The Effect of Inhaled Fluticasone Propionate in
the Treatment of Young Asthmatic Children
A Dose Comparison Study
HANS BISGAARD, JOHN GILLIES, MARCELLE GROENEWALD, and CLAIRE MADEN
on behalf of an International Study Group
Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark; Hamilton, New Zealand; Pretoria, South Africa;and Glaxo Wellcome Research and Development, Greenford, United Kingdom
The response in asthmatic young children to inhaled steroids within the usual pediatric dose range is
unknown. We therefore evaluated the dose-related response in young children with moderate
asthma to inhaled fluticasone propionate (FP) (delivered via the Babyhaler spacer device) within the
pediatric dose range. A total of 237 children (mean age 28 mo, range 12 to 47) with moderate asth-
matic symptoms were studied in this multicenter, randomized, double-blind, parallel group, placebo-
controlled study of 12 wk treatment following a 4-wk run-in period. The median use of rescue medi-
cation was 1 dose in 2 d during the run-in period. FP 50
mg twice daily (FP100) and 100
mg twice daily
(FP200) was compared with placebo inhaled from a pressurized metered-dose inhaler (pMDI) and
the Babyhaler spacer device. With FP200 there was a statistically significant improvement from base-
line, as compared with the placebo group, in 8 of 10 diary card parameters, including the three symp-
tom domains of wheeze, cough, and breathlessness, and use of rescue medication. FP100 produced a
significant reduction in 5 of these 10 parameters, whereas no significant differences were found be-
tween the FP200 and FP100. The numbers of patients with at least one exacerbation during treat-
ment with placebo, FP100, and FP200 were 37%, 26%, and 20%, respectively. This difference be-
tween placebo and FP200, as well as the dose-related order was significant (p
, 0.05). Both FP doses
were as well tolerated as placebo over the 12 wk treatment with a similar incidence of adverse ef-
fects. Asthmatic symptoms in 1- to 3-yr-old children responded in a significant and dose-related man-
ner to treatment with FP within a pediatric dose range. Bisgaard H, Gillies J, Groenewald M,
Maden C on behalf of an International Study Group. The effect of inhaled fluticasone propi-
onate in the treatment of young asthmatic children: a dose comparison study.
AM J RESPIR CRIT CARE MED 1999;160:126–131.
Cough and wheezing are very common in children younger
not have reduced lung function as a predisposing factor, their
than 4 yr of age and are a major cause of illness and admis-
lung function is diminished by 6 yr of age. Diagnosis of asthma
sions to hospital. Up to 40% of all children are reported to
is ambiguous, and objective supportive evidence for the diag-
have wheezing disorders during the first 3 yr of life (1). Recent
nosis is missing. At present the diagnosis of asthma in young
longitudinal studies indicate that approximtely 60% of wheeze
children can only be delineated empirically, and carries no im-
occurring in the first 3 yr of life is transient and benign, and
plication for prognosis or underlying pathology.
may disappear by the age of 6 yr (2, 3). It is suggested that this
Children younger than 4 yr of age with wheeze or asthma
group of children have congenitally narrow airways, which
are a difficult population in which to conduct clinical studies
predisposes them to wheezing in association with viral infec-
because of the variable nature of the symptoms and the lim-
tions in early life (4). Most children who develop chronic
ited outcome measures. Since the first placebo-controlled
asthma in later childhood will have had their first symptoms
study of inhaled corticosteroid in young asthmatic children un-
during the first 3 yr of life (5). These infants have most of the
der 4 yr of age (6), a number of clinical trials with inhaled cor-
risk factors associated with asthma (high serum IgE levels,
ticosteroids have been performed in these age groups. Effi-
positive skin test reactivity to allergens, bronchial hyperre-
cacy of inhaled corticosteroids has been documented in
sponsiveness, family history of asthma) and, although they do
asthmatic children younger than 4 yr of age with moderate tosevere persistent asthma symptoms (6–8). Sodium cromogly-cate was recently reported to be ineffective in a large parallel
(Received in original form November 5, 1998 and in revised form January 25, 1999
study of 167 young children with moderate persistent asth-
Sponsored by Glaxo Wellcome.
matic symptoms, very similar to the present design (9). In the
Correspondence and requests for reprints should be addressed to Hans Bisgaard,
case of episodic viral wheeze in preschool children, modest
Professor of Paediatrics, Dept. of Paediatrics, Rigshospitalet, Copenhagen Univer-
improvements have been shown with intermittent high-dose
sity Hospital, DK-2100 Copenhagen, Denmark. E-mail: Bisgaard@RH.DK
Am J Respir Crit Care Med
Vol 160. pp 126–131, 1999
inhaled corticosteroids (10, 11), but continuous prophylactic
Internet address: www.atsjournals.org
treatment showed no effect (12).
Bisgaard, Gillies, Groenewald, et al.
: Fluticasone Propionate in Young Asthmatic Children
Daily doses of 800 mg budesonide from a pressurized me-
the study. A parent or guardian of every patient provided written in-
tered dose inhaler (pMDI) and spacer or 2,000 mg from a neb-
ulizer were used in the studies documenting the effect of in-
Assessments were performed in the clinic at the beginning and end
haled corticosteroids in asthmatics younger than 4 yr of age.
of the placebo run-in period and thereafter every 3 wk for a totaltreatment period of 12 wk. At the first clinic visit, demographic details
The high doses used in the treatment of persistent young asth-
and a full clinical history were recorded, and a physical examination
matics were justified in such pioneering studies aiming to es-
was performed. On randomization, pulmonary auscultation was con-
tablish a new treatment modality, but should not be used as
ducted, and parents were given a questionnaire about the child's
guideline for the dose range required to control asthma in
asthma symptoms, the impact of the child's asthma symptoms on the
parents' activities in and around the house, leisure activities, work ac-
No formal dose response studies of inhaled steroids have
tivities, the need for alternative childcare arrangements, and the over-
been performed in preschool children, so the optimal dose in
all control of asthmatic symptoms. This questionnaire was repeated at
these age groups is not known. In the present study we have
the end of treatment. At every clinic visit throughout the study, ad-
sought to elucidate the dose response to inhaled corticoster-
verse events, asthma exacerbations, and compliance with the study
oids within a pediatric dose range for the treatment of young
protocol, including inhalation technique, were checked and the oro-pharynx was examined, with a swab taken if there was visual evidence
children with asthmatic symptoms. We have compared the ef-
of fungal infection, to determine the presence of candida.
fect of fluticasone propionate (FP) (Glaxo Wellcome, UK) in-
Throughout the study, parents kept daily record cards of their
haled from a Babyhaler spacer device (Glaxo Wellcome, UK)
child's symptoms, recording daytime and nighttime scores for wheeze,
in a daily dose of 100 mg (FP100) with that of 200 mg (FP200)
cough, and shortness of breath on a scale of 0 to 3. Parents were asked
and with placebo in parallel groups of young children age 1 to
to record the number of occasions during the night that they were
3 yr with a history of moderate asthmatic symptoms.
awoken because of the child's asthma symptoms. The number of occa-sions on which rescue salbutamol was used to relieve asthma symp-toms during each day and night was also recorded.
Exacerbation of asthma was defined as a worsening of the child's
asthmatic symptoms that required either a change in medication
Pediatric outpatients age 12 to 47 mo with a documented history of re-
(other than relief salbutamol) and/or required the parents to contact
current wheeze or asthma symptoms were recruited for the study. Pa-
their general practitioner or the investigator. Treatment of the exacer-
tients were randomized to the study if, on at least 7 d out of the last 14
bation was at the discretion of the investigator, and could include a
d of the run-in period, they had any asthmatic symptoms, as recorded
short course of inhaled or oral corticosteroids if needed. Patients were
in three symptom domains (wheeze, cough, and shortness of breath)
withdrawn from the study if more than one exacerbation occurred
for daytime and nighttime separately, or had required relief salbuta-
that required extra oral or inhaled corticosteroids, or if symptoms be-
mol. Patients were excluded if, in the 2 wk before entering the run-in
came unacceptable or poorly controlled despite backup medication.
period, they received inhaled or systemic corticosteroids or methyl-
All analyses were performed on the intention-to-treat population,
xanthine therapy, had been hospitalized for asthma, had any changes
which consisted of all randomized patients who took at least one dose
in asthma medication, or if they had received antibiotics for a chest in-
of study medication. The primary measures of efficacy were the per-
fection. Patients were also excluded if, after practicing inhalation tech-
centages of cough-free and wheeze-free days, derived from the daily
nique during the run-in period, they were unable to use the Babyhaler
diary card data, over treatment wk 1 to 12. Secondary measures of ef-
ficacy included percentage of nights without cough or wheeze, per-
This was a randomized, double blind, placebo-controlled parallel
centage of days/nights without relief salbutamol medication, percent-
group study, with patients recruited from 33 centers in nine countries
age of overall symptom-free days and nights, and percentage of nights
(as listed in the ACKNOWLEDGMENT). Patients who fulfilled the inclu-
without parental sleep disturbance, as well as the incidence of exacer-
sion and exclusion criteria entered a 4-wk run-in period, during which
bations and data from the parental questionnaires. All daily diary
they received two puffs twice daily of placebo from a pMDI, via the
card variables were analyzed as change from baseline. Baseline was
Babyhaler spacer, and salbutamol as required to relieve symptoms. At
taken as the last 2 wk of the run-in period, which was also the period
the end of the run-in period, patients who fulfilled the eligibility crite-
evaluated before randomization to determine if the child was eligible
ria were randomly assigned to receive either two puffs of FP 25 mg twice
for the study.
daily (total daily dose of 100 mg [FP100]), or two puffs of FP 50 mg
A nonparametric method (the Van Elteren extension to the Wil-
twice daily (total daily dose of 200 mg [FP200]), or two puffs of placebo
coxon rank sum test) was used for each variable to assess pairwise dif-
twice daily via identical CFC-formulated pMDIs delivered through a
ferences between the treatment groups over the treatment period.
Babyhaler spacer device. Parents were taught to actuate the trial in-
Mann-Whitney rank sum test was used to compare exacerbation rates
haler once the spacer was in position, with the face mask over the
in the three treatment groups. Kaplan-Meier estimates of survival
child's nose and mouth, and then to allow at least five tidal breaths (or
times were used to compare times to first exacerbation. Treatment
15 s) for inhalation. This procedure was then repeated for the second
differences were assessed using two-sided significance tests, based at
puff. No instructions were given on priming of the Babyhaler before
the 5% level of significance. The sample size for this study was based
use, although during use, parents were instructed to wash it once a
on the nonparametric analysis of the percentage of asthma symptom-
week in mild soapy water, followed by rinsing and leaving it to dry.
free days during treatment. Based on a standard deviation of 29%
Patient compliance was carefully checked at the clinic visits every 3 wk,
(shown in a previous pilot study), it was calculated that 70 children
though not quantitated.
per treatment group were needed to detect a treatment difference of
Salbutamol was used throughout the study as relief medication in a
15% between groups, with 80% power at the 5% level of significance.
formulation appropriate to each child: either inhaled from a pMDI(100 mg salbutamol per actuation) via the Babyhaler; or as dry powder
(200 mg salbutamol per blister) inhaled using a Diskhaler; or nebu-lized using Ventolin Nebules (2.5 mg/2.5 ml salbutamol); or orally as
A total of 314 patients were recruited to the study of which
Ventolin Syrup (2.0 mg/5 ml salbutamol). Patients continued with any
237 were randomized to treatment and comprised the inten-
regular medication, including sodium cromoglycate, ketotifen, and an-
tion-to-treat population (Figure 1). The majority of the 77
tihistamines, for asthma or other conditions providing the dose re-
patients withdrawn prior to randomization were withdrawn
mained constant. Inhaled or systemic corticosteroids, anticholinergic
because they had insufficient asthma symptoms, others for
agents, nedocromil sodium, b2-agonists (other than salbutamol sup-
reason of asthma exacerbations. Thirty-seven randomized
plied for rescue medication), and methylxanthine derivatives were notpermitted, unless for treatment of an exacerbation. Regulatory ap-
children violated the protocol, equally distributed among
proval was obtained in those countries where it was required, and eth-
treatment groups (12 placebo, 12 FP100, 13 FP200). Reasons
ics committee approval was obtained for each site before the start of
for classification as a protocol violator included age violation
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
(four patients), insufficient symptoms or insufficient salbuta-
mol usage during run-in (18 patients), respiratory tract infec-
tions requiring antibiotics, asthma medication changes or hos-pitalization during run-in (four patients), failing to have diary
card data from at least 50% of the treatment period (11 pa-
tients), and taking disallowed concurrent medications during
the treatment period (four patients). Two patients were with-
drawn during the study by the investigator for reason of non-
compliance. However, the analysis was done on the intention-
to-treat group of children including all protocol violators.
Family history of asthma
The mean age across all three groups was 28 mo (range 12
History of eczema
to 47 mo). Pretreatment characteristics (Table 1), including
Exacerbation upon exercise
weight, height, asthma history, current medical condition, and
Never hospitalized for
current medications, were all generally comparable among the
No excerbations in the last year
groups. The study group of children appeared to have moder-
Use of one or more asthma
ately severe recurrent asthmatic symptoms. During the run-in
medications in the month
period, the children had symptoms on a median of 81% of
prior to randomization
days, and salbutamol was used on a median of 48% of days.
*Values are mean 6 SD.
Forty-six percent had had 1 to 3 exacerbations, and 38% morethan 3 exacerbations during the previous year. Sixty-eight per-cent had not been hospitalized for asthma-related symptoms,
Figure 2 illustrates the median differences in the changes
17% only once, and 15% more than once during the previous
from baseline, and the 95% confidence limits (CL), between
year. Fifty-three percent of the study group had had asthmatic
active and placebo treatments for the various diary card pa-
symptoms for more than 12 mo. A total of 57 patients (24%)
rameters. FP200 produced a significant reduction in 8 of 10 di-
were receiving sodium cromoglycate on entry to the study and18 patients (7%) were receiving ketotifen, and these patientsall continued on these medications during the treatment pe-riod. Over all patients, current asthma control on entry intothe study was rated as 7 by the parents on a scale from 1(poorly controlled) to 10 (well controlled). The groups dif-fered at baseline. The percentages of days with no cough dur-ing the run-in period were 41%, 31%, and 29% in the placebo,FP100, and FP200 groups, respectively. The correspondingpercentages of days with no symptoms of any type were 21%,14%, and 7%. The placebo group used salbutamol on 43% ofthe days, whereas the FP200 group used salbutamol on 64% ofthe days during run-in. A similar trend was consistent through-out the secondary efficacy variables, and indicated that theplacebo group had fewer and milder symptoms at baseline.
Changes from baseline. Differences between the FP
group and the placebo group. Median (95% CL). Eight of 10 diary
card parameters showed significant improvement from FP200
compared with placebo, and 5 of 10 showed significant improve-
Patient flow through the study.
ment from FP100 compared with placebo.
Bisgaard, Gillies, Groenewald, et al.
: Fluticasone Propionate in Young Asthmatic Children
Percentage of symptom-free days (median change from baseline).
ary card parameters compared with placebo, whereas FP100
significant differences between the FP100 group and placebo
produced a significant reduction in 5 of 10 parameters com-
or between the two FP groups.
pared with placebo. No significant differences were found be-
The parents rated the current asthma symptoms on a scale
tween FP200 and FP100. The treatment effect was most
control from 1 (poorly controlled) to 10 (well controlled). In
clearly revealed by reduction in cough and use of salbutamol.
all three treatment groups, the median score on entrance into
Wheeze and shortness of breath also exhibited significant im-
the study was 7 and improvements were seen in all three treat-
provement in the actively treated children compared with pla-
ment groups at completion of the treatment, with a median
cebo treatment, although the numbers of patients recording
score of 9. In the placebo group there was a 12% increase in
these particular symptoms at baseline were relatively low. The
the number of parents reporting current asthma symptoms as
development in symptom-free days is illustrated in Figure 3.
"well controlled," with 18% and 22% increase in the FP100
The number of patients with at least one exacerbation dur-
and FP200, groups, respectively. However, there were no sta-
ing the treatment period was found to be significantly lower in
tistically significant differences (placebo versus FP200, p 5
the FP200 treatment group (15 of 76 patients; 20%) compared
0.06). Impact on parents' activities in and around the house,
with the placebo group (30 of 82 patients; 37%), p 5 0.03, 95%
leisure activities, work activities, the need for alternative
CL for the difference 2 to 32% (Figure 4). Using Kaplan-Meier
childcare arrangements, and the overall control of asthma
estimates of survival times, there was a significant difference
symptoms consistently showed trends of increased improve-
in the distribution of times to first exacerbation between the
ment in the active treatment groups, but there were no statisti-
FP200 group and the placebo group (p 5 0.022), indicating a
cally significant differences.
smaller likelihood of exacerbation in the FP200 group.
A total of 68 patients treated with placebo, 63 patients
The number of children in the FP100 group who experi-
treated with FP100, and 64 patients treated with FP200 re-
enced exacerbations (21 of 80 patients; 26%) was also lower
ported adverse events during treatment. The adverse event
than in the placebo-treated group. The dose-related effect on
profile did not differ markedly among the three treatment
exacerbation rate was significant (p , 0.05). This difference in
groups. Asthma was the most commonly reported adverse
exacerbation rate became apparent early during the study,
event, being reported by 21 patients (26%), 18 patients (23%),
with 10 (12%) of the placebo patients exacerbating during the
and 13 patients (17%) in the placebo, FP100, and FP200 treat-
first 2 wk of treatment compared with 7 (9%) in the FP100group and 3 (4%) in the FP200 group. Rescue treatment withcorticosteroids was required in 16% of the patients in the pla-cebo group compared with 5% in the FP100 group, and 5% inthe FP200 group, and these differences were statistically sig-nificant. (FP200 versus placebo: p 5 0.039; FP100 versus pla-cebo: p 5 0.038).
The number of patient withdrawals did not differ signifi-
cantly among the three treatment groups, with 8, 7, and 10withdrawals from the treatment groups of placebo, FP100, andFP200 respectively (Figure 1). On randomization into thestudy, parents were asked to rate their child's asthma symp-toms as either "much better," somewhat better," "about thesame," "somewhat worse," or "much worse" than 3 mo ago.
The findings revealed a median score of "somewhat better"compared with 3 mo ago. Asked the same question at the endof the 12-wk treatment period, there was a 20%, 43%, and37% increase in the rating of asthma as "much better" in theplacebo, FP100, and FP200 groups, respectively. The scoresfor the parental rating of symptom control were statisticallysignificantly more favorable for the FP200 group comparedwith the placebo group (p 5 0.03). There were no statistically
Exacerbation rate. Dose relation is significant, p , 0.05.
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
ment groups, respectively. Fever and upper respiratory tract
present unable to predict who will respond to treatment. The
infections were also commonly reported.
clinical implication of the present data is therefore that chil-
Of the events considered predictable, skin rashes were re-
dren with moderate asthmatic symptoms may respond to
ported in two patients (2%) on placebo, two (3%) on FP100,
treatment with inhaled FP 100 mg twice daily. A therapeutic
and four (5%) on FP200. Throat irritation was reported in two
trial of 1 to 2 mo may be a feasible approach to help determine
patients (2%) on placebo, two (3%) on FP100, and four (5%)
the optimal treatment of the individual child. Scheduled fol-
on FP200. Hoarseness/dysphonia was reported in only two pa-
low-up visits should ascertain if control is obtained. If convinc-
tients, both on FP100, and candidiasis of the mouth/throat was
ing control is not obtained, treatment should obviously not be
reported as an adverse event in only one patient, who was re-
maintained. If control of symptoms does occur, withdrawal or
dose reduction should be attempted to ascertain the continued
Visual evidence of oral candida was observed during the
need for treatment at the minimal dose level. This would en-
treatment period in 6% of children on placebo, 10% of chil-
sure that treatment with inhaled corticosteroids is only pro-
dren on FP100, and 4% of children on FP200. Fourteen pa-
vided to those deriving benefit. Further, a determined attempt
tients experienced serious adverse events during the treatment
to down-titrate the dose toward no treatment or to the mini-
period, seven (9%) receiving placebo, two (3%) receiving
mal effective dose assures that no child is kept on inhaled cor-
FP100, and five (7%) receiving FP200. The most common seri-
ticosteroids longer than needed. A similar approach is re-
ous adverse event was asthma reported in four patients (5%)
flected in the recent guidelines from the British Thoracic
in placebo, two (3%) on FP100, and two (3%) on FP200. Of
the three serious adverse events on FP200 not related to
In the present study, FP200 was as well tolerated as placebo
asthma, one was a case of gastritis, one presented with fever,
and no unexpected side effects became apparent over this 12-wk
and one had diarrhea.
observation period. A knemometry study in 1 to 3-yr-old tod-dlers has demonstrated systemic activity with inhaled FP 400 mg
daily (twice the daily dosage of the present study) as well asfrom inhaled budesonide 400 mg daily (14). Budesonide was
Toddlers 1 to 3 yr of age with moderate asthmatic symptoms
without systemic activity in a daily dose of 200 mg in a previous
improved significantly from 12 wk treatment with FP 100 mg
knemometry study (15), but clinical efficacy at such a dose of
twice daily inhaled from the Babyhaler spacer device. A clini-
budesonide remains to be documented. The present study
cal effect became apparent within 2 wk of starting treatment,
documents clinical efficacy from 200 mg daily dose of FP, but
as indicated by differences in exacerbation rate and days with-
lack of systemic activity at this dose remains to be docu-
out symptoms. The treatment was dose-related and well toler-
mented. The use of inhaled corticosteroids in young children
ated in the usual pediatric dose range of 100 to 200 mg daily
should be restricted to experienced doctors until more evi-
dence of the safety of this treatment is obtained.
The present study group comprised young children of 1 to 3 yr
Dedicated spacer devices for drug delivery to young chil-
of age with a documented history of recurrent wheeze and
dren have recently become available, and have facilitated the
other asthma symptoms. Because there is no consensus on the
treatment of this poorly compliant patient group (16). This
definition of asthma in young children, there is no recognized
study confirmed spacer with pMDI as a convenient device
grading of the disease severity either. If the grading of inten-
able to deliver a clinically efficacious dose of aerosol to young
sity of symptoms and use of rescue medication in schoolchil-
dren is applied, these children had moderate asthma. During
In conclusion, this study showed a significant clinical effect
the run-in period, rescue salbutamol medication was used on
from both FP200 and FP100 delivered via the Babyhaler
approximately 1 of 2 d, and the children were symptomatic on
spacer device in the treatment of asthmatic symptoms in 1- to
4 of 5 d. The history attested to the persistence of symptoms with,
3-yr-old children, with a dose-related effect and with FP200 as
on average, 3 exacerbations during the previous year and one-
the most effective dose. Symptom control was obtained in some
third of the children having been hospitalized for this reason.
children even in the low dose, and the dose-related response
FP200 resulted in significant improvement in 8 of 10 diary
indicates that dose requirement should be titrated individu-
card parameters, including all three symptom domains of
ally. These findings support the option of inhaled corticoste-
cough, wheeze, shortness of breath, and in the use of salbuta-
roid treatment for asthmatic symptoms in young children.
mol and parental sleep disturbance. FP100 produced signifi-
Thanks are due to the following physicians who partici-
cant improvement in 5 of the 10 diary card parameters. A sig-
pated in and randomized patients into this study: Belgium
: Dr. A. Malfroot,
nificant dose-related effect was observed in the number of
Dr. H. Van Bever, Dr. C. de Boeck. Canada
: Dr. S. Feanny, Dr. M. Gold, Dr.
exacerbations, which is a key outcome measure. It cannot be
S. Lavi, Dr. M. Montgomery, Dr. B. Lyttle, Dr. D. Berube. Denmark
: Dr. H.
known if higher doses would lead to further improvement.
Bisgaard, Dr. K. Ibsen. Ireland
: Dr. D. Lillis, Dr. M. Taylor, Dr. P. Greally.
Disease control, evaluated from percentage of days and
: Dr. J. Gillies, Dr. J. Brown. Poland
: Prof. D. Chmielewska, Prof.
R. Kurzawa, Prof. J. Alkiewicz. South Africa
: Dr. C. Bester, Dr. D. Luyt, Dr. A.
nights with no symptoms, was significantly higher in the FP200
I. Manjra, Dr. M. Groenewald. Spain
: Dr. G. Ferres, Dr. A. Escribano, Dr. M.
treatment group than in the placebo group (median difference
Navarro, Dr. J. Botey, Dr. E. Gonzalez Perez-Yarza. United Kingom
: Dr. J. Ca-
in change from baseline 5 11%). The incidence of exacerba-
ter, Prof. A. Milner, Dr. A. Speight, Dr. D. A. Spencer. Thanks are also due
tions was 37% in the placebo group compared with 20% in the
to Lisa Williams (Glaxo Wellcome) for the statistical analysis, and to MartinPrice (Glaxo Wellcome) for the evaluation of the parent questionnaire data.
FP200 group. These results confirm the concept that inhaledcorticosteroids within a pediatric dose range are efficacious inyoung children with moderate persistent asthmatic symptoms.
However, in clinical practice an improvement of this magni-tude may be insufficient to warrant continued treatment of the
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Toxicité à long terme d'un herbicide Roundup et d'un maïs modifié génétiquement pour tolérer le Roundup Gilles-Eric Séralini*, Emilie Clair, Robin Mesnage, Steeve Gress, Nicolas Defarge, Manuela Malatesta, Didier Hennequin, Joël Spiroux de Vendômois *Correspondance à Traduit en français par les auteurs. Résumé : Nous avons étudié pendant 2 ans sur des rats les effets sanitaires d'un maïs transgénique tolérant à l'herbicide Roundup (introduit dans l'alimentation à 3 doses de 11, 22 et 33%), cultivé avec ou sans épandage de cet herbicide, ou bien de Roundup seul dans l'eau de boisson (à partir de 0,1 parties par milliard). Les femelles, dans tous les groupes traités, sont mortes 2 à 3 fois plus que dans le groupe-témoin, et plus rapidement. Cette différence a été observée dans 3 groupes de mâles nourris avec l'OGM. Tous les résultats obtenus sont hormono-dépendants et liés au sexe,, avec des profils pathologiques comparables dans presque tous les cas. Les femelles ont développé plus fréquemment de grosses tumeurs mammaires et avant le groupe témoin, l'hypophyse étant le second organe le plus touché ; l'équilibre hormonal a été modifié par les traitements à base d'OGM et de Roundup. Chez les mâles traités, les nécroses et congestions du foie étaient de 2,5 à 5,5 fois plus élevées. Cette pathologie a été confirmée macroscopiquement, et en microscopie optique et électronique. Les néphropathies rénales progressives chroniques marquées et sévères étaient généralement de 1,3 à 2,3 plus élevées. Les mâles présentaient jusqu'à 4 fois plus de grosses tumeurs palpables, qui apparaissaient jusqu'à 600 jours plus tôt que le groupe témoin. Les données biochimiques ont confirmé des déficiences chroniques significatives des reins ; pour tous les traitements et les deux sexes, 76% des altérations des paramètres physiologiques étaient liés aux reins. Ces résultats peuvent s'expliquer par les perturbations endocriniennes non linéaires (non proportionnelles à la dose) causées par le Roundup, ainsi que par la surexpression du transgène dans l'OGM, et ses conséquences métaboliques.