comparison of budesonide with oral prednisolone inhaled

comparison of inhaled budesonide with oral prednisolone
at two dose·levels commonly used for the treatment of
moderate asthma
P. Namsirikul*, S. Chalsupamongkollarp*, N. Chantadisai*, P. Bamberg**
of inhokd bucksonltk with oral prednisol~ at two dose-levels
the treoJTMnl of 171/XJerote o.sthmo. P. Nom.firilall, S.
~IJPIO.nllA:OIIt.vp, N. ChanJodisai, P. Damberg.
. The purpose or the study was to compare the anti-asthmatic
two dosu or Inhaled budesonlde with two doses or Or'.ll prednl_,.,mt ii RIV used In cllnJcal practice. The patients studied had not
rtjlular Inhaled glucocortlcosterolds and so there was minimal
(tom previous medication. The Stlldy was conducted as two
crossovers with a washout period between them • firstly,
400 ~g budesonlde with S mg predn isolone per day and secbudesonlde with 10 mg prednisolone per dny. Lung function
IYiftlltonts were Improved s iQnlncantly from run-In by nil treatments
''"'"'""~~~ment on both drugs was dose-dependent. When low-dose
were compared, mean morning peak expiratory now rate was
-durh111 hudesonlde treatment and, as a result, diurnal variation was
than that during prednisolone treatment. At the higher
dJfT,~rt!IH'I!.'I between the drugs were not obser ved, but thlo; may have
to Lbe fact that a "ceiling errect" had been reached.
J., 1989, 2, 317-324.
used
lrnroduclion of topical glucocorLicosteroids (GCS}
has provided physicians with an invaluable
the long-tcnn rreatment of asthma. The lherapeuof the drugs is considerably better than lhat of
as they achieve a potent local antieffect in the lung at doses which produce
$1dc-ofTccLS. Allhough tlte first topical corticosavailable viz beclomethasone dipropionatc (BDP)
widely and successfully used to treat asthma in
children, the more recently developed drug,
has an improved therapeutic ratio over BDP
anli-aslhmatic effect following inhalation,
is only half as active as BDP in suppressing
cortisol [1, 2j.
~Cl anti-asthmatic potency ratio of topical budcs10 oral prednisolone has proved difficult to cswba,nd the results of different studies, produced even by
same investigator, have varied as much as twelvc(31 depending on doses compared and response
measured. Studies comparing oral and inhoJcd
are inherently dif.ficult 10 design and conduct,
of inter-individual variation in pharmahanllling of omJ steroids [4). and partly
lt is difficult to find suitable patients. The popu. Patients which requires oral steroid medication
~eh has the greateSt potential for dose-response
IS, .hy nature, a more severe group, where it is
ly dtfficult LO justify taking them off oral stemids
ftlllllftDl~:t~lu for trial pwposes.
WJIIl1l1LJu ll
• 2nd Aoor Thanal'llt Medical Building, Ptllmonary Function l.abol'lllOry, Pulmonary Dept. Pl'll·
mongkutklao l!oJpiul, Pmnongkutlclao Medical
CoUegc, Rajvll.hi Road, Bangkok, Tha.ibnd .
•• Astra Phannaceuticals IJ1temationaJ, Home P&rlc
Bsute, Kings l.angley, Heru WD4 SOH, UK.
Keywords: Asthma; budesonide; dose·tesponse;
irthaled; oral prednisolone.
Received: Mm:h, 19&8; accepted for publication
October tO, 1988.
The milder patients, on the other hand. are often put
on inhaled GCS as a prophylactic measure, so their scope
for symptomatic improvement is small. We were fortunate in having a group of patients who were generally
well-conlrolled on bronchodilators alone, but who ocea•
sionally required short eow·ses of oral steroid during
periods of exacerbation. They had not been taking regular inhaled GCS.
We have compared the anti-asthmatic efficacy of two
doses of budesonide with two do$es of oral prednisolone
commonly used in clinical practice, in the hope of
assessing their relative potencies in a con1rolled doubleblind fashion, wit!) minimal interference from prevjous
medication.
Patients and methods
Patients
Patients of holh sexes, aged 18-60 yrs. were recruited
from a population of chronic asthmatics. Their lung
function (forced cxpira1ory volume in one second (FEY,)
or peak expiratory flow rate, PEFR) was required 10 be
within 40-80% of lhe predicted value and !hey had 10
show a 15% reversibility during the steroid reversibility
test.
Patients who had used oral steroids on a regular basis
318
P. NAMSIR!KUL ET AL.
within the six months prior to the study were not included. Patients with poor inhaler technique were also
excluded from the study, as were those who experienced
ao exacerbation requiring oral steroids during week I or
week 3 of the run-In period.
releasing 200 ll& drug per actuation. Prcdnisoto
administered orally using 5 mg tablets. Placebo 110
and tablets were taken in conjunction with the
arc active drug to maintain the blindness of the
Withdrawal from the study
Design and drugs
Patients who suffered an exacerbation during the
trial period (i.e. weeks 4-18) were treated at the
tigmor's discretion until stable again and were
to re-enter the study where they loft j(. ttow!l.•vp_r
than one exacerbation occurred during any one
period in the main trial, patients were withdrawn
the study.
Patients were permitted to take oral oro,nciiOditdlli
(be~az-agonists and theophylline) and anti-allergic
as baseline therapy throughout the study but the
had to be consLant. Topical be~az-agonists were pc11rniae111
for use as required, but a record of all concom
was kept in case record forms and diary cards.
who took additional steroids other than for one OJtaCIIIIIIfl
bation in any treatment period, as described above,
withdrawn from the analysis.
The trial was performed as a randomized double-blind
crossover (DBXO) comparison of budesonide, administered by a Mislhaler*, with oral prednisolone, each drug
being tested at two different dose-levels. 1l1e randomization was restricted so that the two prednisolone periods
did not foUow each other, i.e. the two low-dose regimens
were randomizcd and given fi:rst. A washout period was
then allowed prior to administration of the two high-dose
regimens using a separate randomization (fig. t).
Following entry to the trinl, patients continued to use
their standard medication {beta-stimulants and thcophyllines) for one week, during- which Lime their lung function and symptoms were recorded In a diary card at home.
A steroid reversibility test was then carried outro ensure
that patients were steroid sensitive. They received prednisolone, 20 mg daily, for one week and this was followed
by a further week of standard therapy intended as a
washout period.
The patients shown to be steroid sensitive then entered
the main trial and received each of the following four
treatments for a period of 3 weeks, the total study duration being 18 weeks:
Clinical and laboratory assessments
Clinic visits. On admission to the study and at
up visits, patients were examined for signs and
toms of asthma. The following objective meastJI{eJJnenll
were made: pulse rate, respiratory rate, PEFR, FEV 1
forced vital capacity (FVC) before and after i nhalali~
of a beta1 agonist.
Patients were also asked about the quality of their steep,
their level of activity and symptoms of cough, wheeze
and rhonchi. Each of these parameters was measured on
a 0-3 scale as in the diary cards.
n
Trea.tments I and 11. Patients were treated in a randomized DBXO fashion with both budesonide 200 j..lg b.i.d.
and prednisolone 5 mg o.d.
Washout/stabilization period. AH patients were treated
with budesonide 200 j..lg b.i.d.
Home assessments. Patients were equipped with rnlnf.
Wright peak flow meters and diary cards. They wete
requested to record PEFR (3 measurements) and asthma
symptoms (on a scale 0-3, where O=none, l==mlld.
2=moderate and 3=severe) in the morning on rising and
Treatments Ill and IV. Patients were treated in a randomized DBXO fashion with both budesonide 400 ll&
b.i.d. and prednisolone lO mg o.d.
Budesonide was in~aled from a pressurized aerosol
VIsit No.
1
2
3
Treat
Week No.
0
No Steroida
20mg
Run-In
Prednisolone Washoul
1
Treat
3
6
9
Treat
Ill
Ill
Treat
Treat
IV
IV
Washout
11
11
Treat
X
Budesonlde
Treat
g
8
7
TrNI
X
Steroid
2
6
5
4
12
Fig. I. - Treatment schedule showing randomized crossover of inhaled hw.lcsonitle and oral prednisolone treatment periods.
15
18
I
319
OUDESONIDB COMPARED WITH ORAl. PREDNISOl-ONE
evening before retiring to bed (both before using
or bronchodilators). They were also asked to
ttmm•••uuilator consumption in the diary card and
to refrain, if possible, from the use of betaaerosols 3-4 h before their PEFR registration.
lone treatment period and one during the 10 mg prednisolone treatment period. As stipulated above, these
patient<~ were withdrawn from all analyses. Demographic
details of the remaining 28 patients {16 females and 12
males) are listed, along with their lung function at entry,
in table 1.
Table 1. - Demographic data for the 28 patients included
in the study
,.10~~-a1osc
budesonide washout period was inscned
two treatment crossovers to eliminate any
effects which either of the first two treatmight have had on the subsequent treatments.
inclusion of this washout period necessitated
of the data as two separate treatment crossovers,
for the two low doses and one for the two high
the Hru..s and ARMITAOE method (5] to look
or treatment interaction effects.
analyses made it impossible to assess whether
was a carry-over effect from one crossover to the
although presence or absence of session effects
the first crossover gave an indication of whether
had occurred.
card data (PEFR and symptoms) recorded durfirst seven days of each treatment period were
(leaving 2 weeks of analysable data). as were
relating to periods of extra oral steroid use or to
when trial medication was not taken correctly.
ing data for each treatment period (usually 2
but not less than 5 days), were meaned for each
The data from week 1 were also meaned (usually
but not less than 5 days) for use as a baseline.
usage, means were calculated for each palime intervals 6 arn-10 pm for day usage and
am for night usage.
analyses of diary data consisted of calculation of
and session/treatment interaction effects followed
of confidence intervals on changes from
analysis of variance (ANOVA) testing was peron raw data where possible. Where data were
changes from baseline were calculated for
testing.
function data obtained at clinic visits were anaas changes from visit No. 2 for confidence interand by a mixed-model ANOV A on data for each
expressed as % predicted. Percentage predicted
were used in preference to raw data in order to
inter-patient variation. Single ordinal values obfor each symptom at each clinic visit were summed
a total symptom score which was then analysed
U'Catmcnt effects using the Friedman ANOV A.
Results
demographic and lung function data on entry
A total of 30 patients were entered into the study, of
two required additional steroids on two separate
~tllli~:inn during a single treatment period. One patient
the exacerbations during the 5 mg prcdniso-
Parameter
Units
Mean (±so/range)
Age
Weight
Height
yrs
kg
cm
33 (17-60)
53.6±11.0
159.4±6.9
Duration of asthma
yrs
9.4 (0.7-30)
Lung function at entry:
PEFR
PEV 1
PVC
%predicted
%predicted
%predicted
64.3±18.2
52.7±18.1
70.8±16.6
PEFR: peak expiratory flow rate; FEV1 : forced expiratory
volume in one second; FVC: forced vital capcity; so: standard
deviation.
Diary card analyses
Data from the diary cards of 28 patients were available
for analysis although some symptoms were not recorded
by one of the patients.
a) Initial analyses. When the lwo crossovers were examined separately for session effects or scssion/treaUllent
interactions (as described in the methods), no significance was found within either crossover. This provides
indirect evidence that there was no ovenill session effect
during the study.
In view of these results, a mixed-model ANOVA, for
repeated measures on patients, was used to examine each
set of data for evidence of changes due to the treatments
given.
b) Analysis of PEFR. The mean values and 95% confidence limits for morning and evening PEFR during the
run-in and during each treatment period are presented in
table ~ . Values for both morning and evening PEFR
were higher, compared with run-in, for all treatment
sessions. Since none of the confidence limits included
zero, there is evidence of true improvement in PEFR on
all treatments.
As the data for PEFR was normally distributed, the
ANOV A was conducted on the raw data. The ANOV A
indicated that PEFR was significantly higher on highdose than low-dose treatments (p<O.OOl). TI1ere was also
a significant diurnal variation in PEFR values, i.e. morning PEFR was significantly lower than evening PEFR
(pd).Ol), (fig. 2).
fntcractions were also noted between dose and diurnal
variation and between dn1g and diurnal variation, viz
diurnal variation was significantly greater on low-dose
320
P. NAMSTRIKUL ET AL.
Table 2a. - Mean diary PEFR during run-in and each treatment period and confidence limits of
changes from run·in, n-28
Run-in
Bud 400 liS
Pred 5 mg
Bud 800 1-l&
312 (81)
375 (75)
63
43--83
361 (82)
49
27- 71
397 (82)
86
61-110
399 (71)
87
63- 112
332 (78)
388 (72)
56
37- 74
390 (74)
58
42- 74
408 (79)
75
53-98
417 (68)
Prcd 10 mg
AM PEFR
Mean (so)
6 from run-in
Confidence limits for 6
PM PEFR
Mean (so)
6 from run-in
Confidence limits for 6
84
62-107
AM PEFR, PM PEFR: peak expiratory flow rate, morning and evening, respectively; Bud: budesonide; Pred:
prednisolone; so: standard deviation; 6 : change.
of dose on each of the symptoms (p<O.Ol in all
viz the higher the dose the lower the symptoms, but
other significant effects (fig. 3).
Mean PEFR
{±sut) lmfn·•
420
T
I
;
400
rA rf
1
380
360
340
320
!~
l
)
J
r
J.
I
l.
I
1
0
I
300
290
1
budttonld• prtdnlao1on•
Run-in
400 llg
s mg
budt &Onldt prtdnlsolon •
800 110
10 mg
Fig. 2. - Mean diary card peak expiratory flow rate (PBFR) values
(±Sl!M). Open circles: AM (morning) I'EFR; closed circles: I'M
(evening) PEFR 11 run -in and during each treatment period. Differ-
ence between open and closed circle represents mean diurnal variation.
than high-dose treatment (p<O.Ol) and it was also significantly greater on prednisolone than on budesonide
(p<O.Ol).
c) Asthma symptoms. The mean values and 95% confidence limits for day wheeze, cough, activity and sleep
during the run-in and during each treatment period are
presented in table 2b. There was a true reduction in menn
treatment scores on all active treatments when compared
with the run-in period, as indicated by the confidence
intervals.
As the raw data exhibited more skewness than the
change from run-in data, the ANOVA's were perfonncd
on the changes. Each ANOV A showed a significant effect
d) Inhaler usage. Mean inhaler usage was
over twentyfour hour periods as well as separately
day-time (6 am- 10 pm) and night-time (10 pm-6
The means and 95% confidence limits are nr"-~"""....
table 2c. The mean total daily usage is reduced
each treatment compared with run-in. However
dence intervals indicate that this reduction was
true difference during both budesonide
high-dose prednisolone treatment, but not during
dose prednisolone treatment.
As the data were skewed (treatments reduced the
for additional bronchodilator in some patients much
than others). changes from run-in were calculated
to conducting an ANOV A. The only significant
which came out of the analysis was an interaction
tween drug and dose (p<0.05) viz the effect of
lone on inhaler usage was dose-dependent whilst that
budesonide was not.
When inhaler usage was examined separately for da1
and night, the pattern of usage was similar to that seen
for total usage. The results for day-time use showed I
true reduction in usage on all treatments except 5 tnl
prednisolone. Night-time usage was reduced only durhtJ
10 mg prednisolone treaunent. As night usage was vetY
low in any case, there was little scope for improve~~
here. When an ANOV A was conducted on the data. ~.~.~..
wns a significant effect of drug dose (p<0.05) and I
significant day vs night difference (p<0.05).
Clinic data analyses
Since no " session" or "carry-over" effects were observed with the diary card data, it was assumed that lhO
clinic visit data would not show such effects.
a) Lun8 function tests. Clinic lung function data (?E.~
FEV 1 and FVC) were expressed as% predicted value
321
BUDESONIDF. COMPARCO WITH ORAL PREDNISOLONE
Table 2b. - Mean diary symptoms during the run-in and each treatment period and confidence limits of
changes from run-in
Bud 400 ~g
Pred 5 mg
Bud 800 ~g
Pred lOmg
0.94 (0.56)
27
0.48 (0.45)
27
-0.46
-0.65 to -0.26
0.52 (0.48)
27
-0.42
-0.62 to -0.22
0.36 (0.41)
27
-0.57
-0.78 to -0.37
0.31 (0.41)
27
-0.62
-0.83 to -0.41
1.08 (0.49)
27
0.56 (0.45)
27
·0.52
-0.71 to -0.33
0.62 (0.56)
27
-0.46
-0.67 to -0.25
0.35 (0.48)
27
-0.74
-0.94 to -0.53
0.34 (0.46)
27
-0.74
-0.95 to -0.54
1.04 (0.73)
27
0.54 (0.59)
27
-0.50
-0.76 to -0.23
0.60 (0.58)
27
-0.44
-0.72 to -0.17
0.42 (0.53)
27
-0.62
-0.87 to 0.37
0.39 (0.46)
27
0.42 (0.50)
28
-0.62
-0.83 to -0.42
0.53 (0.59)
0.26 (0.43)
28
28
-0.52
-0.74 to -0.29
-0.79
-1.02 to -0.56
0.23 (0.44)
28
-0.81
-1.03 to -0.59
Run-in
n
4 from run-in
Confidence limits for 6
Cough
MCSS1 (so)
fl
t:. from run-in
Confidence limits for 6
Restriction
or activity
Me1111 (so)
n
A from run-in
Confidence limits for 4
-0.65
-0.93 to -0.38
Sleep disturbance
1.05 (0.62)
28
Mean (so)
n
A from run-in
Conudcnce limits for 6
See legend table 2a for abbreviations.
2.0
1.8
1.6
1.4
!!!
1.2
cns
1.0
~
0,8
8
C/)
Q>
0.8
0.4
0.2
0
Wheeze
Cough
Activity
Sleep
! .- Mean ~iary card symptom scores (maximum possible score=3) for symptoms of wheeu, cough, activity and sleep disturbance. @:run·
!Cl• budesonlde 400 jlg; IS): budesonide 800 j.lg; Q : prednisolone 5 mg;
prednisolone 10 mg.
o:
patient and then meaned over all patients in each
............""' period. Ninety five per cent confidence intercalculated (table 3) and as none of them
zero, it was concluded that there was a !rue
·~IIIOive,.,...,,.. in all lung function parameters following
treatment when compared with the end of the run-in
period.
The data were then analysed separately taking drug
and dose effects into account. Although improvement in
PEFR, FEY, and FVC was slightly greater following
322
P . NAMSIRIKUL ET AL .
Table 2c. - Mean total, day-time and night-time inhaler usage during run-in and each treatment period
and confidence limits of changes from run-in
-
Bud 400 J.18
Pred 5 mg
Bud 800 J.L&
Pred 10 mg
0.91 (1.6)
28
-1.69
-2.53 to -0.85
1.81 (2.6)
28
-0.79
-1.77 to +0.19
1.18 (2.0)
28
-1.42
-2.30 to -0.54
0.73 (1.2)
28
-1.88
-2.63 to -1.12
1.85 (1.4)
26
0.48 (0.83)
26
-1.38
-2.00 to -0.73
1.15 (1.9)
26
-0.71
-1.50 to +0.13
0.72 (0.98)
26
-1.13
-1.79 to -0.48
0.49 (0.88)
26
-1.36
-1.99 to -0.73
0.71 (0.79)
26
0.47 (0.91)
26
-0.24
-0.70 to +0.23
0.72 (0.92)
26
-0.01
-0.36 to +0.39
0.55 (1.51)
26
-0.16
-0.88 to +0.56
0.29 (0.43)
26
-0.42
-0.74 to -0.10
Run-in
Total (24 h) usage
Mean (so)
2.6 (1.9)
n
28
6 from run-in·
Confidence limits for 6
Day-time usage
Mean (so)
n
6 from run-in
Confidence limits for 6
Nlgbt· tlme uuge
Mean (so)
n
6 from run-in
Confidence limits for 6
See legend table 2a for abbreviations·.
Table 3. - Mean clinic lung function (% predicted) at run-in and at the end of each treatment period,
changes from run-in and confidence limits of changes from run-in and mean total symptom score, range
and median score
Run-in
Bud 400 J.LS
Pred 5 mg
Bud 800 J.Lg
Pred 10 mg
PEFR
Mean (so)
6 from run-in
Confidence limits for 6
69 (15)
84 (17)
15
9.3 to 21.5
83 (16)
16
7.7 to 20.6
86 (17)
14
10.5 to 22.9
88 (16)
19
12.5 to 25.8
57 (13)
73 (14)
16
9.5 to 22.9
73 (14)
16
10.4 to 22.0
75 (15)
18
11.4 to 25.5
74 (14)
17
10.5 to 24.4
75 (13)
88 (13)
13
7.3 to 18.9
89 (12)
14
10.3 to 18.4
89 (12)
14
7.8 to 19.3
90 (13)
15
9.1 to 20.4
5.4 (2.1)
2-9
1.9 (1.9)
0-7
2
1.9 (1.5)
0-5
2
1.6 (1.6)
0-6
1.3 (1.3)
0-5
FEVI
Mean (so)
6 from run-in
Confidence limits for 6
FVC
Mean (so)
6 from run-in
Confidence limits for 6
Total symptom score
Mean (so)
Range
Median
5
PEFR: peak expiratory flow rate; FEV 1: forced expiratory volume in one second; FVC: forced vital capacity; Bud:
budesonide; Pred: prednisolone; so: standard deviation; 6: chilllgc.
323
BUDESONIDE COMJ>A.RED WITII ORAL PREDNISOLONP.
Table 4. - Summary of side-effects (diary+clinic reports)
Side-effect
R
Tiredness
Palpitations
Tremor and palpital.ions
Fever and headache
Headache
Nausea
Cough
Sore throat
Rhinitis
Finger numbness
Constipation
Ches't pain
Heartburn
Anorexia
Dysuria
Skin rash
Oedema
l
1
2
Total
- - -- P20
2
1
1
2
2
2
1
1
1
1
2
l3
9
Wo
1
3
2
1
I
I
1
BL
PL
B200
2
2
2
1
I
1
2
BH
----
PH
3
2
3
2•
I*•
1
Throughout study
11
5
8
9
5
3
•: on placebo inhalation; ••: on drug inhalation; R: run-in; P20: 20 mg prednisolone o.d.;
PL: 5 mg prednisolone o.d.; PH: 10 mg prednisolone o .d.; Wo: washout; B200: 200 IJ.g
budesonide b.i.d.; BL: 200 J.lg budcsonidc b.i.d.; BH: 400 J.lg budesonidc b.i.d .
dose treatments than l ow-dose treatments, no
differences were found between dose-levels.
As described above, single symptom scores
for sleep, day wheeze, cough, rhon chi and
were summed to produce a tolaJ symptom score.
hoped Lhat such a score would more accuraLCiy
the patient's state of health than a single score
visit M ean and median total scores are presented
3. There was a clear trend towards lower scores
symptom-free patients during study treatment
with the end of run-in. There was aJso some
of a dose effect, with high doses producing
improvemenl than low doses.
ANOV A showed a significant difference
the tive sets of scores (p<O.OOl). The rank
improvement from the end of run-in was
!P~>lOru.~ I 0 mg>budesonide 800 j..lg>budesonide 400
5 mg. No significant differences were
........,t,n treatments, however, when the run-in data
~m1ow•.tt from the ANOV A. Thus, the pattern of
scores recorded at the clinic is consistent wilh
from the diary card data.
SUm~ary of symptoms/side-effects recorded at the
or ·~ the diary cards throughout the study, is
m Ulble 4. No serious adverse events were
and the greatest number of symptoms occurred
run-in period, followed closely by the washThus patients improved, if anything, during
periods. There was no obv ious dosc.
mcrcasc m symptoms during treatment with
either prednisolone or budcsonide. TI1is is perhaps not
surprising as most of Lhe symptoms recorded were unl ikel y to be side-effects of study medicmion.
Discussion
In this study we have been ublc to examine the rel ati ve
ami-asthmatic effects of inhaled budc..~onide and ornl
prednisolone at two dose-levels. The lower doses of each
drug were assessed in patients who hod been receiving
only bronchodllators and hence any long-tcnn prophylactic C.."UT)'·over effect from previous therapy wru:; eliminated. Our results dcmonst.nuc clearly that lung function
and symptoms were significantly i mproved from run-in
b)' all treatmentS. This was noted in both diary card and
clinic data and indicates that the patient population studied benefited from the addition of steroids to their existing therapy.
T he beneficial effect of oral and inhaled steroids on
PEFR during the swd y were also found lO be dosedependent, witJl: prednisolone 5 mg<prcdnisolone lO mg
nnd budcsonide 400 J..l&<budesonide 800 J..lS· These. doseclepcndent effects indicate Lhat the patients' asthma was
not to tall y reversed by the lower dose of each drug. As
full dose-response curves were not conducLCd for each
drug, it is only fe.1sibl c to compare each pair of trcatmcJH!i.
A difference between drugs was noted at the lower
dose- level -;, where morning PEFR was higher during
budcsonidc !lcauncnt t11:111 dwing predn i~olonc, and hence
diunwl variation was sismficantly lc..~s with budcsonide.
This trend was aLo;o visible wi th the high doses (fig. 2),
but was not significant. 11 is possible U1at differences
between the higher doses of U1c two drugs were masked
hccnusc n "cei ling" effect h:ul be~ n reached.
324
P. NAMSIRJKUL ET AL.
A dose of 5 mg oral prednisolone is commonly used
as a back-up therapy in adults not controlled by bronchodilator therapy alone, as this dos~ produces little, if
any, systemic side-effects [6]. Our study demonstrates,
however, that a daily dose of 400 J.l& budesonide (200 J.lg
b.i.d.) provides better control of lung function and
symptoms than 5 mg prednisolone and yet it has previously been demonstrated that 5 mg prednisolone is as
potent as 1.6 mg budesonide in reducing plasma cortisol
[ l].
Thus, for a given anti-asthmatic effect, the systemic
side-effects of prednisolone are several times greater
than those of inhaled budesonide. Although an oral dose
of 5 mg prednisolone does not produce serious sideeffects, doses of more more than 7.5 mg may be associated with unwanted side-effects [6]. It is preferable, therefore, to administer corticosteroid locally to the lung
provided that the patient does not have an acute asthma
att<lck, where mucosal oedema and .constriction of the
bronchi may hinder penetration of the drug into the
airways. The responsiveness of patients on maintenance
oral steroids to additional inhaled steroid has been
demonstrated by TUKIAINEN and LAHDENSUO (7), who
showed a dose-dependent improvement in lung function
and asthma symptoms when 400 J.lg·day· 1 and 1600
J.lg·day- 1 budesonide were compared in the presence of
maintenance oral steroids. Neither budesonide dose
produced a significant reduction in plasma cortisol levels. LAURSEN et al. (8], on the other hand, found that
patients who required large doses of oral steroid in
addition to conventional doses of inhaled steroid and
bronchodilators, could be weaned off oral steroids gradually, or at least have the dose reduced considerably by
adding extra inhaled steroid to their therapy. Some patients were weaned off oral steroids completely and all
patients benefited from the reduction in oral steroids with
respect to systemic side-effects. It is interesting to note
in our study that no patients experienced exacerbations
requiring additional steroids during inhaled steroid therapies. Thus, effective control of their symptoms was
achieved by this route of administration. Studies have
shown that twice daily inhalation of budesonide is as
good as four times daily inhalation (same total daily dose)
[9]. and that one puff containing 200 J.lg of budesonide
is more effective than four puffs each containing 50 J.lg
budesonide [10], probably as a result of improved compliance with the simpler dosage regimens.
In conclusion, we would recommend the use of
inhaled budesonide as the first additional treatment for
patients who are not adequately controlled by bronchodilators alone. In the majority of these patients,
400 J.lg·day- 1 budesonide will provide adequate control
of their symptoms with less systemic side-effects than
5 mg prednisolone and in those patients requiring 10 mg
or more prednisolone per day, control may be achieved
by increasing the dose of budesonide to 800 J.lg or 1.6
mg·day·1 with almost negligible systemic effects. Oral
steroids should be contemplated only after an adequate
trial of inhaled steroids or in situations like acute asthma
where inhalation is impaired.
Aelcnowudgnntnu: We wish to thank
for statistical an~lysis oC the study llJld Dr ~
Cor •ssutance wuh the manuscript.
Rererences
I. Johansson SA, Andersson KE. Brattsand R, Cruv
Hedner P. - Topical and systemic glucocorticoid po 1114
budesonide, beclomelhasone dipropionate and predni: : :
man. Eur J Respir Dis, 1982, 63 (Suppl. 122), 74-82.
2. LOfdahl CG, Mellstrand T. Svedmyr N. - Olucoc:v ·
and asthma. Studies of resistance and systemic errecc.
glucocort.icoids. Ew J Respir Dis, 1984, 65 (Suppl. 136). ~
3. Toogood JH, Baskerville J, Jennings B. - Anti-u
potencies (AAP) of inhaled budesonide (BUD) Ys dail:
prednisolone. Interasthma meeting, Mexico City, 1984, '!J
4. May CS, Caffm JA, Halliday JW, Bochner P. _
lone pharmacokinetics in asthmatic patients. Br J Dis C
1980, 74, 91-92.
5. Hills M, Annitage P. -The two-period cross-over cti
trial. Br J Clin Pharmacol, 1919, 8, 7-20.
6. Williams S.- Safety of inhaled and oral glucoco •
oids. In: Advances in lhe use of inhaled corticosteroids.
Micalcff, Lam, Too good eds, Exce1pta Medica. 1987, pp. 3
7. Tukiainen P, Lahdensuo A. - Effect of inhaled
onide on severe steroid-dependent asthma. Eur J Respif; D
1987, 70. 239-244.
8. Laursen LC. Taudorf E, Weeke B. - High-dose ln.b
budesonide in treatment of severe steroid-dependent as
Eur J Respir Dis, 1986, 68, 19-28.
9. Nyholm E, Frame MH, Cayton RM.- Therapeutic
tages of twice daily over four times daily inhalation of
onide in the treatment of chronic asthma. Eur J Respir D
1984, 65, 339-345.
10. Jorde W, Lazinik: H.- Clinical effects of a new inhal
steroid, budesonide. A comparison of three different ad
sttation regimes. Atemw-LU!tgenkrkh, 1983, 2. 63-66.
Comparaison enlre le budesonide par inhalalion et la pr
so/one par voie orale, adeux niveawc de dosages fdqu.tmll~~l
utilisb pour le traitemenl de l'asthme de gravite moy~ P
Namsirikul, S. Chaisupamongkollarp, N . Chantodisoi, P,
Bamberg.
RESUME: L'objectif de ceue ~tude est de comparer l'erticiCI.IIJ
anti-asthmatique de deux doses de budesonide en inhalatiall
avec deux doses de prednisolone orale utilis~es courammenl•
pratique clinique. Les patients e.tudies n'avaient pas r(!gulibl&->
mcnt de glucocorticostero"ides en inhalation, en sorte que l'ino.
terfcrcnce avec la medication prealable a ete minimale. L'~tudo
a ete conduite en double anonymat avec pcrmuUltion crois~ec
une periode de lavage entre !'etude comparative de 400 }!(de
budesonide avec 5 mg de prednisolone par jour et la deux!~
~tude, comparant 800 ~g de budesonide avce 10 m"g de prednisolone par jour. On a note une amelioration significative de la
fonction pulmonaire et des symptomes a partir du debut pour
tous les traitemcnts, cl pour les deux medicaments l'um6hotftion s'avcre dose-dependante. Quand on compare les u.~.uentdlll
a faible dose, le DEP moyen matinal est plus eleve au cours ~
lraitemcnt par budcsonide et, par voie de consequence. bvariation diume est significativemenl moindre que celle ~
111
servec au cours du traitement a la prednisolone. Aux dos~ ~
elevces, !'on n'a pas remarque de difference entre les rnedt~~
tions, mais ceci pourrait etre du au fait qu'un effet-plafond 1
alteim.
Eur Respir J., /989, 2. 317-324.