Comparison of Fluticasone Propionate and Beclomethasone Dipropionate

1 044 Thorax 1995;50:1044-1050 Comparison of fluticasone propionate and

beclomethasone dipropionate on direct and Thorax: first published as 10.1136/thx.50.10.1044 on 1 October 1995. Downloaded from indirect measurements of bronchial hyperresponsiveness in patients with stable asthma

G P Bootsma, P N R Dekhuijzen, J Festen, P G H Mulder, C L A van Herwaarden

Abstract Inhaled corticosteroids are currently the most Background - Fluticasone propionate is effective anti-inflammatory drugs available for a new inhaled corticosteroid with a 2:1 the treatment of asthma.'-' Dosages above efficacy ratio compared with beclo- 1000 tg/day may be necessary to control severe methasone dipropionate with regard to asthma, but these dosages are associated with lung function and symptom scores, with- systemic effects including a decrease in morn- out increased systemic activity. The aim ing cortisol levels and adverse effects on para- of this study was to investigate whether meters of bone turnover.3 this was also the case for bronchial hyper- Fluticasone propionate is a new inhaled corti- responsiveness, assessed by both a direct costeroid with higher topical anti-inflammatory (histamine) and an indirect (ultrasonically potency in humans than beclomethasone di- nebulised distilled water (UNDW)) pro- propionate and budesonide.4 Comparative vocation test. studies indicate a 2:1 clinical potency ratio of Methods - Fluticasone propionate, 750 igI fluticasone propionate compared with these day, and beclomethasone dipropionate, inhaled steroids over a range of 200-1000 1tg 1500 tg/day, were compared in a ran- fluticasone propionate daily.5-9 In these trials domised, double blind, crossover study forced expiratoryvolume in one second (FEV,), consisting of two six week treatment peak expiratory flow rate (PEFR), and symp- periods, each preceded by a three week tom scores were used to evaluate clinical single blind placebo period. Twenty one efficacy. http://thorax.bmj.com/ non-smoking asthmatics (mean forced ex- No comparisons have been made between piratory volume in one second (FEV,) fluticasone propionate and other inhaled ster- 74*7% predicted, mean PC20histamine oids with regard to bronchial hyperrespons- 0-36 mg/ml) completed the study. iveness, a major characteristic of asthma. Bron- Results - Fluticasone propionate and chial hyperresponsiveness can be measured by beclomethasone dipropionate improved pharmacological (direct) stimuli such as his- FEV,, peak flow rates, asthma symptoms, tamine. Ultrasonically nebulised distilled water

and bronchial hyperresponsiveness to the (UNDW), a physiological stimulus, induces on September 25, 2021 by guest. Protected copyright. same extent. Both fluticasone propionate airway narrowing indirectly and may better and beclomethasone dipropionate caused reflect the clinical severity of asthma.'01" an increase in PC20histamine (mean 2-29 The aim of this study was to compare the [95% confidence interval 1-45 to 3.131 and effects of inhaled fluticasone propionate Department of 195 [1-07 to 2.84] doubling doses, re- (375 gg twice daily) and inhaled beclo- Pulmonary Diseases, spectively) and in PD20UNDW (1-12 [055 methasone dipropionate (750,ug twice daily) University Hospital, to 1.70] and 128 [0.88 to 1-70] doubling on bronchial hyperresponsiveness (assessed by PO Box 9101, 6500 HB Nijmegen, doses, respectively). Neither treatment provocation with histamine and UNDW), and The Netherlands changed morning serum cortisol levels, on clinical efficacy in adult patients with stable GP Bootsma but fluticasone propionate decreased the asthma. P N R Dekhuijzen J Festen number of peripheral blood eosinophils C L A van Herwaarden less than beclomethasone dipropionate, indicating smaller systemic effects of flu- Methods Epidemiology and DESIGN AND TREATMENT Biostatistics, ticasone propionate. was a crossover - show that The study randomised, trial, Erasmus University, Conclusions These findings with a three week single blind washout (pla- Rotterdam, fluticasone propionate is as effective as two six week The Netherlands twice the dose of beclomethasone dipro- cebo) period before each of the P G H Mulder double blind active treatment periods. A pionate on bronchial hyperresponsive- schematic overview is shown in fig. 1. Currently Reprint requests to: ness, assessed by provocation with both Dr G P Bootsma. histamine and UNDW, without increased used inhaled corticosteroids were discontinued Received 7 November 1994 at the start ofthe first placebo (washout) period. Returned to authors systemic activity. Measurements made at the end of the two 5 January 1995 (Thorax 1995;50:1044-1050) Revised version received placebo (washout) periods were regarded as 17 May 1995 Accepted for publication Keywords: bronchial hyperresponsiveness, fluticasone baseline values before the active treatment 16 June 1995 propionate, beclomethasone dipropionate. periods. After the first placebo (run in) period Comparison offluticasone propionate and beclomethasone dipropionate on bronchial hypemsponsiveness 1045 Placebo Placebo wash-out wash-out piratory tract infection within six weeks before (run-in) the start of the study were excluded. The study was approved by the Nijmegen University med- -*FP ical ethics committee. All subjects gave written Thorax: first published as 10.1136/thx.50.10.1044 on 1 October 1995. Downloaded from informed consent.

BRONCHIAL HYPERRESPONSIVENESS AND LUNG FUNCTION - BDP At the end of the four periods a histamine and a UNDW provocation test were performed at 3 weeks 6 weeks 3 weeks 6 weeks the same time on two different days in order I to avoid tachyphylaxis for the different tests.'5 Subjects did not use rescue or study medication for at least eight hours before each visit, and Measurements 1 2 3 4 rested 15 minutes before the measurements were started. Figure 1 Design of the study. FP=fluticasone propionate 750 pg daily; BDP= beclomethasone dipropionate 1500 pg daily. Lung function and responses to provocation with histamine (PC20histamine) and UNDW (PD20UNDW) were assessed by FEVI, mea- a final evaluation was made to check iff the sured with a flow-volume curve recorded on a patient met all inclusion criteria. If so, they heated pneumotachograph (Spiro analyser ST randomly received fluticasone propionate 250; Fukuda Sangyo Co, Tokyo, Japan). Base- 750 gig daily or beclomethasone dipropionate line lung function was recorded as the best of 1500 gg daily for six weeks. three reproducible values of FEV, (within 5%) Throughout the study the patients took tthree before the provocation tests. inhalations ofthe study medication twice claily. The histamine provocation test was carried The inhalations were taken from a met:ered out according to the method of Cockcroft et dose inhaler containing either placebo, flu- al. 14 For two minutes patients inhaled doubling ticasone propionate 125 jg, or beclomethaLsone concentrations of histamine acid phosphate by dipropionate 250 jg per dose. The patiients tidal breathing, increasing from 003 to 16 mg/ used a salbutamol metered dose inlhaler ml. Histamine was nebulised with a DeVilbiss (100 jg) as required as rescue medication. 646 nebuliser (DeVilbiss, Somerset, Penn- Patients were instructed on the correct usage sylvania, USA) with a fixed output of 0 '13 ml/ of their inhaler. No other pulmonary rned- min. PC20histamine was determined in mg/ml ication was allowed. by interpolating the last two points of the dose-

response curve on a semilogarithmic scale. http://thorax.bmj.com/ The UNDW provocation test was performed SUBJECTS according to the method of Groot et al. 15 Thirty adult non-smoking patients with asthma UNDW was generated with an ultrasonic according to the criteria of the American Thor- nebuliser (Ultraneb 99, DeVilbiss, Somerset, acic Society'2 were recruited from the out- Pennsylvania, USA) at a fixed output of 2-00 patient department. Baseline characteristics of (0-05) ml/min. After inhalation of 20 litres of these subjects are shown in table 1. All butt one ambient air through the system, patients in-

used inhaled corticosteroids before enterinjg the haled doubling volumes of air with UNDW (3, on September 25, 2021 by guest. Protected copyright. study, with a mean (SE) daily dose of 790 (54) 5, 10, up to 160 litres), measured with a Wright jig. At the start of the first placebo (was]hout respirometer (British Oxygen Co, London, and run in) period patients discontinued their UK). The respirometer was placed between inhaled steroids. Allergy was defined as raaised the aerosol hose and the mouthpiece by means specific IgE levels or positive skin tests5 for of a two way valve. Before and after each test housedust mite or two of seven other common the nebuliser chamber and aerosol hose were aeroallergens tested.'3 To be included in the weighed to determine the exact amount of study patients needed to be symptomatic, distilled water inhaled. The cumulative amount defined as having > 4 symptom days duiring of inhaled water (ml H20) causing a 20% fall the last week, or > 7 symptom days durinig the in FEV, from post-air values (PD20UNDW) last two weeks of the first placebo (run in) was calculated by linear interpolation on a period. Days were considered as symptom days semilogarithmic curve. when patients recorded at least one asthma symptom on the record cards (see below) during that day. At the end of the run in peiriod, DAILY RECORD CARDS FEV, had to be > 50% of predicted and During the last three weeks of each of the four patients needed to have a provocative con- periods, patients recorded PEFR, use of study centration of histamine causing a 20% faLll in and rescue inhaler, asthma symptoms, and ad- FEV, (PC20histamine) below 4 mg/ml, in- verse events every day. The best ofthree PEFR dicating overt bronchial hyperresponsivene~ss. '4 measurements with a mini-Wright peak flow Subjects with seasonal allergy did not par- meter was recorded every morning and evening, ticipate in the study during that specific sea son. before medication. The severity of dyspnoea None of the patients had used systemic corti- during the day, during the night, and during costeroids in the six months preceding;the exercise was registered on a visual analogue study. Patients with an upper or lower res- scale ranging from 0 to 100 mm.'6 1046 Bootsma, Dekhuijzen, Festen, Mulder, van Henvaarden

LABORATORY EVALUATION 4: ((FP - BDP) - (BDP - FP))/2.'7 Altern- At the end of the four treatment periods a atively, the clinical efficacy of each treatment peripheral blood sample was taken between was also expressed by taking the differences 0700 and 0900 hours (individual patients al- between the measurements at the end of either Thorax: first published as 10.1136/thx.50.10.1044 on 1 October 1995. Downloaded from ways at the same time) for measurement of treatment period and the associated baseline total numbers of eosinophils and cortisol. measurement at the start of the treatment Total numbers ofeosinophils were measured period considered. with a Technicon Hi analyser (Technicon All PC20histamine and PD20UNDW data Instrument Co, Tarrytown, New York, USA). were log2 transformed before analysis, hence Cortisol levels were immediately determined changes in PC20histamine and PD20UNDW using an in-house radioimmunoassay involving were expressed as doubling doses of inhaled heat inactivation of corticosteroid binding histamine and UNDW. The standard deviation globulin. The lower limit of normal for of the differences between two repeated morning serum cortisol levels in our measurements (SD-rm) for these provocation laboratory is 0 19 iimol/l. tests was calculated between the two baseline values.'8 From the parameters recorded on the STATISTICAL ANALYSIS diary card (PEFR, symptom scores, additional Treatments were randomly allocated to five use of bronchodilator) the mean of all values groups of six patients each according to the recorded during the last two weeks of each PACT computer programme. Each con- period was used for statistical analysis. PEFR secutive patient was allocated the next ran- variability was defined as the difference be- domisation number after meeting the entry tween morning and evening reading (highest criteria at visit 1. minus lowest value), expressed as a percentage Four repeated measurements were made, at of the mean of both readings.'9 The Wilcoxon the start and at the end of each of both treat- signed rank test or the paired t test were used for ment periods (measurements 1-4, fig 1). The analysis when appropriate. Correlations were carryover effect of the first treatment at the calculated by means of the Spearman rank start of the second treatment period (measure- correlation coefficient, p values of <0 05 being ment 3) is a first order carryover effect, which considered significant. Data are reported as may still be partly present at the end of the mean (SE) values unless specified otherwise. second treatment period (measurement 4). This latter part is the second order carryover effect which may interfere with the treatment Results effect. The first order carryover effect was Thirty patients entered the first placebo (run tested by comparing the differences of meas- in) period. Two patients did not meet the final urements 3 and 1 between the two randomised criteria after the run in period because they

treatment groups. Theoretically, the second http://thorax.bmj.com/ order carryover effect is tested by comparing NS the sum of measurements 2 and 4 between 8.0 VA ~ the treatment order groups.'7 However, in the p<0.001 4.0 _ pc0 001 present study some imbalance was present in I IT several outcome variables between the two treatment groups at the start of the study, 0,E 2.0 despite randomisation. In order to correct for E I 1.0 this imbalance present at measurement 1, the 0 on September 25, 2021 by guest. Protected copyright. second order carryover effect was tested by 0- comparing the sum of two differences - that 0.50 is, 2 minus 1 and 4 minus 1 - between the two treatment groups. Provided that there was no n- T TS/I1 T o second order carryover effect, the treatment Baseline 6 weeks Baseline 6 weeks effect was tested next by comparing the differ- BDP FP ence of measurements 2 and 4 between the treatment order groups. The treatment effect NS 16.0 FB "fluticasone propionate (FP) minus be- p

Figure 3 Morning (am) (---) and evening (pm) (-) vocation test. http://thorax.bmj.com/ peak expiratory flow rates (PEFR) during the three week PC20histamine and PD20UNDW were sig- placebo (washout) period and after 3-6 weeks of treatment nificantly correlated both after = with (A) fluticasone propionate (FP) 750 pglday and (B) placebo (p beclomethasone dipropionate (BDP) 1500 pglday. 0 74; p<0-001) and after treatment with fluticasone propionate (p = 054; p<0Q05) and beclomethasone dipropionate (p = 0-51; p<0 05). There were no significant differences between the effects of fluticasone propionate and be-

clomethasone dipropionate on bronchial on September 25, 2021 by guest. Protected copyright. 1-5 r hyperresponsiveness and FEV, (table 2). FEV, increased by 0 45 (0 12) 1 after fluticasone propionate (from 74- 1% to 86-9% predicted; p<0 005), and by 0 34 (0-09)l after beclomethasone dipropionate (from 76 4% to 85 8% predicted; p<0001). 1o H

0 E DAILY RECORD CARDS Compared with baseline values, PEFR showed -6 increases in morning and evening values after CD 0 both fluticasone propionate and beclo- 0 0.5 e- methasone dipropionate (all p<001). The diurnal variation in PEFR decreased significantly after fluticasone propionate but not after beclomethasone dipropionate (table 2, fig 3). The treatment effects of fluticasone propionate and beclomethasone dipropionate were not significantly different (table 2). 0.0 Baseline 6 weeks Baseline 6 weeks The use of 12 agonists decreased significantly BDP FP compared with baseline, both with fluticasone propionate and beclomethasone dipropionate, Figure 4 Change in individual morning serum cortisol values from baseline to six weeks the treatment effect not being different with after treatment and mean (E) (SE) values with fluticasone propionate (FP) 750 pglday (0) and beclomethasone dipropionate (BDP) 1500jpg/day (0). The lower limit of either steroid (table 2). Dyspnoea scores, re- normal (019 pmolll) is indicated at the bottom of the figure. corded on a visual analogue scale, decreased 1048 Bootsma, Dekhuijzen, Festen, Mulder, van Hemuaarden Table 2 Clinical efficacy and mutual comparison offluticasone propionate (FP) and beclomethasone dipropionate (BDP) Parameter Baseline After 6 weeks Difference in treatment effect

(mean (SE)) treatmentt FP - BDP Thorax: first published as 10.1136/thx.50.10.1044 on 1 October 1995. Downloaded from (mean (SE)) Mean (SE) 95% CI PC20histamine (mg/ml) FP 0-41 (0-17) 2-42 (0-17)*** 0-55 (0-3) DD -0-10 to 1-21 BDP 0 49 (0 24) 1-63 (0-61)*** PD20UNDW (ml H20) FP 3-77 (1-00) 8-62 (1-93)*** 0-03 (0 3) DD -0-63 to 0-65 BDP 3-29 (0-91) 7-63 (1-78)** FEV,(1) FP 2-83 (0-18) 3-28 (0-13)** 0-06 (0-07) -0-08 to 0-21 BDP 2-90 (0-15) 3-24 (0-14)** PEFR morning (1/min) FP 438-4 (21-2) 489-9 (17-3)*** 5-57 (5-5) 6-31 to 17 5 BDP 433-6 (20 8) 479-9 (17-7)*** PEFR evening (1/min) FP 448-1 (17-2) 487-9 (15-8)*** 2-69 (6 5) - 10-9 to 16-3 BDP 445-3 (16-3) 474-5 (15-0)** Diurnal variation (%)§ FP 6-89 (0 90) 3-97 (0 50)** -0 59 (0 64) - 1-93 to 0-76 BDP 8-70 (1-92) 5-11 (0-59) 12 agonist use (puffs/day) FP 2-23 (0 35) 1-03 (0.29)*** -0-25 (0 22) -0-72 to 0-21 BDP 2-36 (0 43) 1-40 (0.34)** t A treatment effects are calculated as treatment values versus corresponding baseline values. NS= not significant; ** p<0-01; *** p<0-001. t Treatment effects of FP and BDP are directly compared by analysing the difference of their treatment effects between treatment order groups ((FP -BDP) - (BDP-FP))/2. § Difference between morning and evening reading expressed as percenatage of the mean of both readings.

during daytime from 18d1 (2 7) to 7-3 (2-1) Neither fluticasone propionate nor be- mm after fluticasone propionate and from 14-8 clomethasone dipropionate affected morning (3 0) to 6-4 (1-9) mm after beclomethasone cortisol levels significantly, as shown in fig 4. dipropionate (both p<0-001). Night time dys- The seven patients with high values ofmorning pnoea scores decreased from 17-1 (2-9) to 5-6 cortisol (>0.70 pmol/l) were all women, six of (2.0) mm after fluticasone propionate and from whom were taking oral contraceptive drugs.

14-9 (3 6) to 5 9 (2 2) mm after beclo- Oestrogens in oral contraceptive drugs are http://thorax.bmj.com/ methasone dipropionate (both p<0-001). known to increase the production of corti- There were no significant treatment effects costeroid binding globulin, which probably ac- between fluticasone propionate and beclo- counts for the high values of cortisol in these methasone dipropionate. patients.20 The only patient with a large de- No serious adverse events were reported dur- crease (045 jimol/l) in morning cortisol levels ing the study. During treatment with both flu- after treatment with beclomethasone di- ticasone propionate and with beclomethasone propionate also showed a substantial decrease

dipropionate three subjects reported a sore (0.25 gmol/l) after treatment with fluticasone on September 25, 2021 by guest. Protected copyright. throat not related to a common cold. Other propionate. In no patient did the cortisol level adverse events, unlikely to be related to the use fall below the lower limit of normal after treat- of the study drugs, included common cold ment. Mean cortisol values did not change (seven times with fluticasone propionate, four significantly (from baseline 064 to 061 ,umol/ times with beclomethasone dipropionate, and 1 after fluticasone propionate, and from baseline six times with placebo), nausea and stomach 0-60 to 0 59 jimol/l after beclomethasone di- ache (twice with beclomethasone dipro- propionate). There was no difference in treat- pionate), headache (once with fluticasone ment effect between fluticasone propionate and propionate, three times with beclomethasone beclomethasone dipropionate. dipropionate and five times with placebo), diar- rhoea (once both with fluticasone propionate and beclomethasone dipropionate), and gen- eralised itching (three times with placebo). Discussion This study in patients with stable asthma shows that, after six weeks of treatment, fluticasone LABORATORY EVALUATION propionate 750 jg daily is as effective as be- The total number of eosinophils in the peri- clomethasone dipropionate 1500 gg daily. No pheral blood decreased from 0 45 to 0-22 significant differences in beneficial effects were x 109/1 (p<0-001) after beclomethasone di- found with regard to bronchial hyper- propionate, and from 0-41 to 0 30 x 109/1 responsiveness, FEVI, PEFR, and asthma (p<0-001) after fluticasone propionate. This symptoms. BotVfluticasone propionate and treatment effect was significantly different, with beclomethasone dipropionate caused a sig- a mean difference between fluticasone pro- nificant decrease in bronchial hyper- pionate and beclomethasone dipropionate of responsiveness, assessed by both the histamine 0-076 x 109/1 (95% CI 0-024 to 0-13). and the UNDW provocation test. Neither Comparison offluticasone propionate and beclomethasone dipropionate on bronchial hyperresponsiveness 1 049 steroid significantly changed morning cortisol matic response, just as exposure to allergens.26 levels. It has been suggested that inhaled cortico- This is the first study to test the hypothesis steroids may have a greater effect on indirect Thorax: first published as 10.1136/thx.50.10.1044 on 1 October 1995. Downloaded from that fluticasone propionate may provide an than on direct challenges, because they not equal effect on bronchial hyperresponsiveness, only affect smooth muscle responsiveness but a major characteristic of asthma, at half the also reduce the airway mast cell function.27 microgram dose of beclomethasone di- This concept could not be confirmed in the propionate. Until now all comparative studies present study because both fluticasone pro- in mild, moderate, and severe asthmatics have pionate and beclomethasone dipropionate shown a 2:1 ratio in clinical effects. This was caused a strong decrease in bronchial hyper- shown over a wide dose range, from 200 to responsiveness in both tests. Compared with 1000,g fluticasone propionate (400-2000 jg the SD-rm of the challenges, both steroids beclomethasone dipropionate,5-7 and 400,g improved the PC20histamine about sixfold, and budesonide8). Furthermore, in an open study the PD2OUNDW about fivefold, indicating 400 jtg fluticasone propionate was more effect- equal effects on both parameters. Similarly, the ive than 800,g budesonide,9 and both 1000 study of Groot et al25 showed no advantage of and 2000 jig fluticasone propionate were sig- UNDW over histamine. Nevertheless, the low nificantly more effective than 1600 jg bu- correlation coefficient between PC20histamine desonide.2' Fabbri et ar22 compared fluticasone and PD20UNDW after treatment indicates that propionate and beclomethasone dipropionate both challenges test different aspects of bron- in an equal dose (1500 jtg daily) in patients chial hyperresponsiveness. with moderate to severe asthma. Fluticasone A potential drawback of our study was the propionate caused a significantly greater in- crossover design, because it may take several crease in asthma control than beclomethasone weeks before bronchial hyperresponsiveness re- dipropionate. The present study confirms a turns to baseline values after discontinuation similar ratio with regard to lung function, ofinhaled steroids.28 However, after the second PEFR, symptom scores, and use of 12 agonists washout period (measurement 3) all para- as that shown in previous comparative trials.4 9 meters, including bronchial hyperrespons- On all parameters fluticasone propionate was iveness, returned to pretreatment levels as effective as twice the dose ofbeclomethasone (measurement 1). Therefore, carryover effects dipropionate (table 2). are not likely to have affected the outcome in The extent to which fluticasone propionate the present study both from a statistical point and beclomethasone dipropionate reduced of view and in terms of clinical relevance. bronchial hyperresponsiveness is in line with Fluticasone propionate may offer some ad- that in previous studies. In mild asthmatics vantages over previous inhaled steroids due to fluticasone propionate 1000 jg daily for two its negligible oral bioavailability.29 However, the

weeks improved PC20histamine by 1 3 doubling systemic effects of inhaled corticosteroids are http://thorax.bmj.com/ doses.23 The average increase in PC20histamine mainly due to their resorption from the airways. or methacholine after chronic treatment with The use of a spacer device may increase lung beclomethasone dipropionate or budesonide, deposition and thus systemic absorption.3 as recently reviewed by Barnes et al,3 is also of There is no evidence for local metabolism of the order of one or two doubling doses. The fluticasone propionate in the lung. The sys- extent of the response depends on dose, dur- temic concentration will be reduced by con- ation of treatment, and degree of steroid res- tinuous recirculation and inactivation in the

ponsiveness. Treatment with a similar dose of liver; the hepatic extraction ratio of fluticasone on September 25, 2021 by guest. Protected copyright. budesonide (1600 jig daily) during six weeks propionate is almost 100%.4 This may offer improved PD20histamine by 2-4 doubling some advantages over beclomethasone di- doses24 compared with 2-3 doubling doses for propionate. In the lung beclomethasone di- fluticasone propionate and 2-0 doubling doses propionate is hydrolysed to its much more for beclomethasone dipropionate in this study. active metabolite beclomethasone-17-mono- The extent of the increase in PD20UNDW (1 1 propionate (17-BMP), and the majority of 17- and 1-3 doubling doses) is slightly less than in BMP will reach the circulation. We did not use the study of Groot et a125 (1 8 doubling doses a spacer device in the present study. It is pos- after four weeks of beclomethasone di- sible that the use of a spacer would have in- propionate 800 jg daily). This may be ex- creased the systemic effects. However, the use plained by the fact that at baseline our patients of a spacer is not likely to have changed the were less responsive to UNDW, the difference between the two drugs. PD20UNDW being 3-3 and 3 8 ml H20, com- With regard to the systemic effects ofinhaled pared with 1-3 ml H20 in the study by Groot corticosteroids, two studies have shown sig- et al.25 nificant differences in the effect on the hypo- To assess efficacy of treatment an indirect thalamic-pituitary-adrenal (HPA) axis between challenge, as with UNDW, may be preferable fluticasone propionate and beclomethasone di- because it mimicks naturally occurring bron- propionate in adult asthmatics. In the study by choconstrictor stimuli and because it reflects Leblanc et a16 200 jig fluticasone propionate the severity of asthma better.'011 Inhaled his- daily increased serum cortisol levels compared tamine acts mainly directly on the airway with a (non-significant) decrease after 400,ug smooth muscle.1" In contrast, UNDW induces beclomethasone dipropionate. In addition, bronchoconstriction by cell-mediated events." tetracosactrin-stimulated cortisol levels were Challenge with UNDW may increase bronchial significantly higher after fluticasone pro- hyperresponsiveness and induce a late asth- pionate. In the study of Barnes and coworkers7 1050 Bootsma, Dekhuijzen, Festen, Mulder, van Herwaarden ticasone propionate and budesonide via metered-dose in- serum cortisol levels rose from 0'29 to halers in adults with mild-to-moderate asthma. Br 7 Clin 0'31 pmol/l after fluticasone propionate Res 1994;5:73-84. 1000,ug daily, and decreased from 0-26 to 9 Langdon CG, Capsey U, UK study group. Fluticasone propionate and budesonide in adult asthmatics: a com- Thorax: first published as 10.1136/thx.50.10.1044 on 1 October 1995. Downloaded from 0-22 iimol/l after beclomethasone dipropionate parison using dry-powder devices. Br J Clin Res 1994;5: 84-99. 2000,g daily, the treatment effects being sig- 10 Pauwels R, Joos G, Van der Straeten M. Bronchial hyper- nificantly different. In our study serum cortisol responsiveness is not bronchial hyperresponsiveness is not not asthma. Clin Allergy 1988;18:317-21. levels did change significantly with rel- 11 Anderson SD, Smith CM. Osmotic challenges in the as- atively high doses of inhaled steroids, which sessment ofbronchial hyperresponsiveness. Am Rev Respir Dis 1991;143(Suppl):S43-6. corresponds with the findings by Ayres et al.2' 12 American Thoracic Society. Standards for the diagnosis and However, most studies (including ours) only care ofpatients with chronic obstructive pulmonary disease (COPD) and asthma. Am Rev RespirDis 1987;136:225-44. measured morning serum cortisol levels, a 13 Oosterhoff Y, Koeter GH, de Monchy JGR, Postma DS. simple but insensitive method to detect changes Circadian variation in airway responsiveness to meta- choline, propranolol, and AMP in atopic asthmatic sub- in the adrenal function. This was demonstrated jects. Am Rev Respir Dis 1993;147:512-7. in the study by Nicolaizik et a130 who showed 14 Cockcroft DW, Killian DN, Mellon JA, Hargreave FE. serum not Bronchial reactivity to inhaled histamine; a method and that morning cortisol levels did clinical survey. Clin Allergy 1977;7:235-43. change during treatment with budesonide and 15 Groot CAR, Lammers JW, Festen J, van Herwaarden CLA. Refractoriness for ultrasonically nebulized distilled water beclomethasone, but that 24 hour urinary se- and histamine after histamine challenge. J Appl Physiol cretion of free cortisol was decreased. In ad- 1991;70:1011-5. 16 Stark RD. Dyspnoea: assessment and pharmacological ma- dition, our patients inhaled steroids without a nipulation. Eur RespirJ 1988;1:280-7. spacer, and the duration of active treatment 17 Jones B, Kenward MG. Design and analysis ofcross-over rrials. London: Chapman and Hall, 1989:16-88. with each of the drugs studied was only six 18 Bland JM, Altman DG. Statistical methods for assessing weeks. These factors may partly explain our agreement between two methods of clinical measurement. Lancet 1986;ii:307-10. inability to detect any change in adrenal func- 19 Higgins BG, Britton JR, Chinn S, Jones TD, Jenkinson D, tion. On the other hand, we did detect a sig- Burney PGJ, et al. The distribution of peak expiratory flow variability in a population sample. Am Rev Respir Dis nificant difference in absolute eosinophil 1989;140: 1368-72. counts in the peripheral blood, also a sensitive 20 Meulenberg PMM, Ross HA, Swinkels LMJW, Benraad TJ. The effect of oral contraceptives on plasma-free and indicator of systemic activity.3' Absolute num- salivary cortisol and cortisone. Clin Chim Acta 1987;165: bers of eosinophils decreased less with flu- 379-85. 21 Ayres JG, Bateman ED, Lundback B, Harris TAJ, on behalf ticasone propionate than with beclomethasone of an International Study Group. High dose fluticasone dipropionate, the treatment effect being sig- propionate, 1 mg daily, versus fluticasone propionate, 2 mg In this daily or budesonide, 1-6 mg daily, in patients with chronic nificantly different (p<001). respect severe asthma. Eur RespirJ' 1995;8:579-86. fluticasone propionate showed less systemic 22 Fabbri L, Burge PS, Croonenborgh L, Warlies F, Weeke B, Ciaccia A, on behalf of an International Study Group. activity than beclomethasone dipropionate. Comparison of fluticasone propionate with beclo- In conclusion, fluticasone propionate 750 pg methasone dipropionate in moderate to severe asthma treated for one year. Thorax 1993;48:817-23. daily is as effective as beclomethasone di- 23 O'Shaughnessy KM, Wellings R, Gillies B, Fuller RW. propionate 1500 gg daily with regard to bron- Differential effects of fluticasone propionate on allergen-

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