasal symptoms of allergicrhinitis, mucinous secretion, and to some degree, plasmaexudation. We suggest that the latter effects may explain theantirhinorrhea effect associated with the present treatment.

ACKNOWLEDGMENTSThe present study was supported by the Swedish ResearchCouncil, the Vårdal Foundation, the Medical Faculty of LundUniversity, and Schering-Plough.

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4. Persson CG, Erjefalt JS, Greiff L, et al. Plasma-derived proteinsin airway defence, disease and repair of epithelial injury. EurRespir J 1998;11:958–970.

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5. Rogers DF. Airway goblet cells: responsive and adaptable front-line-defenders. Eur Respir J 1994;7:1690–1706.

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9. Yuta A, Ali M, Sabol M, et al. Mucoglycoprotein hypersecre-tion in allergic rhinitis and cystic fibrosis. Am J Physiol 1997;273:L1203–L1207.

10. Yuta A, Doyle WJ, Gaumond E, et al. Rhinovirus infectioninduces mucus hypersecretion. Am J Physiol 1998;274:L1017–L1023.

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14. Svensson C, Pipkorn U, Alkner U, et al. Topical vasoconstrictor(oxymetazoline) does not affect histamine-induced mucosal ex-udation of plasma in human nasal airways. Clin Exp Allergy1992;22:411–416.

15. Mariassy AT, Plopper CG, St. George JA, Wilson DW. Tra-

cheobronchial epithelium of the sheep: IV. Lectin histochemicalcharacterization of secretory epithelial cells. Anat Res 1988;222:49–59.

16. Castells MT, Ballesta J, Madrid JF, et al. Characterization ofglycoconjugates in developing rat respiratory system by meansof conventional and lectin immunochemistry. Histochemistry1991;95:419–426.

17. Lopez-Vidriero M. Individual and group correlations of sputumviscosity and airways obstruction. Bull Physiopathol Respir1973;9:339–347.

18. Keal EE, Reid L. Pathologic alterations in mucus in asthmawithin and without the cell. In: Stein M, editor. New Directionsin Asthma. Park Ridge, IL: American College of Chest Physi-cians, 1975:223–239.

19. Storaas T, Andersson M, Persson CG, et al. Effects of benzal-konium chloride on innate immunity physiology of the humannasal mucosa. in vivo. Laryngoscope 2000;110:1543–1547.

20. Andersson M, Svensson C, Persson CG, et al. Dose-dependenteffects of budesonide aqueous nasal spray on symptoms ofallergic rhinitis in a daily nasal allergen challenge model. AnnAllergy Asthma Immunol 2000;85:279–283.

Requests for reprints should be addressed to:Lennart Greiff, MDDepartment of OtorhinolaryngologyUniversity HospitalSE-221 85Lund, SwedenE-mail: [email protected]

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