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Efficacy and tolerance of fluocortin butyl administered twice daily in adult patients with perennial rhinitis
Efficacy and tolerance of fluocortin butyl administered twice daily in adult patients with perennial rhinitis Thomas F. Hartley, M.D., Phillip L. Lieberman, M.D., Eli O. Meltzer, M.D., John N. Noyes, M.D., David S. Pearlman, M.D., and David G. Tinkelman, M.D. Scottsdale, Ariz., Memphis, Tenn., San Diego, Calif., N e w Bedford, Mass., Aurora, Colo., and Atlanta, Ga.
Fluocortin butyl (FCB) is a newly developed corticosteroid drug with no detectable systemic corticosteroid activity when it is used topically. Previous studies have demonstrated the therapeutic efficacy of FCB applied topically to the nasal mucosa three to four times a day for perennial rhinitis. The therapeutic efficacy of FCB used only twice daily, with total daily dosages similar to those previously found to be effective when these were applied more frequently, was studied in a multicenter, double-blind, placebo-controlled trial. This was a 4-week study with a 1-week observation (baseline) period and a 3-week period during which the response to three dosage regimens (2 mg per day, 4 mg per day, and 8 mg per day) of FCB and placebo were compared to baseline observations of rhinitis. Two hundred thirty-five patients from six centers were studied. Patients had perennial rhinitis of allergic, nonallergic, or combined etiology. Patients" who received FCB exhibited significant amelioration of signs and symptoms of rhinitis as assessed by patients and physicians and had a greater reduction in the use of concomitant antihistamine and~or decongestant therapy compared to placebo-treated patients. Relief tended to occur early and was progressive during the 3 wk of therapy. There were no significant differences in response between the various dosages of FCB used. Side effects were minimal and insignificant and did not differ between FCB-treated and placebo-treated patients. FCB appears to be an effective well-tolerated topical steroid useful in the treatment of perennial rhinitis. (J ALLERGr CLIN IMMUNOL 75.'501-7, 1985.)
The therapeutic effectiveness of adrenal glucocorticoids in allergic and other noninfectious respiratory tract inflammation is well-known. Because of undesirable side effects from the long-term use of systemic corticosteroids, a topically applied medication that could maximize local therapeutic effectiveness and minimize undesirable systemic effects represents an attractive potential alternative to systemic therapy. Topical steroid preparations available in the United States for use in rhinitis include dexamethasone sodium phosphate, beclomethasone dipropionate, and flunisolide. Dexamethasone phosphate is readily absorbed in active form to the point that at least mild adrenal suppression occurs with recommended therapeutic dosage.l' 2 Although systemic steroid effects Received for publication Nov. 21, 1983. Accepted for publication Aug. 24, 1984. Reprint requests: David S. Pearlman, M.D., 1450S. HavanaSt., Suite 500, Aurora, CO 80012.
Abbreviation used
FCB: Fluocortin butyl
of beclomethasone dipropionate and flunisolide have been rare, in many patients their effectiveness has been disappointing when these agents were used in recommended dosages. Greater effectiveness may be obtained with higher dosages. However, such dosages are likely to produce systemic steroid effects as evidenced by the results of studies in asthmatic patients and normal individuals3-S; indeed, at least mild adrenal suppression was observed even when these agents were used in generally recommended dosages. 9, ~0 FCB is a newly developed steroid drug with an especially high ratio of local anti-inflammatory activity to systemic activity when it is applied topically. Studies conducted in healthy subjects demonstrated that oral or nasal inhalation of FCB was tolerated well
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TABLE I. Physician's evaluation of signs and symptoms
Signs
Symptoms
Turbinate/mucosal swelling Nasal discharge Pharyngeal discharge Erythema/cyanosis
Sneezing/itching Nasal congestion Postnasal drip/snorting Runny nose/sniffing
without any adrenal suppression at dosages 20 to 80 times the therapeutic dosage.*' 3.6. 1] FCB has an additional advantage over most other topical corticosteroid preparations currently in use because it is inhaled as a fine powder, therefore requiring no propellant gas such as Freon. A previous study, performed in the United States, has indicated that FCB, when it is applied topically four times a day, is effective in ameliorating symptoms of rhinitis. ~2 The purpose of the multicenter study reported here was to determine the efficacy and tolerance of FCB compared to placebo therapy with various dosages of medication on a twice daily schedule. This article represents the pooled results from six investigative centers throughout the United States.
MATERIAL AND METHODS
Study design. This study was a randomized, doubleblind, parallel-group design comparing FCB in dosages of 2, 4, or 8 mg per day with placebo. Study population. Patients were 16 yr of age or older and were outpatients in the investigators' practices. Patients had perennial allergic or nonallergic, noninfectious rhinitis for at least the 1-year period previous to entrance into the study. In order to qualify for the study, patients were required to exhibit a minimum level of chronic nasal inflammation as judged by a scoring system for signs and symptoms of rhinitis (see below). Patients with the following were excluded from the study: history of nasal polyposis, history of treatment with systemic or topical corticosteroids or cromolyn sodium within the previous 4 wk or with repository corticosteroids within the previous 8 wk, known or suspected intolerance to lactose or hypersensitivity to corticosteroids, chlorpheniramine, or pseudoephedrine, history of convulsive disorder, asthma requiring bronchodilator medications on a regular basis, and hypertension requiring therapy other than diuretics. Patients with any severe active physical disease as evidenced by history, physical examination, and/or laboratory tests also were excluded as well as pregnant women and nursing mothers. An informed consent for participation in the study was obtained from patients who qualified for the study, and the
*Wendt VH, Matthes H: Unpublished data. Berlex Laboratories, Inc., Cedar Knolls, N.J.
patients were assured of freedom to withdraw from the study at any time. Study procedure. This was a 4-week study including an initial l-week observation period and a 3-week treatment period with FCB or placebo. During the observation week, the patients were permitted to take oral chlorpheniramine (4 rag) and/or oral pseudoephedrine (60 mg) single entity products on an as-needed basis for treatment of symptoms. At the end of the observation week, a baseline assessment was made of each patient's condition. Patients whose rhinitis was not well controlled by the use of chlorpheniramine and/ or pseudoephedrine were entered into the 3-week treatment period. All medications were supplied by Berlex Laboratories, Cedar Knolls, N. J. Formulations of FCB were provided in a plastic cylinder for inhalation, which delivered 0.5 rag, 1.0 mg, or 2.0 mg of active drug per inhalation. Seventeen to 19.5 mg of lactose powder was added as an excipient in each case so that approximately 20 mg of FCB-lactose powder was delivered per inhalation; lactose powder (20 mg per inhalation) for placebo was provided in plastic cylinders identical to those containing active medication. Patients received one inhalation of study medication in each nostril every 12 hours. Thus, four groups were treated: group 1, FCB 2 mg per day; group 2, FCB 4 mg per day; group 3, FCB 8 mg per day; and group 4, placebo therapy. Medication was inhaled through a Rhinolator (Schering Aktiengisellschafte, Berlin, West Germany), a plastic device that operates on the Venturi principle. Patients were permitted to continue the use of oral chlorpheniramine and/or pseudoephedrine tablets as needed during the treatment period. The patient's condition was evaluated daily by the patient and was evaluated weekly by the physician. At each visit the physician rated eight signs and symptoms (Table I), each on a 4-point rating scale (0 = absent, 1 = mild, 2 = moderate, and 3 = severe). The patient evaluated the same four symptoms listed in Table 1 by use of the same rating scale. In addition, he/she recorded the number of chlorpheniramine and pseudoephedrine tablets taken each day. The safety evaluations included (1) vital signs and physical examination, (2) laboratory evaluations including hematology, serum chemistries, and urinalysis, and (3) side effects reported by the patients. Patients who incurred an upper respiratory infection during the 3-week treatment period were discontinued temporarily and reentered into the study after a 1-week washout period. Assessment of efficacy. Six variables relating to efficacy were assessed as clinically meaningful and reliable: (I) signs score, the sum of the four clinical signs rated by the physician (0 to 12), (2) physician symptoms score, the sum of the four symptoms rated by the physician (0 to 12), (3) signs and symptoms score, a combination of physician-rated signs and symptoms scores (0 to 24), (4) patient symptoms score, the sum of the four symptoms rated by the patient on a daily basis, (5) chlorpheniramine use, and (6) pseudoephedrine
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40~
35-
30-
25F R 0 M
20-
B A
S E L I N Z
15"
10-I
I
I
1
2
3
TREATMENT
~ ,"3 PLACEBO
WEEK
~ - 2 M G
-~-A-~-4 MG
-I~!1-11- 8MG
FIG. 1. Meari change from baseline as a percentage of the baseline mean, total signs and symptoms score.
use. The patient symptoms score and the daily use of chlorpheniramine and psuedoephedrine were averaged for each week. Statistical methods. The evaluation of efficacy variables at each postbaseline visit was made by use of the analysis of covariance. '~This method produces a more sensitive analysis of taking advantage of the correlation between baseline and change from baseline thereby reducing the error term in the model. The Bonferroni multiple comparison procedure '4 was used to control the overall significance level for one-tailed comparisons of the three FCB-treated groups against the placebo-treated group. In order to ensure that the study groups were comparable before treatment, a preliminary analysis was performed in which the baseline means were compared for each efficacy variable. No significant differences between groups were found at baseline.
RESULTS A total of 235 patients entered the study. Of these patients, 58 received placebo, 58 received 2 mg of FCB per day, 59 received 4 mg of FCB per day, and 60 received 8 mg of FCB per day. Patients ranged in age from 16 to 73 yr; mean age was 33 yr. Seventyseven percent of the study group were female patients. Eighty-three percent of the patients were considered to have perennial rhinitis of allergic origin. There were no significant differences between the various groups in age, sex, diagnosis, or in other discernible historical
or physical characteristics. Of the total 235 patients entered, 227 (97%) accomplished at least one valid postbaseline visit, and 224 (95%) completed the scheduled 3-week treatment period. Eight patients were declared invalid for reasons of noncompliance or inadequate data at baseline or postbaseline period. The data supplied by invalid patients were excluded from efficacy analysis, but such data were included in safety analysis. A total of 11 patients dropped out of the study before the last visit, seven for lack of efficacy, one who also had an adverse reaction, three for intercurrent illness, and one was lost to followup. Of those who dropped out for lack of efficacy, three were in the placebo-treated group, two in the 4 mg FCB-treated group, and two were in the 8 mg FCB-treated group. Data from these 11 patients were included as appropriate in the efficacy and/or safety analyses.
Efficacy Comparisons of mean changes from baseline values among treatment groups were performed for the six efficacy variables, The results displayed in Table II are summarized below. Analyses of signs and symptoms scores. The changes in signs and symptoms scores are graphed as percent change from baseline in Fig. 1. At each postbaseline visit, the FCB-treated groups demonstrated
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TABLE II. Treatment comparisons of mean change from baseline in efficacy variables for valid completers Placebo
2 mg
Mean change From baseline
Signs and symptoms score Signs score Physician symptoms score Patient symptoms score Daily chlorpheniramine use Daily psedueophedrine use
Mean change From baseline
Baseline mean
W1
W2
W3
11.61 5.67 5.94 5.11 1.22 1.27
- 1.41 - 1.00 -0.39 -0.18 0.01 -0.28
-2.76 - 1.81 - 1.04 -0.44 -0.01 -0.26
-2.99 - 1.65 - 1.26 - 1.00 -0.11 -0.37
Baseline mean
10.71 5.20 5.51 4.84 0.99 0.93
Wl
W2
W3
-2.74* - 1.58 - 1.23" -0.75* -0.52:t: -0.50
-3.54 - 1.69 - 1.73 - 1.20" -0.555 -0.46
-4.08 - 2.15 - 2.21t - 1.61 -0.63* -0.54
WI, W2, W3 = treatment weeks 1, 2, and 3, respectively; statistical significance is declared in comparison to placebo-treated group on the basis of Bonferroni t tests. *p < 0.05. ~p < 0,10. :~p < 0,01.
greater improvement in the variable compared to the placebo-treated group. This improvement was statistically significant (p < 0.05) in the 8 mg FCB-treated group after 3 wk of treatment. Analyses of physician signs score. At both weeks 1 and 2 all four groups improved their signs scores. After 3 wk on medication, the FCB-treated groups continued to demonstrate improvement, and the placebo-treated group demonstrated a decrease in improvement. None of these changes were statistically significant compared to the placebo-treated group, however. Analysis of physician symptoms scores. Although the changes in these scores were analyzed, they were considered to represent essentially the same information recorded by the patient and are not further discussed here. The changes, in fact, parallel the trends observed with patient symptoms scores. Analysis of patient symptoms scores. At each postbaseline visit, there was a trend for greater improvement in all FCB-treated groups compared to the placebo-treated group. These differences reached statistical significance for the 2 mg FCB-treated group. Analysis of chlorpheniramine use. The most striking change in efficacy measurements came in diminution in chlorpheniramine use. There was a reduction in use of about 0.5 to 0.6 tablet per day over the course of the study in the various FCB-treated groups compared to an average reduction of only 0.1 tablet per day in the placebo-treated group. When reductions were compared to the placebo-treated group, the reductions in all three FCB-treated groups were statistically significant (p < 0.05) at each treatment week. Analysis ofpseudoephedrine use. At the end of 3
wk, there was a reduction of 0.4 tablet per day in the placebo-treated group and from 0.5 to 0.6 tablet per day in the various FCB-treated groups. The reduction in pseudoephedrine use relative to the placebo-treated group was not statistically significant.
Safety The FCB-treated groups were indistinguishable from the placebo-treated group in regards to both nasal- and nonnasal-related side effects. Nasal side effects during the course of the study were reported by 16% of the placebo-treated group, 14% of the 2 mg group, 19% of the 4 mg group, and 15% of the 8 mg group. The most common nasal side effects were postnasal drip reported by 5% of placebo-treated patients and 8% of all FCB-treated patients and nasal irritation reported by 2% of placebo-treated patients and 5% of all FCB-treated patients. More patients (5%) in the placebo-treated group reported rhinorrhea compared to the FCB-treated groups combined (1%). Nonnasal side effects were reported by 17% of the placebotreated group, 14% of the 2 mg FCB-treated group, 14% of the 4 mg FCB-treated group, and 14% of the 8 mg FCB-treated group. The most common nonnasal side effects were headache, reported by 5% of the placebo-treated patients and 6% of all FCB-treated patients, and nausea, reported by 3% of placebotreated patients and 2% of all FCB-treated patients. None of these side effects were severe in nature except for one patient in the placebo-treated group who discontinued the medication because of nausea. There were no significant changes from baseline in vital signs except for mean reductions of 3 to 5 mm Hg in systolic blood pressure in the 2 mg FCB-treated
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4 mg
8 mg
Mean change From baseline
Mean change From baseline
Baseline mean
Wl
W2
W3
Baseline mean
11.61 5.72 5.89 4.89 1.43 1.32
- 2.26 - 1.17 - 1.07t -0.20 - 0.535 - 0.48
- 3.41 - 1.86 - 1.60 -0.96 - 0.535 - 0.36
- 4.43t -2.04 - 2.28* - 1.35 - 0.63* - 0.57
11.62 5.81 5.82 4.57 1.29 1.25
group at all postbaseline visits. There were no significant changes in mean diastolic blood pressure. No changes were found in the serum chemistry variables nor in urinalysis. Similarly, there were no changes in hematologic findings including the eosinophil count. DISCUSSION
FCB is a new corticosteroid drug developed with the aim of maximizing topical steroid activity while it minimizes and, if it is possible, eliminates the risk of undesirable systemic corticosteroid effect. The theoretic basis for the development of this new compound was the recognition that the therapeutic effects of topically applied corticosteroids do not require a free hydroxyl group in the C-21 position, and a steroid C21 acid does not exhibit systemic corticosteroid effects. This lack of effect may be due to poor binding of the steroid C-21 acid with the cytosol steroid receptor.'5 FCB is a topically active corticosteroid ester produced by combining a steroid C-21 acid with butanol. After absorption C-21 esters are broken down rapidly by intrinsic nonspecific esterases. 1~in contrast with these mechanisms, flunisolide and beclomethasone dipropionate depend on liver metabolism for inactivation of the compound. ,6-,9 Little or no systemic corticosteroid activity has been found when FCB has been administered by the oral, inhalant, or parenteral routes to animals in dosages equivalent to large multiples of human therapeutic doses J'' 20.21 or when FCB has been administered by oral or nasal inhalation in man (see footnote page 502). 3, 6 For example, 160 mg of FCB per day by oral inhalation over a l-week period in normal human volunteers resulted in no adrenal suppression. 3 This dosage is 20 to 80 times the doses found to be therapeutically effective when it is applied nasally, which was done in this study. Previous studies have demonstrated the therapeutic effectiveness of FCB applied topically to the nasal mucosa when it is used three to four times a day in
Wl
- 2.27 - 1.07 - 1.16" -0.55 - 0.54:[: - 0.641"
W2
- 3.34 - 1.58 - 1.77 -0.96 - 0.625 - 0.59
W3
-
4.47* 1.93 2.36* 1.36 0.54* 0.60
the treatment of perennial allergic and nonallergic rhinitis and as a protection against allergen challange.12, 22 Results of the current study demonstrate effectiveness of a twice daily schedule of FCB at 2, 4, and 8 mg per day, which was indicated by an amelioration of signs and symptoms of rhinitis. Statistically significant differences, in comparison with the placebo-treated group, were recorded at various time intervals in each FCB-treated group with effectiveness exhibited as early as the first week of treatment. The clinical effectiveness of FCB was reflected also by at least a fourfold reduction in chlorpheniramine use and to a lesser extent by pseudoephedrine use in FCB-treated patients as compared to placebo-treated patients. The study design permitted the use of sponsor-supplied chlorpheniramine and pseudoephedrine tablets in order to provide a means to minimize discomfort from nasal symptoms. Therefore, the potential for further improvement in signs and symptoms is less than would be the case in studies where concomitant medications are prohibited. However, this study demonstrated a greater control of symptoms and greater reduction of antihistamines and/or decongestant use in FCB-treated patients as compared to placebo-treated patients. Improvement in clinical signs and symptoms also was noted in the placebo-treated group. Whether this relates to the lactose excipient used or to other factors is unknown. Amelioration of signs and symptoms in the placebo-treated group occurred between weeks 1 and 2; no further improvement was noted in the third week. By contrast, there was progressive improvement in symptoms and signs throughout the study in all three FCB-treated groups. This suggests the possibility of added therapeutic benefit had the treatment period been longer than 3 wk. No clear dose-response effect of FCB was recorded in this study. Patients who received the lowest dose
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of FCB (2 mg per day), in fact, tended to exhibit somewhat greater improvement in signs and symptoms initially and to require less chlorpheniramine and pseudoephedrine than patients treated with higher FCB dosages. It remains to be determined whether large dosages of FCB administered topically in similar or different form would offer greater therapeutic benefit in some patients. The administration of significantly larger dosages are unlikely to cause safety problems based on the observations of others that multiples of the FCB doses used in the current study have not produced systemic corticosteroid effects (see footnote page 502). 3' 6 In this study, however, duration of treatment appears to have been more important than dosage per day. Side effects recorded in association with the use of FCB were minimal. None of the side effects reported were serious. Moreover, there were no significant differences in the incidence of side effects between patients treated with the various dosages of FCB and those patients treated with placebo therapy. In fact, the clinical side effects recorded tended to be characteristic of those effects of the rhinitis for which patients were treated. This is similar to previous observations with the use of FCB. ~2,22 Other than a slight reduction in systolic blood pressure in the group of patients treated with 2 mg of FCB (the clinical significance of which, if any, is unknown), there were no changes in vital signs, hemogram, blood chemistries, or urinalyses in patients who received placebo or FCB therapy. Assessment of adrenocortical function was not part of this study. It is of particular interest that there were no significant changes in peripheral blood eosinophil counts in patients treated with FCB since this parameter is known to be influenced by systemic or topical corticosteroid administration.5' 8.23. z4 In summary, FCB, a newly developed topical corticosteroid drug, appears to be effective in ameliorating symptoms of perennial allergic or nonallergic, noninfectious rhinitis when it is used on a twice daily regimen. Therapeutic effects are unassociated with appreciable side effects. We are indebted to our coinvestigators and study coordinators for invaluable assistance in performing the study: Brice Steele Rolston, M.D., Phoenix, Ariz.; John Erffmeyer, M.D., and Maria Bizell, R.N., Memphis, Tenn.; James P. Kemp, M.D., H. Alice Orgel, M.D., and Cindy Stutsman, L.V.N., San Diego, Calif.; Paul Chervinsky, M.D., and Madeline Romeo, R.N., New Bedford, Mass.; Sanford E. Avner, M.D,, Jerome M. Buckley, M.D., and Sharon Donnelly, R.N., Denver, Colo.; M. Scott Caroll, M.D., Gary Z. Lotner, M.D., Dennis L. Spangler, M.D., Gerald E. Vanderpool, M.D., Jean DeCuto, and Lorri Edelman, Atlanta.
We also acknowledge with appreciation Dr. Gene Johnson, Denver, Colo., and the staff of the medical and statistical departments of Berlex Laboratories, Cedar Knolls, N. J., for their review, helpful criticisms, and statistical analysis of the data in this paper. REFERENCES
1. Michels MI, Smith RE, Heimlich EM: Adrenal suppression and intranasallyapplied steroids. Ann Allergy 25:569, 1967 2. NormanPS, WinkenwerderWL, AgbayaniBF, et al: Adrenal functionduringthe use of dexamethasone aerosols in the treatment of ragweed hay fever. J ALLERGY40:57, 1967 3. ShermanB, WeinbergerM, Chen-WaldenH, WendtH: Further studies of the effects of inhaled glucocorticoids on pituitaryadrenal function in healthy adults. J ALLERGYCLINIMMUNOL 69:208, 1982 4. Mygind N, Hansen I: Beclomethasone dipropionate aerosol effect on the adrenalsin normalpersons. Acta Allergol28:211, 1973 5. Harris DM: Some properties of beclomethasone dipropionate and related steroids in man. Postgrad Med J 51(suppl 4):20, 1975 6. Vlasses PH, Ferguson RK, Koplin JR, Clementi RA, Green PJ: Adrenocortical function after chronic inhalation of fluocortin butyl and beclomethasonedipropionate.ClinPharmacol Ther 29:643, 1981 7. Rboades RB, Forbes EF: Clinicallyapparent adrenal suppression with beclomethasone (400 txg a day) inhalation. J ALLERGYCLINIMMUNOL65:218, 1980 (abst) 8. Chaplin MD, Cooper WC, Segre EJ, Oren J, Jones RE, Nerenberg C: Correlationof flunisolideplasma levels to eosinopenic response in humans. J ALLERGYCLI~IMMt~NOL65:445, 1980 9. Wyatt R, Wascbek J, WeinbergerM, Sherman B: Effects of inhaled beclomethasonedipropionate and alternate day prednisone on pituitary adrenal function in children with chronic asthma. N Engl J Med 299:1387, 1978 10. Vaz R, Senior B, Morris M, BinkiewiczA: Adrenaleffects of beclomethasoneinhalationtherapy in asthmaticchildren. J Pediatr 100:660, t982 11. Investigator'sbrochure: Fluocortinbutylfor oral inhalationand nasal application. Cedar Knolls, N. J., 1980. Berlex Laboratories, Inc 12. ArbesmanC, Bemstein IL, BiermanCW, et al: Multi-center, double-blind,placebo-controlledtrial of fluocortinbutyl in perennial rhinitis. J ALLERGYCL1NIMMUNOL71:597, 1983 13. Neter J, Wasserman W: Applied linear statistical models. Homewood, II1., 1974, Richard D. Irwin, Inc, pp 685-721 14. Miller RG Jr: Simultaneousstatistical inference, ed 2. New York, Heidelberg, Berlin, 1980, Springer-Verlag,pp 67-70 15. Kapp JF, Koch H, T6pert M, Kessler HJ, Gerhards E: Unterschungen zur pharmakologie von 6ot-fluor-11[3-hydroxy-16amethyl-3,20-dioxo-1,4-pregnadien-21-saure-butylester (fluocortin butylester). ArzneimForsch 27:2191, 1977 16. ChaplinMD, Rooks W, SwensonEW, Cooper WC, Nerenberg C, Chu NI: Flunisolidemetabolismand dynamicsof a metabolite. Clin Pharmacol Ther 27:402, 1980 17. Kapp JF: Use of topical corticosteroids in the managementof rhinitis. N Engl Soc Allergy Proc 3:482, 1982 18. MartinLE, TannerRJN, ClarkTJH, CochraneGM: Absorption and metabolismof orally administeredbeclomethasonedipropionate. Clin Pharmacol Ther 15:267, 1974 19. Martin LE, Harrison C, Tanner RJN: Metabolism of beclomethasone dipropionateby animals and man. Postgrad Med J 52(suppl 4):11, 1975
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20. Giinzel P, Siegmund F, Bhargava AS, et al: Tierexperimentelle vertraglichkeitsprufung von fluocortin-butylester als reiner wirkstoff und als salbe, fettsalbe und creme. Arzneim Forsch 27:2217, 1977 2l. Bhargava AS, Staben P, Siegmund F, Sch6bel Chr, Giinzel P: Effect of fluocortin butylester and beclomethasone dipropionate on the adrenal gland in beagle dogs. Arzneim Forsch 28(suppl 2):1638, 1978 22. Horak F, Matthes H: The protective action of fluocortin bu-
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tylester (FCB) in the nasal antigen provocation test: a controlled double-blind, crossover study. Ann Allergy 48:305, 1982 23. Thorn GW, Forsham PH, Prunty FFG, Hills AG: A test for adrenal cortical insufficiency. JAMA 137:1005, 1948 24. Blaiss MS, Herrod HG, Crawford LV, Lieberman PL: Beclomethasone dipropionate aerosol: hematologic and immunologic effects. Ann Allergy 48:210, 1982
Bound volumes available to subscribers Bound volumes of THE JOURNALOF ALLERGYAND CLINICALIMMUNOLOGYare available to subscribers (only) for the 1985 issues from the Publisher, at a cost of $49.90 ($60.25 international) for Vol. 75 (January-June) and Vol. 76 (July-December). Shipping charges are included. Each bound volume contains a subject and author index, and all advertising is removed. Copies are shipped within 30 days after publication of the last issue in the volume. The binding is durable buckram with the journal name, volume number, and year stamped in gold on the spine. Payment must accompany all orders. Contact the C. V. Mosby Co., Circulation Department, 11830 Westline Industrial Dr., St. Louis, MO 63146; phone (800) 325-4177, ext. 351. Subscriptions must be in force to qualify. Bound volumes are not available in place of a regular journal subscription.
Fluocortin butyl (FCB) is a newly developed corticosteroid drug with no detectable systemic corticosteroid activity when it is used topically. Previous studies have demonstrated the therapeutic efficacy of FCB applied topically to the nasal mucosa three to four times a day for perennial rhinitis. The therapeutic efficacy of FCB used only twice daily, with total daily dosages similar to those previously found to be effective when these were applied more frequently, was studied in a multicenter, double-blind, placebo-controlled trial. This was a 4-week study with a 1-week observation (baseline) period and a 3-week period during which the response to three dosage regimens (2 mg per day, 4 mg per day, and 8 mg per day) of FCB and placebo were compared to baseline observations of rhinitis. Two hundred thirty-five patients from six centers were studied. Patients had perennial rhinitis of allergic, nonallergic, or combined etiology. Patients" who received FCB exhibited significant amelioration of signs and symptoms of rhinitis as assessed by patients and physicians and had a greater reduction in the use of concomitant antihistamine and~or decongestant therapy compared to placebo-treated patients. Relief tended to occur early and was progressive during the 3 wk of therapy. There were no significant differences in response between the various dosages of FCB used. Side effects were minimal and insignificant and did not differ between FCB-treated and placebo-treated patients. FCB appears to be an effective well-tolerated topical steroid useful in the treatment of perennial rhinitis. (J ALLERGr CLIN IMMUNOL 75.'501-7, 1985.)
The therapeutic effectiveness of adrenal glucocorticoids in allergic and other noninfectious respiratory tract inflammation is well-known. Because of undesirable side effects from the long-term use of systemic corticosteroids, a topically applied medication that could maximize local therapeutic effectiveness and minimize undesirable systemic effects represents an attractive potential alternative to systemic therapy. Topical steroid preparations available in the United States for use in rhinitis include dexamethasone sodium phosphate, beclomethasone dipropionate, and flunisolide. Dexamethasone phosphate is readily absorbed in active form to the point that at least mild adrenal suppression occurs with recommended therapeutic dosage.l' 2 Although systemic steroid effects Received for publication Nov. 21, 1983. Accepted for publication Aug. 24, 1984. Reprint requests: David S. Pearlman, M.D., 1450S. HavanaSt., Suite 500, Aurora, CO 80012.
Abbreviation used
FCB: Fluocortin butyl
of beclomethasone dipropionate and flunisolide have been rare, in many patients their effectiveness has been disappointing when these agents were used in recommended dosages. Greater effectiveness may be obtained with higher dosages. However, such dosages are likely to produce systemic steroid effects as evidenced by the results of studies in asthmatic patients and normal individuals3-S; indeed, at least mild adrenal suppression was observed even when these agents were used in generally recommended dosages. 9, ~0 FCB is a newly developed steroid drug with an especially high ratio of local anti-inflammatory activity to systemic activity when it is applied topically. Studies conducted in healthy subjects demonstrated that oral or nasal inhalation of FCB was tolerated well
501
502
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TABLE I. Physician's evaluation of signs and symptoms
Signs
Symptoms
Turbinate/mucosal swelling Nasal discharge Pharyngeal discharge Erythema/cyanosis
Sneezing/itching Nasal congestion Postnasal drip/snorting Runny nose/sniffing
without any adrenal suppression at dosages 20 to 80 times the therapeutic dosage.*' 3.6. 1] FCB has an additional advantage over most other topical corticosteroid preparations currently in use because it is inhaled as a fine powder, therefore requiring no propellant gas such as Freon. A previous study, performed in the United States, has indicated that FCB, when it is applied topically four times a day, is effective in ameliorating symptoms of rhinitis. ~2 The purpose of the multicenter study reported here was to determine the efficacy and tolerance of FCB compared to placebo therapy with various dosages of medication on a twice daily schedule. This article represents the pooled results from six investigative centers throughout the United States.
MATERIAL AND METHODS
Study design. This study was a randomized, doubleblind, parallel-group design comparing FCB in dosages of 2, 4, or 8 mg per day with placebo. Study population. Patients were 16 yr of age or older and were outpatients in the investigators' practices. Patients had perennial allergic or nonallergic, noninfectious rhinitis for at least the 1-year period previous to entrance into the study. In order to qualify for the study, patients were required to exhibit a minimum level of chronic nasal inflammation as judged by a scoring system for signs and symptoms of rhinitis (see below). Patients with the following were excluded from the study: history of nasal polyposis, history of treatment with systemic or topical corticosteroids or cromolyn sodium within the previous 4 wk or with repository corticosteroids within the previous 8 wk, known or suspected intolerance to lactose or hypersensitivity to corticosteroids, chlorpheniramine, or pseudoephedrine, history of convulsive disorder, asthma requiring bronchodilator medications on a regular basis, and hypertension requiring therapy other than diuretics. Patients with any severe active physical disease as evidenced by history, physical examination, and/or laboratory tests also were excluded as well as pregnant women and nursing mothers. An informed consent for participation in the study was obtained from patients who qualified for the study, and the
*Wendt VH, Matthes H: Unpublished data. Berlex Laboratories, Inc., Cedar Knolls, N.J.
patients were assured of freedom to withdraw from the study at any time. Study procedure. This was a 4-week study including an initial l-week observation period and a 3-week treatment period with FCB or placebo. During the observation week, the patients were permitted to take oral chlorpheniramine (4 rag) and/or oral pseudoephedrine (60 mg) single entity products on an as-needed basis for treatment of symptoms. At the end of the observation week, a baseline assessment was made of each patient's condition. Patients whose rhinitis was not well controlled by the use of chlorpheniramine and/ or pseudoephedrine were entered into the 3-week treatment period. All medications were supplied by Berlex Laboratories, Cedar Knolls, N. J. Formulations of FCB were provided in a plastic cylinder for inhalation, which delivered 0.5 rag, 1.0 mg, or 2.0 mg of active drug per inhalation. Seventeen to 19.5 mg of lactose powder was added as an excipient in each case so that approximately 20 mg of FCB-lactose powder was delivered per inhalation; lactose powder (20 mg per inhalation) for placebo was provided in plastic cylinders identical to those containing active medication. Patients received one inhalation of study medication in each nostril every 12 hours. Thus, four groups were treated: group 1, FCB 2 mg per day; group 2, FCB 4 mg per day; group 3, FCB 8 mg per day; and group 4, placebo therapy. Medication was inhaled through a Rhinolator (Schering Aktiengisellschafte, Berlin, West Germany), a plastic device that operates on the Venturi principle. Patients were permitted to continue the use of oral chlorpheniramine and/or pseudoephedrine tablets as needed during the treatment period. The patient's condition was evaluated daily by the patient and was evaluated weekly by the physician. At each visit the physician rated eight signs and symptoms (Table I), each on a 4-point rating scale (0 = absent, 1 = mild, 2 = moderate, and 3 = severe). The patient evaluated the same four symptoms listed in Table 1 by use of the same rating scale. In addition, he/she recorded the number of chlorpheniramine and pseudoephedrine tablets taken each day. The safety evaluations included (1) vital signs and physical examination, (2) laboratory evaluations including hematology, serum chemistries, and urinalysis, and (3) side effects reported by the patients. Patients who incurred an upper respiratory infection during the 3-week treatment period were discontinued temporarily and reentered into the study after a 1-week washout period. Assessment of efficacy. Six variables relating to efficacy were assessed as clinically meaningful and reliable: (I) signs score, the sum of the four clinical signs rated by the physician (0 to 12), (2) physician symptoms score, the sum of the four symptoms rated by the physician (0 to 12), (3) signs and symptoms score, a combination of physician-rated signs and symptoms scores (0 to 24), (4) patient symptoms score, the sum of the four symptoms rated by the patient on a daily basis, (5) chlorpheniramine use, and (6) pseudoephedrine
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40~
35-
30-
25F R 0 M
20-
B A
S E L I N Z
15"
10-I
I
I
1
2
3
TREATMENT
~ ,"3 PLACEBO
WEEK
~ - 2 M G
-~-A-~-4 MG
-I~!1-11- 8MG
FIG. 1. Meari change from baseline as a percentage of the baseline mean, total signs and symptoms score.
use. The patient symptoms score and the daily use of chlorpheniramine and psuedoephedrine were averaged for each week. Statistical methods. The evaluation of efficacy variables at each postbaseline visit was made by use of the analysis of covariance. '~This method produces a more sensitive analysis of taking advantage of the correlation between baseline and change from baseline thereby reducing the error term in the model. The Bonferroni multiple comparison procedure '4 was used to control the overall significance level for one-tailed comparisons of the three FCB-treated groups against the placebo-treated group. In order to ensure that the study groups were comparable before treatment, a preliminary analysis was performed in which the baseline means were compared for each efficacy variable. No significant differences between groups were found at baseline.
RESULTS A total of 235 patients entered the study. Of these patients, 58 received placebo, 58 received 2 mg of FCB per day, 59 received 4 mg of FCB per day, and 60 received 8 mg of FCB per day. Patients ranged in age from 16 to 73 yr; mean age was 33 yr. Seventyseven percent of the study group were female patients. Eighty-three percent of the patients were considered to have perennial rhinitis of allergic origin. There were no significant differences between the various groups in age, sex, diagnosis, or in other discernible historical
or physical characteristics. Of the total 235 patients entered, 227 (97%) accomplished at least one valid postbaseline visit, and 224 (95%) completed the scheduled 3-week treatment period. Eight patients were declared invalid for reasons of noncompliance or inadequate data at baseline or postbaseline period. The data supplied by invalid patients were excluded from efficacy analysis, but such data were included in safety analysis. A total of 11 patients dropped out of the study before the last visit, seven for lack of efficacy, one who also had an adverse reaction, three for intercurrent illness, and one was lost to followup. Of those who dropped out for lack of efficacy, three were in the placebo-treated group, two in the 4 mg FCB-treated group, and two were in the 8 mg FCB-treated group. Data from these 11 patients were included as appropriate in the efficacy and/or safety analyses.
Efficacy Comparisons of mean changes from baseline values among treatment groups were performed for the six efficacy variables, The results displayed in Table II are summarized below. Analyses of signs and symptoms scores. The changes in signs and symptoms scores are graphed as percent change from baseline in Fig. 1. At each postbaseline visit, the FCB-treated groups demonstrated
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TABLE II. Treatment comparisons of mean change from baseline in efficacy variables for valid completers Placebo
2 mg
Mean change From baseline
Signs and symptoms score Signs score Physician symptoms score Patient symptoms score Daily chlorpheniramine use Daily psedueophedrine use
Mean change From baseline
Baseline mean
W1
W2
W3
11.61 5.67 5.94 5.11 1.22 1.27
- 1.41 - 1.00 -0.39 -0.18 0.01 -0.28
-2.76 - 1.81 - 1.04 -0.44 -0.01 -0.26
-2.99 - 1.65 - 1.26 - 1.00 -0.11 -0.37
Baseline mean
10.71 5.20 5.51 4.84 0.99 0.93
Wl
W2
W3
-2.74* - 1.58 - 1.23" -0.75* -0.52:t: -0.50
-3.54 - 1.69 - 1.73 - 1.20" -0.555 -0.46
-4.08 - 2.15 - 2.21t - 1.61 -0.63* -0.54
WI, W2, W3 = treatment weeks 1, 2, and 3, respectively; statistical significance is declared in comparison to placebo-treated group on the basis of Bonferroni t tests. *p < 0.05. ~p < 0,10. :~p < 0,01.
greater improvement in the variable compared to the placebo-treated group. This improvement was statistically significant (p < 0.05) in the 8 mg FCB-treated group after 3 wk of treatment. Analyses of physician signs score. At both weeks 1 and 2 all four groups improved their signs scores. After 3 wk on medication, the FCB-treated groups continued to demonstrate improvement, and the placebo-treated group demonstrated a decrease in improvement. None of these changes were statistically significant compared to the placebo-treated group, however. Analysis of physician symptoms scores. Although the changes in these scores were analyzed, they were considered to represent essentially the same information recorded by the patient and are not further discussed here. The changes, in fact, parallel the trends observed with patient symptoms scores. Analysis of patient symptoms scores. At each postbaseline visit, there was a trend for greater improvement in all FCB-treated groups compared to the placebo-treated group. These differences reached statistical significance for the 2 mg FCB-treated group. Analysis of chlorpheniramine use. The most striking change in efficacy measurements came in diminution in chlorpheniramine use. There was a reduction in use of about 0.5 to 0.6 tablet per day over the course of the study in the various FCB-treated groups compared to an average reduction of only 0.1 tablet per day in the placebo-treated group. When reductions were compared to the placebo-treated group, the reductions in all three FCB-treated groups were statistically significant (p < 0.05) at each treatment week. Analysis ofpseudoephedrine use. At the end of 3
wk, there was a reduction of 0.4 tablet per day in the placebo-treated group and from 0.5 to 0.6 tablet per day in the various FCB-treated groups. The reduction in pseudoephedrine use relative to the placebo-treated group was not statistically significant.
Safety The FCB-treated groups were indistinguishable from the placebo-treated group in regards to both nasal- and nonnasal-related side effects. Nasal side effects during the course of the study were reported by 16% of the placebo-treated group, 14% of the 2 mg group, 19% of the 4 mg group, and 15% of the 8 mg group. The most common nasal side effects were postnasal drip reported by 5% of placebo-treated patients and 8% of all FCB-treated patients and nasal irritation reported by 2% of placebo-treated patients and 5% of all FCB-treated patients. More patients (5%) in the placebo-treated group reported rhinorrhea compared to the FCB-treated groups combined (1%). Nonnasal side effects were reported by 17% of the placebotreated group, 14% of the 2 mg FCB-treated group, 14% of the 4 mg FCB-treated group, and 14% of the 8 mg FCB-treated group. The most common nonnasal side effects were headache, reported by 5% of the placebo-treated patients and 6% of all FCB-treated patients, and nausea, reported by 3% of placebotreated patients and 2% of all FCB-treated patients. None of these side effects were severe in nature except for one patient in the placebo-treated group who discontinued the medication because of nausea. There were no significant changes from baseline in vital signs except for mean reductions of 3 to 5 mm Hg in systolic blood pressure in the 2 mg FCB-treated
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4 mg
8 mg
Mean change From baseline
Mean change From baseline
Baseline mean
Wl
W2
W3
Baseline mean
11.61 5.72 5.89 4.89 1.43 1.32
- 2.26 - 1.17 - 1.07t -0.20 - 0.535 - 0.48
- 3.41 - 1.86 - 1.60 -0.96 - 0.535 - 0.36
- 4.43t -2.04 - 2.28* - 1.35 - 0.63* - 0.57
11.62 5.81 5.82 4.57 1.29 1.25
group at all postbaseline visits. There were no significant changes in mean diastolic blood pressure. No changes were found in the serum chemistry variables nor in urinalysis. Similarly, there were no changes in hematologic findings including the eosinophil count. DISCUSSION
FCB is a new corticosteroid drug developed with the aim of maximizing topical steroid activity while it minimizes and, if it is possible, eliminates the risk of undesirable systemic corticosteroid effect. The theoretic basis for the development of this new compound was the recognition that the therapeutic effects of topically applied corticosteroids do not require a free hydroxyl group in the C-21 position, and a steroid C21 acid does not exhibit systemic corticosteroid effects. This lack of effect may be due to poor binding of the steroid C-21 acid with the cytosol steroid receptor.'5 FCB is a topically active corticosteroid ester produced by combining a steroid C-21 acid with butanol. After absorption C-21 esters are broken down rapidly by intrinsic nonspecific esterases. 1~in contrast with these mechanisms, flunisolide and beclomethasone dipropionate depend on liver metabolism for inactivation of the compound. ,6-,9 Little or no systemic corticosteroid activity has been found when FCB has been administered by the oral, inhalant, or parenteral routes to animals in dosages equivalent to large multiples of human therapeutic doses J'' 20.21 or when FCB has been administered by oral or nasal inhalation in man (see footnote page 502). 3, 6 For example, 160 mg of FCB per day by oral inhalation over a l-week period in normal human volunteers resulted in no adrenal suppression. 3 This dosage is 20 to 80 times the doses found to be therapeutically effective when it is applied nasally, which was done in this study. Previous studies have demonstrated the therapeutic effectiveness of FCB applied topically to the nasal mucosa when it is used three to four times a day in
Wl
- 2.27 - 1.07 - 1.16" -0.55 - 0.54:[: - 0.641"
W2
- 3.34 - 1.58 - 1.77 -0.96 - 0.625 - 0.59
W3
-
4.47* 1.93 2.36* 1.36 0.54* 0.60
the treatment of perennial allergic and nonallergic rhinitis and as a protection against allergen challange.12, 22 Results of the current study demonstrate effectiveness of a twice daily schedule of FCB at 2, 4, and 8 mg per day, which was indicated by an amelioration of signs and symptoms of rhinitis. Statistically significant differences, in comparison with the placebo-treated group, were recorded at various time intervals in each FCB-treated group with effectiveness exhibited as early as the first week of treatment. The clinical effectiveness of FCB was reflected also by at least a fourfold reduction in chlorpheniramine use and to a lesser extent by pseudoephedrine use in FCB-treated patients as compared to placebo-treated patients. The study design permitted the use of sponsor-supplied chlorpheniramine and pseudoephedrine tablets in order to provide a means to minimize discomfort from nasal symptoms. Therefore, the potential for further improvement in signs and symptoms is less than would be the case in studies where concomitant medications are prohibited. However, this study demonstrated a greater control of symptoms and greater reduction of antihistamines and/or decongestant use in FCB-treated patients as compared to placebo-treated patients. Improvement in clinical signs and symptoms also was noted in the placebo-treated group. Whether this relates to the lactose excipient used or to other factors is unknown. Amelioration of signs and symptoms in the placebo-treated group occurred between weeks 1 and 2; no further improvement was noted in the third week. By contrast, there was progressive improvement in symptoms and signs throughout the study in all three FCB-treated groups. This suggests the possibility of added therapeutic benefit had the treatment period been longer than 3 wk. No clear dose-response effect of FCB was recorded in this study. Patients who received the lowest dose
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J. ALLERGY CLIN. IMMUNOL, APRIL 1985
of FCB (2 mg per day), in fact, tended to exhibit somewhat greater improvement in signs and symptoms initially and to require less chlorpheniramine and pseudoephedrine than patients treated with higher FCB dosages. It remains to be determined whether large dosages of FCB administered topically in similar or different form would offer greater therapeutic benefit in some patients. The administration of significantly larger dosages are unlikely to cause safety problems based on the observations of others that multiples of the FCB doses used in the current study have not produced systemic corticosteroid effects (see footnote page 502). 3' 6 In this study, however, duration of treatment appears to have been more important than dosage per day. Side effects recorded in association with the use of FCB were minimal. None of the side effects reported were serious. Moreover, there were no significant differences in the incidence of side effects between patients treated with the various dosages of FCB and those patients treated with placebo therapy. In fact, the clinical side effects recorded tended to be characteristic of those effects of the rhinitis for which patients were treated. This is similar to previous observations with the use of FCB. ~2,22 Other than a slight reduction in systolic blood pressure in the group of patients treated with 2 mg of FCB (the clinical significance of which, if any, is unknown), there were no changes in vital signs, hemogram, blood chemistries, or urinalyses in patients who received placebo or FCB therapy. Assessment of adrenocortical function was not part of this study. It is of particular interest that there were no significant changes in peripheral blood eosinophil counts in patients treated with FCB since this parameter is known to be influenced by systemic or topical corticosteroid administration.5' 8.23. z4 In summary, FCB, a newly developed topical corticosteroid drug, appears to be effective in ameliorating symptoms of perennial allergic or nonallergic, noninfectious rhinitis when it is used on a twice daily regimen. Therapeutic effects are unassociated with appreciable side effects. We are indebted to our coinvestigators and study coordinators for invaluable assistance in performing the study: Brice Steele Rolston, M.D., Phoenix, Ariz.; John Erffmeyer, M.D., and Maria Bizell, R.N., Memphis, Tenn.; James P. Kemp, M.D., H. Alice Orgel, M.D., and Cindy Stutsman, L.V.N., San Diego, Calif.; Paul Chervinsky, M.D., and Madeline Romeo, R.N., New Bedford, Mass.; Sanford E. Avner, M.D,, Jerome M. Buckley, M.D., and Sharon Donnelly, R.N., Denver, Colo.; M. Scott Caroll, M.D., Gary Z. Lotner, M.D., Dennis L. Spangler, M.D., Gerald E. Vanderpool, M.D., Jean DeCuto, and Lorri Edelman, Atlanta.
We also acknowledge with appreciation Dr. Gene Johnson, Denver, Colo., and the staff of the medical and statistical departments of Berlex Laboratories, Cedar Knolls, N. J., for their review, helpful criticisms, and statistical analysis of the data in this paper. REFERENCES
1. Michels MI, Smith RE, Heimlich EM: Adrenal suppression and intranasallyapplied steroids. Ann Allergy 25:569, 1967 2. NormanPS, WinkenwerderWL, AgbayaniBF, et al: Adrenal functionduringthe use of dexamethasone aerosols in the treatment of ragweed hay fever. J ALLERGY40:57, 1967 3. ShermanB, WeinbergerM, Chen-WaldenH, WendtH: Further studies of the effects of inhaled glucocorticoids on pituitaryadrenal function in healthy adults. J ALLERGYCLINIMMUNOL 69:208, 1982 4. Mygind N, Hansen I: Beclomethasone dipropionate aerosol effect on the adrenalsin normalpersons. Acta Allergol28:211, 1973 5. Harris DM: Some properties of beclomethasone dipropionate and related steroids in man. Postgrad Med J 51(suppl 4):20, 1975 6. Vlasses PH, Ferguson RK, Koplin JR, Clementi RA, Green PJ: Adrenocortical function after chronic inhalation of fluocortin butyl and beclomethasonedipropionate.ClinPharmacol Ther 29:643, 1981 7. Rboades RB, Forbes EF: Clinicallyapparent adrenal suppression with beclomethasone (400 txg a day) inhalation. J ALLERGYCLINIMMUNOL65:218, 1980 (abst) 8. Chaplin MD, Cooper WC, Segre EJ, Oren J, Jones RE, Nerenberg C: Correlationof flunisolideplasma levels to eosinopenic response in humans. J ALLERGYCLI~IMMt~NOL65:445, 1980 9. Wyatt R, Wascbek J, WeinbergerM, Sherman B: Effects of inhaled beclomethasonedipropionate and alternate day prednisone on pituitary adrenal function in children with chronic asthma. N Engl J Med 299:1387, 1978 10. Vaz R, Senior B, Morris M, BinkiewiczA: Adrenaleffects of beclomethasoneinhalationtherapy in asthmaticchildren. J Pediatr 100:660, t982 11. Investigator'sbrochure: Fluocortinbutylfor oral inhalationand nasal application. Cedar Knolls, N. J., 1980. Berlex Laboratories, Inc 12. ArbesmanC, Bemstein IL, BiermanCW, et al: Multi-center, double-blind,placebo-controlledtrial of fluocortinbutyl in perennial rhinitis. J ALLERGYCL1NIMMUNOL71:597, 1983 13. Neter J, Wasserman W: Applied linear statistical models. Homewood, II1., 1974, Richard D. Irwin, Inc, pp 685-721 14. Miller RG Jr: Simultaneousstatistical inference, ed 2. New York, Heidelberg, Berlin, 1980, Springer-Verlag,pp 67-70 15. Kapp JF, Koch H, T6pert M, Kessler HJ, Gerhards E: Unterschungen zur pharmakologie von 6ot-fluor-11[3-hydroxy-16amethyl-3,20-dioxo-1,4-pregnadien-21-saure-butylester (fluocortin butylester). ArzneimForsch 27:2191, 1977 16. ChaplinMD, Rooks W, SwensonEW, Cooper WC, Nerenberg C, Chu NI: Flunisolidemetabolismand dynamicsof a metabolite. Clin Pharmacol Ther 27:402, 1980 17. Kapp JF: Use of topical corticosteroids in the managementof rhinitis. N Engl Soc Allergy Proc 3:482, 1982 18. MartinLE, TannerRJN, ClarkTJH, CochraneGM: Absorption and metabolismof orally administeredbeclomethasonedipropionate. Clin Pharmacol Ther 15:267, 1974 19. Martin LE, Harrison C, Tanner RJN: Metabolism of beclomethasone dipropionateby animals and man. Postgrad Med J 52(suppl 4):11, 1975
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20. Giinzel P, Siegmund F, Bhargava AS, et al: Tierexperimentelle vertraglichkeitsprufung von fluocortin-butylester als reiner wirkstoff und als salbe, fettsalbe und creme. Arzneim Forsch 27:2217, 1977 2l. Bhargava AS, Staben P, Siegmund F, Sch6bel Chr, Giinzel P: Effect of fluocortin butylester and beclomethasone dipropionate on the adrenal gland in beagle dogs. Arzneim Forsch 28(suppl 2):1638, 1978 22. Horak F, Matthes H: The protective action of fluocortin bu-
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tylester (FCB) in the nasal antigen provocation test: a controlled double-blind, crossover study. Ann Allergy 48:305, 1982 23. Thorn GW, Forsham PH, Prunty FFG, Hills AG: A test for adrenal cortical insufficiency. JAMA 137:1005, 1948 24. Blaiss MS, Herrod HG, Crawford LV, Lieberman PL: Beclomethasone dipropionate aerosol: hematologic and immunologic effects. Ann Allergy 48:210, 1982
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