1506
`
`THE NEW ENGLAND JOURNAL OF MEDICINE
`
`June 11, 1987
`
`INHIBITION OF MEDIATOR RELEASE IN ALLERGIC RHINITIS BY PRETREATMENT WITH
`TOPICAL GLUCOCORTICOSTEROIDS
`
`ULF PIPKORN, M.D., DAVID PROUD, PH.D., LAWRENCE M. LICHTENSTEIN, M.D., PH.D.,
`ANNE KAGEY-SOBOTKA, PH.D., PHILIP s. NORMAN, M.D.,
`AND ROBERT M. NACLERIO, M.D.
`
`Abstract Patients with allergic rhinitis often have im(cid:173)
`mediate symptoms after antigen challenge (the early(cid:173)
`phase response), followed several hours later by a recur(cid:173)
`rence of symptoms (the late-phase response). Systemic
`glucocorticosteroids are known to inhibit the late-phase
`but not the early-phase response. We studied the effect
`of one week of pretreatment with topical (rather than
`systemic) glucocorticosteroids on the response to nasal
`challenge with antigen in a double-blind, randomized,
`placebo-controlled crossover study of 13 allergic pa(cid:173)
`tients who had previously had a dual response to nasal
`challenge. The patients were challenged with three
`10-fold increments of allergen, producing an early re(cid:173)
`sponse, and were then followed for 11 hours, encom(cid:173)
`passing the late response, before they were rechallenged
`with the lowest dose of allergen. We monitored their
`responses by means of symptom scores and measure-
`
`ments of the levels of histamine, tosyl-L-arginine meth(cid:173)
`yl ester (T AME)-esterase activity, and kinins in nasal
`lavages.
`Topical glucocorticosteroids significantly reduced both
`the symptoms and the levels of histamine, T AME-esterase
`activity, and kinins in the early, late, and rechallenge al(cid:173)
`lergic reactions. The fact that, in contrast to treatment with
`systemic glucocorticosteroids, prolonged pretreatment
`with topical glucocorticosteroids inhibited the early-phase
`response to antigen suggests that the route and duration
`of administration affect the mechanisms of action of the
`steroids.
`We conclude that inhibition of the early-phase as well
`as the late-phase response by topical glucocorticoster(cid:173)
`oids may provide an advantage over treatment with sys(cid:173)
`temic glucocorticosteroids in patients with allergic rhinitis.
`(N Engl J Med 1987; 316:1506-10.)
`
`SYSTEMICALLY administered glucocorticoste(cid:173)
`
`roids, which are potent agents in the treatment of
`allergic disease, affect the late but not the early phase
`of the biphasic response to antigen challenge, as
`shown in numerous studies involving the lungs and
`skin in animals and humans. 1
`4 For example, in a na(cid:173)
`-
`sal-challenge study, we recently found that pretreat(cid:173)
`ment with systemic prednisone (20 mg three times a
`day for 48 hours) had no effect during the early reac(cid:173)
`tion on either the symptoms reported or the levels of
`histamine, prostaglandin D2, tosyl-L-arginine methyl
`ester (TAME)-esterase activity, or albumin recovered
`in nasal secretions. 5 During the late reaction, how(cid:173)
`ever, prednisone reduced the symptoms reported and
`the mediators recovered in lavages. In addition, when
`antigen was presented again 11 hours after the early
`reaction, prednisone reduced the usual augmented
`response ( "rechallenge reaction"). Combining these
`data with the observation that overnight culture of
`human lung mast cells with glucocorticosteroids does
`not inhibit IgE-mediated histamine release, 6 we spec(cid:173)
`ulated that prednisone had no effect on nasal mast
`cells but affected the inflammatory events that occur
`after the early reaction.
`
`From the Department of Medicine. Division of Clinical Immunology. and the
`Department of Otolaryngology. Johns Hopkins University School of Medicine.
`Baltimore. Address reprint requests to Dr. Naclerio at Good Samaritan Hospital,
`Professional Office Bldg., Suite 402. 5601 Loch Raven Blvd., Baltimore. MD
`21239.
`Supported in part by grants (Al 20136, NS 22488, HL 32272. and Al 08270)
`from the National Institutes of Health. Dr. Pipkorn is the recipient of an Interna(cid:173)
`tional Research Fellowship Award (NIH F05 TWO 3516-01) from the Fogarty
`International Center. Dr. Lichtenstein is the recipient of a Pfizer Biomedical
`Research Award. Dr. Naclerio is the recipient of a Teacher Development Investi(cid:173)
`gator Award (NS 00811) from the National Institute of Neurological and Commu(cid:173)
`nicative Disorders and Stroke.
`
`Topical glucocorticosteroids effectively and safely
`treat allergic rhinitis, 7
`8 although their mode of action
`•
`remains obscure. Several clinical studies suggest that
`pretreatment with topical glucocorticosteroids inhib(cid:173)
`its the early nasal and bronchial allergic reaction,9- 12
`although some have not observed this inhibition. 13, 14
`If the former results are valid, the mechanism of glu(cid:173)
`cocorticosteroid activity could be one or more of the
`following: a direct effect on mast-cell mediator release,
`an effect on end-organ sensitivity after mediator re(cid:173)
`lease, a change in the metabolism of mediators, or
`an effect on the status of the mucosa before anti(cid:173)
`gen challenge. 15
`17 Our investigation was designed to
`-
`ascertain whether pretreatment with topical glucocor(cid:173)
`ticosteroids would inhibit the symptoms of the early
`nasal allergic reaction, as well as the late and re(cid:173)
`challenge reactions, and whether a reduction in symp(cid:173)
`toms correlated with a reduction in mast-cell mediator
`release. 18
`
`Study Design
`
`METHODS
`
`We performed a double-blind, randomized, placebo-controlled
`crossover study of asymptomatic subjects in the pollen-free winter
`months. Nasal challenges with antigen were performed after one
`week's treatment with 200 µg of flunisolide spray or placebo spray
`per day. A one-month washout period separated the two challenges.
`
`Subjects
`
`We selected 13 patients, 4 women and 9 men 20 to 36 years of age
`(mean age, 30.5), with seasonal allergic rhinitis due to grass or
`ragweed pollens. All subjects had a positive intradermal skin test to
`10 PNU (protein nitrogen units) or less of antigen extract, and all
`had previously had a dual response (early and late) to nasal chal(cid:173)
`lenge with antigen. The study was approved by the Joint Committee
`on Clinical Investigation of Johns Hopkins University, and in-
`
`The New England Journal of Medicine
`Downloaded from nejm.org by Raymond Cruitt on December 17, 2019. For personal use only. No other uses without permission.
` From the NEJM Archive. Copyright © 2010 Massachusetts Medical Society. All rights reserved.
`
`

`

`Vol. 316 No. 24
`
`ALLERGIC RHINITIS AND MEDIATOR RELEASE- PIPKORN ET AL.
`
`1507
`
`TAME-esterase activity detected in the immediate response to anti(cid:173)
`gen challenge represents approximately 75 percent plasma kalli(cid:173)
`krein complexed to az-macroglobulin, 25 percent mast-cell tryptase,
`and a small amount of glandular kallikrein.23
`24 EDTA was added
`•
`to the samples for the measurement of kinins to make the samples
`40 mM with respect to this agent, in order to prevent enzymatic
`degradation by kininases. Kinins were assayed in duplicate at two
`or three dilutions by a radioimmunoassay that is sensitive to 20 pg
`per milliliter with an intraassay and interassay variation of less than
`5 percent. 20
`
`Assessment of Symptoms
`
`The patients maintained a symptom score sheet during the chal(cid:173)
`lenge procedure. In addition to the number of sneezes, a six-point
`scale from Oto 5 (with 0 equal to no symptoms and 5 equal to severe
`symptoms) was used to assess nasal secretion, blockage, and itch(cid:173)
`ing. The degree of blockage is, of course, underestimated on these
`score sheets because of the pretreatment with oxymetazoline hydro(cid:173)
`chloride. The presence or absence of symptoms correlates with the
`presence or absence of mediators during the late reaction. 18
`
`Statistical Analysis
`
`To analyze the results, we defined base lines and time intervals
`as follows. The early response was assessed IO minutes after each
`of the 10-, l00-, and 1000-PNU antigen challenges and 20 min(cid:173)
`utes after the 1000-PNU challenge. The late response was defined as
`the response occurring 2 through 11 hours after challenge, and the
`rechallenge reaction was defined as the response occurring 20 min(cid:173)
`utes after the second l0-PNU challenge. The base line for the early
`response was the average of the two diluent challenges, where(cid:173)
`as the base line for the late reaction was the lowest level during
`hours 2 through 4. The base line for the rechallenge reaction was
`the lavage preceding the antigen rechallenge.
`The data were analyzed in several different ways. The threshold
`
`formed consent was obtained from the patients before their partici(cid:173)
`pation in the study. All 13 patients completed the study, and none
`were omitted from the analysis.
`
`Reagents
`
`Ragweed and mixed-grass pollen extracts (timothy, orchard,
`June, and meadow grass in a ratio of 3:2:3:2) were purchased from
`Greer Laboratories (Lenoir, N.C.); lactated Ringer's solution and
`oxymetazoline hydrochloride (Afrin, Schering, Kenilworth, N.J.)
`were purchased from the hospital pharmacy.
`
`Treatment
`
`Identical-looking nasal sprays of flunisolide and placebo were
`provided by Syntex Laboratories (Palo Alto, Calif.) . The patients
`were asked to spray each nostril twice two times a day, starting one
`week before the day of the challenge. The investigators also admin(cid:173)
`istered a dose of the spray one hour before the challenge and again
`two hours after the antigen was administered. Each use of the fluni(cid:173)
`solide spray delivered 25 µ.g of the drug, giving the patients 200 µ.g
`daily. In order to be sure that the intended dose was actually re(cid:173)
`ceived by the patient, the bottles were weighed before and after
`treatment. The measurements suggested that all patients had com(cid:173)
`plied with the instructions for taking the medications. No other
`medications were allowed during the study.
`
`Procedure for Nasal Challenge
`
`The technique used for the nasal challenge has previously been
`19 Briefly, the protocol involved four prechal(cid:173)
`described in detail. 18
`•
`lenge nasal lavages with lactated Ringer's solution to reduce the
`levels of cell-free mediators that are typically present in nasal secre(cid:173)
`tions. Then oxymetazoline hydrochloride was sprayed into the nose
`(two sprays per nostril) to prevent mucosa! congestion, which would
`interfere with the collection of nasal secretions. It has been shown
`previously that this dose of oxymetazoline
`does not affect histamine release during the
`early reaction to antigen. 19 Subsequently,
`two challenges with the diluent for the pol(cid:173)
`len extracts were used to control for nonspe(cid:173)
`cific effects of the diluent or the delivery
`system. Thereafter, serial challenges with
`IO, 100, and 1000 PNU of antigen were un(cid:173)
`dertaken. Nasal lavages with lactated Ring(cid:173)
`er's solution were performed IO minutes
`after each of the procedures described
`above. In addition, lavages were performed
`20 minutes after the last antigen challenge
`and every hour for the next 11 hours. After a
`second dose of oxymetazoline, we repeated
`the challenge with only the l0-PNU antigen
`dose. Lavages were performed IO and 20
`minutes later.
`
`10
`
`0
`
`80
`
`60
`
`D Placebo
`Flunisolide
`•
`
`••
`
`30
`
`20
`
`12
`
`I.II
`8 Z-
`ie
`... .,, 4
`C'
`en£
`:z::
`
`0
`
`24
`
`18
`
`12
`
`en:=
`Z E - ....
`z"' - c
`:l<:~ 6
`
`0
`
`**
`EP
`
`..
`
`LP
`
`RC
`
`40
`
`20
`
`0
`
`EP
`
`LP
`
`RC
`
`Mediator Assays
`
`The assays for histamine, T AME-esterase
`activity, and kinins made use of techniques
`20 In brief,
`previously described in detail. 19
`•
`histamine concentrations in individual sam(cid:173)
`ples, at one dilution, were determined by
`an automated fluorometric technique that
`was sensitive to I ng per milliliter and accu(cid:173)
`rate to within ±5 percent.21 Enzymes dis(cid:173)
`playing arginine esterase activity were meas(cid:173)
`ured as individual samples at one dilution in
`duplicate by the method of lmanari et al.,22
`in which :1H-labeled methanol is liberated
`from the synthetic substrate [3H]TAME.
`The appearance of TAME-esterase activity
`in nasal lavage fluids correlates with the
`acute response to nasal antigen challenge. 19
`
`Figure 1. Mean Net Increases in Mediator Levels (±SEM) in Lavage Fluids and the
`Total Number of Sneezes in 13 Patients.
`For each time period, the sum of the net increases (base-line levels subtracted) is
`presented. In the early phase (EP), the lavage samples were those obtained 10 min(cid:173)
`utes after each of the three antigen challenges plus the lavage samples obtained 20
`minutes after the third antigen challenge; in the late phase (LP), the hourly samples
`during hours 2 through 11 ; and in the rechallenge (RC), the two samples obtained after
`antigen exposure. The base line for the early reaction was the mean level of the two
`diluent challenges; for the late reaction, the lowest value during hours 2 through 4; and
`for the rechallenge, the value in the lavage fluid immediately before rechallenge. All
`variables except TAM E-esterase activity during rechallenge were significantly reduced
`by pretreatment with glucocorticosteroid. * indicates P<0.05; ** indicates P<0.01 .
`
`The New England Journal of Medicine
`Downloaded from nejm.org by Raymond Cruitt on December 17, 2019. For personal use only. No other uses without permission.
` From the NEJM Archive. Copyright © 2010 Massachusetts Medical Society. All rights reserved.
`
`

`

`1508
`
`THE NEW ENGLAND JOURNAL OF MEDICINE
`
`June II, 1987
`
`w
`
`z ~e
`
`<( --
`..... 01
`<1) C
`::r:
`
`20
`
`15
`
`10
`
`5
`
`PLACEBO TOPICAL STEROID
`
`Figure 2. Comparison of the Maximal Level of Histamine during
`the Early Response to Antigen after Pretreatment with Placebo or
`Topical Glucocorticosteroid (Steroid).
`The significant reduction (P<0.01) after topical glucocorticoste(cid:173)
`roid pretreatment also occurred with symptoms and levels of
`TAME-esterase activity and kinins (data not shown).
`
`for the early response was the first dose of antigen that led to a
`twofold increase over the base-line value. The maximum response
`was the highest level of mediators in the lavage fluids collected. The
`net increase in the level of mediators was the sum of the levels of the
`mediators above the base-line value in the lavage fluids collected
`during a particular time period.
`The statistical evaluation was performed on an Apple Macintosh
`microcomputer with use of the Statfast statistical software package.
`The nonparametric Wilcoxon signed rank-sum test was used to
`evaluate differences between placebo and active treatment. No
`crossover effect was observed.
`
`RESULTS
`In general, after pretreatment with the placebo, in(cid:173)
`creasing doses of antigen caused an immediate in(cid:173)
`crease in symptoms associated with an increase in re(cid:173)
`covered nasal lavage fluids of the levels of histamine,
`TAME-esterase activity, and kinins (early response).
`The response dissipated over the next several hours
`and was typically followed by a spontaneous recur(cid:173)
`rence of symptoms and mediators (late reaction). Re(cid:173)
`challenge with the lowest dose of antigen ( IO PNU)
`used 11 hours previously induced another immediate
`response. The patients' individual response patterns
`after pretreatment with placebo were similar to those
`in our previous study 18 in that the number of peaks
`and the timing of peaks varied. These results contrast
`with the response after pretreatment with topical glu(cid:173)
`cocorticosteroids, which, like prednisone, dramatical(cid:173)
`ly reduced both the symptoms and the expected in(cid:173)
`crease in the mediators measured in the late and
`rechallenge reaction. Topical flunisolide, unlike sys(cid:173)
`temic prednisone, 5 also reduced the early response.
`Not only did symptoms and mediators decrease abso(cid:173)
`lutely, but the dose-response curves appeared to be
`shifted approximately IO-fold.
`Group data for the early, late, and rechallenge re(cid:173)
`sponses are shown in Figure l. During the early reac-
`
`tion, both indexes of clinical response -
`sneezes and
`symptom score (data not shown) - were decreased
`significantly by topical glucocorticosteroid treatment
`(P<0.0 I). The net increase in the amount of hista(cid:173)
`mine released during the entire early response was
`decreased by about 75 percent (P<0.01), as was the
`amount of histamine released during the maximal
`response to antigen (P<0.0 I) (Fig. 2). Kinin levels
`during the early response were decreased about 80
`percent (P<0.01). The decrease in TAME-esterase
`activity, though less dramatic (55 percent), was signif(cid:173)
`icant (P<0.0 I). There was also an increase in the
`threshold dose for a positive response to antigen (i.e.,
`the dose required to cause a twofold or greater in(cid:173)
`crease in the level of mediators above base line) in 9 of
`the 13 patients (P<0.01) (Fig. 3).
`The decrease in clinical indexes after pretreatment
`with glucocorticosteroids, as compared with placebo,
`was, as expected, more striking during the late phase
`than during the early phase (P<0.01). The same per(cid:173)
`tained to the levels of histamine (P<0.01), TAME(cid:173)
`esterase activity (P<0.01), and kinins (P<0.05). Fur(cid:173)
`thermore, the response to IO PNU of antigen at 11
`hours was reduced by pretreatment with topical glu(cid:173)
`cocorticosteroids. This was also true for symptoms
`and the net increase above the base-line value (lavage
`before rechallenge) for histamine and kinins. The in(cid:173)
`crease in sensitivity is examined in Figure 4. After
`pretreatment with placebo, rechallenge with the low(cid:173)
`est dose of antigen ( IO PNU) caused increases in the
`levels of histamine, T AME-esterase activity, and kin(cid:173)
`ins to levels equivalent to those seen after a IO-fold
`higher dose of antigen ( 100 PNU) given l l hours be(cid:173)
`fore (P<0.0 1 for each comparison). After pretreat(cid:173)
`ment with topical glucocorticosteroids, the levels of
`histamine, kinins, and T AME-esterase activity and
`
`-:::,
`
`NR
`
`z
`~ w
`Cl) 1000
`0
`C
`C
`...J
`0
`::I:
`Cl)
`w
`a:
`::I:
`I-
`
`100
`
`10
`
`PLACEBO TOPICAL STEROID
`
`Figure 3. The Threshold Dose for a Positive Histamine Response.
`The threshold dose (the first dose of antigen that caused a twofold
`or greater increase in the level of histamine relative to the diluent
`challenges) increased significantly (P<0.01) with pretreatment
`with topical glucocorticosteroids. Similar results were seen for
`symptoms and the threshold levels of TAME-esterase activity and
`kinins. NR denotes no response (i.e., a threshold was not
`reached). Steroid denotes glucocorticosteroid.
`
`The New England Journal of Medicine
`Downloaded from nejm.org by Raymond Cruitt on December 17, 2019. For personal use only. No other uses without permission.
` From the NEJM Archive. Copyright © 2010 Massachusetts Medical Society. All rights reserved.
`
`

`

`Vol. 316 No. 24
`
`ALLERGIC RHINITIS AND MEDIATOR RELEASE- PIPKORN ET AL.
`
`1509
`
`30
`
`20
`
`w
`a:
`0
`0
`Cl)
`:::IE
`0
`I-
`D. 10
`::E
`► Cl)
`
`::::E
`
`z ..... - _,
`w
`:::IE <-I- C,
`Cl)~
`:i:
`
`0
`8
`
`6
`
`4
`
`2
`
`0
`
`0 PLACEBO
`■ FLUNISOLIDE
`
`Cl) ..... z--E z--a
`
`:i-= a.
`
`► I-s:
`
`j::
`0
`4(
`wo'
`Cl) 8
`4( ...
`
`··~ ffi e
`
`* *
`
`I- a.
`Cl)~ w
`w
`:IE
`<
`I-
`
`p C 0.01
`
`**
`
`5000
`
`4000
`
`3000
`
`2000
`
`1000
`
`0
`40
`
`30
`
`20
`
`10
`
`0
`
`BASELINE 10
`PNU
`1
`
`100
`PNU
`
`1000
`PNU
`
`BASELINE 10
`PNU
`2
`
`BASELINE 10
`PNU
`1
`
`100
`PNU
`
`1000
`PNU
`
`BASELINE 10
`2
`PNU
`
`Figure 4. Levels of Histamine, TAME-Esterase Activity, and Kinins and Symptom Scores (Includes Number of Sneezes) 1 0 Minutes after
`Each Challenge (Means ±SEM).
`Statistical comparison of results after placebo and topical glucocorticosteroid pretreatment are indicated (* = P<0.05; ** = P<0.01;
`NS = not significant). The vertical line indicates 11 hours' separation in time between challenges. The connecting line indicates the
`comparison between the two 10-PNU challenges on the placebo day. The second challenge, 11 hours after the first, is augmented and is
`not statistically different from the initial 100-PNU challenge.
`
`the symptom scores were significantly reduced after
`each antigen challenge, as compared with placebo,
`and the increased sensitivity following rechallenge was
`no longer evident.
`
`DISCUSSION
`Our results clearly demonstrate that one week of
`pretreatment with topical glucocorticosteroids inhib(cid:173)
`its both the symptoms and the release of histamine
`and other inflammatory mediators during not only the
`late and rechallenge reactions to nasal challenge with
`antigen but also the early response. These experi(cid:173)
`ments thus demonstrate inhibition of mediator release
`by glucocorticosteroids during the immediate phase of
`an IgE-mediated anaphylactic reaction in humans.
`The early response to nasal challenge is believed to
`reflect mast-cell activation on the basis of the follow(cid:173)
`ing observations: ( l) biopsy specimens of the nasal
`mucosa after antigen challenge show an increased
`number of degranulated mast cells, 25 (2) prostaglan(cid:173)
`din D2, the major cyclooxygenase product of mast
`cells (but not made by basophils), increases during the
`early response, 19 (3) topical administration of azata(cid:173)
`dine, a drug that inhibits lgE-mediated mast-cell his(cid:173)
`tamine release in vitro, also inhibits histamine release
`in vivo, 26 and ( 4) pretreatment .,with aspirin inhibits
`the release of prostaglandin D2 without augmenting
`the release of leukotriene C 4 or histamine -
`a pattern
`similar to that seen after pretreatment of human
`
`lung mast cells with nonsteroidal antiinflammatory
`drugs. 27 In vitro studies have shown that human lung
`mast cells, unlike basophils, are not inhibited by pre(cid:173)
`treatment with glucocorticosteroids.6·28 The lack of
`effect of a high dose of prednisone on antigen-induced
`histamine release in the nose supported this notion,
`and the medical literature is quite clear in showing a
`lack of effect of systemic glucocorticosteroids on
`the early response to antigen. 1
`5 Our unexpected
`•
`results indicate that glucocorticosteroids affect the
`pathophysiology of nasal challenge between antigen
`presentation and histamine release, and thus give rise
`to several hypotheses. High doses of steroids may
`reduce the numbers of mast cells in the nasal muco(cid:173)
`sa,29 a change that could markedly alter the early re(cid:173)
`sponse. Another likely possibility is that direct appli(cid:173)
`cation of soluble glucocorticosteroids to the nasal
`mucosa may increase the dose to local cells sufficiently
`to bring out glucocorticosteroid effects not detected
`during systemic administration or in vitro. Or the in(cid:173)
`creased time of exposure to glucocorticosteroids (sev(cid:173)
`en versus two days) may explain the difference be(cid:173)
`tween the inhaled and orally administered drug. It is
`also possible that the epithelial barrier may have been
`altered to reduce antigen presentation to mast cells.
`Our data do not differentiate among these alternatives
`and several others.
`The reduction in the late and rechallenge reactions
`may be the mechanism by which this class of drugs
`
`The New England Journal of Medicine
`Downloaded from nejm.org by Raymond Cruitt on December 17, 2019. For personal use only. No other uses without permission.
` From the NEJM Archive. Copyright © 2010 Massachusetts Medical Society. All rights reserved.
`
`

`

`1510
`
`THE NEW ENGLAND JOURNAL OF MEDICINE
`
`June 11, 1987
`
`achieves clinical efficacy. Unfortunately, our experi(cid:173)
`ments do not indicate whether this is a direct effect on
`the cells and mediators involved in the late reaction or
`an indirect effect related to the reduction of the early
`reaction.
`Since these drugs take several days to achieve an
`effect, clinicians usually recommend beginning their
`use several days before the pollen season occurs. Our
`data provide a strong, scientific rationale for this prac(cid:173)
`tice. When one can anticipate seasonal exposure, pre(cid:173)
`medication with glucocorticosteroids reduces the early
`response to antigen, in addition to suppressing inflam(cid:173)
`mation associated with more chronic aspects of aller(cid:173)
`gic rhinitis.
`In summary, the present study shows that pro(cid:173)
`longed pretreatment with topical glucocorticosteroids
`reduces symptoms and the release of mediators not
`only during the late reaction but also during the early
`allergic reaction in the nose. This effect is at least
`partly due to a reduction in the generation of inflam(cid:173)
`matory mediators. The decrease in the late reaction
`may be either a direct effect of the treatment with
`glucocorticosteroids on components of that reaction or
`an indirect effect of a decrease in the early reaction.
`This study points to differences between the mecha(cid:173)
`nisms of action of topical and systemic glucocortico(cid:173)
`steroids and suggests additional reasons for preferring
`topical administration.
`We are indebted to Denise Bartenfelder, Indira Nimmagadda,
`and Curt Reynolds for technical support and to Carol Dankelman
`for assistance with the preparation of the manuscript.
`
`REFERENCES
`
`I. Oertel H, Kaliner M . The biologic activity of mast cell granules in rat skin:
`effects of adrenocorticosteroids oo late-phase inflammatory responses in(cid:173)
`duced by mast cell granules. J Allergy Clin Immunol 1981; 68:238-45.
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