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AIR Research
Pulm Pharmacol Ther 2003 Feb;16(1):53-59
Health-related quality
of life in asthma studies. Can we combine data from
different countries?
Stahl E, Postma DS, Juniper EF, Svensson K, Mear I, Lofdahl C.
Department of Respiratory Medicine, University Hospital, Lund, Sweden
The aim was to compare
health-related quality of life (HRQL) in patients with
asthma from 4 countries, and to investigate the correlations between HRQL
and
clinical indices.341 patients; 140 (Sweden), 54 (Norway), 65 (the Netherlands)
and 82 (Greece) were treated with formoterol fumarate 4.5&mgr;g or with
terbutaline sulphate 0.5mg for 12 weeks inhaled 'on demand' via Turbuhaler((R)).
The Asthma Quality of Life Questionnaire (AQLQ) and clinical indices were
assessed.The mean baseline AQLQ overall scores in Sweden (4.97), in the
Netherlands (5.04), in Norway (4.68) and in Greece (4.68) were in the same
range, however, with a significant difference between the four countries
(p=0.038). When comparing AQLQ, activity limitation and symptoms domains,
the
differences between the countries were not statistically significant. The
cross-sectional correlations between AQLQ overall score and the clinical indices
were similar in all four countries.The magnitude of change in AQLQ was
consistent with the other clinical variables. The correlations between change
in
AQLQ overall score and change in clinical indices were low to medium in all
countries.In conclusion, the consistency of cross-sectional correlations between
the AQLQ overall and clinical indices across countries supports the validity
of
translations of the AQLQ used in this study. There were differences in baseline
values between the countries. The treatment response in AQLQ differed to the
same extent as other clinical indices. When combining HRQL data from different
countries, there might be cultural, gender and socio-economic differences,
explaining different responses to treatment.
Electrophoresis 2003 Jan;24(1-2):276-85
Activation of platelet-derived
growth factor pathway in human asthmatic
pulmonary-derived mesenchymal cells.
Malmstrom J, Tufvesson
E, Lofdahl CG, Hansson L, Marko-Varga G,
Westergren-Thorsson G.
Department of Cell & Molecular Biology, BMCC13, Lund University.
Cell cultures of mesenchymal
type were obtained from biopsies taken after
bronchoscopy from patients with asthma. It was possible to achieve outgrowth
of
fibroblast-like cells from these lung biopsies, which stained for alpha-smooth
actin indicating that they were of myofibroblast type. Morphologically, two
types of myofibroblasts could be observed: one intermediate form with more
stretched cell shape and lamellipodia protrusions, and one more differentiated
compact form of myofibroblast. The intermediate form was the most dominant
type
in these patients, indicating an active ongoing remodelling process. Further
studies showed that platelet-derived growth factor (PDGF) might be the factor
that stimulates the formation of the intermediate type of myofibroblasts,
since
it enhance migration of normal human lung fibroblasts 4-fold compared to control
through an induced formation of stress fibers and lamellipodia protrusions.
Additionally, intracellular signalling pathways involved in migration, such
as
RhoA and MAPkinase were stimulated 1.5-fold and 3.5-fold, respectively. By
using
two-dimensional (2-D) gel electrophoresis and protein identification by peptide
mass finger printing matrix assisted laser desporption/ionization - time of
flight - massspectrometry (MALDI-TOF-MS) it was possible to confirm that PDGF
affected the synthesis of proteins involved in the remodelling process, such
as
collagen VI and post-translational forms thereof. PDGF also stimulated the
production of FK506 binding protein of 65 kDa, a protein involved in smooth
muscle differentiaition, and proteins involved in the rearrangement of the
cytoskeleton connected to migration such as the actin related protein ARP3,
the
T-complex protein and the heat shock protein 60. We demonstrate that PDGF
has a
potential pathological role in asthma and formation of subepithelial fibrosis
by
inducing changes in the proteome.
Respir Med 2003 Mar;97 Suppl C:S1-2
The economic impact
of COPD in North America and Europe. Analysis of the
Confronting COPD survey. Introduction.
Dahl R, Lofdahl CG.
Department of Respiratory Diseases, Aarhus University Hospital, Denmark.
Thorax 2003 Mar;58(3):217-21
Bronchodilation by
an inhaled VPAC(2) receptor agonist in patients with stable
asthma.
Linden A, Hansson
L, Andersson A, Palmqvist M, Arvidsson P, Lofdahl CG, Larsson
P, Lotvall J.
Department of Respiratory
Medicine and Allergology, Goteborg University,
Guldhedsgatan 10A, S-413 46 Goteborg, Sweden. anders.linden@lungall.gu.se
BACKGROUND: The synthetic
vasoactive intestinal peptide (VIP) analogue Ro
25-1553 is a selective VIP-PACAP type 2 (VPAC(2)) receptor agonist that causes
a
bronchodilatory effect in guinea pigs in vivo. The effect of Ro 25-1553 given
by
inhalation to patients with asthma was studied and compared with that of a
long
acting beta(2) adrenoceptor agonist. METHODS: Twenty four patients with moderate
stable asthma participated in a double blind, randomised, placebo controlled,
crossover study. The primary variable was bronchodilatory effect (increase
in
forced expiratory volume in 1 second, FEV(1)) after inhalation of Ro 25-1553
(100 microg or 600 microg) and formoterol (4.5 microg), respectively. Putative
side effects were characterised by monitoring sitting blood pressure, serum
potassium, electrocardiography and echocardiography. RESULTS: Inhalation of
600
microg Ro 25-1553 caused a rapid bronchodilatory effect (geometric mean increase
in FEV(1) compared with placebo) within 3 minutes of 6% (95% CI 4 to 9), as
did
inhalation of formoterol (8% (95% CI 5 to 10)). The corresponding maximum
bronchodilatory effect during 24 hours was similar for 600 microg Ro 25-1553
(7%
(95% CI 4 to 10)) and the reference bronchodilator formoterol (10% (95% CI
7 to
12)). However, for both doses of Ro 25-1553 the bronchodilatory effect was
attenuated 5 hours after inhalation whereas formoterol still had a
bronchodilatory effect 12 hours after inhalation. Neither Ro 25-1553 nor
formoterol produced any clinically relevant side effects. No drug related
difference in adverse events was observed. CONCLUSION: Inhalation of a synthetic
selective VPAC(2) receptor agonist constitutes a promising approach for
bronchodilation in patients with asthma.
Publication Types:
Clinical Trial
Randomized Controlled Trial
Thorax 2003 Feb;58(2):135-42
Relationship between
inflammatory cells and structural changes in the lungs of
asymptomatic and never smokers: a biopsy study.
Amin K, Ekberg-Jansson A, Lofdahl CG, Venge P.
Department of Medical
Sciences, Clinical Chemistry, University of Uppsala,
Uppsala, Sweden. kawa.amin@medsci.uu.se
BACKGROUND: A study
was undertaken to investigate the relationship between
inflammatory cells and structural changes in the mucosa of the airways in
an
epidemiological sample of a group of asymptomatic smokers (smokers who had
never
sought medical attention for respiratory problems) and in non-smoking subjects.
METHODS: Bronchial biopsy specimens were taken from 29 smokers and 16 never
smokers and stained with monoclonal antibodies HNL, EPO, AA1, CD68 in order
to
identify neutrophils, eosinophils, mast cells, and macrophages, respectively.
The biopsy specimens were also stained with monoclonal antibodies to the
cytokines interleukin (IL)-1beta and IL-8. Structural changes were identified
by
staining the biopsy specimens with antibodies to tenascin and laminin and
by
evaluating the condition of the epithelial layer. RESULTS: The numbers of
all
inflammatory cells and of cytokine staining cells were significantly increased
in smokers. The thickness of the tenascin and laminin layers was increased
in
the smoking group and the integrity of the epithelial layer was significantly
reduced. In smokers the epithelial integrity was negatively correlated with
the
number of eosinophils and macrophages. The thickness of the tenascin and laminin
layers was positively correlated with AA1 and EPO positive cells only.
CONCLUSION: High numbers of inflammatory cells are present in the bronchial
mucosa of asymptomatic smokers which have a clear relationship with the impaired
epithelial integrity. The increased thickness of the laminin and tenascin
layers
in these subjects was strongly related to the presence of eosinophils and
mast
cells, suggesting a role for these cells in tissue remodelling of the airways
of
smokers.
Eur Respir J 2002 Nov;20(5):1138-46
Effects of formoterol
and ipratropium bromide in COPD: a 3-month
placebo-controlled study.
Wadbo M, Lofdahl CG,
Larsson K, Skoogh BE, Tornling G, Arwestrom E, Bengtsson T,
Strom K; Swedish Society of Respiratory Medicine.
Dept of Respiratory
Medicine in Malmo General University Hospital, Malmo,
Sweden.
The aim of this study
was to compare the effects of formoterol, ipratropium
bromide and a placebo on walking distance, lung function, symptoms and quality
of life (QoL) in chronic obstructive pulmonary disease (COPD) patients. A
total
of 183 patients (mean age 64 yrs, 86 female) with moderate-to-severe
nonreversible COPD participated in this randomised, double-blind, parallel-group
study. After a 2-week placebo run-in, patients were randomised to formoterol
Turbuhaler 18 microg b.i.d. (delivered dose), ipratropium bromide 80 microg
t.i.d. via a pressurised metered dose inhaler, or placebo for 12 weeks. Inhaled
short-acting beta2-agonists were allowed as relief medication and inhaled
glucocorticosteroids were allowed at a constant dose. The primary variable
was
walking distance in the shuttle walking test (SWT). Baseline mean SWT distance
was 325 m, mean forced expiratory volume in one second (FEV1) was 40% predicted.
Clinically significant improvements in SWT (>30 m) were seen in 41, 38
and 30%
of formoterol, ipratropium and placebo patients, respectively (not significant).
Mean increases from run-in were 19, 17 and 5 m in the formoterol, ipratropium
and placebo groups, respectively. Both active treatments significantly improved
FEV1, forced vital capacity, peak expiratory flow and daytime dyspnoea score
compared with placebo. Formoterol reduced relief medication use compared with
placebo. Neither active treatment improved QoL. Formoterol and ipratropium
improved airway function and symptoms, without significant improvements in
the
shuttle walking test.
Publication Types:
Clinical Trial
Multicenter Study
Randomized Controlled Trial
Lakartidningen 2002 Oct 17;99(42):4176-80
[Better routines in
connection with nebulizer therapy are required. New European
guidelines serve as a guidance in Swedish health care, too]
[Article in Swedish]
Lannefors L, Persson O, Lofdahl CG.
Hjart- och lungdivisionen, Universitetssjukhuseti Lund.
Respir Med 2002 Nov;96(11):927-33
Natural allergen exposure
does not diminish the sensitivity of cytokine
production to glucocorticosteroids in blood cells of seasonal allergic asthma
and rhinitis patients.
Larsson S, Hansson L, Greiff L, Lofdahl CG, Persson CG, Broberg P, Linden M.
Department of Respiratory
Medicine, Lund University Hospital, Sweden.
susannelarsson.lund@telia.com
Glucocorticosteroid
(GCS) inhibition of cytokine production is a major
anti-inflammatory mechanism. However, increased production of pro-inflammatory
cytokines during allergic airway inflammation has been proposed to reduce
GCS
effects. This study aimed to investigate whether allergic airway inflammation
due to natural allergen exposure might decrease the sensitivity of
granulocyte-macrophage colony-stimulating factor (GM-CSF) production to GCS
in
blood cells. Blood samples were collected from patients with seasonal allergic
asthma (n = 10) and rhinitis (n = 8) and healthy subjects (n = 9), before,
during, and after the birch pollen season. Whole blood cultures were stimulated
with LPS (10 ng/ml) and treated with budesonide (10(-11)-10(-7) M) for 20
h.
GM-CSF levels were analysed using immunoassay. Birch pollen exposure did not
alter LPS-stimulated GM-CSF production, although disease symptoms and blood
eosinophils increased in the patients. There were no significant differences
in
budesonide inhibition of GM-CSF production by blood cells of asthma and rhinitis
patients compared with cells of healthy subjects before, during or after the
birch pollen season and no change in response to allergen exposure. A
concentration of 1 nM budesonide inhibited GM-CSF production by more than
50% at
all time points. In conclusion, natural allergen exposure did not reduce the
sensitivity of GM-CSF production to GCS inhibition in blood cells of seasonal
allergic asthma and rhinitis patients.
Proteomics 2002 Apr;2(4):394-404
Proteoglycan and proteome
profiling of central human pulmonary fibrotic tissue
utilizing miniaturized sample preparation: a feasibility study.
Malmstrom J, Larsen
K, Hansson L, Lofdahl CG, Norregard-Jensen O, Marko-Varga G,
Westergren-Thorsson G.
Cell & Molecular Biology, University of Lund, Sweden.
The objective of this
study was to isolate fibrotic cells from human lung
biopsies taken from different central pulmonary locations. A comparison was
made
of cell morphology, proteoglycan- and protein-expression in mesenchymal cell
cultures obtained from human bronchial biopsies from patients with
asthmatic-like disorders. We isolated viable cells from 10 out of the 12
biopsies. The fibroblast-like cells were positive for the biomarker a-smooth
muscle actin, indicating that the cells were in an activated state. Two
different types of fibroblast-like cells were observed from human pulmonary
connective tissue; one of contractile type with lamellipodia that facilitate
migration and a second cell type with an increased cell size, which most likely
is of a synthetic phenotype. This is the first evidence of alterations in
the
proteoglycan expression pattern of versican, perlecan, biglycan and decorin
which can be linked to the pathophysiological state of asthmatics proven by
a
combination of solid-phase extraction by reversed phase and by peptide mass
fingerprinting using matrix-assisted laser desorption/ionization-time of flight
mass spectrometry. Protein expression analysis using two-dimensional
electrophoresis was interfaced to miniaturized sample preparation techniques
using microcapillary extraction. Four protein groups were identified;
cytoskeletal, adhesion, scavenger and metabolic proteins. These patient's
proteomes showed a high degree of heterogeneity between patients but larger
homogeneity within biopsies derived from different locations of the same
patient.
Fam Pract 2002 Aug;19(4):365-8
Accuracy of a first diagnosis of asthma in primary health care.
Montnemery P, Hansson L, Lanke J, Lindholm LH, Nyberg P, Lofdahl CG, Adelroth E.
Department of Clinical
Neuroscience/Division of Occupational Therapy, PO Box
157, Umea University, SE-221 00 Lund, Sweden. peter.montnemery@arb.lu.se
BACKGROUND: In a postal
questionnaire study, the prevalence of asthma in
southern Sweden has been found to be 5.5%. However, the register prevalence
of
asthma obtained from the medical records in the same municipality and age
groups
was found to be only 2.1%. OBJECTIVES: The aims of the study were to investigate
whether the low register prevalence of asthma was caused by an underdiagnosis
of
asthma in primary health care and to validate a first diagnosis of asthma
set by
GPs in primary health care. METHODS: During a period of 3 months in 1997,
all
patients seeking care in the primary health care units of the municipality
of
Lund (population 171 877) with upper or lower airway infections, prolonged
cough, allergic rhinitis, fatigue or a first positive diagnosis of asthma
were
recorded ( n = 3025). RESULTS: In the whole group of 3025 patients, 99 patients
were found to have received a diagnosis of asthma for the first time during
the
study period. The diagnosis was verified in 52 of those 68 patients who attended
a follow-up and examination by a respiratory physician. Among the remaining
2926
patients, 221 patients were selected randomly to constitute a control group.
In
this group, three patients were found to have asthma. Thus, the specificity
of
an asthma diagnosis set in primary health care was 0.99 [95% confidence interval
(CI) 0.99-1.00] and the sensitivity was 0.59 (95% CI 0.31-0.81). CONCLUSIONS:
The GPs in this study were good at excluding those who did not have asthma
(specificity 99%) but less good in correctly diagnosing those who actually
had
current asthma (sensitivity 59%), which suggests an underdiagnosis of asthma.
Eur Respir J 2002 Jun;19(6):1058-63
Bone mineral density
in patients with chronic obstructive pulmonary disease
treated with budesonide Turbuhaler.
Johnell O, Pauwels R, Lofdahl CG, Laitinen LA, Postma DS, Pride NB, Ohlsson SV.
Dept of Orthopaedics,
Malmo University Hospital, Sweden.
olof.Johnell@orto.mas.lu.se
There is a need for
studying the effects of long-term inhaled corticosteroid
therapy on bone mineral density (BMD) and vertebral fracture rates in patients
with mild chronic obstructive pulmonary disease (COPD). Patients (n=912, mean
age 52 yrs) with mild COPD (mean forced expiratory volume in one second (FEV1)
77% of predicted; mean FEV1/slow vital capacity ratio 62%) were randomized
to
receive budesonide 400 microg, or placebo twice daily via Turbuhaler. BMD
was
measured at the L2-L4 vertebrae and the femoral neck, trochanter and Ward's
triangle by dual-energy X-ray absorptiometry at baseline and after 6, 12,
24 and
36 months (n=161). Radiographs of the thoracic and lumbar spine were obtained
at
the beginning and end of treatment (n=653). Previous fractures were present
at
baseline in 43 budesonide-treated patients (13.4%) and 38 placebo-treated
patients (11.5%). New fractures occurred in five budesonide-treated patients,
compared with three in the placebo group (p=0.50). There were no significant
changes in BMD at any site in budesonide-treated patients, compared with the
placebo group, during the course of the study. Budesonide treatment was
associated with a slight but statistically significant decrease in the area
under the concentration-time curve for serum osteocalcin. In the present study,
involving a large group of patients with chronic obstructive pulmonary disease,
long-term treatment with budesonide 800 microg x day(-1) via Turbuhaler had
no
clinically significant effects on bone mineral density or fracture rates.
Publication Types:
Clinical Trial
Randomized Controlled Trial
Br J Clin Pharmacol 2001 Nov;52(5):529-38
Pharmacokinetics and
systemic activity of fluticasone via Diskus and pMDI, and
of budesonide via Turbuhaler.
Thorsson L, Edsbacker S, Kallen A, Lofdahl CG.
Experimental Medicine, AstraZeneca, Lund, Sweden. Lars.Thorsson@astrazeneca.com
AIMS: To determine
the basal pharmacokinetics, lung uptake and plasma cortisol
suppression for two commonly prescribed inhaled corticosteroids. METHODS:
Twenty-one subjects (13 healthy and 8 mild asthmatic patients) received
fluticasone propionate via a chlorofluorocarbon-propelled pressurized
metered-dose inhaler (pMDI) (healthy subjects only) and Diskus and budesonide
via Turbuhaler, 1000 microg twice daily for 7 days. Intravenous doses (200
microg) of both compounds were used as references. Plasma concentrations of
fluticasone and budesonide were determined during 48 h by liquid chromatography
plus tandem mass spectrometry (LC-MS-MS). Plasma concentrations of cortisol
were
determined by LC-MS every second hour for 24 h at baseline, and following
each
treatment. RESULTS: The volume of distribution was found to be larger and
the
elimination half-life and mean absorption time longer for fluticasone than
for
budesonide. The systemic availability of budesonide via Turbuhaler (39%) was
significantly higher than that of fluticasone via Diskus (13%) (ratio 3.0
[2.5,
3.6] with 95% confidence interval [CI]), and via pMDI (21%) (ratio 1.8 [1.3,
2.3]). In addition, at steady state the systemic availability of fluticasone
via
pMDI was significantly higher than via Diskus (ratio 1.6 [1.1, 2.2]). The
lung
deposition of budesonide via Turbuhaler was 2.2-fold [1.7, 2.9] higher than
that
of fluticasone pMDI and 3.4-fold [2.8, 4.0] higher than that of fluticasone
Diskus. In addition, the lung deposition of fluticasone via pMDI was 1.5-fold
[1.1, 2.9] higher than that via the Diskus inhaler. Plasma cortisol (24 h)
was
significantly reduced vs baseline for all three treatments. The cortisol
concentration vs baseline was 12% for fluticasone pMDI, which was significantly
lower (ratio 0.32 [0.24, 0.42]) than that for fluticasone Diskus (39%), and
for
budesonide Turbuhaler (46%) (ratio 0.27 [0.21, 0.37]). The plasma cortisol
concentration did not differ significantly between treatments with fluticasone
Diskus and budesonide Turbuhaler (ratio 0.87 [0.65; 1.15]). CONCLUSIONS:
Budesonide and fluticasone differ in their pharmacokinetic properties in that
although clearance is the same, the rate of uptake and elimination is slower
for
fluticasone. Despite a significantly higher pulmonary availability of budesonide
via Turbuhaler, the plasma cortisol suppression is less than that of fluticasone
via pMDI and similar to that of fluticasone via Diskus. There is no indication
of any difference between healthy subjects and mild asthmatic patients in
the
pharmacokinetics and plasma cortisol suppression of fluticasone and budesonide.
Publication Types:
Clinical Trial
Randomized Controlled Trial
Respir Med 2001 Sep;95(9):744-52
Prevalence of obstructive
lung diseases and respiratory symptoms in relation to
living environment and socio-economic group.
Montnemery P, Bengtsson P, Elliot A, Lindholm LH, Nyberg P, Lofdahl CG.
Department of Clinical Neuroscience, Lund University, Sweden.
We wanted to test
whether living environment, occupation and social position are
risk factors for asthma and chronic bronchitis/emphysema (CBE). The prevalence
of bronchial asthma, CBE, respiratory symptoms and smoking habits in a random
sample of 12,071 adults aged 20-59 years was assessed in a postal survey with
a
slightly modified questionnaire previously used in central and northern Sweden
(The OLIN studies). Occupation was coded according to a socio-economic
classification system. Six different living environment areas were defined;
city-countryside, seaside-not seaside and living close to heavy traffic-not
living close to heavy traffic. Multiple logistic regression analysis (forward
conditional) was applied to estimate the association between the proposed
set of
risk factors and self-reported obstructive lung diseases and lower respiratory
symptoms controlling for age, gender and smoking. After two reminders, the
response rate was 70.1% (n=8469); 33.8% of the responders were smokers. In
all,
469 subjects (5.5%) stated that they had asthma and 4.6% reported CBE. Besides
smoking, which was a risk for both asthma and CBE, there were different risk
patterns for self-reported asthma and CBE. In the economically active population
there was a tendency that CBE was more common among 'unskilled and semi-skilled
workers'. This fact was further emphasized when the population was merged
into
the two groups 'low social position' and 'middle/high social position', with
'low social position' as a risk for CBE (OR=1.35, 95% CI=1.06-1.72). No social
risk factors were identified for asthma. Living close to heavy traffic was
a
risk factor for asthma (OR=1.29, 95% CI=1.02-1.62) but not for CBE. Apart
from
this no living environmental risk factors for obstructive pulmonary diseases
were identified. Asthma symptoms and long-standing cough were more common
among
those subjects living close to heavy traffic compared to those not living
close
to heavy traffic. To conclude, low social position was a risk factor for CBE
and
living close to heavy traffic was a risk factor for asthma.
Scand J Clin Lab Invest 2001;61(5):341-7
Increased serum levels
of carbohydrate-deficient transferrin in patients with
chronic obstructive pulmonary disease.
Nihlen U, Montnemery P, Lindholm LH, Lofdahl CG.
Department of Respiratory
Medicine, University Hospital, Lund, Sweden.
ulf.nihlen@lung.lu.se
OBJECTIVE: The reason
that only a minority of smokers develop chronic
obstructive pulmonary disease (COPD) is still largely unknown. Glycosylation
defects are involved in the pathological mechanisms in cystic fibrosis (CF),
where chronic progressive obstructive lung disease dominates the clinical
picture. Whether defects of protein glycosylation occur in COPD has not
previously been examined. Increase in carbohydrate-deficient transferrin (CDT)
in serum seems to function as an indicator of general defects of
N-glycosylation. Recently, one study observed high serum CDT concentrations
in
CF patients. We examined whether subjects with COPD also have increased serum
CDT levels. METHOD AND RESULTS: A total of 131 randomly selected individuals,
45-64 years of age, underwent a medical examination, spirometry and blood
tests.
Serum CDT was determined using high performance liquid chromatography. In
subjects diagnosed as having COPD (n = 15), multiple logistic regression
analyses demonstrated a significant relationship between the diagnosis of
COPD
and CDT, even after all efforts were made to take the influence of age and
smoking into account (odds ratio 3.16, 95% CI 1.11-8.95). Also, in subjects
with
COPD there was an inverse partial correlation between forced expiratory volume
in 1 s (FEV1) and serum CDT (r = -0.81, p = 0.001). CONCLUSION: These results
suggest that protein glycosylation defects occur in COPD and, in addition,
might
be involved in the pathogenetic mechanisms of the disease. It seems that further
investigation of the protein glycosylation in COPD is warranted.
Respir Med 2001 Jun;95(6):505-12
Adding formoterol
to budesonide in moderate asthma--health economic results from
the FACET study.
Andersson F, Stahl
E, Barnes PJ, Lofdahl CG, O'Byrne PM, Pauwels RA, Postma DS,
Tattersfield AE, Ullman A; Formoterol and Corticosteroid Establishing Therapy.
International Study Group.
AstraZeneca R&D Lund, Sweden. fredrik.l.andersson@astrazeneca.com
The FACET (Formoterol
and Corticosteroid Establishing Therapy) study established
that there is a clear clinical benefit in adding formoterol to budesonide
therapy in patients who have persistent symptoms of asthma despite treatment
with low to moderate doses of an inhaled corticosteroid. We combined the
clinical results from the FACET study with an expert survey on average resource
use in connection with mild and severe asthma exacerbations in the U.K., Sweden
and Spain. The primary objective of this study was to assess the health
economics of adding the inhaled long-acting beta2-agonist formoterol to the
inhaled corticosteroid budesonide in the treatment of asthma. The extra costs
of
adding the inhaled beta2-agonist formoterol to the corticosteroid budesonide
in
asthmatic patients in Sweden were offset by savings from reduced use of
resources for exacerbations. For Spain the picture was mixed. Adding formoterol
to low dose budesonide generated savings, whereas for moderate doses of
budesonide about 75% of the extra formoterol costs could be recouped. In the
U.K., other savings offset about half of the extra cost of formoterol. All
cost-effectiveness ratios are within accepted cost-effectiveness ranges reported
from previous studies. If productivity losses were included, there were net
savings in all three countries, ranging from Euro 267-1183 per patient per
year.
In conclusion, adding the inhaled, long-acting beta2-agonist formoterol to
low-moderate doses of the inhaled corticosteroid budesonide generated
significant gains in all outcome measures with partial or complete offset
of
costs. Adding formoterol to budesonide can thus be considered to be
cost-effective.
Eur J Epidemiol 2000;16(11):1003-7
Familial related risk-factors
in the development of chronic bronchitis/emphysema
as compared to asthma assessed in a postal survey.
Montnemery P, Lanke
J, Lindholm LH, Lundback B, Nyberg P, Adelroth E, Lofdahl
CG.
Department of Community
Health Sciences, Lund University, Sweden.
peter.montnemery@arb.lu.se
There is a lack of
knowledge to which extent heredity or familial risk factors
are involved in the development of chronic bronchitis/emphysema (CBE). Smoking
is regarded as the most important risk factor, but only about 15% of smokers
develop airway obstruction. We evaluated the importance of familial risk factors
compared to smoking and ex-smoking using an epidemiological approach. In 1992,
a
postal questionnaire was distributed to a study sample. In all, 43 questions
were asked, in a previously evaluated questionnaire, regarding respiratory
symptoms, self-reported lung diseases, smoking habits and familial occurrence
of
chronic bronchitis and asthma. The questionnaire was sent to 12,073 adults
living in the southernmost part of Sweden. The age range was 20-59 years with
an
equal gender distribution. The study sample was drawn from the population
records. The questionnaire was answered by 8469 subjects (70.1%), of whom
392
subjects (4.6%) stated that they had or had had CBE and 469 subjects (5.5%)
stated that they had or had had asthma. In a model with logistic regression
using the five explanatory variables gender, age, familial occurrence for
asthma, familial occurrence for CBE and current or ex-smoking the most important
risk factors for CBE were familial occurrence for chronic bronchitis [Odds
ratios (OR): 5.19, 95% confidence interval (CI): 4.09-6.60, p = 0.000] and
current or ex-smoking (OR: 1.74, 95% CI: 1.41-2.14, p = 0.000). The most
important risk factors for asthma were familial occurrence for asthma (OR:
3.71,
95% CI: 3.06-4.51, p = 0.000) and current or ex-smoking (OR: 1.33, 95% CI:
1.09-1.61, p = 0.004). We have found that familial occurrence for CBE in first
degree relatives together with smoking is a stronger risk factor for the
development of CBE than is smoking.
Eur Respir J 2001 Apr;17(4):596-603
Comment in:
Eur Respir J. 2002 Jan;19(1):202-3.
Prevalence of nasal
symptoms and their relation to self-reported asthma and
chronic bronchitis/emphysema.
Montnemery P, Svensson
C, Adelroth E, Lofdahl CG, Andersson M, Greiff L, Persson
CG.
Dept of Community Health Sciences, Umea University, Sweden.
Little information
is available on associations between rhinitis and chronic
bronchitis/emphysema (CBE). Self-reported upper airway symptoms, asthma, and
CBE
were examined in 12,079 adults living in southern Sweden. The response rate
was
70% (n=8,469), of whom 33% reported significant nasal symptoms: a blocked
nose
was reported by 21%; sneezing by 18%; nasal discharge by 17%; and thick yellow
nasal discharge by 5.7%. Nasal symptoms and combined nasal and self-reported
bronchial disease were generally more common among smokers than nonsmokers.
There was little overlap between asthma and CBE, but 46% of those with asthma
and 40% of those with CBE had significant nasal symptoms. Best predicting
factors (odds ratios >3) for asthma and CBE were nasal symptoms due to
exposure
to animals and damp/cold air, respectively. One-third of an adult, southern
Swedish population, had significant allergic and/or nonallergic nasal symptoms.
Nasal symptoms were frequently found to coexist with both asthma and chronic
bronchitis/emphysema, suggesting that pan-airway engagement is common in both
diseases. Differing associations between types of nasal symptoms and allergic
and irritant triggers of nasal symptoms, with regard to asthma and chronic
bronchitis/emphysema, emphasize the different natures of these bronchial
diseases.
Publication Types:
Clinical Trial
Randomized Controlled Trial
Respir Med 2001 May;95(5):363-73
Neutrophil-associated
activation markers in healthy smokers relates to a fall in
DL(CO) and to emphysematous changes on high resolution CT.
Ekberg-Jansson A,
Andersson B, Bake B, Boijsen M, Enanden I, Rosengren A, Skoogh
BE, Tylen U, Venge P, Lofdahl CG.
Department of Pulmonary
Medicine, Sahlgrenska University Hospital, Goteborg,
Sweden. ann.ekberg-jansson@hjl.gu.se
Smoking is a risk
factor for developing chronic obstructive pulmonary disease
(COPD), but there are no good indicators for early identification of subjects
who will develop symptomatic COPD. The aim of this study was to investigate
inflammatory mechanisms related to changes in lung function and emphysematous
changes on high resolution computed tomography (HRCT) in 'healthy' smokers.
Subjects were 60-year-old men from a population study. Bronchoscopy was
performed in 30 smokers and 18 who had never smoked. Blood tests, lung function
measurements and HRCT were carried out in 58 and 34 subjects, respectively.
In
comparison with never-smokers, smokers had higher levels of myeloperoxidase
(MPO), human neutrophil lipocalin (HNL), eosinophil cationic protein (ECP)
and
lysozyme in blood, higher levels of MPO, interleukin-8 (IL-8) and HNL in
bronchial lavage (BL), and of IL-8, HNL and interleukin-lbeta (IL-1beta) in
bronchoalveolar lavage (BAL). Smokers also had lower levels of Clara cell
protein 16 (CC-16) in blood. HNL in BL and BAL showed strong correlations
to
other inflammatory markers (MPO, IL-8, IL-1beta). The variations in MPO in
BL
were explained by variations in HNL (R2 =0.69), while these variations in
BAL
were explained by variations in HNL and IL-1beta (R2 = 0.76). DL(CO) was the
lung function variable most closely related to MPO and IL-8 in BL and BAL
and to
IL-1beta in BAL. In a multiple regression analysis, MPO, IL-1beta, IL-8 and
CC-16 in BL and MPO in BAL contributed to the explanation of variations in
DL(CO) to 41% and 22%. respectively, independent of smoking habits. In smokers
with emphysematous lesions on HRCT, HNL in BAL correlated to emphysema score
(r(s) = 0.71). We conclude that 'healthy' smoking men with a near normal FEV1
show signs of inflammation in the lower airways that are related to a decrease
in DL(CO) and to emphysematous lesions on HRCT. This inflammation seems to
be
the result of both monocyte/macrophage and neutrophil activation.
Respir Med 2001 May;95(5):313-8
Exudation of plasma
and production of thromboxane in human bronchi after local
bradykinin challenge.
Arvidsson P, Lofdahl CG, Skoogh BE, Lotvall J.
Department of Respiratory
Medicine and Allergology, Goteborg University, Sweden.
peter.arvidsson@hjl.gu.se
Plasma exudation has
been suggested to be an important component of the
inflammatory response in asthma. Bradykinin elicits many of the features of
asthma, including bronchoconstriction, cough, plasma exudation and mucus
secretion. In an attempt to quantify local plasma exudation, we have employed
a
novel low-trauma technique with the aim of challenging and lavaging a central
part of the bronchial tree, by selecting a medium sized bronchus. A fibreoptic
bronchoscopy was performed in non-smoking healthy volunteers. The instrument
was
placed proximally in the right upper lobe bronchus. A plastic catheter, equipped
with an inflatable latex balloon, was inflated with air (2-4 cmH2O). A solution
(100 microl of either two different concentrations of bradykinin: 0.09 and
0.9
mg ml(-1) or normal saline) was instilled through the catheter and distal
to the
balloon. Eight minutes later a lavage procedure with 10 ml of saline was
performed through the catheter. The procedure was then repeated twice, with
the
other solutions, but from the lingular and middle lobe bronchi. All solutions
were given in a blinded fashion, and two different studies were performed.
Lavage concentrations of albumin and IgG were quantified as measurements of
plasma exudation. In our first study we found that bradykinin challenge
significantly increased concentrations of albumin and IgG. In study two, there
was no numeric increase in plasma proteins after local bradykinin challenge,
but
the concentration of thromboxane was significantly increased in lavages from
bradykinin-challenged bronchi. Thus, local bronchial administration of
bradykinin has the capacity to induce exudation of large plasma macromolecules
into the bronchial lumen, as well as local thromboxane production.
BMJ 2001 May 26;322(7297):1259-61
Comment on:
BMJ. 2001 May 26;322(7297):1271-4.
Preventing exacerbations of chronic bronchitis and COPD.
Ekberg-Jansson A, Larsson S, Lofdahl CG.
Publication Types:
Comment
Editorial
Lancet 2001 Jan 27;357(9252):257-61
Comment in:
ACPJournal Club 2001 Jul-Aug;135(1):23
Lancet. 2001 Jun 9;357(9271):1882-3.
Lancet. 2001 Jun 9;357(9271):1882; discussion 1882-3.
Comparison of formoterol
and terbutaline for as-needed treatment of asthma: a
randomised trial.
Tattersfield AE, Lofdahl
CG, Postma DS, Eivindson A, Schreurs AG, Rasidakis A,
Ekstrom T.
Respiratory Medicine
Unit, City Hospital, Nottingham, UK.
anne.tattersfield@nottingham.ac.uk
BACKGROUND: Asthma
guidelines recommend that long-acting inhaled beta-agonists
should be used as maintenance therapy for patients with asthma inadequately
controlled on an inhaled corticosteroid. We studied the safety and efficacy
of
the long-acting beta-agonist formoterol compared with terbutaline, each taken
as
needed, in patients with moderate to severe asthma. METHODS: Patients were
taking an inhaled corticosteroid (mean dose 870 microg daily) and had a forced
expiratory volume in 1 s (FEV1) of at least 50% predicted (mean 74%). Those
requiring an inhaled beta-agonist three to eight times a day during the study
run-in period (362 of 621 who started) were randomly assigned formoterol 4.5
microg or terbutaline 0.5 mg as needed by Turbuhaler in daily doses up to
54
microg and 6 mg, respectively, for 12 weeks in a double-blind, parallel-group
study. Analyses were by intention to treat. FINDINGS: The 362 randomised
patients (157 men, 205 women) had a mean age of 47 years. Patients taking
formoterol had a longer time to their first severe asthma exacerbation
(relative-risk ratio 0.55 [95% CI 0.34-0.89]), took fewer inhalations of study
drug, and had larger increases in FEV1 (5%) and morning and evening peak
expiratory flow (mean difference in increase 11 L/min and 8 L/min) than those
taking terbutaline. No safety issues were identified. INTERPRETATION: When
taken
as needed, formoterol 4.5 microg provided better asthma control than terbutaline
0.5 mg in patients requiring moderate doses of relief medication despite inhaled
corticosteroid treatment. Safety studies should be extended to a wider
population of patients with asthma.
Publication Types:
Clinical Trial
Randomized Controlled Trial
Respir Med 2001 Jan;95(1):40-7
Respiratory symptoms
relate to physiological changes and inflammatory markers
reflecting central but not peripheral airways. A study in 60-year-old 'healthy'
smokers and never-smokers.
Ekberg-Jansson A, Bake B, Andersson B, Skoogh BE, Lofdahl CG.
Department of Pulmonary
Medicine, Sahlgrenska University Hospital, Goteborg,
Sweden. ann.ekberg-jansson@hjl.gu.se
The aim of this study
was to evaluate the relationship between respiratory
symptoms, lung function and inflammatory markers in 'healthy' smokers. The
study
population was recruited from an epidemiological study with subjects of the
same
age, 60 years. Only smokers who considered themselves healthy (n=58) and a
random sample of never-smokers (n=34) were investigated. All subjects underwent
lung function tests--spirometry, carbon monoxide transfer (DLco) and the
single-breath N2 method (N2 test)--together with high-resolution computed
tomography (HRCT). A flexible bronchoscopy with a bronchoalveolar lavage (BAL)
was performed in 30 smokers and 18 never-smokers. Bronchial biopsies were
also
taken. Smokers who reported non-specific respiratory problems, chronic
bronchitis and wheezing in a symptom questionnaire had a lower forced expiratory
volume in 1 sec (FEV1), FEV% and specific airway conductance (sGaw), lung
function tests supposed to reflect the more central airways, than smokers
without respiratory symptoms. A limited number of smokers with occasional
non-specific respiratory problems also had more cytotoxic T cells (CD8) in
bronchial biopsies. No differences were found in DLCO and the N2 test, lung
function tests supposed to reflect the more peripheral airways including the
alveoli, HRCT-diagnosed emphysema or inflammatory markers in blood and BAL
between smokers with and without respiratory symptoms. It is concluded that
even
when smokers consider themselves 'healthy' they have mild symptoms that are
related more to physiological changes and inflammatory markers that may reflect
events in the central airways than to changes that may reflect events in the
peripheral airways.
Respir Med 2000 Mar;94(3):264-72
The expression of
lymphocyte surface antigens in bronchial biopsies,
bronchoalveolar lavage cells and blood cells in healthy smoking and
never-smoking men, 60 years old.
Ekberg-Jansson A, Andersson B, Avra E, Nilsson O, Lofdahl CG.
Department of Allergology
and Pulmonary Medicine, Sahlgrenska University
Hospital, Goteborg, Sweden.
In this study we investigated
if smoking subjects with a normal or slightly
decreased lung function differ in the lymphocyte pattern compared to
never-smokers. In a group of 'healthy' smokers (n = 58) and never-smokers
(n =
34) 60 years old, we investigated the lymphocyte pattern in both BAL (n =
30 and
n = 18 respectively), bronchial epithelium and lamina propria (n = 14 and
n = 10
respectively) and blood. We found that all subjects, despite smoking history,
had a higher number of CD8+ cells per mm2 in the epithelium compared to the
lamina propria in the bronchial biopsies. In smokers, these CD8+ cells were
significantly negatively correlated to FEV1 (r = -0.56, P = 0.04). In smokers,
the number of CD8+ lymphocytes was higher and the T cell activation markers
(CD57+ and CD28+) were lower in BAL, than in never-smokers. This last finding
was also seen in blood for CD3+ 57+. We conclude, that in 'healthy' smokers
the
lymphocyte patterns are different compared to never-smokers, to some extent
in
BAL. There is also a relation between lymphocytes in the bronchial mucosa
and
lung function. This has previously been shown in patients with chronic
obstructive pulmonary disease (COPD) and chronic bronchitis but not in
asymptomatic smokers.
Respir Med 2000 Mar;94(3):247-55
The economic impact
of asthma and chronic obstructive pulmonary disease (COPD)
in Sweden in 1980 and 1991.
Jacobson L, Hertzman P, Lofdahl CG, Skoogh BE, Lindgren B.
Department of Community Medicine, Lund University, Sweden.
This study was carried
out to estimate the direct and indirect costs associated
with asthma and chronic obstructive pulmonary disease (COPD) in Sweden in
1980
and 1991, and to identify trends in the use of outpatient care, drugs and
inpatient care, and the development of temporary morbidity, permanent disability
and mortality for asthma and COPD. Routinely published administrative and
population data were used to estimate the costs of asthma and COPD, and these
figures were compared to corresponding estimates and trends for all respiratory
diseases as well as for all diseases. Asthma and COPD each accounted for about
SEK 3 billion, together roughly 2% of the economic cost of all diseases.
Although the total costs associated with each disease were similar, the
distribution of the different cost components and changes in each component
over
time differed. During the 1980s, the cost of drugs and out-patient care
increased for both diseases. The cost of inpatient care for asthma decreased,
whereas that for COPD increased. This study shows that asthma therapy has
changed from inpatient to ambulatory care in Sweden, while the treatment of
COPD
to a higher degree still is based on inpatient care.
Respir Med 2000 Jan;94(1):38-43
Emphysematous lesions and lung function in healthy smokers 60 years of age.
Tylen U, Boijsen M, Ekberg-Jansson A, Bake B, Lofdahl CG.
Goteborg University,
Department of Radiology, Sahlgrenska University Hospital,
Sweden. ulf.tylen@rtg.gu.se
We aimed to study
the occurrence of emphysematous lesions in symptom free
smoking men of about 60 years of age and in a matching group of never-smoking
men and the relationship between pulmonary changes at high resolution computed
tomography (HRCT) and lung function tests. Our investigation included 57 smoking
and 32 never-smoking healthy men from a randomized epidemiological study.
HRCT
was performed at full inspiration with a 1.5 mm slice thickness and a 3 cm
inter-slice distance. Evaluation was made by two radiologists unaware of smoking
history. Emphysematous lesions were scored visually. Pulmonary function tests
were performed including spirometry and diffusion capacity test (DLCO).
Emphysematous changes were demonstrated in 25 of 57 smokers but in only one
never-smoker. DLCO/VA was the most sensitive test for early emphysematous
lesions. It also correlated with radiographical scoring. Emphysematous lesions
were evident in 44% of the healthy symptom free smokers. HRCT may reveal early
emphysematous lesions in smokers before clinical symptoms have developed.
Scand J Prim Health Care 1999 Dec;17(4):232-7
Detection of chronic
obstructive pulmonary disease (COPD) in primary health
care: role of spirometry and respiratory symptoms.
Nihlen U, Montnemery P, Lindholm LH, Lofdahl CG.
Department of Community Health Sciences, Lund University, Sweden.
OBJECTIVE: To evaluate
the role of spirometry and respiratory symptoms in the
detection of chronic obstructive pulmonary disease (COPD) in primary health
care. DESIGN: A cross-sectional study. SETTING: A primary health centre in
Landskrona, southern Sweden. SUBJECTS: 164 subjects who in 1992 had answered
a
postal questionnaire concerning obstructive pulmonary diseases and respiratory
symptoms. They were aged 45-64 years, with a mean of 55 years. MAIN OUTCOME
MEASURES: In 1997, the subjects were invited to perform a spirometry and a
medical examination and to answer the same questionnaire as in 1992. Subjects
with a forced expiratory volume in 1 second (FEV1) < 85% of the predicted
normal
value performed reversibility tests. RESULTS: 131 subjects participated in
the
examinations. 15 subjects (11.5%) were diagnosed as having COPD. Only three
of
them had been previously diagnosed as having a respiratory disease. Many
commonly occurring respiratory symptoms were associated with a reduction in
FEV1. CONCLUSIONS: Spirometry examinations in primary health care improve
the
probability of detecting COPD. A spirometry examination should be considered
for
patients with respiratory symptoms. It should also be considered for middle-aged
smokers, even if they are symptom-free.
Eur Respir J 1999 Nov;14(5):1038-43
Asthma quality of
life during 1 year of treatment with budesonide with or
without formoterol.
Juniper EF, Svensson
K, O'Byrne PM, Barnes PJ, Bauer CA, Lofdahl CG, Postma DS,
Pauwels RA, Tattersfield AE, Ullman A.
Dept of Clinical Epidemiology
& Biostatistics, McMaster University, Hamilton,
Ontario, Canada.
The Formoterol and
Corticosteroids Establishing Therapy (FACET) study has
provided the first opportunity to examine the long-term effects of inhaled
steroids and long-acting beta2-agonists on asthma-specific quality of life.
The
objectives of the present study were to: evaluate the effects of long-term
(1
yr) formoterol and increasing doses of budesonide on asthma quality of life;
2)
to determine whether initial improvements in quality of life are sustained
when
improvements in clinical indices persist; and 3) to evaluate the long-term
relationship between changes in clinical indices and changes in quality of
life.
Of the 852 asthmatic adults enrolled, 470 from five countries participated
in
this quality of life evaluation. After a 4-week run-in on 1,600 microg
budesonide, patients were randomized to either 200 microg (Bud200) or 800
microg
budesonide (Bud800) in combination with either 24 microg formoterol (F) or
placebo daily for 1 yr. The Asthma Quality of Life Questionnaire (AQLQ) was
completed and conventional clinical indices measured at enrolment and
randomization and on seven occasions during the following 12 months. During
the
run-in, there was an improvement in AQLQ score (changes (delta) in overall
score
approximately 0.50; p<0.0001). After randomization, there was a further
improvement in the Bud800+F group (delta=0.21; p=0.028). One month
post-randomization, improvements in all groups stabilized and were sustained
throughout the 12 months in a pattern very similar to that observed for the
conventional clinical indices. The correlation of individual patient changes
in
clinical indices and changes in AQLQ score during the 12-month randomized
period
were weak to moderate (maximum r=0.51). Improvements in quality of life, which
were greatest in the 800 microg budesonide plus 24 microg formoterol group,
were
sustained throughout the 12 months in a similar manner to the clinical indices.
Long-term changes in conventional clinical indices cannot be used to predict
the
effect of treatment on individual patient experience.
Publication Types:
Clinical Trial
Multicenter Study
Randomized Controlled Trial
Respir Med 1999 Aug;93(8):563-70
A comparison of the
expression of lymphocyte activation markers in blood,
bronchial biopsies and bronchoalveolar lavage: evidence for an enrichment
of
activated T lymphocytes in the bronchoalveolar space.
Ekberg-Jansson A, Arva E, Nilsson O, Lofdahl CG, Andersson B.
Department of Pulmonary Medicine, University of Goteborg, Sweden.
In this study healthy
never-smoking subjects (n = 18) were recruited from a
population study. Bronchoalveolar lavage (BAL), blood lymphocytes and bronchial
biopsies, analysed both in the epithelium and lamina propria, were stained
for T
and B lymphocytes, natural killer (NK) cells and different subpopulations
of T
lymphocytes. In BAL, significantly higher proportions of T lymphocytes (CD3),
T
lymphocyte activation markers; HLA-DR, CD26+, CD49a+, CD54+ and CD69+, helper
T
(CD3+4+) and memory helper T lymphocytes (CD4+45RO+29+) and memory T lymphocytes
(CD3+45RO+) were found, compared to blood. However, the proportion of IL-2
receptor-positive T lymphocytes (CD25+) was lower in BAL than in blood. A
previously described higher ratio of CD3+4+/CD3+8+ in BAL than in blood (3.4
vs
1.7; P = 0.001) was confirmed. In bronchial biopsies, we found significantly
higher numbers of CD8+ cell profiles per mm2 in the epithelial compared to
the
lamina propria compartment. We conclude that healthy never-smoking men have
higher levels of activated memory T lymphocytes in BAL than in blood, and
that
the T-cell subpopulations differ in the epithelial compared to the lamina
propria compartment in the bronchial mucosa and these compartments should
be
analysed separately. It is reasonable to think that there is a gradient from
blood to the airway lumen where T cells are recruited from blood to take part
in
the defense towards damaging agents.
Br J Pharmacol 1999 Jun;127(4):980-6
IL-2 and IL-4 counteract
budesonide inhibition of GM-CSF and IL-10, but not of
IL-8, IL-12 or TNF-alpha production by human mononuclear blood cells.
Larsson S, Lofdahl CG, Linden M.
Department of Respiratory Medicine, Lund University Hospital, Sweden.
1. The combination
of interleukin-2 (IL-2) and IL-4 reduces the inhibitory
effects of glucocorticoids on granulocyte-macrophage colony-stimulating factor
(GM-CSF) production, in agreement with the hypothesis that this combination
causes glucocorticoid resistance. Whether a general cytokine resistance to
glucocorticoids is induced by IL-2 and IL-4 has not been reported. 2.
Mononuclear blood cells from healthy individuals were pre-treated with IL-2,
IL-4, or IL-2+ IL-4 (31.3-500 U ml(-1)) for 48 h, prior to lipopolysaccharide
(LPS; 10 ng ml(-1); 20 h) and budesonide addition. Cytokine levels in the
supernatants were analysed using specific immunoassays. DNA content was analysed
to estimate cell numbers. 3. GM-CSF production was totally inhibited by
budesonide at 10(-8) M in vehicle treated cultures, while IL-10 was inhibited
to
33.4+/-4.3% of control. IL-2, IL-4, or IL-2 + IL-4 reduced the inhibitory
effects of budesonide on GM-CSF to similar levels (23.7 6.7, 31.6+/-8.5 and
35.1+/-4.3% of control, respectively). IL-2, IL-4, or IL-2 + IL-4 also reduced
the inhibitory effects of budesonide on IL-10 production (46.5+/-6.6,
55.9+/-7.3%, and 68.3+/-9.9% of control, respectively). In contrast, IL-8,
IL-12
and TNF-alpha production did not become resistant to budesonide. 4. Thus,
glucocorticoid resistance induced by IL-2 and IL-4 is not general at the
cytokine production level. While the glucocorticoid sensitivity of GM-CSF
and
IL-10 production decreased, the sensitivity of IL-8, IL-12 or TNF-alpha
production was unchanged. Also, the mixture of IL-2 and IL-4 is not crucial
for
induction of glucocorticoid resistance of GM-CSF production.
Am J Respir Crit Care Med 1999 Aug;160(2):594-9
Exacerbations of asthma:
a descriptive study of 425 severe exacerbations. The
FACET International Study Group.
Tattersfield AE, Postma
DS, Barnes PJ, Svensson K, Bauer CA, O'Byrne PM, Lofdahl
CG, Pauwels RA, Ullman A.
Division of Respiratory
Medicine, Nottingham University, Nottingham, and
National Heart and Lung Institute, Imperial College, London, United Kingdom.
anne.tattersfield@nottingham.ac.uk
The identification,
prevention, and prompt treatment of exacerbations are major
objectives of asthma management. We looked at change in PEF, symptoms, and
use
of rescue beta-agonists during the 425 severe exacerbations that occurred
during
a 12-mo parallel group study (FACET) in which low and high doses of budesonide
with and without formoterol were compared in patients with asthma. Oral
corticosteroids were prescribed for severe exacerbations, the main study end
point, defined as the need for a course of oral corticosteroids (n = 311)
or a
reduction in morning PEF of > 30% on two consecutive days. PEF, symptoms,
and
bronchodilator use over the 14 d before and after the exacerbation were obtained
from diary cards. Exacerbations were characterized by a gradual fall in PEF
over
several days, followed by more rapid changes over 2 to 3 d; an increase in
symptoms and rescue beta-agonist use occurred in parallel, and both the severity
and time course of the changes were similar in all treatment groups.
Exacerbations identified by the need for oral corticosteroids were associated
with more symptoms and smaller changes in PEF than those identified on the
basis
of PEF criteria. Female sex was the main patient characteristic associated
with
an increased risk of having a severe exacerbation. Exacerbations may be
characterized predominantly by change in symptoms or change in PEF, but the
pattern was not affected by the dose of inhaled corticosteroid or by whether
the
patient was taking formoterol.
Publication Types:
Clinical Trial
Randomized Controlled Trial
Eur Respir J 1999 May;13(5):1198-208
Comment in:
Eur Respir J. 2000 Jan;15(1):233.
Difficult/therapy-resistant
asthma: the need for an integrated approach to define
clinical phenotypes, evaluate risk factors, understand pathophysiology and
find
novel therapies. ERS Task Force on Difficult/Therapy-Resistant Asthma. European
Respiratory Society.
Chung KF, Godard P,
Adelroth E, Ayres J, Barnes N, Barnes P, Bel E, Burney P,
Chanez P, Connett G, Corrigan C, de Blic J, Fabbri L, Holgate ST, Ind P, Joos
G,
Kerstjens H, Leuenberger P, Lofdahl CG, McKenzie S, Magnussen H, Postma D,
Saetta M, Salmeron S, Sterk P.
National Heart &
Lung Institute, Imperial College School of Medicine, London,
UK.
Publication Types:
Consensus Development Conference
Review
Review, Tutorial
BMJ 1999 Jul 10;319(7202):87-90
Randomised, placebo
controlled trial of effect of a leukotriene receptor
antagonist, montelukast, on tapering inhaled corticosteroids in asthmatic
patients.
Lofdahl CG, Reiss
TF, Leff JA, Israel E, Noonan MJ, Finn AF, Seidenberg BC,
Capizzi T, Kundu S, Godard P.
University Hospital, Lund, Sweden.
OBJECTIVE: To determine
the ability of montelukast, a leukotriene receptor
antagonist, to allow tapering of inhaled corticosteroids in clinically stable
asthmatic patients. DESIGN: Double blind, randomised, placebo controlled,
parallel group study. After a single blind placebo run in period, during which
(at most) two inhaled corticosteroids dose decreases occurred, qualifying,
clinically stable patients were allocated randomly to receive montelukast
(10 mg
tablet) or matching placebo once daily at bedtime for up to 12 weeks. SETTING:
23 academic asthma centres in United States, Canada, and Europe. PARTICIPANTS:
226 clinically stable patients with chronic asthma receiving high doses of
inhaled corticosteroids (113 randomised to montelukast and 113 to placebo).
INTERVENTIONS: Every 2 weeks, the inhaled corticosteroids dose was tapered,
maintained, or increased (rescue) based on a standardised clinical score.
MAIN
OUTCOME MEASURES: Last tolerated dose of inhaled corticosteroids. RESULTS:
Compared with placebo, montelukast allowed significant (P=0. 046) reduction
in
the inhaled corticosteroid dose (montelukast 47% v placebo 30%; least square
mean difference 17.6%, 95% confidence interval 0.3 to 34.8). Fewer patients
on
montelukast (18 (16%) v 34 (30%) placebo, P=0.01) required discontinuation
because of failed rescue. CONCLUSIONS: Montelukast reduces the need for inhaled
corticosteroids among patients requiring moderate to high doses of
corticosteroid to maintain asthma control.
Publication Types:
Clinical Trial
Multicenter Study
Randomized Controlled Trial
Regul Pept 1999 May 31;81(1-3):49-53
Effect of nedocromil
sodium on non-adrenergic, non-cholinergic neural responses
in guinea pig bronchi in vitro.
Linden A, Bergendal A, Lotvall J, Skoogh BE, Lofdahl CG.
Lung Pharmacology
Group, Department of Respiratory Medicine and Allergology,
Goteborg University, Gothenburg, Sweden. anders.linden@pharm.gu.se
OBJECTIVE: Nedocromil
sodium (nedocromil) improves the clinical condition of
asthmatic subjects but its mechanism of action is not fully understood. This
study aimed to determine whether nedocromil alters the ability of contractile
and relaxant non-adrenergic, non-cholinergic neural (NANC) responses to
stabilise tone by inhibiting or potentiating these responses in bronchial
smooth
muscle and, if so, whether the action is on a pre- or postjunctional level.
RESULTS: Nedocromil attenuated contractile but not relaxant NANC responses
(elicited by electric field stimulation) significantly (P < 0.05) in guinea
pig
main bronchi in vitro. However, the ability of NANC responses to stabilise
tone
(convergence effect) was not significantly impaired by nedocromil. Furthermore,
nedocromil did not significantly shift the concentration response curve (-log
EC50) to neurokinin A (NKA), the dominating contractile NANC transmitter,
or
alter the maximum response to NKA (P > 0.05). Submaximum or maximum contractile
responses to histamine were not markedly affected by nedocromil (P > 0.05).
CONCLUSIONS: Nedocromil exerts selective neural inhibition of the contractile
but not of the relaxant NANC responses on a pre-junctional level in bronchial
smooth muscle. Nedocromil does not, however, markedly impair the ability of
NANC
response to stabilise bronchial smooth muscle tone.
N Engl J Med 1999 Jun 24;340(25):1948-53
Comment in:
N Engl J Med. 1999 Jun 24;340(25):1990-1.
Long-term treatment
with inhaled budesonide in persons with mild chronic
obstructive pulmonary disease who continue smoking. European Respiratory Society
Study on Chronic Obstructive Pulmonary Disease.
Pauwels RA, Lofdahl
CG, Laitinen LA, Schouten JP, Postma DS, Pride NB, Ohlsson
SV.
Department of Respiratory
Diseases, University Hospital, Ghent, Belgium.
romain.pauwels@rug.ac.be
BACKGROUND: Although
patients with chronic obstructive pulmonary disease (COPD)
should stop smoking, some do not. In a double-blind, placebo-controlled study,
we evaluated the effect of the inhaled glucocorticoid budesonide in patients
with mild COPD who continued smoking. After a six-month run-in period, we
randomly assigned 1277 subjects (mean age, 52 years; mean forced expiratory
volume in one second [FEV1], 77 percent of the predicted value; 73 percent
men)
to twice-daily treatment with 400 microg of budesonide or placebo, inhaled
from
a dry-powder inhaler, for three years. RESULTS: Of the 1277 subjects, 912
(71
percent) completed the study. Among these subjects, the median decline in
the
FEV1 after the use of a bronchodilator over the three-year period was 140
ml in
the budesonide group and 180 ml in the placebo group (P=0.05), or 4.3 percent
and 5.3 percent of the predicted value, respectively. During the first six
months of the study, the FEV1 improved at the rate of 17 ml per year in the
budesonide group, as compared with a decline of 81 ml per year in the placebo
group (P<0.001). From nine months to the end of treatment, the FEV1 declined
at
similar rates in the two groups (P=0.39). Ten percent of the subjects in the
budesonide group and 4 percent of those in the placebo group had skin bruising
(P<0.001). Newly diagnosed hypertension, bone fractures, postcapsular cataracts,
myopathy, and diabetes occurred in less than 5 percent of the subjects, and
the
diagnoses were equally distributed between the groups. CONCLUSIONS: In patients
with mild COPD who continue smoking, the use of inhaled budesonide is associated
with a small one-time improvement in lung function but does not appreciably
affect the long-term progressive decline.
Publication Types:
Clinical Trial
Multicenter Study
Randomized Controlled Trial
Respir Med 1998 Dec;92(12):1337-45
Prevalence of obstructive
lung diseases and respiratory symptoms in southern
Sweden.
Montnemery P, Adelroth
E, Heuman K, Johannisson A, Johansson SA, Lindholm LH,
Lundback B, Lofdahl CG.
Department of Community Health Sciences, Lund University, Sweden.
The prevalence of
obstructive lung diseases is increasing in Scandinavia and
worldwide. The reasons for this are not known. The prevalence varies between
countries but also between different areas within the same country. In northern
Europe a north-south gradient and also an east-west gradient have been proposed.
To our knowledge this is the first comprehensive epidemiological study
concerning obstructive lung diseases and respiratory symptoms in the southern
part of Sweden. The prevalence of bronchial asthma, chronic
bronchitis/emphysema, respiratory symptoms, smoking habits and medication
in a
random sample of 12,071 adults aged 20-59 years was assessed in a postal survey
with a slightly modified questionnaire previously used in central and northern
Sweden (the OLIN Studies). The questionnaire was based on the British Medical
Research Council (BMRC) questionnaire. We also compared the prevalence figures
of asthma found in the postal survey with those reported in the medical records
in a part of the study area. After two reminders, the response rate was 70.1%
(n
= 8469); 33.8% of the responders were smokers. Among younger (20-39 year age
group) individuals, smoking was most common in women, whereas in those aged
40-59 years, smoking was more common in men. In all, 469 subjects (5.5%) stated
that they had asthma, 41.6% of whom reported a family history of asthma compared
to 15.9% of the study sample not reporting asthma. Of all subjects reporting
asthma, 60.1% (n = 282) answered that they used asthma drugs. Inhaled steroids
were used by 20.7%. Chronic bronchitis and/or emphysema was reported by 4.6%
(n
= 392), 28.6% of whom reported a family history of chronic bronchitis or
emphysema compared to 6.8% of the study sample not reporting chronic bronchitis.
The most common respiratory symptom in the study population was 'phlegm when
coughing' reported by 15.1% (n = 1279). Our data show a prevalence of
self-reported asthma of 5.5% compared with 7% reported by Lunback et al. in
northern Sweden, which indicates a north-south gradient.
J Asthma 1998;35(8):647-55
High-dose inhaled
budesonide may substitute for oral therapy after an acute
asthma attack.
Nana A, Youngchaiyud
P, Charoenratanakul S, Boe J, Lofdahl CG, Selroos O, Stahl
E.
Department of Medicine, Siriraj Hospital, Bangkok, Thailand.
Patients attending
the emergency room with acute asthma, participating in a
study comparing salbutamol (albuterol in the United States) via a dry powder
inhaler (Turbuhaler) with pressurized metered-dose inhaler (pMDI), were included
in this 1-week follow-up study with the aim of assessing whether inhaled
budesonide via Turbuhaler may be an alternative to prednisolone tablets after
an
acute asthma attack. Eighty-one patients with a mean age of 38 years and forced
expiratory volume in 1 sec (FEV1) of 64% predicted normal value after treatment
with salbutamol were randomized in this double-blind, double-dummy,
parallel-group study. The doses given were budesonide 1600 microg b.i.d. or
prednisolone in daily doses from 40 mg (day 1) decreased to 5 mg (day 7).
FEV1
was recorded before and after the 7-day treatments and peak expiratory flow
(PEF) morning and evening, clinical symptoms (visual analogue scale 0-100),
and
doses of rescue medication (terbutaline Turbuhaler 0.25 mg/dose) were recorded
daily. The mean increase in FEV1 from baseline to day 7 was 17.3% in the
budesonide Turbuhaler group and 17.6% in the prednisolone group. Mean values
of
morning PEF increased from day 1 to day 7 by 67 L/min in the budesonide
Turbuhaler group and by 57 L/min in the prednisolone group (not significant).
There were no statistically significant differences between the groups in
clinical symptoms and in the number of doses of rescue medication. Because
of
disease deterioration, five patients in the Turbuhaler group and three in
the
prednisolone group needed additional symptomatic as well as corticosteroid
treatment. Inhaled budesonide in high doses may be a substitute for oral therapy
as follow-up treatment after an acute asthma attack.
Publication Types:
Clinical Trial
Randomized Controlled Trial
Rev Mal Respir 1998 Sep;15 Suppl 2:S42-4
[Corticosteroids]
[Article in French]
Lofdahl CG.
Publication Types:
Clinical Trial
Randomized Controlled Trial
Allergy 1998 Jul;53(7):712-5
Efficacy of cumulative
doses of salbutamol administered via Turbuhaler or
Diskhaler in patients with reversible airway obstruction.
Carlsson LG, Arwestrom E, Friberg K, Kallen A, Lunde H, Lofdahl CG.
Department of Medicine at Uddevalla Hospital, Sweden.
The study aimed to
estimate the relative dose potency of salbutamol inhaled via
Turbuhaler and Diskhaler. The 24 adult patients participating had chronic
reversible airway obstruction. The study was of a double-blind, double-dummy,
crossover, randomized design. Five doses of salbutamol Turbuhaler, 50, 50,
100,
200, and 400 microg, were given on one study day at intervals of 30 min. On
another study day, five doses of salbutamol Diskhaler, 200, 200, 400, 800,
and
1600 microg, were given with the same interval. The treatment days were
separated by a washout period of at least 24 h. The inhalation technique was
standardized and supervised. Efficacy variables were recorded before and after
each study dose. The primary efficacy variable was forced expiratory volume
in 1
s (FEV1). When parallel and linear cumulative dose-response curves were
statistically compared on a logarithmic scale, the dose potency of salbutamol
Turbuhaler vs salbutamol Diskhaler was 1.99 (95% confidence interval 1.52-2.54).
This study indicates that only half the dose of salbutamol is required via
Turbuhaler as via Diskhaler for the same bronchodilating effect.
Publication Types:
Clinical Trial
Multicenter Study
Randomized Controlled Trial
Respir Med 1998 Mar;92(3):467-72
The European Respiratory
Society study on chronic obstructive pulmonary disease
(EUROSCOP): recruitment methods and strategies.
Lofdahl CG, Postma DS, Laitinen LA, Ohlsson SV, Pauwels RA, Pride NB.
Department of Pulmonology, University Hospitals of Lund, Sweden.
The European Respiratory
Society's study on chronic obstructive pulmonary
disease (EUROSCOP) is a multicentre study performed initially in 12 countries
to
assess the effect of 3 years' treatment with inhaled corticosteroids on lung
function decline in smokers with chronic obstructive pulmonary disease (COPD).
It aimed at recruiting 50 subjects in 50 European centres. This study discusses
the most successful, countrywise, recruitment strategies, an important issue
since many multicentre European studies may follow in the future. The total
number of recruited subjects was 2147 in 39 participating centres. In total,
at
least 25,000 screening spirometries were performed, and about 80,000 hospital
records were checked. The most effective way of recruiting subjects was to
screen subjects by spirometry after mass media campaigns (eight out of nine
countries). Others used workplace screenings and different types of population
survey, and only a few centres successfully recruited participants by hospital
records. Inclusion criteria were slightly changed upon low initial accrual
rate.
Initial surveys in one country, where 2405 subjects were screened by spirometry,
gave an important indication for the change of the inclusion criteria. Extension
of the upper age limit from 60 to 65 yr considerably improved recruitment,
as
did a change of the upper limit of FEV1 from below 80% predicted normal to
below
100% predicted normal, while maintaining the FEV1/VC ratio below 70%. A
tremendous effort is needed to recruit individuals with preclinical COPD,
but
this is certainly feasible with adequate strategies adjusted to each country.
Publication Types:
Clinical Trial
Multicenter Study
Randomized Controlled Trial
Respir Med 1998 Feb;92(2):325-30
Safety and efficacy
of a high cumulative dose of salbutamol inhaled via
Turbuhaler or via a pressurized metered-dose inhaler in patients with asthma.
Bondesson E, Friberg K, Soliman S, Lofdahl CG.
Astra Draco AB, Lund, Sweden.
An open, crossover
and randomized study was carried out to compare the safety
and efficacy of salbutamol inhaled using the dry-powder inhaler Turbuhaler,
and
using a pressurized metered-dose inhaler (pMDI). Twelve patients with moderate
to severe asthma, aged 47-68 years, were included in the study. On two separate
days, patients received a total dose of 1600 micrograms of salbutamol
administered in a cumulative dose fashion: 100, 100, 200, 400 and 800 micrograms
at 3-min intervals. Salbutamol inhaled via Turbuhaler caused a larger decrease
in serum potassium concentration than did salbutamol inhaled via pMDI. The
estimated relative dose potency of the hypokalaemic effect of salbutamol
Turbuhaler vs salbutamol pMDI was 2.0 with a 95% confidence interval of 1.3-3.6.
Turbuhaler caused a small (but statistically significantly greater than with
pMDI) increase in heart rate, QTc interval and tremor. Blood pressure was
unaffected by the treatments. No adverse events of clinical relevance were
reported. The estimated relative dose potency of the bronchodilating effect
(FEV1) of salbutamol Turbuhaler vs salbutamol pMDI was 3.0 with a 95% confidence
interval of 1.8-5.8. In conclusion, salbutamol inhaled via Turbuhaler was
more
potent and seemed to have a better therapeutic ratio than salbutamol inhaled
via
pMDI. Both treatments were equally well tolerated.
Publication Types:
Clinical Trial
Randomized Controlled Trial
Respir Med 1998 Feb;92(2):167-72
Beta 2-agonists administered
by a dry powder inhaler can be used in acute
asthma.
Nana A, Youngchaiyud P, Maranetra N, Boe J, Lofdahl CG, Selroos O, Stahl E.
Department of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand.
Patients with acute
asthma attending the emergency room were included in a
double-blind, double-dummy and parallel group study to investigate whether
a dry
powder inhaler (Turbuhaler) can be used in acute asthma. If so, the aim was
to
establish the potency relationship between a beta 2-agonist (salbutamol)
administered by the dry powder inhaler and the pressurized metered-dose inhaler
(pMDI). Eighty-six patients with a mean age of 38 years and forced expiratory
volume in 1 s (FEV1) of 37% of predicted normal value were randomized at Siriraj
Hospital in Bangkok to either Turbuhaler (50 micrograms dose -1) or pMDI (100
micrograms dose -1) with spacer (Volumatic). Doses of 100 + 300 + 300 + 300
micrograms salbutamol were given at 0, 15, 30 and 45 min via Turbuhaler and
repeated at 90, 105, 120 and 135 min (total dose 2000 micrograms). The same
inhalation schedule with identical number of doses was used for the pMDI with
spacer but in double doses (total 4000 micrograms), assuming a dose-potency
ratio of salbutamol administered via Turbuhaler compared with the pMDI of
2:1.
At 85 min after the first dose, 60 mg prednisolone was given orally. FEV1
was
measured 10 min after each dosing. Peak inspiratory flow (PIF) through
Turbuhaler was measured on each dosing occasion. Plasma (P)-salbutamol, serum
(S)-potassium concentrations, pulse rate, blood pressure and adverse events
were
recorded. No statistically significant differences were observed in the increase
in FEV1 between the groups: 55 min (165 min) after the first dose, the increase
was 0.47 l and 47% (0.64 l and 63%) in the Turbuhaler group, and 0.46 l and
42%
(0.68 l and 65%) in the pMDI group. Mean PIF though Turbuhaler was 49 l min
-1
(range 26-68) at first inhalation and increased to 60 l min -1 (range 38-86).
There was no correlation between the initial PIF through Turbuhaler and the
initial FEV1 response. P-salbutamol and S-potassium values correlated well.
A
larger decrease in S-potassium was noticed after 75 min in the pMDI group
(0.38
mmol l -1) compared with the Turbuhaler group (0.23 mmol l -1) (P = 0.02).
In
conclusion, the use of a dry powder inhaler, Turbuhaler, was investigated
in the
emergency room treatment of acute asthma, and was as effective as a pMDI with
spacer. Half the dose of salbutamol administered via Turbuhaler was as effective
as the full dose given via a pMDI with spacer.
Publication Types:
Clinical Trial
Randomized Controlled Trial
Eur Respir J 1997 Nov;10(11):2474-8
Differences in bronchodilating
potency of salbutamol in Turbuhaler as compared
with a pressurized metered-dose inhaler formulation in patients with reversible
airway obstruction.
Lofdahl CG, Andersson
L, Bondesson E, Carlsson LG, Friberg K, Hedner J, Hornblad
Y, Jemsby P, Kallen A, Ullman A, Werner S, Svedmyr N.
Division of Pulmonary
Medicine, Sahlgrenska University Hospital, University of
Goteborg, Sweden.
Two studies are presented,
with the aim of establishing the dose potency ratio
for salbutamol given via Turbuhaler and via a pressurized metered-dose inhaler
(pMDI). Both studies were of a double-blind, randomized design. Outpatients
with
mild-to-moderate chronic reversible airway obstruction were given single doses
of salbutamol administered via Turbuhaler and via pMDI. Efficacy and safety
variables were measured before and during 6 h after each dose. The first study
was a four-way crossover study including 12 patients. The salbutamol doses
given
were: 50, 100 and 2x100 microg via Turbuhaler and 2x100 microg via pMDI
(Ventolin). The study showed that 2x100 microg of salbutamol inhaled via
Turbuhaler is more potent than 2x100 microg salbutamol inhaled via a pMDI,
and
that 100 microg salbutamol via Turbuhaler is at least as potent as 2x100 microg
salbutamol inhaled via a pMDI. The second study including 50 patients was
a
placebo-controlled five-way crossover, study. Two doses of salbutamol via
Turbuhaler, 50 and 2x100 microg, and via pMDI, 100 and 2x200 microg, were
given.
There was a dose-dependent response in forced expiratory volume in one second
(FEV1) for both inhalers. Adjusted for differences in baseline FEV1 values,
the
estimated relative dose potency for Turbuhaler versus pMDI was 1.98:1 (95%
confidence interval 12-3.2). These studies showed that the same bronchodilating
effect can be achieved when half the dose of salbutamol given via a conventional
pressurized metered-dose inhaler is given via Turbuhaler.
Publication Types:
Clinical Trial
Randomized Controlled Trial
N Engl J Med 1997 Nov 13;337(20):1405-11
Erratum in:
N Engl J Med 1998 Jan 8;338(2):139
Comment in:
ACP J Club. 1998 May-Jun;128(3):67
N Engl J Med. 1997 Nov 13;337(20):1461-31
N Engl J Med. 1998 Apr 9;338(15):1071-2; discussion 1072.
N Engl J Med. 1998 Apr 9;338(15):1072.
Effect of inhaled
formoterol and budesonide on exacerbations of asthma.
Formoterol and Corticosteroids Establishing Therapy (FACET) International
Study
Group.
Pauwels RA, Lofdahl
CG, Postma DS, Tattersfield AE, O'Byrne P, Barnes PJ, Ullman
A.
Department of Respiratory Diseases, University Hospital, Ghent, Belgium.
BACKGROUND: The role
of long-acting, inhaled beta2-agonists in treating asthma
is uncertain. In a double-blind study, we evaluated the effects of adding
inhaled formoterol to both lower and higher doses of the inhaled glucocorticoid
budesonide. METHODS: After a four-week run-in period of treatment with
budesonide (800 microg twice daily), 852 patients being treated with
glucocorticoids were randomly assigned to one of four treatments given twice
daily by means of a dry-powder inhaler (Turbuhaler): 100 microg of budesonide
plus placebo, 100 microg of budesonide plus 12 microg of formoterol, 400 microg
of budesonide plus placebo, or 400 microg of budesonide plus 12 microg of
formoterol. Terbutaline was permitted as needed. Treatment continued for one
year; we compared the frequency of exacerbations of asthma, symptoms, and
lung
function in the four groups. A severe exacerbation was defined by the need
for
oral glucocorticoids or a decrease in the peak flow to more than 30 percent
below the base-line value on two consecutive days. RESULTS: The rates of severe
and mild exacerbations were reduced by 26 percent and 40 percent, respectively,
when formoterol was added to the lower dose of budesonide. The higher dose
of
budesonide alone reduced the rates of severe and mild exacerbations by 49
percent and 37 percent, respectively. Patients treated with formoterol and
the
higher dose of budesonide had the greatest reductions -- 63 percent and 62
percent, respectively. Symptoms of asthma and lung function improved with
both
formoterol and the higher dose of budesonide, but the improvements with
formoterol were greater. CONCLUSIONS: In patients who have persistent symptoms
of asthma despite treatment with inhaled glucocorticoids, the addition of
formoterol to budesonide therapy or the use of a higher dose of budesonide
may
be beneficial. The addition of formoterol to budesonide therapy improves
symptoms and lung function without lessening the control of asthma.
Publication Types:
Clinical Trial
Multicenter Study
Randomized Controlled Trial
Lakartidningen 1996 Oct 30;93(44):3910, 3915-6
[Reduced lung volume
means better respiration. A new surgical technique for
emphysema in a Swedish study]
[Article in Swedish]
Hillerdal G, Lofdahl
CG, Orre L, Skoogh BE, Gyllstedt E, Strom K, Nilsson F,
Nettelbladt O, Kling PA.
Lungkliniken, Karolinska sjukhuset, Stockholm.
Allergy 1996 Oct;51(10):745-8
Formoterol inhaled
as dry powder or via pressurized metered-dose inhaler in a
cumulative dose-response study.
Ullman A, Lofdahl CG, Melander B, Svedmyr N.
Department of Clinical Pharmacology, Sahlgrenska Hospital, Goteborg, Sweden.
Formoterol administered
by a dry-powder (DP) capsule inhaler was compared with a
pressurized metered-dose inhaler (pMDI) with regard to bronchodilating and
systemic effects. The study used a double-blind, crossover, double-dummy
technique. Twelve patients with moderate reversible asthma in a stable phase
were examined on two separate study days, and the inhalers were given in
randomized order. After baseline measurements, increasing doses of formoterol
were given at intervals of 75 min. FEV1 and heart rate and tremor measurements
were repeated after each dose, and the doses were 12 + 12 + 24 + 48 micrograms,
giving a total dose of 96 micrograms. The peak expiratory flow rate (PEFR)
was
recorded in the morning before the first dose, after the last dose, and then
repeatedly at home until 19 h after the last dose. There was an equal increase
in ventilatory capacity at each dose level, independent of inhaler device.
Repeated PEFR measurements after the last dose did not reveal any differences
in
duration of effect. There was a slight but statistically significant increase
in
heart rate and tremor after the highest doses of the DP formulation compared
to
the pMDI. These systemic effects can probably be explained by the reduced
oral
deposition of the aerosol caused by using a spacer. This study indicates that
the DP and pMDI formulations of formoterol are equipotent in bronchodilation.
Publication Types:
Clinical Trial
Randomized Controlled Trial
J Pharmacol Exp Ther 1996 Jul;278(1):268-76
U46619 (a thromboxane
A2 mimetic) induces airflow obstruction and airway plasma
extravasation in the guinea pig: the role of histamine, cyclooxygenase
metabolites, leukotrienes and PAF.
Kawikova I, Arakawa H, Skoogh BE, Lofdahl CG, Lotvall J.
Department of Respiratory
Medicine and Alergology, University of Goteborg,
Sweden.
The aim of the present
study was to characterize the airway effects of U46619, a
stable thromboxane A2 mimetic, instilled into the trachea of guinea pigs in
vivo, and to investigate the role of different mediators in these effects.
The
airflow obstruction was evaluated by measurement of airway insufflation pressure
(P1) and plasma extravasation by quantification of Evans Blue dye (EBD) in
airways. U46619, given as a single dose to each animal (1 pmol-10 nmol), caused
a dose-dependent increase in P1 and extravasation of EBD. The threshold dose
required to induce an increase in P1 was 30 times lower than the threshold
dose
necessary to evoke EBD extravasation. The role of inflammatory mediators was
studied when 10 pmol (inducing only the increase in P1) or 10 nmol (inducing
the
increase in both P1 and EBD extravasation) of U46619 was administered. The
effects of both doses of U46619 were abolished by ICI192,605, an antagonist
of
prostanoid receptor for thromboxane A2 (0.5 mg/kg i.v.). The airflow obstruction
induced by 10 nmol of U46619 was potentiated by indomethacin, a cyclo-oxygenase
inhibitor (10 mg/kg i.v.). EBD extravasation induced by 10 nmol U46619 was
attenuated by BW70C (6 mg/kg i.v.), a selective 5-lipoxygenase inhibitor,
by
ICI198,615 (0.5 microgram/kg i.v.), a leukotriene D4/E4 receptor antagonist
and
by WEB2086 (1 mg/kg i.v.) a platelet-activating factor receptor antagonist.
Pyrilamine (2 mg/kg i.v.), a histamine H1 receptor antagonist, did not have
any
influence on U46619-induced airway effects. We conclude that U46619 possesses
a
higher potency in the induction of airflow obstruction than in the induction
of
plasma extravasation and that U46619-induced plasma extravasation may be partly
mediated via leukotrienes and platelet-activating factor.
Br J Pharmacol 1996 Mar;117(6):1009-15
Extent of salmeterol-mediated
reassertion of relaxation in guinea-pig trachea
pretreated with aliphatic side chain structural analogues.
Bergendal A, Linden A, Skoogh BE, Gerspacher M, Anderson GP, Lofdahl CG.
Institute of Physiology and Pharmacology, Goteborg University, Sweden.
1. Salmeterol is a
potent, selective and long acting beta 2-adrenoceptor
agonist. In vitro, salmeterol exerts 'reassertion' relaxation of airways smooth
muscle. Reassertion relaxation refers to the capacity of salmeterol to cause
repeated functional antagonism of induced contraction when airway smooth muscle
is intermittently exposed to, then washed free from, beta-adrenoceptor
antagonists such as sotalol. The mechanism(s) underlying reassertion relaxation
are unknown but may relate to high affinity binding of the long aliphatic
side
chain of salmeterol to an accessory site, distinct from the agonist recognition
site, in or near the beta 2-adrenoceptor (exosite binding hypothesis). 2.
In
order to test the exosite hypothesis, three pure analogues of salmeterol,
each
exactly preserving the molecular structure of the aliphatic side chain but
with
zero or low efficacy at the beta 2-adrenoceptor were synthesized. The effect
of
pre-incubating guinea-pig tracheal smooth muscle with these analogues on
salmeterol-induced reassertion relaxation was determined. 3. Computer Assisted
Molecular Modelling of these molecules revealed that each of them exactly
preserved the low energy linear conformation of the aliphatic side chain of
salmeterol. Measurement of lipophilicity (octanol:water partition coefficient;
log P) and direct partition into synthetic membranes (membrane partition
coefficient; Kpmem) showed that all compounds had high affinity for lipids
and
membranes. In particular the biophysical properties of CGP 59162 (log P 1.89,
Kpmem 16500) were very similar to salmeterol (log P 1.73, Kpmem 16800). 4.
Two
of the analogues, CGP 54103 and D 2543 (1 microM), which are structural mimics
of the side chain of salmeterol, differing slightly in their length, did not
prevent either the initial relaxation induced by salmeterol (0.1 microM) or
the
reassertion relaxation; however, it was not possible to determine whether
either
of these molecules occupied the beta 2-adrenoceptor. 5. The third analogue,
CGP
59162, which has the substituents on the active saligenin head group of
salmeterol in transposed positions, itself exerted a weak beta
2-adrenoceptor-mediated relaxation antagonized by ICI 118551 (beta 2-selective
antagonist) but not CGP 20712 (beta 1-selective antagonist) and, at higher
concentrations CGP 59162 caused reassertion relaxation suggesting that it
may
occupy and activate the beta 2-adrenoceptor in a manner analogous to salmeterol.
6. CGP 59162, at concentrations up to ten fold molar excess, did not prevent
or
reduce salmeterol-induced reassertion relaxation. 7. In conclusion these data
are not consistent with the existence of a distinct 'exosite' recognising
the
aliphatic side chain of salmeterol mediating reassertion.
Lung 1996;174(1):1-22
Pharmacological basis
for duration of effect: formoterol and salmeterol versus
short-acting beta 2-adrenoceptor agonists.
Linden A, Rabe KF, Lofdahl CG.
Division of Pulmonary
Medicine, Sahlgrenska Hospital, University of Gothenburg,
Sweden.
The mechanisms behind
the long duration of bronchodilating action of the beta
2-adrenoceptor agonists formoterol and salmeterol are only partially understood.
This review compares pharmacological characteristics of long-acting versus
short-acting beta 2-adrenoceptor agonists in human and animal airways. Based
upon the reviewed evidence, it is concluded that for beta 2-adrenoceptor
agonists, long duration of action may depend upon several factors. Both
formoterol and salmeterol display a higher lipophilicity and have a higher
affinity, selectivity, and potency than most short-acting agonists at the
beta
2-adrenoceptor. Of these factors, lipophilicity may prove to be one of the
most
important ones by determining the amount of drug entering into the cell membrane
in the vicinity of the beta 2-adrenoceptor. However, the receptor affinity,
maximal relaxant effect (efficacy or intrinsic activity), potency, and receptor
selectivity may also be of importance in determining how much beta
2-adrenoceptor agonist must remain at the receptor for sustained action.
Publication Types:
Review
Review, Tutorial
Pharmacol Toxicol 1996 Jan;78(1):3-11
The use of beta 2-adrenoceptor agonists in the treatment of bronchial asthma.
Svedmyr N, Lofdahl CG.
Division of Clinical
Pharmacology, Sahlgrenska University Hospital, Goteborg,
Sweden.
All guidelines recommend
short-acting inhaled beta 2-adrenoceptor agonists as
the first-line drugs in acute asthma attacks and inhaled corticosteroids as
the
drugs of choice when regular daily treatment is needed. Short-acting inhaled
beta 2-adrenoceptor agonists are not effective in reducing nocturnal awakenings
because of their short duration of action. In addition there has been an intense
debate about the regular use of these drugs. This debate is reviewed. They
should only be used on "as needed basis". The Swedish guidelines
for the
treatment of asthma were the first to recom
