Antiallergic activity of H1-receptor antagonists assessed by nasal challenge

Comparison

VOLUME 82 NUMBER 5, PART 1

10. Bousquet J, Djoukhadar F, Hewitt B, G&in B, Michel FB. Shelf life of a pollen and a mite standardized extract. Clin Allergy 1985;15:29-36. 11. Bousquet J, Calvayrac P, G&in B, et al. Immunotherapy with a standardized Dermurophagoides pteronyssinus extract. I. In vivo and in vitro parameters after a short course of treatment. J ALLERGY CLIN IMMUNOL1985;76:734-45. 12. Didierlaurent A, Foglietti MJ, GuCrin B, Hewitt B, Percheron F. Comparative study on cat allergens from fur and saliva. Int Arch Appl Immunol 1984;73:27-31. 13. Horst M, Bousquet J, Gouyon B, et al. Allergy to Alternaria [in press]. Clin Allergy. 14. Belin L. Biological standardization-the HEP unit. In: Sisk C, et al. Proceedings of the Fourth International Paul Ehrlich Seminar. Stuttgart: Gustav Fischer Verlag, 1987:145-53. 15. Dreborg S. The skin prick-test-methodological studies and clinical applications [Dissertation]. Linkoping, Sweden: 1987.

between

prick

test

and

Phazet

16. Einarsson R, Dreborg S. Manufacturers criteria for in-house reference preparations. In: Sisk C, et al. Proceedings of the Fourth International Paul Ebrlich Seminar. Stuttgart: Gustav Fischer Verlag, 1987:131-8. 17. Uhlin T, Reuterby I, Einarsson R. Antigen/allergenic composition of poodle/alsatian dandruff extract. Allergy 1984;39:125-33. 18. Galen RS, Gambino SR. Beyond normality: the predictive value and efficiency of medical diagnoses. New York: John Wiley, 1975. 19. Petersson G, Dreborg S, Ingestad R. Clinical history, skin prick test, and RAST in the diagnosis of birch and timothy pollinosis. Allergy 1986;41:398-407. 20. Argawal MK, Jones RT, Yunginger JW. Immunochemical and physicochemical characterization of commercial Alternaria extracts: a model for standardization of mold allergen extracts. J ALLERGY CLIN IMMUNOL1982;70:432-6.

Antiallergic activity of H,-receptor antagonists assessed by nasal challenge Jean Bousquet, MD, PhD,* Bernard Lebel, PhD,** lsabelle Anne Morel, PhD,*** and Frangois-Bernard Michel, MD* Montpellier

and Marseille,

Chanal,

MD,*

France

Most oral drugs used for the treatment of allergic rhinitis are classified as HI-receptor antagonists, and although they represent major sales throughout the world, their mechanism of action is still poorly known. In an attempt to understand better the in vivo therapeutic effects of these drugs, a double-blind, crossover study was carried out. The study compared the effects of terfenadine and loratadine, nonsedative H,-receptor antagonists, on the immediate allergic response of the upper airways to challenge with orchard-grass pollens in 14 highly allergic subjects. Increasing numbers of pollen grains were insupated into the nostrils, and the response of the subjects was assessed by examining symptoms and measuring the release of histamine and prostag‘landin D, in nasal secretions. Each drug was administered for a week before challenge. This study demonstrated the clinical efficacy of both drugs by comparison to that of a control day, since symptoms were observed for a significantly (p = 0.014) greater number of pollen grains. Only one patient had a significant release of histamine when they were treated with loratadine versus 10 during control day (p < 0.0023) and six when they were treated with terfenadine (p < 0.01). Prostaglandin D, release occurred with a higher allergen dose when patients were treated with both drugs. This study indicates that some H, antagonists also possess antiallergic activities. (J ALLERGY CLIN IMMUNOL 1988;82:881-7.)

From the *Clinique des Maladies Respiratoires, Montpellier, **INSERM U58, Montpellier, and ***Immunotech, Marseille, France. Received for publication Nov. 12, 1987. Accepted for publication May 7, 1988. Reprint requests: J. Bousquet, MD, Clmique des Maladies Respiratories, Centm Hospitalier Universitaire, Hopital L’Aiguelongue, 34059 Montpellier Cedex, France.

Histamine is one of the mediators of the nasalallergic reaction, but recent studies in pollen-allergic individuals examining the release of mediators in nasal secretions during allergen challenge have suggested that lipid-derived mediators may also be relevant.‘-‘o Moreover, the mechanism of action of H, antagonists may not only be antagonism of H, receptors, 881

882

Bousquet et al.

J ALLERGY CLIN. IMMUNOL. hI)VEMBER 1988

TABLE I. Symptom score Abbreviations

used

Symptom

MO: Methoxamine

LTC,: Leukotriene C, PGD,: Prostaglandin D?

since animal studies have demonstrated that some of these compounds also have antiallergic properties.“-‘4 These findings suggest that drugs used in the treatment of allergic rhinitis should be defined as allergic mediator-receptor antagonists or antiallergic compounds when they inhibit the release of mediators during allergen challenge. Loratadine is a new nonsedative H, histamine antagonist devoid of anticholinergic properties”-” that may also possess antiallergic activities, as demonstrated in animal studies” and as suggested by a pilot study of human subjects performed by means of skin prick tests. * Terfenadine20-22 is another nonsedative

Score

Sneezing 3-4 >5

Rhinorrhea Minor anterior Posterior Both symptoms Blockade Patient can breathe freely Patient can only breathe with difficulty (changing frequency and depth) One nostril is blocked Both nostrils blocked Pruritus Nose Palate or ear Conjunctivitis

I 3

1 1 3 0 1 2 3 I I I

H, histamine antagonist that appears to be almost

purely an H, antagonist. Nasal challenge with pollen grains’, 23.24resembles natural exposure and appears to be one of the tech-

niques to insufflate allergenic materials into nostrils. It is easy to assessthe positivity of the challenge when mediators released in nasal secretions are titrated,‘-I0 and this method may be complemented by a clinical evaluation of the response with a score previously defined.‘* This method has also been used to demon-

strate the antiallergic activities of drugs, such as oral methylxanthines, and nasal azatadine or corticosteroids .“-” A double-blind, controlled study was performed in grass-pollen allergic patients to assessthe clinical efficacy of loratadine and terfenadine and to test their

antiallergic activity. Fourteen patients had nasal challenges with increasing numbers of orchard grasspollen grains, and membrane-associated mediators (PGD,) and histamine were serially titrated in nasal washes.

MATERIAL Patients

AND METHODS

Fourteen subjectsranging in age from 2 1 to 26 years were studied after being informed of the risks and giving consent. Approval was obtained for the study from the Ethical Committee of the University. Subjectswere selectedon the following criteria: 1. All subjects had symptoms of rhinitis during the grasspollen season. The duration of symptoms ranged from 4 to 12 years. *Bousquet

J. Manuscript

in preparation.

2. All subjectshad a positive prick test performed according to the modified method of Pepys” with a l/ 100 (wt/vol) of standardizedorchard grass-pollen extract” (Stallergenes Laboratories, Fresnes, France) and the presence of orchard grass pollen-specific IgE determined by PhadebasRAST (PharmaciaDiagnostics AB, Uppsala, Sweden). 3. All subjects had Severesymptoms and a positive challenge with low numbers of orchard-grasspollet~s.~’ 4. No subject had received any form of specifjc immunotherapy to pollen extracts. 5. The patients did not present any infectious or allergic episode during the month before nasal challenge.

Investigations Nasalprovocation tests. All patients were tested between 8 and 12 hours to avoid possibIecirca&an variations by the same investigator within 2 months (February and March) at a time when no grasspollen is found in the atmosphere. None of the patients was under treatment that might affect the performance of nasal challenges. Anti-H, histamines, nasal beclomethasone, oral corticosteroids, and cyclooxygenase inhibitors were stopped 1 week before challenge. Nasal cromoglycate was withdrawn 2 days before testing. Ketotifen, astemizole,or imipramines were stopped 1 month before testing. Capsulescontaining lactose or increasing coWentrations of orchard-grasspollens from 59 to 156,250 (increasing in fivefold increments) grains were prepared by the StallergenesLaboratoires. Grains were insufWed into the nostrils according to a technique modified from Rosenberg et al.‘* with a nasalSpinhaler(Fisons Laboratories, Lou&borough, U.K.) and with the subjst refraining from breathing during the insufflation. For each concentration, the Spinhaler was actuated five times. Each capsule was opened after insuf-

Activity

of H,-receptor

antagonists

883

r n-./ .O

50 250 1.250 6,250 31,250 CRASS POLLEN GRAINS/CHALLENGE DOSE

156.250

FIG. 1. Cumulative numbers of petients responding with significant symptoms (score >5f after orchard grass-pollen challenge; control day (-A,); loratadine ( - - - - 0); terfenadine (- . - 0).

flation to assurethat it was completely empty. and if there was lactose remaining, the Spinhafer was again actuated five

--. .I’ ________------0 1’ /L ___--I I I 0

50 CRASS

250

POLLEN

I.250

GRAINS/CHALLENGE

I 6.2-50

1 31.250 DOSE

FIG. 2. Cumulative numbers of patients with tignificant rise (twice the basefine level measured after Eecto-hie insufflationl in histamine in nasal secretiona Z&W orchard grass-pollen challenge; control day (--A); ioratadine (- - - - 0);

tetfenadine

(-

-

0).

times.

To reduce the levels of cell-free mediators that are typically present in nasal secretions,‘.“’ three prechaffenge washes were performed according to the technique of Nacferio et al.’ with the instillation of 5 ml of saline into each nostril. Then, 0.01 ml of a 0.05% qxymetazofine hydrochloride solution (Afrin; Schering-Plough Corp., Kenilworth. N.J.) was sprayedinto both nostrils to maintain nasal patency during the allergic reaction and to collect nasal secretionsmore easily. Challenges with either lactose or pollen grains were done in the right nostril. Lactose was insufflated initially. Symptoms were recorded for 30 minutes, and a score was cafcufated (Table I). A wash with 5 ml of saline in each nostril was performed 15 minutes after the insufflation of lactose, and then increasing numbers of grains were deposited on the nasal mucosa every 30 minutes until a symptom score of 5 was obtained. according to Table I. This score was previouslyvalidated by studying the releaseof PGD, in nasal secretions” and by comparing nasal challengeswith symptoms during the pollen season.‘”Fifteen minutes after each allergen insufflation. nasal washes were performed with 5 ml of saline into each nostril. Collection of nasal washes. The wash fluid was stored on ice until the conclusion of the experiment. It was then centrifuged at +4’ C for 15 minutes at 15.000 g. The sol phase was separated from the gel phase by pipetting and stored at - 20“ C until it was assayed. Titration of histamine in nnsal washes. Histamine was assayedby a radioimmunoassay based on the competition of acylated histamine and “‘I-labeled acyfated histamine for binding to a highly specific mouse monocfonaf antibody fixed on polystyrene tubes. according to the technique of

Morel and Defaage (Immunotech. Marseille, France; patent No. 84.05783). Acyfation is an essential sfep for the antibody recognition. This assaycan detect histamine levels of IO pg/mf. and it is specific for histamine in biofogic fluids. It has been found to be significantly correlated with the continuous flow fluorometric assay. Brieffy. 100 l.~fof nasal wash is acyfated after centrifugation by the addition of I mg of acyfating reapnt and 50 ~1 of borate buffer, pH 8.2. Then. I ml of “‘I-labeled acyfated histamine is added and mixed with vortex. The mixture is transferredto coatedtubescontaining antiacyfated histamine monocfonal antibodies. The tubes are then incubated for 18 hours at + 4” C. After aspiration of the IIuid, emptied tubes are counted in a gamma counter. Titration

of PGD, in nasal washes. PGD, was as~yed

by a competitive enzymatic immunoassay with a rabbit pofycfonaf antiserum agaihst I I-MO PGDZ.“”Pure acetylchofinesterasefrom electric eel is used as a label, according to the technique of Pradeifeset at.” Briefly, 50 p,f of centrifuged nasal wash was incubated with 50 p.1 of anti-PGD-&IQ and 50 ~1 of acetyfchofinesterase-la&fedPGD,MO in a microtiter plate well-coated with purified swine antirabbit 186 used as a second antibody. After an overnight inure at +4’ C. the plates were washed. and 200 ~1 of Elfman’s reagent was added to each well. The absorbance at 414 nm was measured by use of the Muftiskan MC (Mukiskan. Flow Laboratories, Rockvifle, Md.) spectophotometer.

Design of the study Patientshad a first nasalchallenge without fmatment. and only patients who presented a symptom score >5 for a

834

Bousquet

J. ALLERGY CLIN. IMMUNOL. NOVEMBER 1988

et al.

3

8

5

h

n q

control group ioratadine terfenadine

50

grains

1I lactose

baseline flG. 3. Mean levels of histamine challenge with 50 grass-pollen

in nasal secretions grains, and at the

maximal release

at baseline, after lactose insufflation, maximal release of the mediator.

after

and after a week of daily treatment. a second nasal challenge was performed. Then the treatment was stopped for 1 week, and the crossover drug was taken daily for a subsequent week. after which a third nasal provocation test was done. Histamine and FCD, were considered to he released in nasal secretions when their level was twice the baseline level measured after the lactose insufflation. The interval between two nasal challenges was examined carefully to avoid possible priming effect? We observed that no priming effect was noticeable when challenges were done at intervals of 2 or more weeks. Statistical analysis was performed with nonparametric tests: chi-square test, Wilcoxon W test for paired data. and Mann-Whitney U test.

RESULTS 0 50

0 GRASS

POLLEN

250

1,250

GRAINS/CHALLENGE

6,250

31,250 DOSE

FIG. 4. Cumulative number of patients with a significant rise (twice the baseline value after lactose insufflation) in PGDl in nasal secretions after orchard grass-pollen challenge; control day (A); loratadine ( - - - - 0); terfenadine (- - . 0).

number of pollen grains S I250 were entered into the study. Then they received in a double-blind, crossover manner loratadine (IO mg once daily) or terfenadine (60 mg twice daily). The treatment was started a week after the challenge.

Before treatment, patients had significant symptoms for a number of pollen grains ranging from 50 to 1250 (mean k SD: 321 + 405 grains). After loratadine treatment, the mean number of orchard-grass pollens inducing

a symptom

score

>5

was

significantly

(p

=

0.011, Wilcoxon W test) increased (mean + SD: 15,378 + 41,359 grains). With terfenadine treatment, the mean number of pollen grains was also significantly (p = 0.014, Wilcoxon W test) increased (mean + SD: 18,992 rfr 41,486 grains) (Fig. 1). There was no significant difference between loratadine-treated and terfenadine-heated groups. patients, a release of histamine in nasal In untreated

VOLUME 82 NUMBER 5, PART 1

Activity

of H--receptor

antacJonlsts

885

600 de

n q

f

control group loratadine terfenadine

baseline

lactose

50

grains

maximal response

FIG. 5. Mean levels of PGD, in nasal secretions at baseline, after lactose challenge with 50 grains, and at the maximal release of the mediator; significant; pc, < 0.05; pb h ( 0.02 (Wilcoxon W test); pa br not significant; pb C, not significant (Mann-Whitney U test).

TABLE

II. Release

of mediators

Mediator

PGD, 1. Loratadine: Results Statistical

c. control

indicate analysis

day;

the number

Loratadine

IO

1

8

8

f, terfenadine; of patients

by chi-square

after

in nasal secretions

Control

Histamine

insufflation,

p. d < 0.01; p. e, not p, c, not significant;

who

PI/.

Terfenadine

6 6

PIi.

<0.0023 NS

~:o.ol NS

NS. not significant. had a release

of mediators

in nasal secretions

when

the challenge

was positi\t*

test.

secretions was observed in IO/ 14 cases, whereas with loratadine treatment, there was only one patient who presented a release of this mediator (p = 0.0023, chisquare test) (Fig. 2; Table II). Six patients treated with terfenadine had a release of histamine in nasal secretions. In these patients, the release of histamine usually occurred with a higher allergen dose by comparison to the dose on control day. Mean values of histamine in nasal secretions demonstrate that there is no main difference between the three groups (Fig. 4). This lack of effect was due to the wide variations in baseline values (0.5 to 34.1 rig/ml). The number of patients releasing PGD, in nasal secretions was not significantly different in the three experiment series (Table II; Fig. 4) but occurred for a higher pollen number in most patients placed in the

treated groups. There was a significantly ip < 0.02) lower release of PGD, in nasal secretions, when the challenge was positive in patients treated by loratadine or terfenadine, than was released during the control day (Fig. 5).

DtSCUS8tCW This study confirms the clinical efficacy of loratadine and terfenadine by comparison to that of a control day and indicates that loratadine possessesantialkrgic properties besides the known anti-H,-receptor activity. For terfenadine, the antiallergic activity is less clear. Nasal challenge with pollen grains have been popularized by Naclerio et al.’ and. in our clinic, this method has been demonstrated to be highly reproducible when nasal challenges have been done

J. ALLERGY CLIN. IMMUNOL. NOVEMBER 1988

886 Bousquet et al. twice.“‘, 33Because we wanted to study high responders, we started the study by a control day, including patients who had symptoms for a low number of pollen grains according to previous studies.“’ ‘A,x3 Because of a possible priming effect when nasal challenges are often repeated,j6 we decided to avoid a fourth challenge with placebo. The results obtained in this study indicate that both loratadine and terfenadine are effective in decreasing the nasal response to grass-pollen grains. Both compounds had similar activities in reducing symptoms, and these findings confirmed clinical studies with symptom-medication scores.‘x-“’ Naclerio et al.’ used the titration of mediators released in nasal secretions to evaluate the allergic reaction in vivo. This method made it possible to determine that histamine is not released in all challenges, and lipid-derived mediators, such as PGD, and LTC,, may even be more important,‘-6. ‘-“’ although cyclooxygenase inhibitors were found to inhibit the release of prostaglandins in nasal secretions but not to alleviate symptoms.7 This method was also used to assess the antiallergic activity of theophylline,“’ azatadine,‘6 and corticosteroids.‘9 These two drugs and specific immunotherapy”’ have been demonstrated to block, at least partly, the release of histamine and kinins, but their effect on the release of membrane-associated mediators has not been studied. In vitro studies with purified human lung mast cells have demonstrated that azatadine is effective in inhibiting anti-IgE-induced histamine and LTC, release, but the drug is significantly more effective in blocking LTC, release.‘6 Such an effect has also been demonstrated for other antihistamines with human chopped lung cells.” Our results demonstrate that loratadine inhibits almost completely the release of histamine and only partly the release of PGD2. The blockage of mediator release by loratadine appears to be greater than that of theophylline’5 or terfenadine. However, the use of larger doses of- terfenadine, as proposed recently,“’ may have enhanced the effect of this drug. In a previous study we have examined the antiallergic activity of clenbuterol, an oral &-agonist. Although this drug was less potent than loratadine in reducing nasal symptoms during challenge, the spectrum of inhibition of allergic mediators was similar; that is, the release of histamine was blocked in 85% of patients and the release of PGD, was only partly inhibited. Thus, loratadine can be classified as an antiallergic compound.40 Terfenadine has a lower inhibitory activity on histamine release and a similar blocking activity on the release of PGD,. It also appears that granule and lipid-derived mediators are not released similarly and that drugs can modulate the activation of mast

cells because these two med:ators are mainly released by this cell type. Moreover, as suggested in previous studies on nasal challenges, histamine may not be the major nasal mediator.“” This study confirms previous animal and in vitro results”-‘4 and indicates that some anti-H,-receptor antagonists also have antiallergic activities. These compounds, especially loratadine, have broader activities than initially believed, and such findings highlight the necessity of new studies to assess the mechanism of action of drugs used in the treatment of allergic rhinitis. REFERENCES I.

NaclerioRM. Meier HL. Kagey-Sobotka Meyers after

DA,

Norman

nasal airway

A. Adkinson LM. Mediator

PS. Lichtenstein

challenge

with allergen.

NF Jr. release

Am Rev Respir

Dis

1983;128:597-602. 2. Creticos P.S. Peters SP. Adkinson NF Jr. Naclerio RM. Hayes EC. Norman PS, Lichtenstein LM. Peptide leukotriene release after antigen

challenge

in patients

J Med 1984;310:1626-30. 3. Naclerio RM, Togias AG. diators

in the late

RM.

Proud

to ragweed.

N Engl

D. et al. Inflammatory

antigen-induced

1985;3 13:65-70. 4. Togias AC, Naclerio cold. sible

Proud

sensitive

rhinitis.

me-

N Engl

J Med

D. et al. Nasal challenge

with

dry air results in release of inflammatory mediators: posmast cell involvement. J Clin Invest 1985:76: 1375-8 I.

5. Togias AG, Naclerio RM. Peters SP. et al. Local generation of sulfidopeptide leukotrienes upon nasal-provocation with cold. dry air. Am Rev Respir 6. Proud D. Togias AC. Naclerio in vivo following nasal airway

Dis 1986; 133: I 133-7. RM. et al. Kinins are generated challenge

of allergic

individuals

with allergen. J Clin Invest 1983;72: 1678-85. 7. Brown MS. Peters PS, Adkinson NF Jr. et al. Arachidonic acid metabolites 1987; I 13: 179-83. 8. Shaw

during

RJ, Fitzharris

nasal

challenge.

P, Cromwell

0.

Wardlaw

Allergen-induced release of sulfidopeptide A) and LTB, in allergic rhinitis. Allergy 9. Miadonna in nasal

Arch

Otolaryngol AJ.

symptoms challenge

12.

and release with pollen

MUNOL 1987;79:247. Kreutner W, Chapman tiallergic Allergy

AB. (SRS-

A, Tedeschi A. Leggieri E. et al. Mediators release secretions after grass-pollen challenge [Abstract].

J ALLERGY CLIN IMMUNOL 1986:77: 177. 10. Michel FB. Bousquet J, Lebel B. et al. Correlation

II.

Kay

leukotrienes 1985:40:1-6.

RW,

activity of loratadine. 1987;42:57-63.

RossoniG. OminiC, of mequitazine.

Arch

between

of mediators in secretions during nasal grains [Abstract]. J ALLERGY CLIN IMGulbelkian

A.

Siegel

a nonsedating

MI.

An-

antihistamine.

Folco CC. et al. Bronchodilating activity Int Pharmacodyn 1984:268: 128-35.

13. Tasaka induced

K. Mio M. Okamoto M. Intracellular calcium release by histamine releasers and its inhibition by some anti-

allergic 14. Chand

drugs. Ann Allergy 1986:56:464-9. N, Nolan K, Diamantis W. Sofia

acutelung sensitized 58:344-9. 15.

RD.

anaphylaxis by aerosolized azelastine by three different procedures. Ann

BamettA. Iorio LC. KreutnerW. et

al. Evaluation

Inhibition

of

in guinea pigs Allergy 1987: of the CNS

VOLUME 82 WJMRER 5, PART 1

propertIes mine. 16

of SCH

Agents

Batenhorst cologic

RL.

lJ.

AS,

of SCH

LEKGY CLIN IMMUNOL

Graves

N, Gural

RP. Herron

wheal response man. Ann Allergy

IX

Skasba-Brociek

W.

19

.~LLI.KGI’ CLIN IMMUNOL 1986~77: 137. Oei f-11). Verhci,j E. Schwab D. Lherminier

treatment

A comparative tcmizole 190. 20.

uith Rc\ 71.

dine 22.

HC.

J. Poisson

Woodward

a new

Beltman

(L)

Tsai TH.

effect Drug

Res

safety.

and

Blumstein

tii.

24.

tation. and indicanons. J ALLERGY 1937:8:321-7. Bouhquet 1. Lebel B. Dhivert H. et al. Nasal challenge

25.

allergic saclcrio reduces

26.

The dry pollen

prick

histamine

release

t.t.wy

CLIN IMMCW~L

Togiaa

AG.

Naclerm

nasal

Drug

Res

35.

interprewith

37.

RN.

Warner

2X

RM, LM.

38.

allergic

medications.

Arch

Otolaryngol

1984;l

of

E, Wang

I I-methoxime 123-9.

prostaglandin

macol Bantz

39.

PS. Lichof topical

40.

10:25-7.

A. Proud D. Kapey-Sobotka A. et al. The effect of a tricycllc antihistamine on the response of the nasal

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This collection of “state-of-the-art” presentations from the XII Congress held October ZOO25, 1985. in Washington, D.C., brings together the current advances in basic and applied aspects of allergy and allergic diseases. It includes 528 pages covering such topics as I&E. roles of the different cell types and their products, clinical problems. asthma, rhinitis. and reactions to foods and drugs and occupational agents. collected and reviewed by Editor Charles E. Reed, MD (USA) and Associate Editors Joseph Bellanti. MD (USA), Robert J. Davies, MD (UK). Sidney Friedlaender. MD (USA). Albert Oehling. MD (Spain). and Raymond G. Slavin, MD (USA).

international

asthmatics.

Z. Development D? usinp

cate analogues in human lung in v!tro: passive cutaneous anaphylaxis and clinical

human mast cells by azaevaluation. JAMA 1986;

Meier HL. Kagey-Sobotka A. Norman An m vivo model for the evaluation

Arch

for prostaglandin

of skm test suppression

Naclerlo tenstein Tog~as topical

J, Corvazier

1984:73:141. Church MK.

155~229-9. 27.

Int

immunoassay

ragweed

J AL-

rhinitis.

J. et al. Demonstration

release from and m vitro

Clin

Creticos PS. Marsh DC, Adkinson NF Jr, et di. Evaluation by nasal pollen challenge of immunotherapy with iapidly released

19X6:78:874-6.

Inhibition of mediator tadine base: in vtvo

allergolds.

82:550-X Maclouf

priming

IgE in grass pollen

pollen-induced

tionated

to radioimmunoassay. Anal Chem Connell JT. Quantitative intranasal

36.

Clin Allergy. D. Proud D. et al. Theophylline during

FB.

extract.

M. Hejjaoui A. immunotherapy

Pradelles P, Grassi J. Maclouf eicosanoids using acetylcholine

19X2:32:

test: its technic.

tests, and specific

patients [in press]. RN. Bartenfelder

Drug

Develop

Terfenadine.

trials.

standardized

ragweed pollen in ragweed-sensitive CLIN IMMUNOL 1983;71:302-IO.

Bousquet J. Frank E. Soussana Double-blind placebo controlled

of tertena-

23.

\kin

33.

studies

in France.

with

J ALIERGY

1987;79:

J. Climcal

rhinitis

lenge

and as-

in controlled

gram,.

J

and a mite

32. Rosenberg CL. Rosenthal RR, Norman PS. Inhalation chal-

Antihistaminic

clinical

J. Skin testing. Br J Hosp Med 1975:11:412. J, Djoukhadar F. Hewitt B. Guerin E. Michel

Shelf life of a pollen Allergy 1985:15:29-34.

PLB.

tolerunce 1115-7.

pollen

Pepys

29851

M, Bruynzeel

A. Charpin

antihistamine.

RE.

1987:316:1506-10. 30.

34.

JK.

1987:79:599-604.

31. Bousquet

[Abstract].

of loratadine

allergic

plperidine-type

i9X2~~:181-96. .‘. Barlo\ JLR.

rhinitis

of

2985 I)

et al. SCH

J ALLERGY CLIN IMMUNOL

terfenadine in seasonal 1982:32:1206-X.

C’heng

J. Suppression

M.

allergic

of the efficacy

/Abstract].

P. Bimbaum

F. Verdier

seasonal

study

(AJ

Dupue

Montes of

and pla-

by loratadine (SCH 1986;57:253-6.

887

29. Pipkorn U. Proud D. Kagey-Sobotka A. Norman PS. Nacierio RM. Inhibition of mediator release in allqic rhrnitis by pretreatment with topical glucocortico\teroidh \: Engl J Med

et al. Pharma-

Pharmacol.

hiatamme-Induced over 2X days m in the

DA,

antagonists

mucosa to challenge with cold, dry air and t!l\t:iminc. I PII..-

antihista-

2985 1, chlorpheniramine,

Eur .I Clin

Kassem

non-sedating

1984; 14590-8.

Batenhorst

[m press].

Roman

2985 I. a potential

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evaluation

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