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					Thematic Poster Session                                                                                                                        Hall 3-32 - 12:50-14:40
                                                              T UESDAY, S EPTEMBER 21 ST 2010

                                                                                          Conclusion: Allergen-induced Th2-cytokines and RNA profiles can be repro-
                                                                                          ducibly quantified using sensitive detection techniques in ultracentrifuged sputum
                                                                                          and cell pellets, respectively. This response is blunted by FP. This methodology
                                                                                          offers possibilities for evaluation of targeted anti-asthma drugs.

                                                                                          Basement membrane, eosinophilic inflammation and urinary LTE4 in cough
                                                                                          variant asthma and GER-induced chronic cough
                                                                                          Claudio Micheletto, Silvia Tognella, Fiorenza Trevisan, Stefano Bertacco,
                                                                                          Marilia Visconti, Roberto Dal Negro. Respiratory Unit, Orlandi Hospital,
                                                                                          Bussolengo, VR, Italy

                                                                                          Cough variant asthma (CVA) and GER ares known as two major causes of chronic
                                                                                          cough. CVA is regarded as a precursor of asthma, being the eosinophilic inflam-
                                                                                          mation the pathologic feature of the condition. Cys-leukotrienes (LTs) are products
                                                                                          of the arachidonic acid cascade, synthesised in inflammatory cells, particularly in
                                                                                          eosinophils. Urinary leukotriene E4 (LTE4 ) reflects the whole body production of
                                                                                          cys-LTs. It could be hypothesized that the pathophysiology of CVA may involve
                                                                                          the activation of cys-LTs.
                                                                                          Aim: to compare the Basal Membrane Thickness (BMT); eosinophil count (EOS)
                                                                                          and Eosinophil Cationic Protein (ECP) in BAL, and urinary LTE4 in patients with
                                                                                          CVA and GER-induced chronic cough (CC-GER)
                                                                                          Methods: after their informed consent, 14 patients with CC-GER (18–37y, 7m.,
                                                                                          FEV1 = 96.6% pred ± 6.3sd, negative MCh) and 8 patients with CVA (22 -34 y,
                                                                                          4m, FEV1 = 99.8% pred. ± 7.6sd, MCh = 1990 PD20 FEV1 ± 230 sd), underwent
                                                                                          an endobronchial biopsy + BAL. Urine were collected for the quantitative LTE4
                                                                                          immunoenzimatic assay (Cayman Chemical, Mi, USA). Statistics: t test, p<0.05

                                                                                                                      CC-GER                     CVA                    p
                                                                                          FEV1 (%pred.)             96.6% ± 6.3sd              99.8±7.6                ns
                                                                                          BMT (μm)                     2.1±1.9                 4.2 ± 2.7             < 0.05
                                                                                          EOS (%)                      0.6±0.1                 6.3±2.6               < 0.001
                                                                                          ECP (ng/ml)                10.87±12.32              227.2±89.3             < 0.001
                                                                                          LTE4 (pg/ml)                133.4±45.1             445.6±345.9             < 0.02

                                                                                          Conclusions: 1) early GER-induced cough is not characterized by eosinophilic
                                                                                          inflammation and substantial LTs production; 2) the extent of eosinophilic in-
                                                                                          flammation proves significantly greater in CVA; 3) CVA should be regarded as a
                                                                                          condition leading to the future remodelling of bronchial structures.

402. Pharmacological modulation of biomarkers
             and management

Reproducible measurements of Th2-cytokines and RNA gene expression
obtained in sputum from patients with allergic asthma following allergen

Marcella Ruddy 1 , Catherine Triboulay 1 , Robert Zuiker 3 , Neil Morelli 3 ,
George Tokiwa 1 , Robin Mogg 1 , Veronica Rivas 1 , Kristian Van Dyck 3 , Inge De
Lepeleire 3 , Michael Tanen 1 , Arnoldo Pica-Mendez 1 , Peter Hu 1 , Vlad Malkov 1 ,
Zuzana Diamant 4 . 1 Early Stage Development and Molecular Profiling, Merck
Research Laboratories, Rahway, New Jersey, United States; 2 Early Stage
Development, Merck, Sharp,& Dohme, Brussels, Belgium; 3 Respiratory, Centre
for Human Drug Research, Leiden, Netherlands; 4 Allergology & Pulmonology,
Erasmus MC, Rotterdam, Netherlands
                                                                                                            W      IT
Rationale Allergen challenge (AC) allows evaluation of anti-inflammatory drug
effect, though few readouts are pathway-specific.
Aim: To evaluate the reproducibility of AC-induced sputum Th2-cytokines and
gene expression and their response to fluticasone (FP).
Methods: Following a placebo run-in, 13 asthmatics participated in a randomized,
placebo (P)-controlled, cross-over study. Subjects randomly inhaled FP (5x500
mcg) or P pre- until 24 h post-allergen. At 24 h pre- and 7 & 24 h post-allergen, spu-
tum was induced, split into 2 parts (A+B): A) ultracentrifuged and Th2-cytokines
were measured by a multiplex platform; B) RNA was isolated from cell pellets,
amplified by NUGEN and profiled on Affymetrix arrays. Effects of FP vs P on
allergen-induced changes in cytokine levels and gene expression were analyzed by
a mixed ANCOVA.
Results: At 7 h post-allergen, sputum IL-13, IL-5 and eotaxin-3 were increased
by 9.76, 5.67 and 2.24-fold, resp. (all p<0.001), with reductions by FP of 89%
(p<0.001), 83% (p<0.001) and 45%, resp. (p=0.01). Fold changes between the
placebo run-in and treatment periods indicated good reproducibility (observed
range 0.7 to 1.6). Allergen also increased sputum gene expressions of IL-13, IL-5
and IL-4 by 7.73, 5.57 and 5.98-fold, resp. (all p<0.001) with reductions by FP of
88%, 91% and 84%, resp. (all p<0.001).

                      Abstract printing supported by Chiesi Farmaceutici SpA. Visit Chiesi Farmaceutici SpA. at Stand G.90
Thematic Poster Session                                                                                                                      Hall 3-32 - 12:50-14:40
                                                           T UESDAY, S EPTEMBER 21 ST 2010

P4577                                                                                P4579
Predictive factors for asthma control according to ACQ5 in asthma patients           Relationship between airway response to direct and indirect challenges and
treated with budesonide/formoterol maintenance and reliever therapy.                 eosinophilic airways inflammation in elite athletes
Results from the EuroSMART study                                                     Neil Martin 1 , Martin Lindley 2 , Bev Hargadon 1 , Will Monteiro 1 , Ian Pavord 1 .
Michel Aubier 1 , Roland Buhl 2 , John Haughney 3 , Juliette Ostinelli 4 ,           1
                                                                                       Institute for Lung Health, Glenfield Hospital, Leicester, Leicestershire, United
Tommy Ekström 5 , Leif Jörgensen 5 , Onno C.P. van Schayck 6 . 1 Service de          Kingdom; 2 Human Sciences, Loughborough University, Loughborough,
Pneumologie A, Hôpital Bichat, Paris, France; 2 Pulmonary Department, Mainz          Leicestershire, United Kingdom
University Hospital, Germany; 3 Centre of Academic Primary Care, University of
Aberdeen, Aberdeen, Scotland, United Kingdom; 4 Medical Department,                  Sports bodies advocate objective demonstration of airway dysfunction prior to use
Astrazeneca France, Rueil-Malmaison, France; 5 Medical Department,                   of asthma treatment in elite sport. Indirect challenge tests may be best as they are
Astrazeneca Sweden, Södertälje, Sweden; 6 Maastricht University/CAPHRI,              thought to induce bronchoconstriction via inflammatory pathways and relate more
Maastricht University, Netherlands                                                   closely to eosinophilic, steroid responsive inflammation. We set out to test this
                                                                                     hypothesis in a cohort of 26 elite athletes.
Background: EuroSMART, an open, randomised, 6-month budesonide/formoterol            All subjects had symptoms of exercise asthma and were steroid naïve or withdrew
(BUD/FORM) maintenance and reliever therapy (Symbicort SMART®                        steroids for ≥ 4 weeks. They completed a symptom score, exhaled nitric oxide
Turbuhaler® ) study (NCT00463866), compared two maintenance doses of                 (FENO ), methacholine PC20 , induced sputum eosinophil count (eos), mannitol
BUD/FORM 160/4.5 μg, 1x2 and 2x2, in asthma patients (n=8053) with symptoms          PD15 (n=19), eucapnic voluntary hyperventilation (EVH) (n=19) and standardized
when treated with ICS or ICS+LABA. The study showed that lung function was           laboratory exercise challenge (n=16) ≥ 48 hours apart.
a predictor for a better response to 2x2 vs. 1x2 in terms of time to first severe     Meth PC20 and % fall FEV1 after EVH had significant correlation with log sputum
asthma exacerbation.                                                                 eos % (r=-0.46, p=0.002; r=0.66, p=0.002). Mannitol PD15 and % change FEV1
Methods: To determine which factors may predict a better response to 2x2 in          after exercise did not (r=-0.19, p=0.4; r=0.15, p=0.6). A 10% drop in FEV1 after
terms of change in the 5-item asthma control questionnaire (ACQ5 ), the following    EVH was sensitive (100%) but not specific (42%) for sputum eos >3%. A 25%
baseline factors were used in a univariate Cox regression analysis: gender, age,     drop was the optimum (sens 86%; spec 83%). There was close correlation between
BMI, duration of asthma, exacerbations in the preceding year, PEF, FEV1 , number     log FENO and log sputum eos % (r=0.73, p<0.001), the optimum being FENO >45
of as-needed SABA inhalations/day, smoking status, use of LABA and change in         ppb (sens 63%; spec 89%). A composite of >10% fall FEV1 after EVH and FENO
PEF from baseline.                                                                   >45 ppb was best predictor of sputum eos >3% (sens 75%; spec 91%).
Results: A clinically relevant improved response (>0.5 ACQ5 units) to 2x2 vs.        Our findings suggest a complex relationship between airway responsiveness and
1x2 in ACQ5 was found for patients with BMI >40 kg/m2 (0.6% of patients),            eosinophilic airway inflammation in elite athletes. FENO was closely related to
those who used >6 SABA inhalations/day (1.1%), those with an ICS dose >1600          eosinophilic airway inflammation and might be the best way to identify corticos-
μg budesonide eq/day (1.2%) and patients with an ACQ5 >4 (2.1%). Patients            teroid responsive disease either alone or in combination with EVH.
with a BMI >40 kg/m2 were predominantly female. Other factors did not predict
a better response to 2x2.
Conclusion: Overall a small proportion of patients benefited selectively from the     P4580
2x2 compared with 1x2 regimen. Predictive factors for a better response to the 2x2   Associations between clinical, laboratory and therapeutical parameters on
than 1x2 regimen were ACQ5 , number of as-needed inhalations or steroid dose at      admission and adverse outcomes in patients hospitalized for COPD
baseline. Females with a high BMI formed a cluster where the higher dose (2x2)       exacerbations
was beneficial for improving ACQ5 .                                                   Andriana Papaioannou 1 , Konstantinos Bartziokas 1 , Markos Minas 1 ,
                                                                                     Aikaterini Haniotou 2 , Konstantinos Gourgoulianis 1 , Konstantinos Kostikas 1 .
                                                                                       Respiratory Medicine Department, University of Thessaly Medical School,
P4578                                                                                Larissa, Greece; 2 Respiratory Medicine Department, Amalia Fleming General
Sodium cromoglycate inhibits release of mast cell mediators and                      Hospital, Athens, Greece
bronchoconstriction following hyperpnea in athletes
Johan Larsson 1 , Pascale Kippelen 3 , Sandra Anderson 4 , John Brannan 4 ,          Background: COPD exacerbations (ECOPD) represent a significant burden to
Barbro Dahlén 2 , Sven-Erik Dahlén 1 . 1 Division of Physiology, The National        patients and health systems. Several parameters have been identified as risk factors
Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden;       for adverse outcomes during ECOPD.
  Division of Respiratory Medicine and Allergy, Department of Medicine,              Aims and objectives: To identify clinical, laboratory and therapeutical predictors
Karolinska University Hostpital Huddinge, Stockholm, Sweden; 3 Centre for            of short term outcomes in ECOPD.
Sports Medicine and Human Performance, Brunel University, West London,               Methods: We studied 245 patients hospitalized for ECOPD included in a longitu-
United Kingdom; 4 Department of Respiratory and Sleep Medicine, Royal Prince         dinal study on the role of statins on long-term outcomes. Patients’ characteristics
Alfred Hospital, Camperdown, Australia                                               and medication (including statins) prior to admission, laboratory and physical ex-
                                                                                     amination parameters were recorded. COPD severity and optimal treatment were
Background: The role of mast cells in the airway response to exercise and the        based on GOLD guidelines. Length of hospitalization, requirement for mechanical
benefit of sodium cromoglycate (SCG) in athletes is unclear.                          ventilation and mortality were evaluated.
Aims and objectives: To clarify the role of mast cell mediators in the airway        Results: In hospital mortality was 11.4% and median hospital stay was 8 days.
response to exercise in athletes and to investigate the effect of SCG.               26.7% of survivors had prolonged hospitalization. Factors related to prolonged
Methods: Eleven athletes with exercise-induced bronchoconstriction (EIB+) and        hospitalization were the level of dyspnea on admission (p=0.002), GOLD stage
eleven without (EIB-) performed an eucapnic voluntary hyperpnea (EVH) test (a        (p=0.001), and prior use of long-term oxygen therapy (p=0.019). Short-term sur-
surrogate for exercise) 10 min after inhalation of placebo or 40 mg of the mast      vival from ECOPD was related to GOLD stage (p=0.011), hematocrit on admission
cell stabilizing agent sodium cromoglycate (SCG). The urinary concentrations of      (p<0.001), smoking history (p=0.017), and optimal treatment before admission
9α,11β-PGF2 (a metabolite of PGD2 and marker of mast cell activation) and LTE4       (p=0.012). Requirement for mechanical ventilation was related to white blood
were measured by enzyme immunoassay 60 min before and for 90 min after               cell count (p=0.041), hemoglobin (p=0.002) and arterial blood pH on admission
challenge.                                                                           (p=0.05).
Results: In the EIB+ group, the maximum fall in forced expiratory volume in          Conclusions: Short-term adverse outcomes during ECOPD are related to different
1 s (FEV1 ) of 20.3±3% on placebo was reduced to 11.5±1.9% following SCG             clinical, laboratory and therapeutical parameters on admission. Global assessment
(P=0.003). There was an increase in the urinary excretion of 9α,11β-PGF2 on the      of COPD patients and development of clinical models are crucial for proper
placebo day after EVH in both groups (P<0.05) that was abolished by SCG. In the      evaluation of ECOPD.
EIB+ group, there was also an increase of urinary LTE4 on the placebo day that
was abolished by SCG, whereas the urinary excretion of LTE4 was inconsistent in
the EIB- group.                                                                      P4581
Conclusion: The results support mast cell activation with release of bronchocon-     Paradoxical trough effects of ’triple therapy’ on pulmonary function
strictive mediators following hyperpnea in athletes, with and without EIB, and       outcomes in COPD
inhibition of this release by SCG. The findings suggest that development of bron-     Peter A. Williamson, Philip M. Short, Karine L. Clearie, Sriram Vaidyanathan,
choconstriction after EVH requires increased airway responsiveness to the released   Tom C. Fardon, Laura Howaniec, Brian J. Lipworth. Asthma and Allergy
mediators.                                                                           Research Group, University of Dundee, Dundee, United Kingdom
Sponsors: The Swedish Heart Lung Foundation, MRC and Stockholm Count
Council Research Funds (ALF).                                                        Background: The period of lowest receptor occupancy for a drug is at trough, prior
                                                                                     to the next dose. Previous studies have focussed on the effects of ’triple therapy’
                                                                                     at peak dose intervals using forced expiratory manoeuvres. Impulse oscillometry
                                                                                     (IOS) and body plethysmography (PLETH) are more sensitive than spirometry to
                                                                                     assess inhaled therapies in COPD.
                                                                                     Methods: 19 COPD patients (FEV1/FVC<0.7, FEV1<60%) completed a double-
                                                                                     blind randomised crossover trial of tiotropium (TIO) 18μg/day or placebo for
                                                                                     2wks in a crossover fashion, with a 1wk washout. Prior to randomisation there
                                                                                     was a 4wk run-in of Symbicort 200/6 2puffs bid which continued throughout.
                                                                                     Spirometry, IOS and PLETH were performed pre and post Symbicort run-in, and

                     Abstract printing supported by Chiesi Farmaceutici SpA. Visit Chiesi Farmaceutici SpA. at Stand G.90
Thematic Poster Session                                                                                                                         Hall 3-32 - 12:50-14:40
                                                           T UESDAY, S EPTEMBER 21 ST 2010

at trough following the first and last dose of TIO; i.e. 24h post TIO and 12h post    on 4 visits: at baseline (no cough or mannitol), with mannitol (240 and 480
Symbicort.                                                                           mg) and cough control (no mannitol) over total of 90 min using a radioaerosol
Results: Mean (SEM) age and FEV1 were 65 (2) years and 42%(2) respectively.          technique and imaging with a gamma camera. Cough clearance was assessed after
Following initial Symbicort there were no significant changes in spirometry, how-     MCC by asking subjects to cough 100 times over last 30 minutes. Premedication
ever all measures of IOS and PLETH deteriorated (p<0.01 for all outcomes).           with eformoterol (12 μg) on all visits protected all subjects from significant
Compared to placebo, TIO was additive to Symbicort after single and chronic dos-     bronchoconstriction (fall in FEV1>15%) in response to mannitol.
ing measured by FEV1 (p<0.001, p=0.014 respectively) and FEF25-75 (p=0.001,          Results: Mean (±SD) clearance over 60 min increased from 5.5±5.6% at baseline
p=0.026); while sRaw, X5, RF and AX showed additive benefits at single dose           and 7.3±6.6% with cough control to 19.5±14.6% and 26.4±11.5% with 240mg
only.                                                                                (p<0.003) and 480 mg (p<0.0001) of mannitol respectively. Total clearance
Conclusions: Treatment with Symbicort caused an unexpected worsening of IOS          (MCC+CC) over 90 min increased from 6.9±6.5% (baseline) and 12.6±8.3%
and PLETH outcomes compared to a washed-out baseline, not seen on spirometry.        without mannitol (cough control) to 34.6±13.5 and 36.6±10.4% with 240 and 480
Subsequent addition of TIO improved lung function outcomes with all techniques       mg mannitol respectively (p<0.0001). Clearance over 90 min at baseline was not
after single dose, but only for spirometry after chronic dosing. These paradoxical   significantly different to cough control (p>0.05). Mannitol improved clearance in
findings may reflect β2ADR down-regulation and M3 receptor crosstalk.                  all lung regions (p<0.005).
                                                                                     Conclusions: Inhaled mannitol improves mucociliary and cough clearance in
                                                                                     asthmatics with mucociliary dysfunction and ineffective cough clearance.
Proof of concept study to evaluate step down therapy with inhaled
corticosteroid alone or additive therapy on surrogate inflammatory markers            P4584
in asthma                                                                            The effect of phosphogliv admission on exhaled nitric oxide level in patients
Lorna McKinlay, Peter A. Williamson, Philip M. Short, Brian J. Lipworth. Asthma      with bronchial asthma
& Allergy Research Group, University of Dundee, Dundee, United Kingdom               Alexander Lisitsa, Igor Klimanov, Svetlana Soodaeva. Clinical and Experimental
                                                                                     Biophysics, Pulmonology Research Institute, Moscow, Russian Federation
Background: The use of serum ECP and exhaled nitric oxide are traditional
research tools in tertiary centres for asthma and although guidelines recommend      Background: Phosphogliv (Russia) is a new liposomal preparation containing
stepping down inhaled steroids to achieve the lowest effective maintenance dose,     phosphatidylcholine and glycirrizinic acid. It demonstrates an antioxidant activity
it is unclear as to whether such inflammatory markers may be used to guide dose       in the treatment of various diseases, confirmed both by experimental and clinical
reduction.                                                                           studies.
Methods: A parallel double blind study was performed in 18 mild-moderate             Aim: The aim is to carry out a prospective study of antioxidant features of new
asthmatics. Subjects were divided into two groups following high dose ICS            liposomal preparation Phosphogliv in patients with bronchial asthma.
(FP500BID). Group A; fixed dose ICS (Fluticasone proprionate FP250BID)                Materials and methods: We enrolled 30 patients (age=27.3 year, men=56%) with
vs Group B; ICS alone (125BID) or in combination with add on therapies               mild bronchial asthma (FEV1≤80%, steroid-naive) in prospective comparison
(FP/Salmeterol (SM) 125/25BID) or FP 125BID and montelukast 10 mg. AMP               study. All patients were divided in two groups: group 1 contains 15 nonsmokers
challenge, serum ECP, FENO , PFTs were recorded.                                     and group 2 contains 15 smokers. Phosphogliv inhalation by compression nebulizer
Results: No differences seen in inflammatory measures between fixed dose ICS           has been performed once a day (300 mg of phospholipids in each admission) during
and reduced dose ICS alone or with combination therapies.                            10 days. Antioxidant activity was determined by the estimation of the exhaled
                                                                                     nitric oxide level (ENO) before and after the investigation period. Exhaled NO
                                                                                     level was measured by the chemiluminescence analyzer (Logan Research 2149,
                                                                                     Great Britain) daily before and after the inhalation of Phosphogliv.
                                                                                     Results: After observing period there was a significant decrease of ENO level in
                                                                                     both groups. The ENO level in group 1 was decreased from 27.8±8.4 to 2.1±4.4
                                                                                     ppb (p<0.001); in group 2 from 9.7±3.9 ppb to 5.0±2.5 (p<0.001).
                                                                                     Conclusion: The results obtained demonstrate that Phosphogliv administrated
                                                                                     once a day during 10-days period has a significant antioxidant effect in patients
                                                                                     with mild bronchial asthma both in smokers and non-smokers.

                                                                                     Lipopolysaccharide challenge in healthy smokers
                                                                                     Raminder Aul, Jane Armstrong, Rachel Dockry, Ashley Woodcock, Dave Singh.
                                                                                     University of Manchester, Medicines Evaluation Unit, University Hospital of
                                                                                     South Manchester, United Kingdom

                                                                                     Introduction: LPS inhalation causes neutrophilic airway inflammation in healthy
                                                                                     non smokers. We studied LPS challenge in healthy smokers (HS).
                                                                                     Aims: To assess the effects of inhaled LPS challenges in HS; specifically safety
                                                                                     and sputum cell counts.
                                                                                     Methods: We recruited 12 HS (>10 pack years). Subjects had baseline sputum
                                                                                     induction. LPS challenge was performed with 5μg and 30μg administered at least
                                                                                     2 weeks apart. Vital signs and FEV1 were monitored for 6 hours. Sputum induction
                                                                                     was performed 6 and 24 hours post LPS.
                                                                                     Results: There was a mean maximum fall in FEV1 of 8.2% and 13.9% and mean
                                                                                     temperature rise of 0.51°C and 0.9°C from baseline post 5 and 30μg LPS inhalation
                                                                                     respectively (p<0.05). Total cell count, differential and absolute neutrophil count
Conclusions: AMP challenge conferred no additional benefit in guiding step down       significantly increased post LPS challenge (Table 1). Differential macrophage
therapy. The role of inflammatory surrogates to monitor and guide therapy remains     count was decreased.
                                                                                     Table 1 (medians)

                                                                                                                      Baseline   5μg - 6H   5μg - 24H   30μg - 6H   30μg - 24H
The effect of inhaled mannitol and cough in asthmatics with mucociliary              Total cells, 106                  2.69       11.46      15.36*      23.35*       9.99*
dysfunction                                                                          Neutrophil, %                     61.38      80.81*     70.93*      83.69*       69.63*
Evangelia Daviskas 1 , Sandra Anderson 1 , Stefan Eberl 2 , Iven Young 1 .           Absolute neutrophil count, 106    1.86       8.40*      9.68*       18.49*       6.50*
1                                                                                    Macrophage, %                     29.38      12.25*       29        13.38*         19
  Respiratory and Sleep Medicine, Royal Prince Alfred Hospital, Sydney, NSW,
Australia; 2 PET and Nuclear Medicine, Royal Prince Alfred Hospital, Sydney,         *p<0.05.
NSW, Australia
                                                                                     Conclusions: LPS challenges are safe and lead to neutrophilic airway inflammation
Background: Asthmatics with hypersecretion of mucus have impaired mucocil-           in healthy smokers.
iary clearance (MCC) leading to mucus plugs and airway obstruction. Inhaled
mannitol improves mucus hydration and clearance of mucus in other diseases.
We investigated the effect of mannitol and cough in asthmatics with mucociliary
Methods: Seven stable asthmatics, age 52±20 yr, lifelong non-smokers, without
the diagnosis of bronchiectasis, with chronic cough and sputum production, treated
with ICS participated in the study. MCC and cough clearance (CC) was measured

                     Abstract printing supported by Chiesi Farmaceutici SpA. Visit Chiesi Farmaceutici SpA. at Stand G.90
Thematic Poster Session                                                                                                                     Hall 3-32 - 12:50-14:40
                                                            T UESDAY, S EPTEMBER 21 ST 2010

P4586                                                                                 All 41 patients reported improved ease of sputum clearance with a median 3 point
Monitoring of monoclonal antibody therapy with a new recovery ELISA                   increase on a 10 unit Visual Analogue Scale.
assay technique (R-ELISA® )                                                           49% reported increase in sputum volume.
Pavel Strohner 1 , Antonia Staatz 1 , Astrid Schäfer 1 , Gunther Becher 2 ,           10 patients had baseline oxygen saturation ≤95% with ≥ 2% rise on HTS.
Dieter Sarrach 1 , Jens Reich 3 , Jens-Oliver Steiss 4 , Thomas Häupl 5 . 1 R&D,      59% reported an increase in quality of life on a Juniper mini asthma quality of
BioTeZ Berlin GmbH, Berlin, Germany; 2 R&D, BecherConsult GmbH, Bernau,               life questionnaire (mean 0.6 unit rise overall and 1.0 for responders; rise of > 0.5
Germany; 3 Molecular Medicine, Max-Delbrueck Institut, Berlin, Germany;               units is significant).
  Dept. Pediatrics, Univ. Giessen, Germany; 5 CCM Clinic Rheumatology, Charite,       Mean FEV1/FVC rose slightly from 1.7/2.5 to 1.8/2.7. (Mann Whitney test NS)
Berlin, Germany                                                                       All patients had a noticeable improvement in their condition (12% reported “life
                                                                                      changing improvement”).
Introduction: Therapy with monoclonal antibodies (mAb) is becoming a very             Conclusion: Despite standard therapies some adults with bronchiectasis have per-
effective therapeutic method. More than 10 mAb’s are already in clinical use. The     sistent troublesome hypersecretion. Two thirds of our patients reported a significant
therapeutic targets are specific proteins which are correlated with certain diseases   improvement in symptoms using HTS and, for some, this was life changing. This
like asthma, tumors, rheuma, e.g. Traditional ELISA are disturbed by therapeutic      audit suggests that Mucoclear® is a viable option but controlled trials are needed.
antibodies in blood.
Methods: An in-vitro test procedure was developed for the estimation of both the
therapeutic antibody and the antigen in serum samples. In samples of unknown          P4589
composition the recovery was estimated from the addition of a certain amount of       Difficulties of recurrent bronchoobstructive syndrome treatment in pediatric
the antigen.                                                                          patients with remote sequelae of bronchopulmonary dysplasia
Results: R-ELISA was performed in samples of patients treated with Omalizumab         Oksana Matsyura, Lesya Besh. Allergology, Lviv City Children’s Clinical
(Xolair)/IgE or with Adalimumab (HUMIRA)/TNF-a. Actual levels of antibodies,          Hospital, Ukraine
e.g. Xolair or Humira, and free antigen in serum were measured.
In asthmatic patients treated with Omalizumab® (n=7) was found a mean total           Delivery of adequate treatment and organization of appropriate follow-up for
IgE of 783±864 IU/mL before and of 14±23 IU/mL 4 weeks after injection. The           pediatric patients with remote sequelae of bronchopulmonary dysplasia (BPD) are
recovery of added IgE was 100% in samples before treatment, resp. 3±2% in             urgent problems of contemporary medicine.
presence of the mAb.                                                                  Purpose: The purpose of the work was to analyze the efficacy of recurrent bron-
The re-finding of added Omalizumab was reduced to 32% 4 weeks after injection.         choobstructive syndrome (BOS) treatment in children with remote sequelae of
In patients with rheumatoid arthritis, treated with HUMIRA® , were found free         BPD.
TNF-a (ng/mL) concentrations of 4,3±6 before and 4,2±9 after injection, respec-       Study group: 72 children with recurrent BOS, aged 6 months to 12 years, who
tively. The recovery of added TNF-a was 100% before injection and about 1% 4          were provided mechanical ventilation in the neonatal period. Investigation was
weeks after injection of HUMIRA. The remaining HUMIRA-concentration was               conducted in 2 groups of patients, consisting of 36 individuals each. Group I
about 10 μg/mL 4 wks. after injection.                                                (study) included children with BPD development in the neonatal period vs group
Discussion: The R-ELISA enables the monitoring of therapeutic antibodies and          II (control) that included ones without BPD.
the target antigen during treatment. Irregular recovery also will give a hint for     Methods: Assessment of the patients included immunological investigation (serum
auto-antibodies, side effects and for necessary correction of dose.                   IgA, IgM, IgG, IgE); modified test with bronchial spasmolytic; chest X-ray exam-
                                                                                      ination. Efficacy of therapy was estimated before the treatment and on the 6th and
                                                                                      12th weeks of therapy.
P4587                                                                                 Results: Patients of group I required administration of repeated courses of high
Nebulised 7% hypertonic sodium chloride improves lung function and airway             doses of systemic and inhalation glucocorticoid drugs, antibiotic therapy and ad-
clearance in non cystic fibrosis bronchiectasis                                        ministration of cholinolithics. Control of the disease was achieved in 47,2% (17)
Fiona Kellett 1 , Robert Niven 2 . 1 Independent Practitioner, Stockton Heath and     group I and 66,7% (24) group II.
Lymm Physiotherapy Clinic, Warrington, Cheshire, United Kingdom; 2 North West         Conclusions: 1. BPD is not only neonatological but a general pediatric problem.
Lung Centre, University Hospital of South Manchester & The University of              Therapeutic protocol of recurrent BOS treatment in patients with and remote
Manchester, United Kingdom                                                            sequelae of BPD can be recommended for wide application in the clinical pediatric
Background: Sputum retention is a distressing feature of non cystic fibrosis
bronchiectasis and is arguably the most important factor in maintaining the vi-
cious cycle of infection. A previous study (Kellett et al, 2005) demonstrated that    P4590
nebulised 7% saline (HS) was both safe and effective in this patient popula-          Key attributes of inhalers for patients versus physicians
tion.                                                                                 Nicolas Roche 1 , Mark Small 2 , David Price 3 . 1 Pneumologie et Réanimation,
Methods: Patients with a clinical diagnosis of non CF bronchiectasis, confirmed        Hôtel-Dieu, Paris, France; 2 Adelphi Real World, Adelphi Group, Macclesfield,
by HRCT, were entered into a randomised single blind cross over study to evaluate     United Kingdom; 3 Centre of Academic Primary Care, University of Aberdeen,
0.9% soduium chloride (IS) and 7% HS. Following a 4 week run in patients              Aberdeen, United Kingdom
received in a random order, active HS or IS daily for 3 months. A 4 week wash
out phase was included between phases. We report lung function, health care           Background: Inhalation is the preferred route of drug administration in bronchial
utilisation and sputum clearance measures.                                            diseases such as asthma and COPD. Correct inhalation technique is key to op-
Results: 30 patients mean age 56.6 years (SD14.6), 16 male, were recruited 28         timise lung deposition and therapeutic effect. Dry powder inhalers (DPIs) were
completed the study. There were reductions in annualised antibiotic usage (HS 2.4,    developed to ease inhalation by patients. It is important to identify which inhaler
IS 5.4 courses per patient per year). Annualised emergency health care utlisation     characteristics drive physician choice and which are the main barriers to patient
visits were reduced (HS 2.1, IS 4.9 events per patient per year). Lung function       adherence.
(% change from baseline) improved in HS v IS (Fev1: 15.1, -1.8% p<0.01; FVC           Objectives and methods: A multinational, cross-sectional survey was conducted
11.2, -0.7 p<0.01). There were also significant improvements in sputum viscosity       in 2008 to investigate perceptions of patients (n=928) and physicians (n=355) on
and ease of expectotation (visual analogue scale).                                    key inhaler attributes. Physicians were asked to rate the importance of inhaler
Conclusion: HS improves lung function, health care utilisation and airway sputum      characteristics and invited up to six asthma patients to fill out a questionnaire.
clearance in non CF bronchiectasis patients with regular use.                         Results: Physician top 5 priorities for an inhaler device were: simple and easy
                                                                                      instructions (83%), same lung delivery every time (82%), minimal effort needed
                                                                                      to inhale drug (73%), easy to hold and portable (71%), and consistent penetration
P4588                                                                                 to lower and peripheral airways (69%).
Audit of once daily nebulised hypertonic 6% saline (HTS) in adult                     Areas of inhaler dissatisfaction most frequently mentioned by patients were: lack
bronchiectasis                                                                        of feedback when the dose has been inhaled correctly (44%), change in inhaler
Helen Pyne, Binita Kane, Ronan O’Driscoll. Respiratory Medicine, Salford Royal        with each prescription (25%), need to breathe hard to inhale the dose (25%), lack
University Hospital, United Kingdom                                                   of dose counter (24%), and inconsistent dose delivered in each inhalation (22%).
                                                                                      Conclusions: Both physicians and patients identify key issues with inhalers that
Background/Objectives: Nebulised hypertonic 7% saline enhances sputum clear-          are not restricted to metered dose inhalers (MDIs) but also apply to DPIs (e.g., need
ance in patients with bronchiectasis and hypersecretion (Kellett F et al Respir Med   to breathe hard to inhale the dose). Patient satisfaction should thus be accounted
2005; 99:27-31) but is not licensed for this purpose. It is expensive to produce,     for when choosing an inhaler.
has short shelf life and is difficult to administer. Mucoclear® 6% saline does not
have these negative features so we wished to evaluate its clinical benefits.
Method: Patients with troublesome bronchiectasis were invited for a nebulised
6% HTS challenge. If no adverse reaction occurred, they administered HTS once
daily for 2 months.
Results: 60 patients were assessed over 18 months.
Ten had bronchospasm after HTS, 9 did not wish to continue treatment and 41
patients reported an initial positive response and self-administered 6% HTS daily
for two months.

                     Abstract printing supported by Chiesi Farmaceutici SpA. Visit Chiesi Farmaceutici SpA. at Stand G.90
Thematic Poster Session                                                                                                                    Hall 3-32 - 12:50-14:40
                                                             T UESDAY, S EPTEMBER 21 ST 2010

P4591                                                                                   for pharmacokinetic (PK) interactions when ROF is coadministered with typical
Patient-reported outcomes (PROs) and reliever use in Japanese and                       representatives of drug classes commonly used in COPD.
European patients with chronic obstructive pulmonary disease receiving                  Methods: Drug–drug interaction studies of ROF with antibiotics, bronchodilators,
formoterol 4.5 and 9μg twice daily: Results of the OCEAN phase III study                inhaled corticosteroids and other medications commonly prescribed in COPD were
Masakazu Ichinose 1 , Hisamichi Aizawa 2 , Yoshinosuke Fukuchi 3 ,                      analysed for PK parameters of ROF, RNO and concomitant drugs. Safety outcomes
Michiaki Mishima 4 , Masaharu Nishimura 5 , Miron Bogdan 6 . 1 Wakayama                 were evaluated throughout each study.
Medical School, Wakayama Medical University, Wakayama, Japan; 2 Medical                 Results: PK results are summarised in the table below. No clinically relevant
School, Kurume University, Japan; 3 Medical School, Juntendo University, Tokyo,         interactions were observed for ROF and RNO with any of the coadministered
Japan; 4 Medical School, Kyoto University, Japan; 5 Medical School, Hokkaido            drugs. The use of rifampicin may reduce the therapeutic efficacy of ROF. No
University, Sapporo, Japan; 6 Medicina Interna Pneumologie, Clinica Medic Or,           safety concerns were revealed and coadministration of ROF was generally well
Bucharest, Romania                                                                      tolerated with each drug class.

Background: We evaluated the secondary endpoints of PROs and reliever medica-
tion use in Japanese and European patients (pts) with COPD receiving formoterol         Coadministered drug                           Result
4.5 and 9μg twice daily (bid).                                                          Rifampicin                     Decreased AUC and Cmax (ROF and RNO)
Methods: In this double-blind phase III study, pts ≥40 years of age with moderate       Erythromycin                               No interaction
to severe COPD were randomised to formoterol 4.5 or 9μg bid via Turbuhaler®             Enoxacin                                  Weak interaction
or placebo for 12 weeks. Salbutamol 100μg/actuation via pMDI was used as a              Salbutamol                                 No interaction
reliever medication (inhalations/day). PROs were assessed using the St George’s         Formoterol                                 No interaction
Respiratory Questionnaire (SGRQ).                                                       Montelukast                                No interaction
Results: 613 pts received treatment (4.5μg n=206; 9μg n=199; placebo n=208);            Budesonide                                 No interaction
539 (88%) male; 324 (53%) Japanese. Formoterol 4.5 and 9μg bid significantly             Warfarin                                   No interaction
improved SGRQ total score vs. placebo; there was no significant difference be-           Midazolam                                  No interaction
                                                                                        Digoxin                                    No interaction
tween the two formoterol groups (Table). The proportion of pts with an SGRQ
                                                                                        Sildenafil                                  No interaction
improvement of ≥4 was 50.2% for formoterol 4.5μg (p=0.0682 vs. placebo),
                                                                                        Antacid                                    No interaction
59.2% (p=0.0004) for 9μg, and 41.3% for placebo. For salbutamol use, formoterol
9μg bid was statistically significantly superior to 4.5μg bid (Table).
                                                                                        Conclusions: ROF is generally well tolerated when coadministered with other
Differences (ratio) between treatments                                                  medications likely to be prescribed to COPD patients. ROF treatment in common
Variable                   9μg vs. Placebo     4.5μg vs. Placebo       9μg vs. 4.5μg    polypharmacy of COPD patients can be initiated with once-daily doses of 500 μg.
SGRQ total score           -4.448 (<0.001)      -3.741 (0.001)         -0.707 (0.553)
Use of salbutamol          -0.548 (<0.001)      -0.274 (0.027)         -0.274 (0.029)

Conclusion: Both formoterol 4.5μg and 9μg bid significantly improved SGRQ
total scores and reduced reliever medication use in Japanese and European pts
with COPD, with some added value for 9μg bid compared with 4.5μg bid.

Airway resistance assessed by impulse oscillometry at varying respiratory
rate and the effect of pretreatment with short-acting β2 agonist in COPD
Hiroshi Iwamoto, Yoshinori Haruta, Misa Nakagawa, Shintaro Miyamoto,
Noboru Hattori, Nobuoki Kohno. Department of Molecular and Internal
Medicine, Graduate School of Biomedical Sciences Hiroshima University, Japan

Background: In COPD patients, tachypnea is commonly observed on exertion.
It may further exacerbate exertional dyspnea, but the underlying mechanism is
undetermined yet.
Objectives: This study was conducted to examine airway resistance at varying
respiratory rate and evaluate the effect of short-acting β2 agonist (SABA) on
airway resistance during hyperventilation in COPD patients.
Methods: Airway resistance was measured in 12 COPD patients during baseline
breathing and metronome-paced hyperventilation using impulse oscillometry. The
effects of SABA (100 mcg x 3 puffs of salbutamol or 10 mcg x 2 puffs of pro-
caterol) on airway resistance was assessed in 6 moderate to severe COPD patients
receiving 18 mcg of tiotropium bromide daily.
Results: Resistances of total (R5) and distal airways (R5-R20) significantly in-
creased at respiratory rate (RR) of 20 (p < 0.05), 30 (p < 0.01), and 40/min (p
< 0.005) compared with those at baseline breathing. In particular, significant in-
creases in distal airway resistance were observed during expiration. Only procaterol
significantly reduced hyperventilation-induced increase in airway resistances of
total (R5 at RR40 – R5 at baseline, p < 0.05) and distal airways (R5-R20 at RR40
– R5-R20 at baseline, p < 0.05). Both SABA significantly reduced reactance at 5
Hz at RR40 (p < 0.05).
Conclusions: Elevation in airway resistance of distal airway during expiration was
induced by hyperventilation. This condition may aggravate air-trapping on exertion
in COPD patients. Pretreatment (so-called “assist-use”) with SABA, especially
procaterol, may attenuate airway resistance induced by tachypnea.

Roflumilast in coadministration with medications commonly prescribed for
COPD: An overview of existing studies
Gezim Lahu 1 , Udo-Michael Goehring 2 , Andreas Hünnemeyer 1 , Nassr Nassr 3 .
  Department of Pharmacometrics and Pharmacokinetics, Nycomed GmbH,
Konstanz, Germany; 2 Department of Medical Scientific Strategy & Medical
Marketing, Nycomed GmbH, Konstanz, Germany; 3 Department of Exploratory
Clinical Sciences, Nycomed GmbH, Konstanz, Germany

Background/Rationale: Roflumilast (ROF) is an oral, selective phosphodiesterase
4 (PDE4) inhibitor developed for anti-inflammatory treatment of COPD. It is
catalysed by cytochrome P450 (CYP) 1A2 and 3A4 to its active metabolite
roflumilast N-oxide (RNO). This analysis evaluated the safety and the potential

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