Spectrum of Seasonal Allergic
`Rhinitis Symptom Relief with
`Topical Corticoid and Oral
`Antihistamine Given Singly
`or in Combination
`
`Carter D. Brooks, M.D., Steven F. Francom, Ph.D., Bruce G. Peel, B.S.,
`Brenda L. Chene, R.N., and Karen A. Klatt, R.N.
`
`ABSTRACT
`Sixty ragweed-sensitive volunteers participated in a 2-week
`study that compared symptom profiles during treatment with
`antihistamine (loratadine, LOR) alone,
`topical corticoid (be-
`clomethasone, BEC) alone, or the two drugs combined. For 5
`days commencing shortly after the beginning of the ragweed
`bloom, patients took no treatment while we collected baseline
`data. They were then randomized to one of the three treat-
`ments, receiving that treatment for the balance of the 2-week
`study term. Twice each day they recorded the severity of
`congestion, eye symptoms, running and blowing,
`itching, and
`sneezing. At the end of the study they provided an estimate of
`overall symptom relief, which favored combined treatment (vs
`LOR P = 0.001, vs BEC P = 0.042). To gain an estimate of
`disease severity and treatment effectiveness over time, and to
`smooth out day-to-day variation, we divided symptom diary
`reports into three segments (days 2-4, 5-7, and 8-10) for
`
`From The Upjohn Research Clinics and Michigan State Uni-
`versity College of Human Medicine, Department of Pediatrics
`and Human Development
`This study was conducted in a clinic wholly supported by The
`Upjohn Company
`Address correspondence and reprint requests to Dr. Carter D.
`Brooks, Clinical Research Director, 7000 Portage Road,
`Kalamazoo, M149001-0199
`
`analysis. Combined treatment controlled symptoms better than
`antihistamine alone in nearly all study segments. Corticoid
`alone or combined with antihistamine provided similar control
`of congestion, running and blowing, and eye complaints. Com-
`bination therapy controlled itching and sneezing better, espe-
`cially through the study segments 1 and 2. Patient preference
`for combined treatment seems to relate to control of itching
`and sneezing and rapid onset of effect. (American Journal of
`Rhinology 10, 193-199, 1996)
`
`Inseveral previous studies we have examined profiles of
`
`individual symptoms in allergic rhinitis and the selective
`effects of various treatments on these profiles. We showed that,
`compared to placebo, terfenadine suppressed sneeze, itch, and
`eye symptoms, benefitted congestion marginally, and failed to
`improve running and blowing. Of these, only control of sneez-
`ing 'appeared quickly after introduction of the drug in midsea-
`son.! Another study intended to establish minimal effective
`doses of oral methylprednisolone
`found, at 6 mg per day,
`significant suppression of congestion, postnasal drainage, and
`eye symptoms, but not itching, sneezing, and running? These
`fmdings could be a clinical expression of the reported inability
`of systemic corticoid to prevent
`release of mediators from
`human mast cells?
`to anti-
`the symptoms most responsive
`It appeared that
`responded least well
`to low dose cor-
`histamine treatment
`ticoid and vice versa, providing a rational basis for combi-
`nation of the two drug types for seasonal allergic rhinitis
`
`Exhibit 1038
`193
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`
`000001
`
`

`

`treatment. We have carried out preliminary studies docu-
`menting additive protection with combined antihistamine/
`corticoid treatment, and the equivalence of oral and topical
`corticoid when given as part of the combination.
`Others have studied symptom control with combined
`antihistamine/topical
`corticoid treatment and have reported
`variable findings.4-7 Most
`reported a more modest
`incre-
`ment of patient-perceived
`benefit with combined treatment
`than our preliminary studies led us to expect.
`The goal of the study reported here was to compare profile
`and severity of individual symptoms, and overall patient per-
`ception of benefit during seasonal allergic rhinitis treatment
`with antihistamine
`(loratadine, Claritin, Schering-Plough,
`LOR) alone, topical nasal corticoid (bedomethasone, Vance-
`nase AQ, Schering-Plough, BEC) alone, and the two drugs in
`combination. The study did not contain a concurrent placebo
`control group, but all study participants entered the treatment
`comparison from an untreated baseline observation period.
`
`STUDY DESIGN AND EXECUTION
`
`Subject Selection
`
`Sixty subjects enrolled in and completed the study. Each
`
`treatment group contained 20 people; sex distribution
`in the LOR group was IOM/IOF, whereas the BEC and the
`LORIBEC groups both had 7M/13F. The three treatment
`groups were roughly comparable in age, height, and weight.
`All had reliable histories of seasonal
`rhinitis compatible
`with ragweed seasonal allergic rhinitis and strongly positive
`ragweed skin (prick) tests. Many had participated in previ-
`ous studies and had provided records of the severity of their
`seasonal symptoms. None had evidence of significant com-
`plicating
`disease
`on history,
`physical
`examination,
`or
`screening laboratory
`testing; women had negative preg-
`nancy tests on entry and again in mid-study. All alleged that
`they understood the design, demands, and risks of the study
`and signed
`their
`consent
`to participate.
`The Bronson
`
`Hospital Human Use Committee reviewed and approved the
`study design and documents.
`
`Treatment Schedule
`
`In this community,
`
`to bloom
`ragweed typically begins
`around August 15. Subjects came under study observa-
`tion on 18 August
`(Thursday) and were seen each Monday
`and Thursday through 1 September. From August 18 to 22
`they used no treatment;
`this provided baseline information
`documenting seasonal allergic rhinitis severity at the begin-
`ning of the observation period. After 22 August
`they used
`their
`randomly assigned therapy,
`remaining
`on the same
`treatment
`through 1 September. At all visits we reviewed
`and verified hay fever symptom severity diaries, checked
`apparent study drug consumption,
`and inquired for possible
`treatment side effects or other medical events.
`Table I shows the pollen counts obtained during the study
`confirming the appearance of reasonable levels by mid-Au-
`gust. (James L. McDonald, M.D., provided aeroallergen counts
`obtained from a rotobar sampler located at an elevated urban
`site about one mile from the clinic where we ran the study.)
`Absolute counts never exceeded 169 grains per cubic meter,
`relatively low compared with prior years' experiences. How-
`ever,
`they seemed to provide an adequate allergic stimulus,
`both in study subjects and nonstudy patients under our care.
`
`Experimental Drug Treatment
`
`We randomly allocated volunteers
`
`to three drug treat-
`
`ment groups consisting of:
`(LOR) 10 mg
`1. Loratadine
`(Claritin, Schering-Plough)
`once a day, plus a placebo spray twice a day.
`2. Bedomethasone
`(Vancenase AQ, Schering-Plough)
`(BEC)
`two sprays
`(about 84 meg) each side of the
`nose twice a day, plus placebo LOR.
`3. BEC twice a day plus LOR once daily.
`During the treatment
`comparison,
`subjects
`treatment
`that might affect
`their hay fever.
`
`took no other
`
`TABLE I
`
`Ragweed Pollen Grain Count in Particles Per CU Meter. Counts Made Using A Rotobar Sampler Running
`Intermittently on a Downtown Rooftop
`Ragweed Count
`Study Segment
`1
`I
`6
`1
`19
`I
`14
`2
`16
`2
`40
`2
`71
`3
`27
`3
`14
`3
`59
`23
`
`Study Segment
`
`Baseline
`Baseline
`Baseline
`
`Date
`August 12
`August 13
`August 14
`August 15
`August 16
`August 17
`August 18
`August 19
`August 20
`August 21
`August 22
`
`Date
`August 23
`August 24
`August 25
`August 26
`August 27
`August 28
`August 29
`August 30
`August 31
`September 1
`September 2
`
`Ragweed Count
`83
`162
`169
`95
`144
`144
`116
`76
`67
`45
`19
`
`194
`
`May-June 1996, Vol. 10, No. 3
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` 2017 00:35:07
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`000002
`
`

`

`Observations
`
`and Evaluations
`
`Symptom Severity Diaries recorded the level of discom-
`
`fort perceived by the subjects for each of five classes
`of seasonal allergic rhinitis symptoms. The diary has served
`us well
`in earlier studies.
`All subjects made twice daily entries for the following
`hay fever-related problems:
`
`• Congestion
`• Running and blowing
`• Sneezing
`•
`Itching
`• Eye symptoms
`For each symptom the diary contained a scale specifically
`describing five levels of severity. The diary also provided
`space for recording use of study drug, need for any inter-
`current medications, possible adverse reactions to the study
`drugs, and amount of time spent
`in air-conditioning.
`
`Global Assessment
`
`On th~ final treatment day, we asked all subjects to rate
`
`theIr response to treatment as excellent, good, fair, or
`poor. Although
`crude and subjective,
`this approach
`has
`clearly differentiated
`among treatments
`in past studies.
`
`DATA HANDLING AND STATISTICAL
`
`ANALYSIS
`
`We omitted symptom severity scores from the first and
`
`last days, as these typically included half day re-
`ports only, as well as the first full treatment day, feeling that
`it still reflected a transition day providing questionable data.
`To allow comparison with baseline and perception of de-
`veloping trends, we collapsed symptom severity reports into
`four intervals; days - 3 to -1 (pretreatment),
`and treatment
`days 2-4, 5-7, and 8-10. We averaged AM and PM scores and
`calculated change from mean pretreatment
`score for each
`subject and each follow-up day. Each symptom change score
`was analyzed using a repeated measures analysis of variance
`model incorporating factors associated with treatment, subject
`nested within treatment,
`study day, and treatment by day
`interaction. In addition,
`the mean pretreatment
`response was
`used as a covariate. We used contrast statements
`to make
`treatment comparisons within each of the 3-day follow-up
`periods. A pooled error term containing both the within- and
`between-subject errors was used in testing. All analyses were
`done using SAS (SAS Institute, Cary, NC).
`
`RESULTS
`
`Symptom Severity During Baseline
`
`Table II contains overall mean symptom severity scores
`
`collected during the baseline period. During this in-
`the volunteers
`took no medications
`to suppress their
`terval,
`rhinoconjunctivitis.
`Diaries allowed description
`of symp-
`toms on a discrete scale from 1 (no symptoms)
`to 5 (max-
`imum symptoms). Baseline values largely between 2 and 3
`suggest
`that patients experienced mild to moderate symp-
`
`TABLE II
`
`Mean (± STD DEV) Severity Scores By Symptom and
`Treatment Group for the Untreated Baseline Period
`(BEC & LOR)
`BEC
`LOR
`2.78 :t 1.00 2.90 :t 0.77
`2.72 :t 0.61
`1.93 ± 0.72
`2.35 :t 0.89 2.28 ± 0.79
`2.83 ± 1.07 2.28 ± 0.83
`2.62 ± 0.55
`
`Congestion
`Eye symptoms
`Running/
`blowing
`Itching
`Sneezing
`
`2.30 ± 0.79 2.00 ± 0.88
`2.48 ± 0.70 2.23 ± 0.69
`
`2.44 ± 0.96
`2.22 ± 0.76
`
`toms during this time and that symptom severity was rea-
`sonably homogeneous
`across the three groups.
`
`At
`
`Overall Patient Assessment
`the last clinic visit, on the last day of study-imposed
`therapy, we asked each subject for an overall estimate
`of the effectiveness
`of the treatment
`they had just com-
`pleted. Their options were excellent, good, fair, or poor; we
`did not qualify these further.
`ratings. Combi-
`Table III contains results of the patient
`nation treatment provided superior
`symptom control with
`19/20 reporting
`good (8) or excellent
`(11)
`results. The
`combination was significantly
`superior
`to topical
`steroid
`alone (P = 0.042), and to antihistamine
`alone (P = 0.001).
`BEC alone appeared to protect
`slightly better
`than LOR
`alone, but statistical
`testing did not confirm the significance
`of this trend (P = 0.122).
`
`Diary Symptom Severity Scores
`
`Figures 1 through 5 show mean changes
`
`in symptom
`to the indicated treatment
`severity from pretreatment
`segment. We looked for treatment
`effect by determining
`symptom severity decrements
`from baseline
`and testing
`these for significance using the paired (-test.
`alone
`The figures
`show several patterns. Antihistamine
`(LOR, L) produced relatively modest benefit, almost always
`less than that seen with either of
`the topical
`corticoid-
`
`TABLE III
`
`Effectiveness
`
`Treatment Result
`
`of Treatment
`Overall Patient Assessment
`Statistical Testing
`Treatment
`(BEC + LOR)
`LOR
`BEC
`11
`4
`6
`Excellent
`8
`5
`9
`Good
`1
`9
`4
`Fair
`0
`2
`1
`Poor
`(BEC & LOR) vs BEC P = 0.042; (BEC & LOR) vs LOR
`P = 0.001; BEC vs LOR P = 0.122.
`
`American Journal of Rhinology
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`
`000003
`
`

`

`Mean Change
`0.1
`
`S=Congestlon
`
`L Group
`B B+L
`L
`B B+L
`B B+L
`-:-1----1
`t---2-·
`t--- 3 ----1
`Segment
`Figure 1. Congestion Mean Change by Treatment Group and Study Segment. B = Beclomethasone
`alone, L = Loratadine alone, B+L =
`and Loratadine. Segment 1 = Treatment Days 2-4, Segment 2 = Treatment Days 5-7, Segment 3 = Treatment
`Combined Beclomethasone
`Days 8-10.
`
`L
`
`S= Eye Symptom
`
`Mean Change
`0.00
`-0.02
`-0.04
`-0.06
`-0.08
`-0.10
`-0.12
`-0.14
`-0.16
`-0.18
`-0.20
`-0.22
`-0.24
`-0.26
`-0.28
`-0.30
`-0.32
`-0.34
`-0.36
`-0.38
`-0.40
`-0.42
`-0.44
`-0.46
`-0.48
`
`Figure 2. Eye Symptoms Mean Change by Treatment Group and Study Segment. Group and Segment as in Figure 1.
`
`L
`B B+L
`t--- 1 ----1
`
`B B+L
`
`L
`
`L Group
`B B+L
`Segment
`'-. - 3 ----i
`
`benefitted congestion
`contammg regimens. Antihistamine
`(Fig. 1) slightly in segments
`1 and 2, and not at all
`in
`segment 3. Eye symptoms
`(Fig. 2) improved minimally
`though never
`significantly, while
`running
`and blowing
`(Fig. 3) showed no LOR-induced
`improvement.
`Itching
`
`lessening during
`(Fig. 4) showed consistent and significant
`LOR treatment, whereas
`sneezing
`(Fig. 5)
`improved
`in
`segments 1 and 2, but not 3.
`three diary entries,
`Comparing
`among the treatments,
`congestion,
`eye symptoms,
`and runninglblowing
`showed
`
`196
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`000004
`
`

`

`Mean Change
`0.2
`
`S=Runnlng
`
`0.1
`
`-0.1
`-0.2
`
`-0.3
`
`-0.4
`-0.5
`
`-0.6
`
`-0.8
`
`-0.9
`
`-1.0
`
`Figure 3. Running/Blowing Mean Change by Treatment Group and Study Segment. Group and Segment as in Figure 1.
`
`B B+L
`1-1----1
`
`L
`
`L
`B B+L
`c--- 2---;
`
`B B+L
`3 ---;
`I-
`
`L Group
`Segment
`
`Mean Change
`0.0
`
`S=ltching
`
`-0.1
`
`-0.2
`
`-0.3
`
`-0.4
`
`-0.5
`
`-0.6
`
`-0.7
`
`-0.8
`
`-0.9
`
`-1.0
`
`B B+L
`L Group
`B B+L
`B B+L
`1-2--·
`3 ---;
`Segment
`1-1--;
`I-
`Figure 4. Itching Mean Change by Treatment Group and Study Segment. Group and Segment as in Figure 1.
`
`L
`
`L
`
`improvement with BEC and BEC/LOR combined
`similar
`treatment. Combined
`treatment
`benefitted
`sneezing
`and
`itching significantly better than BEC alone (see Table IV) in
`most of the treatment
`segments. With BEC alone suppres-
`sion of sneezing
`increased
`gradually
`from Segments
`1
`
`from baseline was sig-
`through 3, though the difference
`combined
`BEC/LOR
`nificant
`in all
`segments. With
`sneeze
`suppression
`appeared
`promptly
`and already was
`maximum in Segment
`1; by Segment 3, BEC and BEC/
`LOR provided
`similar
`suppression
`of sneezing
`(albeit
`
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`
`000005
`
`

`

`Mean Change
`0.0
`
`S=Sneezing
`
`-0.1
`
`-0.2
`
`-0.3
`
`-0.4
`
`-0.5
`
`-0.6
`
`-0.7
`
`-0.8
`
`-0.9
`
`-1.0
`
`Figure 5. Sneezing Mean Change by Treatment Group and Study Segment. Group and Segment as in Figure 1.
`
`B B+L
`1 --1
`I-
`
`L
`
`L
`B B+L
`2 ---1
`I-
`
`B B+L
`3 --I
`I-
`
`L Group
`Segment
`
`TABLE IV
`of BEC vs BEC + LOR Difference
`Probability
`for
`Symptom Severity and Study Segment.
`Indicated
`(BEC vs LOR Showed a High Probability
`of
`Difference
`for all Segments
`and Symptoms
`Except
`Itching, Segment 1.)
`Symptom
`Segments
`
`Congestion
`Eye symptoms
`Runninglblowing
`Itching
`Sneezing
`
`1
`0.4461
`0.0474
`0.0923
`0.0532
`0.0001
`
`2
`0.4461
`0.0550
`0.0244
`0.0001
`0.0001
`
`3
`0.6649
`0.2778
`0.6659
`0.0400
`0.0589
`
`at a 0.0589 level). With
`different
`testing statistically
`still
`itching, BEC/LOR provided
`significantly
`greater
`sup-
`pression than BEC alone in all segments. Unlike sneez-
`ing, control of itching with BEC alone did not
`increase
`progressively
`nor approach that achieved with combina-
`tion treatment. The difference
`in itching
`intensity
`be-
`tween LOR and LOR/BEC,
`although suggestive
`in seg-
`(P = 0.1298). With
`ment 1, tested less than significant
`segments 2 and 3, and every other symptom,
`combined
`therapy performed
`highly significantly
`better
`than anti-
`alone (P < 0.001).
`histamine
`
`DISCUSSION
`
`Inanalyzing studies of seasonal allergic rhinitis treatment,
`
`we have compared symptom responses day by day, or
`alternatively looked at an integrated response over the entire
`study. Both approaches have presented problems. Looking
`at days individually produces a great deal of variation and
`more data than is really necessary to compare effectiveness
`of several
`treatments.
`It will allow insight
`into developing
`trends and is necessary if one wishes to correlate symptom
`severity with something
`peculiar
`to that day,
`such as
`weather conditions. A single integrated symptom severity
`score representing the typical experience of subjects on a
`given treatment may suffice to compare treatments, but
`it
`cannot sense differences
`in the profile of development
`of
`symptom control over
`time. Trying to benefit
`from the
`strengths of each of these approaches, we divided this study
`into 3-day segments, which provided satisfactory indication
`of
`temporal
`patterns while
`smoothing
`out day-to-day
`variation.
`We had originally noted that low dose corticoid primarily
`benefitted
`congestion,
`drainage,
`and
`eye
`symptoms,
`whereas antihistamine
`affected primarily itching and sneez-
`ing.I
`,2 This led us to postulate
`that combination
`of these
`drug types would benefit more symptoms but not provide
`improved control of individual parts of the syndrome.
`In
`fact, our results suggest additive symptom suppression al-
`most across the board. With itching and sneezing, which
`showed the greatest
`increment of benefit from combination
`treatment,
`the data suggest
`that both drugs contributed some
`
`198
`
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`000006
`
`

`

`symptom control and the improvement seen with the combi-
`nation resulted from addition of the effects of the component
`drugs. This suggests other possible avenues of inquiry: what
`different drug mechanisms affect a given symptom; what about
`dose-response relationships with the component drugs?
`We have examined both single drugs and the combination
`in an acute nasal allergen challenge model,
`looking only at
`clinical endpoints. For sneezing and secretion,
`combined
`treatment had no more effect than corticoid alone. However,
`allergen-induced
`rises in measured nasal airway resistance
`showed no protection from antihistamine
`alone, partial sup-
`pression with corticoid alone and total suppression with the
`combination.8 Adding antihistamine, which typically affects
`measured
`nasal
`resistance
`or perceived
`congestion
`very
`little,
`to topical steroid seemed to facilitate its antiobstruc-
`tive effect in the acute challenge model, but seemed to affect
`that part of the real disease minimally.
`Others have examined combination treatment and typically
`reported a modest
`increment of benefit with combined com-
`pared with single drug treatment. D'Souza found similar num-
`bers of symptom-free days with nasal steroid or nasal steroid
`plus antihistamine. A retrospective patient judgement on suc-
`cess in controlling nasal symptoms yielded 76.6% for steroid
`alone and 85.5% for the steroid/antihistamine
`combination?
`There was a similar, modest increment for eye symptoms and
`headache. Backhouse et al.6 found a substantial
`increment of
`benefit
`in all symptoms examined comparing antihistamine
`alone to antihistamine plus nasal steroid. That study did not
`include a steroid-alone arm.
`and the two
`In a study of astemizole, beclomethasone,
`drugs combined,
`Juniper et al.5 found that bec]omethasone
`plus astemizole provided no better control of rhinitis than
`beclomethasone
`alone.
`Symptoms
`examined
`included
`sneezing,
`runny nose, stuffy nose, and eye complaints. They
`did find a significantly higher use of rescue medication for
`eye problems among those taking nasal steroid alone.
`Simpson4
`compared
`placebo,
`budesonide,
`terfenadine,
`and budesonide/terfenadine,
`looking at severity scores for
`nasal blockage,
`runny nose, nasal
`itching,
`and sneezing.
`Among these, only sneezing showed better control with the
`combination
`than with budesonide
`alone. Patients' overall
`assessment
`showed definite preference for the budesonide-
`containing regimens, but essentially no difference between
`corticoid alone and combined with terfenadine.
`Splitting our patient
`responses
`into early, mid, and late
`segments
`allowed us to smooth out short-term variability
`and gauge therapeutic
`effects
`that
`take some time to de-
`velop. Symptoms
`that showed gradual onset of control with
`BEC alone included sneezing and possibly itching and eye
`symptoms
`(Figs. 5, 4, and 2 respectively). These
`same
`symptoms
`showed rapid development of maximum control
`with combined BEC/LOR treatment. Several articles have
`looked at the effect of topical corticoid treatment on nasal
`mucosal mast cell populations, and all have agreed that over
`a period of time such as we studied here,
`total mast cell
`numbers changed little.9,lo One group found decreased his-
`
`in the steroid-treated nasal mucosa without
`tamine content
`accompanying change in mast cell numbers. This suggested
`to them that the topical corticoid had decreased the mast cell
`histamine poo1.9 Others found no changes
`in overall num-
`bers but a corticoid-associated
`reduction
`in numbers
`of
`formalin-sensitive mast cells,
`indicating differential effects
`on mast cell subpopulations.1O Sneezing responds quickly to
`treatment, 1 and we have felt
`antihistamine
`that
`it
`largely
`represents
`the effects of locally elaborated histamine. The
`pattern of control of sneezing seen in this study may reflect
`the gradual onset of corticoid influence on the local mast
`cell population in the BEC alone group, and this effect plus
`immediate histamine blockade in those getting both corti-
`coid and antihistamine.
`of com-
`the overall effectiveness
`This study confirms
`bined corticoid/antihistamine
`treatment
`for
`ragweed
`sea-
`sonal allergic rhinitis and shows that some symptoms remit
`better and sooner when combined treatment
`is applied.
`It
`has not afforded us any additional
`insight
`into possible
`reasons
`for
`this complementary
`effect.
`In contrast with
`earlier studies, our patients preferred combined treatment by
`a substantial margin,
`a finding that may correlate with
`quicker and overall better control of sneezing and itching.
`We believe that combined antihistamine-topical
`corticoid
`treatment will provide a very satisfactory level of comfort
`for most seasonal allergic rhinitis patients and should be the
`preferred treatment at this time.
`
`5.
`
`REFERENCES
`I. BrooksCD, Karl KJ, FrancomSF. Profile of ragweedhay fever
`symptomcontrol with terfenadinestarted before or after symp-
`toms are established.C]in Exp Allergy 20:21-26, 1990.
`2. Brooks CD, Karl KJ, Francom SF. Ora] methylprednisolone
`acetate (Medrol Tablets) for seasonal rhinitis: Examination of
`dose and symptomresponse.J Clin Pharm 33:816-822, 1993.
`3. Cohan VL, Undem BJ, Fox CC, et a!. Dexamethasone does
`not inhibit the release of mediators from human mast cells
`residing in airway, intestine, or skin. Am Rev Resp Dis
`140:951-954, ]989.
`4. SimpsonRJ. Budesonideand terfenadine,separatelyand in com-
`bination,in the treatmentof hayfever. Ann Allergy73:497-502,
`1994.
`JuniperEF, KlinePA, HargreaveFE, DolovichJ. Comparisonof
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`the combinationin the prophylactictreatmentof ragweedpollen-
`induced rhinoconjunctivitis.J Allergy Clin lmmunol 83:627-
`633, 1989.
`6. Backhouse CI, FinnamoreVP, Gosden CWoTreatmentof sea-
`sonal allergicrhinitiswith flunisolideand terfenadine.J lnt Med
`Res] 4:35-41, ]986.
`7. D'Souza MF, BurchessN, TooleyM. Prophylactictreatmentof
`seasonal allergic rhinitis.Clin Exp Allergy 20S:100, 1990.
`8. Brooks CD, Chene BL, Klott KA, Francom SF. Single and
`combined drug treatment effect on sequential nasal allergen
`challenge.J Allergy Clin Immunol95:192, 1995.
`9. Pipkom U, EnerbackL. Nasal mucosalmastcells and histamine
`in hay fever: Effectof topicalglucocorticoidtreatment.Jnt Arch
`Allergy App] lmmunol 84:123-128, 1987.
`10. Otsuka H, DenburgJA, Befus AD, et al. Effect of beclometha-
`sone dipropionateon nasal metachromaticcell sub-populations.
`0
`Clin Allergy 16:589-595, 1986.
`
`American Journal of Rhinology
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