Comparison of beclomethasone dipropionate
`aqueous nasal spray, astemizole, and the
`combination in the prophylactic treatment of
`ragweed po|len—induced rhinoconjunctivitis
`
`E. F. Juniper, MSc, P. A. Kline, RN, F. E. Hargreave, MD, and J. Dolovich, MD
`Hamilton, Ontario, Canada
`
`The clinical eflicacy and side eflect of (I) beclomethasone dipropionate aqueous nasal spray,
`400 pg daily, (2) astemizole, 10 mg daily, and (3) beclomethasone, 400 Mg, plus astemizole,
`10 mg daily, were compared in a double-blind, randomized, parallel-group trial. Ninety adults
`were matched into groups of three according to sensitivity to ragweed pollen. One -of each of
`the three subjects was assigned to nasal spray alone, one was assigned to astemizole alone, and
`one subject was assigned to both medications. Medications were started I week before and
`continued daily until I week after the ragweed-pollen season (6 weeks). If rhinoconjunctivitis
`was inadequately controlled with the trial medications, pressurized steroid nasal spray and /or
`antihistamine-decongestant eye drops were used in the minimum dose that would ensure relief.
`Nose and eye symptoms and concomitant medication use were recorded daily in a diary.
`Sneezing, nasal obstruction, and rhinorrhea were significantly better, and less additional nasal
`spray was used in subjects taking beclomethasone alone than in subjects taking astemizole
`alone. Beclomethasone plus astemizole provided no better control of rhinitis than
`beclomethasone alone. Eye symptoms and eye drop use tended to be less in subjects taking
`astemizole alone than in subjects taking beclomethasone alone, but the best control of eye
`symptoms was recorded in the subjects taking both trial medications. Side effects were mild or
`transient. (J ALLERGY CLIN IMMUNOL 1 989,83 :62 7-33. )
`
`Antihistamine tablets and intranasal steroid spray
`have been used successfully to treat rhinoconjuncti—
`vitis induced by seasonal pollens." 2 Most previous
`comparisons have suggested that nasal symptoms may
`be controlled better by steroid nasal sprays,” although
`the conclusions are not unanimous] and that con-
`
`junctivitis is treated more effectively by antihista-
`mines.“ These results and the different pharma-
`cologic properties of the two types of treatment
`suggest that a combination of nasal steroid and anti-
`histamine may be the most effective approach of over-
`all treatment.
`
`In the last few years, effective, nonsedative anti-
`
`From the Departments of Medicine and Paediatrics, St. Joseph’s
`Hospital and McMaster University, Hamilton, Ontario, Canada.
`Supported by Glaxo Canada, lnc., Toronto, Ontario, Canada.
`Received for publication April 15 , 1988.
`Accepted for publication July 15, 1988.
`Reprint requests: E. F. Juniper, MSc, Department of Clinical
`Epidemiology and Biostatistics, McMaster University Medical
`Center, 1206 Main St., West, Hamilton, Ontario, Canada
`L8N 325.
`
`histamines have become popular for the treatment of
`seasonal allergic rhinoconjunctivitis. More recently,
`aqueous steroid nasal sprays, with efficacy compa-
`rable to the original Freon—pr0pelled delivery system,
`but with less nasal bleeding and drying, have been
`introduced.“ The pharmacologic profile of nasal ste-
`roids suggests that the most effective approach to treat«
`ment
`is
`regular prophylactic useg;
`therefore, an
`aqueous delivery system should be effective in achiev-
`ing this with a reduced risk of side effects. In this
`study, we have compared the clinical efficacy of
`beclomethasone dipropionate aqueous nasal spray
`(Aq. Beconase; Glaxo Canada, lnc., Toronto, On—
`tario, Canada),
`taken before and continued daily
`throughout the ragweed-pollen season, with that of
`astemizole (Hismanal; Janssen Pharmaceutica, lnc.,
`Mississauga, Ontario, Canada), a nonsedative anti-
`histamine whose pharmacologic profile also recom-
`mends prophylactic and continuous treatment for al~
`lergic rhinoconjunctivitis.’° We have also examined
`whether taking the two medications together produces
`better symptom control than taking either medication
`individually.
`
`$27
`
`000001
`
`ARGE
`
`Emma
`
`|PR201
`
`Exhibit 1039
`IPR2017-00807
`ARGENTUM
`
`000001
`
`

`

`528 Juniper at al.
`
`.5. ALLERGY CLlN. EMMUNOL.
`MARCH 3989
`
`TABLE I. Subject characteristics
`
`
`Beclomethasone
`Beclomethasone
`alone
`Astemizole alone
`plus astemizole
`
`No.
`Sex (M/F)
`Age (mean, SD)
`Initial ragweed skin sensitivity
`(mean wheal diameter)
`<25 m
`2.5-3.0 mm
`3.0-3.5 mm
`3.5-4.0 mm
`4.0-4.5 mm
`>45 mm
`
`Severity of ragweed rhinocon—
`junctivitis the previous year
`1*
`21"
`33?
`4§
`5!!
`
`History of asthma
`Sensitivity to fungal spores
`Sensitivity to grass pollen
`
`30
`16/14
`39.8 (13.5)
`
`30
`15/15
`
`30
`15/15
`
`41.3 (11.8)
`
`42.2 (13.8)
`
`
`
`>—AOO£llUIL»J>—*C\UIlIl-5>C\LI100-BU.)
`
`>—-A
`
`-3>Co"\O'\r-J4>§aJ
`
`
`
`I-ID1‘Ul-D-\ll\)O’\l\)U\U\U\U\~JO\-l>-U)
`
`*Syrnptoms were well controlled with antihistamine or nasal spray.
`i'Symptoms were well controlled with antihistamine plus nasal spray or mild symptoms when subject was treated with antihistamine or
`nasal spray.
`iMild symptoms when subject was treated with antihistamine plus nasal spray or moderate symptoms when subject treated with antihistamine
`or nasal spray.
`'
`§Moderate symptoms when subject was treated with antihistamine plus nasal spray or severe symptoms when subject was treated with
`antihistamine or nasal spray.
`||Severe symptoms when subject was treated with antihistamine plus nasal spray.
`
`MATERIAL AND METHODS
`Subjects
`
`Ninety ragweed pollen—sensitive adults, aged 18 to 70
`years, who were either attending the Firestone Regional
`Chest and Allergy Clinic or who responded to a newspaper
`article, participated in the study. All subjects gave a history
`of rhinoconjunctivitis that required treatment during the pre-
`vious two ragweed-pollen seasons, and all subjects had a
`positive response to skin prick test with ragweed-pollen
`extract. None of the subjects had perennial rhinitis, and
`none were more than mildly sensitive to the fungal spores
`that are in the air at the same time as ragweed pollen.
`None of the subjects had serious illness other than sea-
`sonal rhinitis or asthma. Pregnant and nursing mothers were
`excluded, and women of childbearing potential were ad-
`vised to use an effective method of birth control through-
`out the study and for 2 months thereafter. None of the
`subjects had taken astemizole, steroid nasal spray, or oral
`steroid within 6 weeks of enrollment. All subjects signed
`an informed consent, which, with the study protocol, had
`been approved by the St. Joseph’s Hospital Research
`Committee.
`
`Study design
`
`random-
`The study was designed as a double-blind,
`ized, parallel-group comparison of (1) beclomethasone
`dipropionate aqueous nasal spray, 50 pg per nostril four
`times daily,
`(2) astemizole, 10 mg once daily, and (3)
`beclomethasone dipropionate aqueous nasal
`spray, 50
`pg per nostril four times daily plus asternizole, 10 mg
`daily. A double-dummy technique was used to achieve
`blinding.
`the
`anticipated start of
`the
`Three weeks before
`ragweed-pollen season, subjects had duplicate skin prick
`tests with tenfold serial dilutions of ragweed-pollen extract
`(25 to 25,000 Noon units, Bencard Allergy Service, Wes-
`ton, Ontario), with single dilutions of Alternaria tennis and
`Cladosporium (Hormodendrum) (Hollister Steir Laborato-
`ries of Canada, Rexdale, Ontario), and mixed grass-pollen
`extract (Bencard Allergy Service). An allergy history was
`obtained by questionnaire. Severity of rhinoconjunctivitis
`during the previous ragweed season was estimated from
`symptoms and medication requirements (Table 1). Subjects
`were matched into groups of three according to skin sen-
`sitivity to the ragweed extract,
`the severity of ragweed
`
`000002
`
`000002
`
`

`

`VOLUME 33
`NUMBER 3
`
`Comparison of nasal sprays $29
`
`0.8
`
`SNEEZING
`
`RUNNY NOSE
`
`SCORE
`
`MEANDAILY
`
`3
`2 ‘
`anseuns 1
`‘nu: (WEEKS)
`
`4
`
`5
`
`\
`
`\
`
`Ll
`
`/
`
`EYES
`
`O .8
`
`
`
`
`
`MEANDAILYSCORE
`
`0.1
`
`0.9
`0.7
`1
`~
`.
`/ \l-4l\- .
` /,7
`0.50.4 0.3
` 0.2
`
`3
`2
`BASELINE 1
`TIME (WEEKS)
`
`4
`
`5
`
`SCORE
`
`MEANDAILY
`
`3
`2
`BASELINE 1
`TIME (WEEKS)
`
`4
`
`5
`
`0.9
`
`STUFFY NOSE
`
`/1//I\\
`
`\J
`\
`
`\
`
`/
`
`/
`
`/
`
`/
`
`0.8
`0.7
`0.6
`
`
`
`
`
`SCORE BASELINE 1MEANDAILY
`
`3
`2
`TIME (WEEKS)
`
`4
`
`6
`
`FIG. 1. Mean daily nose and eye symptom scores (SEM) before and throughout the ragweed-
`pollen season; astemizole alone (0); aqueous beclomethasone nasal spray alone (A); astemizole
`plus aqueous beclomethasone nasal spray (0).
`
`sensitivity to Alter-
`pollen—induced rhinoconjunctivitis,
`naria and Cladosporium (Hormodendrum), history of
`asthma, grass-pollen sensitivity, and gender. One of each
`of the three subjects was assigned randomly to beclometh-
`asone alone, one was assigned to astemizole alone, and one
`subject was assigned to the combination of beclomethasone
`and astemizole.
`
`Subjects started taking the trial medication 1 week before
`ragweed pollen was expected in the air (Monday, August
`10) and continued daily until 1 week after the pollen season
`(Monday, September 21), that is, for a total of 6 weeks,
`Subjects were instructed to take the tablet in the morning
`either 1 hour before or 2 hours after food and to use the
`
`nasal spray -four times per day. If they had difficulty re-
`membering to use the spray at regular intervals, they were
`allowed to take two doses in the morning and two in the
`evening. If, during the season, symptoms were not ade-
`quately controlled by the trial medications, subjects were
`instructed to take additional medications in the minimum
`
`dose that would keep them well controlled. For nasal symp-
`toms they used Freon-propelled beclomethasone dipropio-
`nate nasal spray, one puff (50 ug) into each nostril, when
`it was needed, up to four times a day. Even for subjects
`taking the trial beclomethasone, this additional dose pro-
`vided a total daily amount that was lower than the recom-
`mended maximum dose. For eye symptoms, subjects used
`naphazoline HCl and anatazoline ophthalmic drops, one
`
`drop into each eye, when it was needed, up to four times
`per day. If this treatment was insufficient, sodium creme-
`glycate eye drops, up to four times per day, were added.
`Subjects were instructed not to use other medication for
`rhinoconjunctivitis. Nasal spray and eye drops were selected
`over an antihistamine tablet as the concomitant medication
`
`so that nose and eye symptoms could be evaluated sepa-
`rately. Subjects with asthma used salbutamol aerosol, 200
`ug, when it was needed, up to four times per day and those
`with more severe asthma took beclomethasone dipropionate,
`100 pg, up to four times per day. No oral steroids were
`used. The provision and use of standardized concomitant
`medications allowed the efficacy of the trial medications to
`be estimated from the amount of additional medication used,
`prevented subjects dropping out of the study because of
`inadequate symptom control, and reduced the risk of sub-
`jects using unauthorized hay fever medications.
`Subjects made entries in a diary each morning and each
`evening throughout the study.“ They recorded the severity
`(0, absent; 1, mild; 2, moderate; and 3, severe) and duration
`(0, absent; 1, a few short episodes; 2, many episodes; and
`3, continuous) of sneezing, stuffy nose, runny nose, eye
`symptoms, and asthma. At the end of each day, they re-
`corded the amount of concomitant medication needed in the
`
`previous 24 hours.
`Subjects attended the clinic after 1, 3, and 6 weeks of
`treatment. At each visit, symptoms were reviewed to ensure
`
`000003
`
`000003
`
`

`

`630 Juniper et al.
`
`J. ALLERGY CLlN. QMMUNOL.
`MARCH 1339
`
`>-
`E
`E
`E
`E
`u.
`E
`
`(fl
`
`l’
`
`1.6
`
`ADDITIONAL NASAL SPRAY
`
`
`
`1.6
`Q
`E 1.2
`E
`° °’8
`E
`
`Lu
`
`0.4
`
`T
`J
`EYE DROPST
`L/' \‘
`/
`/ / T’
`' /
`[I
`,/
`/
`
`v’,
`
`'
`
`3
`2
`3Asei.me 1
`TIME (WEEKS)
`
`4
`
`5
`
`3
`2
`BASELINE 1
`TIME (WEEKS)
`
`T
`
`
`
`\\ T\-\]
`\\i
`
`\
`
`\
`
`5
`
`i
`
`4
`
`FIG. 2. Mean daily additional medication use (SEM) before and throughout the ragweed-pollen
`season; astemizole alone (0); aqueous beclomethasone nasal spray alone (A); astemizole plus
`aqueous beclomethasone nasal spray (0).
`
`TABLE ll. Efficacy results (mean daily score)
`
`Beclomethasone
`Beclomethasone v
`Astemizole alone
`alone
`plus astemizole
`
`
`Overall (mean of 6 weeks)
`Sneezing
`Stuffy nose
`Runny nose
`Eye symptoms
`Asthma
`Beclomethasone use
`
`Eye drop use
`Asthama aerosol use
`
`0.395
`0.594
`0.406
`0.424
`0.030
`0.871
`
`0.707
`0.195
`
`0.193
`0.319
`0.152
`0.563
`0.015
`0.206
`
`1.016
`0.049
`
`0.155
`0.322
`0.192
`0.355
`0.048
`0.241
`
`0.354
`0.113
`
`that they were adequately controlled and diaries were ex-
`amined for accuracy and completeness. Subjects reported
`all nonrhinoconjunctivitis symptoms that they had experi-
`enced since the previous visit, irrespective of whether they
`perceived them as trial-medication related. The nasal spray
`bottles were weighed and tablets were counted for compli-
`ance. At all visits except the last. each subject gave a dem-
`onstration of the technique of nasal spray application to
`confirm correct use.
`
`Regular daily ragweed-pollen counts were not available
`throughout this study. However, intermittent counts were
`made with a Hirst volumetric spore trap (Burkard Manu-
`facturing Co., Ltd., Richmansworth, Hertfordshire, En-
`gland). These counts suggested that the duration and severity
`of the local ragweed-pollen season of the year 1987 was
`very similar to duration and severity of each of the previous
`10 years when regular daily counts were made.” ‘Z
`
`Analysis
`
`Mean daily symptoms and medication scores were cal-
`culated for each subject for each of the 6 weeks of the study.
`These data were analyzed for treatment effect with a
`
`repeated measures analysis of variance. Differences be-
`tween the three. treatments were examined with Student’s-
`
`Newman-Keuls method for multiple comparisons.” These
`data demonstrated instability of variance across the time
`periods, and therefore, a square root transformation was
`used to improve their statistical properties. Percent com-
`pliance was estimated from the observed and expected
`bottle-weight loss and tablet use. Differences were consid-
`ered significant at p < 0.05 (two-tailed).
`
`RESULTS
`
`Ninety subjects were enrolled, and eighty-nine
`completed the study. One subject withdrew because
`‘he could not remember to take the trial medication.
`
`Demographic and allergy characteristics were Well
`balanced across the three treatment groups (Table I).
`In all three treatment groups, nose and eye symp-
`toms were well controlled, as indicated by the highest
`mean weekly score for any symptom <0.8 (maxi-
`mum, 3.0) (Figs.
`l and 2). Nevertheless, aqueous
`beclomethasone was more effective in controlling
`
`000004
`
`000004
`
`

`

`VOLUME 83
`NUMBER 3
`
`Comparison of nasai sprays
`
`63'?
`
`TABLE lll. Statistical comparison of trial medications (with Student's-Newman-Keuls method for
`multiple comparisons)
`Astemizole vs
`
`Astemizole vs
`Beclomethasone vs
`beclomethasone
`astemizole plus beclomethasone
`astemizole plus beclomethasone
`
`
`Symptoms
`Sneezing
`Stuffy nose
`Runny nose
`Eye symptoms
`Asthma
`Concomitant medication
`use
`
`.
`
`p < 0.05*
`p < 0.05*
`p < 0.05*
`NS
`NS
`
`p < 0.05)‘
`p < 0.05?
`p < 0.05‘i
`NS
`NS
`
`NS
`NS
`NS
`NS
`NS
`
`NS
`p < 0.05’r
`p < 0.05*
`Nasal spray
`Eye drops
`NS
`NS
`NS
`Asthma aerosols
`NS
`NS
`NS
`
`
`NS, Not significant.
`*Beclomethasone alone was better than astemizole alone.
`
`lAstemizole plus beclomethasone was better than astemizole alone.
`
`TABLE IV. Compliance (% observed/expected)
`
`Beclomethasone
`Astemizole alone
`plus astemizole
`Beclomethasone alone
`
`Pills (mean, SD)
`Nasal spray (mean, SD)
`
`99.3 (2.8)
`91.8 (14.0)
`
`100.2 (4.1)
`94.1 (7.6)
`
`99.2 (4.7)
`91.3 (12.6)
`
`sneezing, stuffy nose, and runny nose than astemizole
`(p < 0.05), as demonstrated both by lower symptom
`scores and less need for additional nasal spray (Figs.
`1 and 2; Tables II and III). For nasal symptoms, the
`subjects who took both aqueous beclomethasone and
`astemizole were better protected than subjects taking
`astemizole alone but no different from subjects taking
`nasal spray alone. For each of the 6 weeks of the
`study, sneezing, stuffy nose, and runny nose dem-
`onstrated similar treatment differences, suggesting the
`treatments had similar time courses on each of these
`
`symptoms (Fig. 1). As might have been expected,
`subjects taking astemizole alone had lower eye symp-
`tom scores than subjects taking beclomethasone alone,
`but the lowest eye scores and the least need for ad-
`ditional eye drops was demonstrated by the subjects
`taking both astemizole and beclomethasone. However,
`these differences for eye symptoms and eye drops did
`not reach statistical significance, possibly as a result
`of poor statistical power, since not all subjects gave
`a history of allergic conjunctivitis. Asthma symptoms
`and medication requirements were similar in the three
`groups.
`Compliance with taking the trial medications was
`very good (Table IV) with no differences between the
`
`three treatment groups. The most common side effect
`was drowsiness, which was reported on one or more
`occasions by nine subjects taking astemizole alone,
`four subjects taking beclomethasone alone, and four
`subjects taking the combined medications (Table V).
`In most cases the drowsiness was mild and transient.
`
`it was troublesome in one subject taking
`However,
`astemizole alone, but he elected to continue taking
`the medication because his rhinoconjunctivitis was
`well controlled. The subjects who reported drowsiness
`experienced a wide range of rhinoconjunctivitis se-
`verity;
`therefore,
`it was not possible to evaluate
`whether the drowsiness was caused by persistent
`symptoms, the trial medications, the direct effect of
`the ragweed,” or factors unrelated to the study. Al-
`though some subjects reported hunger during the
`study, none experienced inappropriate weight gain.
`
`DISCUSSION
`
`The results of this study have demonstrated that
`seasonal allergic rhinitis is more effectively controlled
`by the regular use of beclomethasone dipropionate
`aqueous nasal spray (400 pg daily) than by the regular
`use of astemizole (10 mg daily). Results have also
`demonstrated that there is no further improvement in
`
`000005
`
`000005
`
`

`

`632 Juniper et al.
`
`J. ALLERGV CL{N. IMMUNOL.
`MARCH 1989
`
`TABLE V. Number of subjects reporting adverse experiences
`
`Beclomethasone plus
`Astemizole alone
`Beclomethasone alone
`estemizoie
`Adverse experience
`m
`
`9
`3
`3
`
`Drowsiness
`Hunger
`Dry
`nose/ lips / mouth/ throat
`3
`0
`Nasal bleeding
`1
`Headache
`3
`l
`0
`Thirst
`l
`2
`0
`Skin irritation/ rash
`i
`2
`O
`Nausea
`
`O 2
`
`4
`
`4
`
`3 2 2
`
`nasal symptoms when astemizole is added to the be-
`clomethasone. For eye symptoms, astemizole alone
`tended to be more effective than beclomethasone
`
`alone, but the addition of beclomethasone to the as-
`
`temizole provided even lower eye scores.
`The prophylactic and continuous use of steroid na-
`sal sprays has been limited in the past by nasal dryness
`and bleeding, apparently induced by the Freon-
`propelled aerosol delivery system?’ However,
`the
`aqueous delivery system appears to have reduced the
`side effects without loss of efficacyf‘ thus permitting
`optimal use of this medication. In the present study,
`care was taken to instruct subjects in the correct use
`of the aqueous nasal spray because the technique of
`application appears to be a little more subject to error
`than the Freon-pressurized delivery system. Each sub-
`ject’s technique was checked regularly, and the spray
`bottles were weighed to ensure that maximum efficacy
`was being achieved.
`Comparisons between the the new nonsedative anti-
`histamines have demonstrated that astemizole is one
`
`of the most effective in controlling symptoms of sea-
`sonal allergic rhinoconjunctivitisfz’ ‘5= ‘6 It has a slow
`onset of action, not reaching steady-state serum levels
`for l to 2 weeks.” Therefore, it would be expected
`to achieve maximum therapeutic effect when it was
`used in a schedule similar to that for steroid nasal
`
`spray, namely, started before and continued daily
`throughout the pollen season.
`Previous comparisons of antihistamines and steroid
`nasal sprays have suggested that nasal symptoms are
`controlled more effectively by nasal sprays, but the
`results are not unanimous. Two studies have suggested
`that the nasal sprays are more effective for controlling
`nasal blockage but similar to antihistamines for sneez-
`ing and rhinorrhea.“ One study suggested that sneez-
`ing and rhinorrhea are controlled better by steroid
`nasal spray but similar for nasal blockage.6 Another
`study suggested that all nasal symptoms, except sneez-
`
`ing, are better with nasal spray treatment? One study
`concluded that nasal spray and antihistamines are
`of similar effectiveness for all nasal symptoms.7
`Differences in conclusions may have occurred as a
`result of variation in the types of trial medications and
`differences in closing schedules. In this study, when
`both trial medications were used in a manner that
`
`would appear optimal for their pharmacologic prop-
`erties, the aqueous beclomethasone nasal. spray was
`significantly more effective than astemizole for all
`three nasal symptoms monitored. The results also
`demonstrated that subjects who used both astemizole
`and beclomethasone had less nasal symptoms than
`subjects receiving astemizole alone. This conclusion
`is in agreement with Wihl et al.” who demonstrated
`that, even after subjects had demonstrated symptom-
`atic improvement with astemizole, further improve-
`ment could be achieved by adding beclomethasone
`dipropionate nasal spray. The results of the present
`study add the further observation that beclomethasone
`nasal spray alone is just as effective as beclomethasone
`plus astemizole for nasal symptoms, suggesting that
`nasal spray alone may be sufficient for the optimal
`treatment of symptoms.
`Astemizole was more effective than the aqueous
`nasal spray at controlling eye symptoms. However, it
`was interesting to observe that the best control of eye
`symptoms was achieved by the subjects taking the two
`medications together. The same observation has been
`made with another aqueous
`steroid nasal
`spray,
`budesonidef but the mechanism by which this may
`occur is unclear. It maybe that, by keeping the nasal
`passages clear, nasolacrimal duct drainage and eyelid
`venous congestion are improved. It could be that some
`nasal spray reaches the eye through the nasolacrimal
`duct, but this appears unlikely, and, at present, there
`is no evidence to support this hypothesis. It may also
`be that, if nasal symptoms are minimal, psychologi-
`cally the patient is not so troubled by eye symptoms
`
`000006
`
`000006
`
`

`

`VOLUME 83
`NUMBER 3
`
`Comparison of nasal sprays
`
`$33
`
`these are only
`and records lower scores. However,
`speculations, and further studies will be required to
`confirm the finding and determine the mechanism.
`
`We thank all the subjects for their diligent participation
`in the study, Professor Robin Roberts for statistical advice,
`and Mrs. Laurie Whitely for assisting in the preparation of
`the manuscript. We thank Iolab Pharmaceuticals for sup-
`plying Vasocon-A eye drops and Fisons Pharmaceuticals for
`Opticrom eye drops.
`
`REFERENCES
`1.
`2.
`
`Mygind N. Nasal allergy. Oxford: Alden Press, 1978:257-9.
`Mygind N. Nasal allergy. Oxford: Alden Press, 19781312-7.
`3. Sibbald B, Hilton S, D’Souza M. An open crossover trial
`comparing two doses of astemizole and beclomethasone di-
`propionate in the treatment of perennial rhinitis. Clin Allergy
`1986;16:203-11.
`4. Munch EP, Soborg M, Norreslet TT, Mygind N. A comparative
`study of dexchlorpheniramine maleate sustained-release tablets
`and budesonide nasal spray in seasonal allergic rhinitis. Allergy
`1983;38:517-24.
`5. Beswick KBJ, Kenyon GS, Cherry JR. A comparative study
`of beclomethasone dipropionate aqueous nasal spray with ter-
`fenadine tablets in seasonal allergic rhinitis. Curr Med Res
`Opin 1985;9:560—7.
`6. Dickson DJ, Cruickshank JM. Comparison of flunisolide nasal
`spray and terfenadine tablets in hay fever. Br J Clin Pract
`1984;38:416-211.
`7. Wood SF. Oral antihistamine or nasal steroid in hay fever: a
`double-blind double-dummy comparative study of once—daily
`oral astemizole vs twice-daily nasal beclomethasone dipro-
`pionate. Clin Allergy 1986;16:195-201.
`. Dunn AM, Wilson RSE, Baggott PJ. A comparison of be-
`
`ll.
`
`10'
`
`clorrethasone dipropionate aqueous nasal spray and heele-
`metlasone dipropionate pressurized nasal spray in the man-
`agement of seasonal rhinitis. Postgrad Med J 1984:60:404-6.
`9. Brogden RN, Heel RC, Speight TM, Avery GS. Bec1ometh-
`ason e dipropionate: a reappraisal of its pharrnacodynarnic prop-
`erties and therapeutic efficacy after a decade of use in asthma
`and -hinitis. Drugs l984;28:99-126.
`Hovrarth PH, Emanual MB, Holgate ST. Astemizole, a potent
`histamine H,-receptor antagonist: effect in allergic rhinocon-
`junctivitis on allergen and histamine-induced skin wheai re-
`sponses, and relationship to serum levels. Br J Clin Pharrnacol
`1984;l8:1-8.
`Juniper EF, Cartier A, Trebilcock AL, Frith PA, Dolovich J,
`Hargreave FE. Effects of oxatomjde compared with chlor-
`pheniramine in allergic rhinoconjunctivitis. Clin Allergy 1981;
`11:61-6.
`12. Kleinbaum DG, Kupper LL. Applied regression analysis and
`other multivariable methods. Boston: Duxbury Press, 1978:
`264-77.
`13. Juniper EF, White J, Dolovich J . Efficacy of continuous treat-
`ment with astemizole (Hismanal) and terfenadine (Seldane) in
`ragweed pollen—induced rhinoconjunctivitis. J ALLERGY CLIN
`IMMUNOL l988;82:670»5.
`14. Straus SE, Dale JK, Wright R, Metcalfe DD. Allergy and the
`chronic fatigue syndrome. J ALLERGY CLIN IMMUNOL 1988;
`812791-5.
`15. Howarth PH, Holgate ST. Comparative trial of two nonsedative
`H, antihistamines, terfenadine and astemizole, for hay fever.
`Thorax 1984;339:668-72.
`16. Wood SF. Astemizole and terfenadine compared in hay fever.
`Practitioner 1986;230:411-4.
`17. Wihl J-A, Petersen BN, Petersen LN, Gundersen G, Bresson
`K, Mygind N. Effect of the nonsedative H,-receptor antagonist
`astemizole in perennial allergic and nonallergic rhinitis. 1 AL-
`LERGY CLIN IMMUNOL 1985;75:720-7.
`
`AVAILABLE NOW! The FIVE-YEAR (1981-1985) CUMULATIVE INDEX T0 THE
`JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY can be purchased from the
`Publisher for $42.00. This comprehensive, 156-page reference guide is a current presentation
`of all topics included in the JOURNAL from January 1981 to December 1985 (volumes 67-
`76)—the past 10 volumes. It incorporates complete references to over 672 original articles,
`abstracts, case reports, letters, editorials, and CME articles. It features 1,525 Subject Head-
`ings, under which there are 5,316 references. Each subject entry lists the complete article
`title, author(s), volume, page, and year of publication. It also includes 4,780 Author Entries,
`listing contributors, along with their respective titles, author—to—author referral, volume, page,
`and publication date.
`To purchase, call or write: The C.V. Mosby Company, 11830 Westline Industrial Dr.,
`St. Louis, MO 63146-3318, or telephone FREE 1-800-325-4177, Journal Fulfillment, ext.
`531 (in Missouri call collect at 314-872-8370, Journal Fulfillment, ext. 531). Please reference
`book code number 2605-6 when placing your order. PREPAYMENT REQUIRED. Make
`checks payable to The CV. Mosby Company. (All payments must be in US funds drawn
`on a US bank.) Price: $42.00 in the US, $44.75 international (price includes mailing
`
`charges).
`
`000007
`
`000007
`
`