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Oral Presentation Asthma bs_bs_banner Respirology (2014) 19 (Suppl. 3), 1–62 doi: 10.1111/resp.12416 O-A-003 ORAL PRESENTATION – ASTHMA TRACHEOBRONCHIAL WALL VESSEL REMODELING AND ENDOTHELIAL CELL ACTIVATION IN A MURINE O-A-001 ASTHMA MODEL PLUME TEMPERATURE AND FORCE OF FLUTICASONE SU X, YU N, KONG L, KANG J PROPIONATE/FORMOTEROL pMDI COMPARED WITH Department of Respiratory Disease, the First Hospital of China Medical FLUTICASONE PROPIONATE/SALMETEROL pMDI University, Shenyang, China 1 2 3 JOHAL B , TUOHY J , MARSHALL J Background and Purpose: Vascular changes in asthma include Increasing 1 2 Mundipharma Research Ltd, Cambridge, UK, Prior PLM Medical, Carrick in vessel number/unit area and increasing in vessel activity: namely vasodila- 3 on Shannon, Co., Leitrim, Ireland, Mundipharma International Ltd, tation, leakage, and cell migration to target tissue. These changes will lead to Cambridge, UK airway wall thickening and reduced air flow. With these backgrounds in mind, we attempted to obtain in-depth information on microvascular network of Background: Aerosol inhaler characteristics such as low plume temperature bronchial walls and the phenotypes of their endothelial cells in a mouse model and high force may result in greater impaction of drug in the mouth and throat of asthma. and reduced lung deposition.1 This study compared plume temperature and Methods: Male BALB/C mice were initially immunized intraperitoneally four force of two ICS/LABA combination products: fluticasone propionate/formoterol times with ovalbumin (OVA) + aluminum hydroxide gel (on weeks 0, 4, 5, 7). 125/5 μg (flutiform®, FP/FORM) and fluticasone propionate/salmeterol 125/ Subsequently, the OVA inhalations were done everyday for 1 week (early 50 μg (Seretide®, FP/SAL), delivered via metered-dose inhalers. phase) or 5 weeks (prolonged phase). Untreated mice were used for normal Methods: Inhalers were held in a fixed device and operated according to control subjects. The mice were perfused with FITC-dextran through the manufacturers’ instructions. A thermal imaging video camera, operating at 30 ascending aorta to probe tracheobronchial wall microvascular network. frames per second, recorded plume temperature from the side of the device. Tracheobronchial tissues were obtained and examined by light and laser The same test rig, with a copper disc attached to a sensitive load cell measured confocal microscopy. plume force over a range of distances 25 mm to 95 mm from the device. Results: We confirmed that the tracheobronchial walls underwent Results: At 25 mm the FP/FORM plume was +6°C, while that of the FP/SAL remodeling as indicated by epithelial cell metaplasia (mucin producing type), plume was −38°C. The FP/SAL plume was colder over a longer distance. The sub-epithelial edema, and inflammatory cell infiltration. Capillary networks force of the FP/SAL plume was greater than that of the FP/FORM device at all increased and became dilated and endothelial cells proliferated as judged by distances measured: mean force recorded for FP/SAL was 218.0 mN com- Ki67 positivity in the early phase. Normal capillaries in the cartilage zone pared to 104.0 mN for FP/FORM. showed the phenotype of TM (previously shown) and CD31 positive, but not Conclusion: The FP/SAL plume was considerably colder than the FP/FORM vWF, aSMA, or Desmin positive phenotype. Endothelial cell phenotypes plume particularly over shorter distances. The FP/SAL plume was more force- changed into vWF, aSMA, and Desmin positive phenotype, suggesting a ful, approximately twice that of the FP/FORM device. These differences may transformation into the phenotype of microvessels like venule or arteriole. be due to different types of HFA propellant with different boiling points, the Conclusion: The vascular remodeling confirmed in the mouse model of excipients in each formulation, and actuator geometry. The plume character- asthma provides evidence that this model may be used for further studies to 1) istics of the FP/FORM device may facilitate lung deposition and lessen impac- analyse serum components of coagulation factors related, 2) identify key tion in the throat. players in the bronchial microvascular remodeling, and 3) provide novel targets for therapeutic interventions. Reference: 1 Gabrio BJ. Int J Pharm 1999;186:3–12 Sponsor: MUNDIPHARMA RESEARCH LTD O-A-002 THERAPEUTIC EFFECTS OF HISTONE DEACETYLASE ENZYME 6 INHIBITORS (HDAC6I) IN A MURINE ASTHMA MODEL REN Y, SU X, KANG J Department of Respiratory Disease, The First Hospital of China Medical University, Shenyang, China Background and Purpose: Airway inflammation, airway remodeling and airway hyperresponsiveness are major aspects of asthma pathology. Histone deacetylase inhibitors have a broad effects that demonstrate therapeutic effects in animal models of chronic inflammatory diseases. In this study, we investigated the effects of Tubastatin A Hcl, a selective HDAC6 inhibitor, on the development of chronic allergic airway disease mice with airway inflammation, airway remodeling and airway hyperresponsiveness. Methods: Wild-type BALB/C mice were sensitized intraperitoneally three times with ovalbumin (OVA) and aluminum hydroxide gel (on weeks 0, 1, 2) and nebulized 1 week (early phase) or 8 weeks (prolonged phase). Ovalbumin- exposed mice were treated with Tubastatin A Hcl or vehicle control. Airway inflammation was assessed by bronchoalveolar lavage fluid cell counts and HE staining of lung tissue sections. Airway remodeling was assessed by Alcian blue-Periodic acid Schiff staining and Masson trichrome staining. Airway hyperresponsiveness was assessed by plethysmography measurement of airway resistance. Results: Tubastatin A Hcl treatment reliefed airway inflammation compared with vehicle treated mice (P < 0.05), but its effect was worse than dexametha- sone treatment. However, Tubastatin A Hcl treatment reduceded the thickening of airway smooth muscle (P < 0.05), the quantity of goblet cell (P < 0.05) and subepithelial collagen deposition (P < 0.05). Moreover, Tubastatin A Hcl treat- ment attenuated airway resistance (P < 0.05). Conclusion: These results demonstrate that treatment with HDAC6 inhibi- tors can reduce airway inflammation, airway remodeling and airway hyperresponsiveness, suggesting that blockage of HDAC6 may be a useful treatment for bronchial asthma. © 2014 The Authors Respirology © 2014 Asian Pacific Society of Respirology 2 Respirology (2014) 19 (Suppl. 3), 1–62 O-A-004 O-A-005 OMALIZUMAB IMPROVES QUALITY OF LIFE AND A NOVEL THROMBOXANE A2 RECEPTOR INHIBITOR, ASTHMA CONTROL IN CHINESE PATIENTS WITH SERATRODAST SHOWS GREATER IMPROVEMENT IN PEAK MODERATE-TO-SEVERE ASTHMA: A RANDOMIZED EXPIRATORY FLOW, EXPECTORATION SCORE, SPUTUM PHASE III STUDY EOSINOPHIL CATIONIC PROTEIN AND ALBUMIN LEVELS AS COMPARED TO MONTELUKAST IN A DOUBLE BLIND LI J1, KANG J2, CANVIN J3, WANG C4, ZHONG Nanshan1, YANG J5, COMPARATIVE CLINICAL TRIAL HUMPHRIES M5 1State Key Laboratory of Respiratory Disease, The First Affiliated Hospital, DEWAN B, NAVALE S, SHAH D Guangzhou Medical University, Guangzhou, China, 2Institute of Respiratory Zuventus Healthcare Limited, Chandivali Mumbai, India Disease, First Hospital of China Medical University, Shenyang, China, 3Novartis Pharmaceuticals UK Ltd, Horsham, UK, 4Department of Background: Thromboxane A2 (TXA2) has shown to play an important role Respiratory Disease, Xinqiao Hospital, Third Military Medical University, in the pathogenesis of asthma. Various international guidelines recommend Chongqing, China, 5Primary Care, Beijing Novartis Pharma Co. Ltd, China controller therapy for mild to moderate persistent asthma. Seratrodast, a spe- cific TXA2 receptor antagonist, given orally, has demonstrated consistent Introduction: Omalizumab, an anti-IgE monoclonal antibody, has been benefit in controlling symptoms of asthma. Therefore, we designed a found to be effective and safe in the treatment of patients of different ethnicities randomized, double blind, double dummy, multi-centre, parallel group study with moderate-to-severe allergic asthma. We report here the effect of with non inferiority design to assess the efficacy, safety and tolerability of omalizumab on the quality of life, asthma control and safety in Chinese patients seratrodast versus montelukast, a leukotriene receptor antagonist, in control- with moderate to severe allergic asthma. ling mild to moderate asthma in adult patients. Methods: This was a randomized, double blind, parallel group, placebo Methods: Patients (n = 205) with mild to moderate asthma continuing on the controlled, phase III study to assess the quality of life, asthma control and lowest dose of inhaled corticosteroid were recruited from 3 different centers safety of 24 weeks of omalizumab therapy in Chinese patients, aged 18−75 across India. Patients were randomly assigned to receive either seratrodast years, with moderate-to-severe persistent allergic asthma. Asthma Quality of 80 mg (n = 103) or montelukast 10 mg (n = 102) once daily for 28 days. The Life Questionnaire (AQLQ) and Asthma Control Questionnaire (ACQ) scores objective was to compare the treatments in terms of improvement from the were assessed at baseline and at week 24. Asthma exacerbation rates were baseline values, as per the changes in asthma symptom score (wheezing, also analysed. shortness of breath, expectoration, cough and chest tightness), lung function Results: Among the 608 patients included in the full analysis set, at week 24 parameters (PEF, FVC and FEV1), sputum and mucociliary parameters a higher proportion of patients treated with omalizumab
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