Ashley Woodcock

University Hospital Of South Manchester NHS Foundation Trust, Manchester, England, United Kingdom

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Publications (215)1917.64 Total impact

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    ABSTRACT: Neuroplasticity of bronchopulmonary afferent neurons that respond to mechanical and chemical stimuli may sensitize the cough reflex. Afferent drive in cough is carried by the vagus nerve and vagal afferent nerve terminals have been well defined in animals. Yet, both unmyelinated C-fibres and particularly the morphologically distinct, myelinated, nodose derived, mechanoreceptors described in animals are poorly characterized in humans. To date there are no distinctive molecular markers nor detailed morphologies available for human bronchopulmonary afferent nerves. Morphological and neuromolecular characterization of the afferent nerves that are potentially involved in cough in humans Methods: A whole mount immunofluorescence approach, rarely employed in human lung tissue, was used, utilizing antibodies specific to protein gene product 9.5 (PGP9.5) and, for the first time in human lung tissue, 200kDa neurofilament subunit. We have developed a robust technique to visualize fibres consistent with autonomic and C-fibres as well as pulmonary neuroendocrine cells. A group of morphologically distinct, 200kDa neurofilament immunopositive myelinated afferent fibres, a sub-population of which did not express PGP9.5 were also identified. PGP9.5 immuno-negative nerves are strikingly similar to myelinated airway afferents; the cough receptor and smooth muscle associated airway receptors described in rodents. These have never before been described in humans. Full description of human airway nerves is critical to the translation of animal studies to the clinical setting.
    American Journal of Respiratory and Critical Care Medicine 04/2015; DOI:10.1164/rccm.201412-2293OC · 11.99 Impact Factor
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    ABSTRACT: We created Asthma e-Lab, a secure web-based research environment to support consistent recording, description and sharing of data, computational/statistical methods and emerging findings across the five UK birth cohorts. The e-Lab serves as a data repository for our unified dataset and provides the computational resources and a scientific social network to support collaborative research. All activities are transparent, and emerging findings are shared via the e-Lab, linked to explanations of analytical methods, thus enabling knowledge transfer. eLab facilitates the iterative interdisciplinary dialogue between clinicians, statisticians, computer scientists, mathematicians, geneticists and basic scientists, capturing collective thought behind the interpretations of findings. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
    Thorax 03/2015; DOI:10.1136/thoraxjnl-2015-206781 · 8.56 Impact Factor
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    ABSTRACT: Background The inhaled corticosteroid fluticasone furoate (FF) in combination with the long-acting β2-agonist vilanterol (VI) is under development for the treatment of asthma and chronic obstructive pulmonary disease. Objective To compare the efficacy and safety of FF-VI and FF in patients (≥12 years old) with persistent asthma. Methods In a randomized, double-blind, parallel-group study, patients (n = 609) (intent-to-treat population) received FF-VI 100-25 mcg, FF 100 mcg, or placebo once daily (evening) by using a dry powder inhaler for 12 weeks. Coprimary end points were change from baseline in trough FEV1 and serial (0-24 hours) weighted mean FEV1 (wmFEV1). Rescue-free 24-hour periods and safety also were assessed. Results Placebo increased trough FEV1 (196 mL) and wmFEV1 (212 mL) versus baseline. Compared with placebo, FF-VI and FF significantly improved trough FEV1 (172 mL [P < .001] and 136 mL [P = .002]), respectively, and serial wmFEV1 (302 mL [P < .001] and 186 mL [P = .003]), respectively. Treatment differences between FF-VI and FF approached significance for serial wmFEV1 (116 mL; P = .060) but not for trough FEV1 (36 mL; P = .405). The percentage of rescue-free 24-hour periods with FF-VI was 10.6% greater than FF and 19.3% greater than placebo. Statistically significant (P = .032) urinary cortisol suppression was observed with FF-VI (ratio, 0.82) relative to placebo, but not with FF. Adverse event and safety profiles were similar across treatment groups. Conclusions Significant improvement in lung function was observed with FF-VI and FF versus placebo in patients with persistent asthma. Improvement of FEV1 when VI was added to FF was not significant. The high placebo response in evening trough FEV1 may have influenced the assessment of efficacy.
    09/2014; DOI:10.1016/j.jaip.2014.02.010
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    ABSTRACT: Background Fluticasone furoate (FF) is a novel, once-daily inhaled corticosteroid (ICS) that has been shown to improve lung function vs. placebo in asthma patients. This study evaluated the efficacy and safety of FF 50 mcg compared with placebo in asthma patients uncontrolled by non-ICS therapy.Methods This 12-week, multicentre, randomized, double-blind, placebo-controlled, parallel-group, phase III study randomized 248 patients (aged ¿12 years) to once-daily FF 50 mcg administered via the ELLIPTA¿a dry powder inhaler or placebo. The primary endpoint was change from baseline in pre-dose evening trough forced expiratory volume in one second (FEV1). Secondary endpoints were change from baseline in percentage of rescue-free 24-h periods (powered), evening and morning peak expiratory flow, symptom-free 24-h periods and withdrawals due to lack of efficacy. Other endpoints included Asthma Control Test¿, Asthma Quality of Life Questionnaire and ELLIPTA ease of use questions. Safety was assessed throughout the study.ResultsThere was a significant difference in evening trough FEV1 between FF 50 mcg and placebo (treatment difference: 120 mL; p¿=¿0.012). There was also a significant difference in rescue-free 24-h periods (11.6%; p¿=¿0.004) vs. placebo. There were numerically greater improvements with FF vs. placebo for all remaining secondary endpoints. The incidence of adverse events was lower with FF (31%) than with placebo (38%); few were treatment-related (FF 50 mcg: n¿=¿1, <1%; placebo: n¿=¿4, 3%).ConclusionFF 50 mcg once daily significantly improved FEV1 and percentage of rescue-free 24-h periods experienced over 12 weeks vs. placebo, and was well tolerated.Trial registration www.clinicaltrials.gov, registration number: NCT01436071.
    Respiratory research 08/2014; 15(1):88. DOI:10.1186/s12931-014-0088-z · 3.38 Impact Factor
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    ABSTRACT: Inhaled corticosteroids are a mainstay of therapy for persistent asthma, but suboptimal adherence with twice-daily use is widespread. Fluticasone furoate (FF) is a new inhaled corticosteroid (ICS) suitable for once-daily dosing in asthma. This study was performed to descriptively assess the efficacy and safety of two doses of FF, with no planned formal statistical hypothesis testing.
    BMC Pulmonary Medicine 07/2014; 14(1):113. DOI:10.1186/1471-2466-14-113 · 2.49 Impact Factor
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    ABSTRACT: Background Inhalation of capsaicin, the extract of hot chili peppers, induces coughing in both animals and human subjects through activation of transient receptor potential vanilloid 1 (TRPV1) on airway sensory nerves. Therefore the TRPV1 receptor is an attractive target for the development of antitussive agents. Objective We sought to assess the antitussive effect of TRPV1 antagonism in patients with refractory chronic cough. Methods Twenty-one subjects with refractory chronic cough (>8 weeks) attending a specialist clinic were recruited to a randomized, double-blind, placebo-controlled crossover trial assessing a TRPV1 antagonist (SB-705498). Cough reflex sensitivity to capsaicin (concentration of capsaicin inducing at least 5 coughs) and 24-hour cough frequency were coprimary end points assessed after a single dose of SB-705498 (600 mg) and matched placebo. Cough severity and urge to cough were reported on visual analog scales, and cough-specific quality of life data were also collected. Results Treatment with SB-705498 produced a significant improvement in cough reflex sensitivity to capsaicin at 2 hours and a borderline significant improvement at 24 hours compared with placebo (adjusted mean difference of +1.3 doubling doses at 2 hours [95% CI, +0.3 to +2.2; P = .0049] and +0.7 doubling doses at 24 hours [95% CI, +0.0 to +1.5; P = .0259]). However, 24-hour objective cough frequency was not improved compared with placebo. Patient-reported cough severity, urge to cough, and cough-specific quality of life similarly suggested no effect of SB-705498. Conclusion This study raises important questions about both the role of TRVP1-mediated mechanisms in patients with refractory chronic cough and also the predictive value of capsaicin challenge testing in the assessment of novel antitussive agents.
    The Journal of allergy and clinical immunology 07/2014; DOI:10.1016/j.jaci.2014.01.038 · 11.25 Impact Factor
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    ABSTRACT: Background Inhaled glucocorticosteroids (ICS) are the mainstay of treatment in asthma. Fluticasone furoate (FF) is a novel, once-daily ICS asthma therapy. This study investigated the efficacy and safety of FF 50mcg in patients with mild to moderate persistent asthma.MethodsA 24-week, multicenter, randomized, placebo- and active-controlled, double-blind, double-dummy, parallel-group, phase III study. 351 patients (aged ≥12 years; uncontrolled by non-ICS therapy) were randomized to treatment (1:1:1) with once-daily FF 50mcg dosed in the evening, twice-daily fluticasone propionate (FP) 100mcg or placebo. The primary endpoint was change from baseline in evening trough forced expiratory volume in 1s (FEV1) at Week 24. Secondary endpoints were change from baseline in the percentage of rescue-free 24h periods (powered endpoint), change from baseline in evening and morning peak expiratory flow, change from baseline in the percentage of symptom-free 24h periods and number of withdrawals due to lack of efficacy.ResultsEvening trough FEV1 at Week 24 was not statistically significantly increased with FF 50mcg once daily (37mL [95% CI: –55, 128]; P=0.430), but was with FP 100mcg twice daily (102mL [10, 194]; P=0.030), versus placebo. No consistent trends were observed across other endpoints, including the powered secondary endpoint. No safety concerns were raised for either active treatment.ConclusionsFP 100mcg twice-daily improved evening trough FEV1 in patients with mild to moderate persistent asthma, but FF 50mcg once–daily did not demonstrate a significant effect. Secondary endpoints showed variable results. No safety concerns were identified for FF or FP.This article is protected by copyright. All rights reserved.
    Allergy 07/2014; 69(11). DOI:10.1111/all.12480 · 6.00 Impact Factor
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    ABSTRACT: Current maintenance therapies for asthma require twice-daily dosing. Vilanterol (VI) is a novel long-acting beta2 agonist, under development in combination with fluticasone furoate, a new inhaled corticosteroid (ICS). Findings from a previous 4-week study suggested that VI has inherent 24-hour activity and is therefore suitable for once-daily dosing. The study described here was a double-blind, double-dummy, randomised, placebo-controlled trial, the aim of which was to assess the efficacy of once-daily VI compared with placebo in patients with persistent asthma. The primary endpoint was change from baseline in 24-hour weighted mean forced expiratory volume in 1 second after 12 weeks of treatment vs. placebo. An active control arm received salmeterol (SAL) twice daily. All patients were maintained on a stable background dose of ICS.
    Journal of Negative Results in BioMedicine 06/2014; 13(1):9. DOI:10.1186/1477-5751-13-9 · 1.47 Impact Factor
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    ABSTRACT: Combination therapy with an inhaled corticosteroid (ICS) and long-acting β2 agonist (LABA) is recommended for patients with asthma symptomatic on ICS alone. However, there is ongoing debate regarding the risk-benefit ratio of using LABA in asthma. To evaluate the effect of the addition of a novel LABA, vilanterol (VI), to a once-daily ICS, fluticasone furoate (FF), on the risk of severe asthma exacerbations in patients with uncontrolled asthma. This randomised double-blind comparative study of variable duration (≥24-78 weeks) was designed to finish after 330 events (each patient's first on-treatment severe asthma exacerbation). 2019 patients with asthma aged ≥12 years with ≥1 recorded exacerbation within 1 year were randomised and received FF/VI 100/25 μg or FF 100 μg, administered once daily in the evening. The primary endpoint was time to first severe exacerbation; secondary endpoints were rate of severe asthma exacerbations per patient per year and change in trough evening forced expiratory volume in 1 s (FEV1) from baseline. Compared with FF, FF/VI delayed the time to first severe exacerbation (HR 0.795, 95% CI 0.642 to 0.985) and reduced the annualised rate of severe exacerbations (rate reduction 25%, 95% CI 5% to 40%). Significantly greater improvements in trough FEV1 (p<0.001) were observed with FF/VI than with FF at weeks 12, 36, 52 and at endpoint. Both treatments were well tolerated with similar rates of treatment-related adverse events and on-treatment serious adverse events. Once-daily FF/VI reduced the risk of severe asthma exacerbations and improved lung function compared with FF alone, with good tolerability and safety profile in adolescents and adults with asthma currently receiving ICS. NCT01086384.
    Thorax 11/2013; 69(4). DOI:10.1136/thoraxjnl-2013-203600 · 8.56 Impact Factor
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    ABSTRACT: Inhaled corticosteroids (ICSs) improve asthma disease control; once-daily ICS administration may have advantages for patients. Our objective was to assess the efficacy and safety of the novel ICS fluticasone furoate (FF) over 24 weeks versus placebo. This was a 24-week double-blind, double-dummy, placebo- and active-controlled study (NCT01159912) of 343 asthma patients (≥12 years) not controlled by their current ICS. Patients were randomised (1:1:1) to FF100 μg, placebo (both administered once-daily [OD] via ELLIPTA™ dry powder inhaler in the evening) or fluticasone propionate (FP) 250 μg (administered twice-daily (BD) via DISKUS™/ACCUHALER™). Primary endpoint was change from baseline in pre-dose evening forced expiratory volume in 1s (FEV1) at Week 24; change from baseline in % rescue-free 24-h periods was a powered secondary endpoint. Adverse events (AEs) were assessed. FF100 μg OD and FP250 μg BD significantly improved pre-dose evening FEV1 compared with placebo at Week 24 (+146 ml [p = 0.009] and +145 ml [p = 0.011], respectively). Percentage of rescue-free 24-h periods was increased with FF100 μg OD (+14.8%) and FP250 μg BD (+17.9%) compared to placebo (both p < 0.001). On-treatment AEs were reported by 53% (FF100 μg OD), 42% (FP250 μg BD) and 40% (placebo) of patients. On-treatment severe asthma exacerbations were lower with FF100 μg OD (3%) and FP250 μg BD (2%) than placebo (7%). There was significant suppression of urinary cortisol at week 24 with FF100 μg OD (p = 0.030) and FP250 μg BD (p = 0.036) relative to placebo. FF100 μg OD, administered in the evening, achieves significant improvements in lung function and rescue inhaler use over 24 weeks, comparable to FP250 μg BD with similar safety profile.
    Respiratory medicine 11/2013; 108(1). DOI:10.1016/j.rmed.2013.11.009 · 2.92 Impact Factor
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    ABSTRACT: The inhaled corticosteroid fluticasone furoate (FF) and the long-acting β2 agonist vilanterol (VI) are in development as a combined once-daily therapy for asthma and COPD. Study objectives were to compare the efficacy and safety of once-daily FF/VI with FF alone and twice-daily fluticasone propionate (FP) in patients ≥12 years of age with moderate-to-severe persistent asthma.Patients (N=586) received FF/VI 200/25 μg or FF 200 μg once-daily (evening dosing), or FP 500 μg twice-daily for 24 weeks. Co-primary endpoints: change from baseline in trough FEV1; weighted mean (wm) 0-24 h serial FEV1. Secondary endpoints included change from baseline in percentage rescue-free 24-h periods, percentage symptom-free 24-h periods and Total Asthma Quality of Life Questionnaire (AQLQ). Safety assessments included adverse events (AEs), 24 h urinary cortisol (UC) excretion, vital signs and ECG.FF/VI significantly improved trough FEV1 and wm FEV1 versus FF and FP. Significantly more rescue-free and symptom-free 24-h periods were reported with FF/VI versus FF. Treatment differences for AQLQ were not significant. Incidence of AEs was similar across groups. No clinically significant differences were seen for 24 h UC excretion, vital signs or ECG.FF/VI resulted in statistically greater improvements in lung function and symptomatic endpoints versus FF, and was well tolerated in this asthma population.
    European Respiratory Journal 10/2013; DOI:10.1183/09031936.00064513 · 7.13 Impact Factor
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    ABSTRACT: The combination of fluticasone furoate (FF), a novel inhaled corticosteroid (ICS) and vilanterol (VI), a long-acting beta2 agonist, is under development as a once-daily treatment for asthma and chronic obstructive pulmonary disease. The aim of this study was to compare the efficacy of FF/VI with fluticasone propionate (FP)/salmeterol (SAL) in patients with persistent asthma uncontrolled on medium-dose ICS. In a randomized, double-blind, double-dummy, parallel-group study, 806 patients received FF/VI (100/25 μg, n = 403) once daily in the evening via dry powder inhaler, or FP/SAL (250/50 μg, n = 403) twice daily via Diskus™/Accuhaler™. The primary efficacy measure was 0-24 h serial weighted mean forced expiratory volume in 1 second (wmFEV1) after 24 weeks of treatment. Improvements from baseline in 0-24 h wmFEV1 were observed with both FF/VI (341 ml) and FP/SAL (377 ml); the adjusted mean treatment difference was not statistically significant (-37 ml [95% confidence interval: -88, 15], p = 0.162). There were no differences between the 0-4 h serial wmFEV1, trough FEV1, and asthma control and quality of life questionnaire scores. There was no difference in reported exacerbations between treatments. Both treatments were well tolerated, with no clinically relevant effect on urinary cortisol excretion or vital signs, and no treatment-related serious adverse events. The efficacy of once-daily FF/VI was similar to twice-daily FP/SAL in improving lung function in patients with persistent asthma. No safety issues were identified. ClinicalTrials.gov; No.: NCT01147848; funded by GSK (HZA113091).
    Chest 07/2013; 144(4). DOI:10.1378/chest.13-0178 · 7.13 Impact Factor
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    ABSTRACT: BACKGROUND: Inhaled capsaicin elicits cough reproducibly in human subjects and is widely used in the study of cough and antitussive therapies. However, the traditional end points C2 and C5 (the concentrations of capsaicin inducing at least 2 or 5 coughs, respectively) display extensive overlap between health and disease and therefore might not best reflect clinically relevant mechanisms. OBJECTIVES: We sought to investigate capsaicin dose responses in different disease groups. METHODS: Two novel capsaicin cough challenges were compared in patients with chronic cough (CC; n = 20), asthmatic patients (n = 18), and healthy volunteers (HVs; n = 20). Increasing doubling doses of capsaicin (0.48-1000 μmol/L, 4 inhalations per dose) were administered in challenge 1, whereas the order of the doses was randomized in challenge 2. A nonlinear mixed-effects model compared dose-response parameters by disease group and sex. Parameters were also correlated with objective cough frequency. RESULTS: The model classified subjects based on maximum cough response evoked by any concentration of capsaicin (Emax) and the capsaicin dose inducing half-maximal response (ED50). HVs and asthmatic patients were not statistically different for either parameter and therefore combined for analysis (mean ED50, 38.6 μmol/L [relative SE, 28%]; mean Emax, 4.5 coughs [relative SE, 11%]). Compared with HVs/asthmatic patients, patients with CC had lower ED50 values (14.7 μmol/L [relative SE, 28%], P = .008) and higher Emax values (8.6 coughs [relative SE, 11%], P < .0001). Emax values highly correlated with 24-hour cough frequency (r = 0.71, P < .001) and were 37% higher in female compared with male subjects, regardless of disease group (P < .001). CONCLUSIONS: Nonlinear mixed-effects modeling demonstrates that maximal capsaicin cough responses better discriminate health from disease and predict spontaneous cough frequency and therefore provide important insights into the mechanisms underlying CC.
    The Journal of allergy and clinical immunology 06/2013; 132(4). DOI:10.1016/j.jaci.2013.04.042 · 11.25 Impact Factor
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    ABSTRACT: RATIONALE: Cough is one of the principle symptoms of COPD but the potential drivers of cough are likely to be multi-factorial and poorly understood. OBJECTIVES: To quantify cough frequency in an unselected group of COPD subjects and investigate the relationships between cough, reported sputum production, smoking, pulmonary function and cellular airway inflammation. Method: We studied 68 subjects with COPD (mean age 65.6yrs(±6.7), 67.6% male, 23 smokers, 45 ex-smokers) and 24 healthy volunteers (mean age 57.5yrs(±8.9), 37.5% male, 12 smokers, 12 non-smokers). Subjects reported cough severity, cough specific quality of life and sputum expectoration and performed spirometry, sputum induction, cough reflex sensitivity to capsaicin and 24hr ambulatory cough monitoring. MEASUREMENTS AND MAIN RESULTS: COPD current smokers had the highest cough rates [median 9.0c/h (IQR 4.3-15.6), almost double that of COPD ex-smokers [4.9c/h (2.3-8.7) (p=0.018)] and healthy smokers [5.3c/h (1.2-8.3), (p=0.03)], whereas healthy volunteers coughed the least [0.7c/h (0.2-1.4)]. Cough frequency was not influenced by age or gender and only weakly correlated with cough reflex sensitivity to capsaicin (logC5 r=-0.36, p=0.004). Reported sputum production, smoking history and current cigarette consumption strongly predicted cough frequency, explaining 45.1% variance in a general linear model (p<0.001). In subjects producing a sputum sample, cough frequency was related to current cigarette consumption and percentage of sputum neutrophils (p=0.002). CONCLUSION: Ambulatory objective monitoring provides novel insights into the determinants of cough in COPD, suggesting sputum production, smoking and airway inflammation may be more important than sensitivity of the cough reflex.
    American Journal of Respiratory and Critical Care Medicine 03/2013; 187(9). DOI:10.1164/rccm.201211-2000OC · 11.99 Impact Factor
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    ABSTRACT: BACKGROUND: The inhaled corticosteroid fluticasone furoate (FF) in combination with the long-acting β(2) agonist vilanterol (VI) is in development for asthma and chronic obstructive pulmonary disease. OBJECTIVE: To assess the safety and tolerability of FF/VI over 52 weeks in patients with asthma. METHODS: Patients (aged ≥12 years; on inhaled corticosteroid) were randomised (2:2:1) to FF/VI 100/25 µg or FF/VI 200/25 µg once daily in the evening, or fluticasone propionate (FP) 500 µg twice daily. Safety evaluations included adverse events (AEs), non-fasting glucose, potassium, 24-h urinary cortisol excretion, ophthalmic assessments, heart rate and pulse rate. RESULTS: On-treatment AEs were similar across groups (FF/VI 66-69%; 73% FP). Oral candidiasis/oropharyngeal candidiasis was more common with FF/VI (6-7%) than FP (3%). Twelve serious AEs were reported; one (worsening hepatitis B on FP) was considered drug related. Statistically significant cortisol suppression was seen with FP compared with both FF/VI groups at Weeks 12 and 28 (ratios [95% CI] to FP ranged from 1.43 [1.11 to 1.84] to 1.67 [1.34 to 2.08]; p≤0.006), but not at Week 52 (ratios to FP were 1.05 [0.83 to 1.33] for FF/VI 100/25 µg and 1.09 [0.87 to 1.38] for FF/VI 200/25 µg). No clinically important changes in non-fasting glucose, potassium, QT interval corrected using Fridericia's formula (QTc[F]) or ophthalmic assessments were reported. Pulse rate (10 min post dose [T(max)], Week 52) was significantly increased with FF/VI versus FP (3.4 bpm, 95% CI 1.3 to 5.6; p=0.002 [FF/VI 100/25 µg]; 3.4 bpm, 95% CI 1.2 to 5.6; p=0.003 [FF/VI 200/25 µg]). Mean heart rate (24-h Holter monitoring) decreased from screening values in all groups (0.2-1.1 bpm FF/VI vs 5 bpm FP; Week 52). CONCLUSIONS: FF/VI (100/25 µg or 200/25 µg) administered once daily over 52 weeks was well tolerated by patients aged ≥12 years with asthma. The overall safety profile of FF/VI did not reveal any findings of significant clinical concern. CLINICALTRIALS.GOV: NCT01018186.
    Thorax 02/2013; 68(6). DOI:10.1136/thoraxjnl-2012-202606 · 8.56 Impact Factor
  • Rayid Abdulqawi, Ashley Woodcock, Jaclyn A Smith
    The Lancet 02/2013; 381(9867):623. DOI:10.1016/S0140-6736(13)60337-2 · 39.21 Impact Factor
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    ABSTRACT: IntroductionThe spinal and vagal innervation of the respiratory tract is well defined, particularly in animals. These discoveries include the identification of pathways involved in provoking cough and descriptions of the guinea pig cough receptor'. However, many of the immunochemical features of the airway afferents described in animals have yet to be defined in humans, yet plasticity of these airway afferents may be important in the pathophysiology of chronic cough. ObjectivesTo define and characterise the innervation present in bronchoscopic biopsies from patients with chronic cough. We aimed to carry out the first ever whole mount immunohistochemical studies of airway nerves in cough patients, a technique that should improve visualisation of these neuronal structures and their sites of termination. MethodsBiopsy tissue was gifted from patients undergoing clinical investigation for chronic cough. Tissue, sampled from throughout the extrapulmonary airways, was immediately fixed in 4% paraformaldehyde. Non-specific antibody binding was blocked using 10% normal serum and 1% skimmed milk powder, diluted in PBS, before application of primary antibodies. Polyclonal rabbit anti-PGP9.5 (Ultraclone, UK) and monoclonal mouse anti-neurofilament (NF200, Leica Biosystems, UK) were applied at a dilution of 1:1000 and 1:200 respectively. Primary antibody binding was detected using appropriate Alexa-fluor conjugated secondary antibodies and whole mount preparations were visualised using epifluorescence and confocal microscopy. Images of biopsy staining were subject to morphometric analysis. ResultsMany epithelial, subepithelial and intramuscular fibres were detected using both antibodies. Co-staining revealed that only PGP9.5 defined pulmonary neuroendocrine cells and better elucidated varicose epithelial fibres. A proportion of all fibre types were only immunopositive for one marker. Notably NF200 exclusively detected some epithelial fibres and a group of larger diameter neurons (O3-6 microm) some of which are consistent with observations of Adelta-fibre airway mechanoreceptors. ConclusionsWe have described neuronal structures in whole-mount preparations of tissue from patients suffering from chronic cough. Notably, we described a population of PGP9.5 negative fibres within the airways. Some of these fibres are morphologically consistent with thinly myelinated Adelta-fibres described in animal models as cough receptors'. These ongoing studies could help define the plasticity of airway nerves in patients with chronic cough.
    Thorax 11/2012; 67(Suppl 2):A129-A130. DOI:10.1136/thoraxjnl-2012-202678.216 · 8.56 Impact Factor
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    ABSTRACT: Fluticasone furoate (FF) is an inhaled corticosteroid (ICS) with 24-hour activity in development as a once-daily treatment for the long-term management of asthma. To assess the efficacy and safety of 4 doses of once-daily FF administered using a dry powder inhaler in patients (≥12 years) with moderate asthma, uncontrolled on low-dose ICS (fluticasone propionate [FP] 200 μg/day or equivalent). This double-blind, placebo-controlled, dose-ranging study randomized 622 patients to 1 of 6 treatments: FF (100, 200, 300, or 400 μg) once daily in the evening, FP 250 μg twice daily (active control), or placebo for 8 weeks. The primary endpoint was the change from baseline in predose evening forced expiratory colume in 1 second (FEV(1)) at week 8. At week 8, relative to placebo, all doses of FF once daily and FP twice daily demonstrated significantly (P < .001) greater increases from baseline and greater than 200-mL increases in predose FEV(1). There was no evidence of a dose-response relationship between FF doses. Improvement with once-daily FF was similar to or greater than that for twice-daily FP. Secondary efficacy endpoint findings generally supported the efficacy of FF 100 to 400 μg once daily, although statistically significant improvements versus placebo in symptom-free 24-hour periods were only reported for FF 400 μg. There were few withdrawals due to lack of efficacy. Oral candidiasis was reported in 0 to 4% of patients; 24-hour urinary cortisol excretion ratios were similar across active treatment groups and not significantly different from placebo. FF 100 to 400 μg once daily in the evening is effective and well tolerated in patients with asthma uncontrolled on low-dose ICS, with 100 μg and 200 μg, considered the most applicable doses in this asthma population. clinicaltrials.gov Identifier: NCT00603278.
    Annals of allergy, asthma & immunology: official publication of the American College of Allergy, Asthma, & Immunology 11/2012; 109(5):353-358.e4. DOI:10.1016/j.anai.2012.08.017 · 2.75 Impact Factor
  • Ashley Woodcock
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    ABSTRACT: The Montreal Protocol was signed 25 years ago. As a result, the irreversible destruction of the ozone layer was prevented. However, stratospheric ozone will not recover completely until 2060 and the consequent epidemic in skin cancer cases will persist until 2100. Many millions of patients with asthma and chronic obstructive pulmonary disease have safely switched from chlorofluorocarbon (CFC)-powered metered-dose inhalers (MDIs) to either hydrofluorocarbon (HFC) or DPIs. China will be the last country to phase out CFCs by 2016. HFCs are global warming gases which will be controlled in the near future. HFCs in MDIs may be phased out over the next 10-20 years.
    Thorax 09/2012; 67(12). DOI:10.1136/thoraxjnl-2012-202628 · 8.56 Impact Factor
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    ABSTRACT: BACKGROUND: Viral respiratory tract infection is the most frequent cause of acute cough and is reported at onset in about one third of patients with chronic cough. Persistent infection is therefore one possible explanation for the cough reflex hypersensitivity and pulmonary inflammation reported in chronic cough patients. METHODS: Bronchoscopic endobronchial biopsies and bronchoalveolar lavage cell counts were obtained from ten healthy volunteers and twenty treatment resistant chronic cough patients (10 selected for lavage lymphocytosis). A screen for known respiratory pathogens was performed on biopsy tissue. Chronic cough patients also underwent cough reflex sensitivity testing using citric acid. RESULTS: There was no significant difference in incidence of infection between healthy volunteers and chronic cough patients (p = 0.115) or non-lymphocytic and lymphocytic groups (p = 0.404). BAL cell percentages were not significantly different between healthy volunteers and chronic cough patients without lymphocytosis. Lymphocytic patients however had a significantly raised percentage of lymphocytes (p < 0.01), neutrophils (p < 0.05), eosinophils (p < 0.05) and decreased macrophages (p < 0.001) verses healthy volunteers. There was no significant difference in the cough reflex sensitivity between non-lymphocytic and lymphocytic patients (p = 0.536). CONCLUSIONS: This study indicates latent infection in the lung is unlikely to play an important role in chronic cough, but a role for undetected or undetectable pathogens in either the lung or a distal site could not be ruled out.Trials registrationCurrent Controlled Trials ISRCTN62337037 & ISRCTN40147207.
    Cough 09/2012; 8(1):5. DOI:10.1186/1745-9974-8-5 · 1.26 Impact Factor

Publication Stats

7k Citations
1,917.64 Total Impact Points

Institutions

  • 2006–2015
    • University Hospital Of South Manchester NHS Foundation Trust
      Manchester, England, United Kingdom
  • 2013
    • University of Wisconsin–Madison
      Madison, Wisconsin, United States
  • 2003–2013
    • The University of Manchester
      • • Respiratory Medicine Research Group
      • • School of Translational Medicine
      Manchester, England, United Kingdom
  • 2004
    • University of Otago
      • Department of Microbiology and Immunology
      Dunedin, Otago, New Zealand
  • 2002
    • University of Central Lancashire
      Preston, England, United Kingdom
    • Kuwait University
      Al Kuwayt, Al Asimah, Kuwait
    • Aintree University Hospital NHS Foundation Trust
      Liverpool, England, United Kingdom
    • Universitätsspital Basel
      Bâle, Basel-City, Switzerland
    • The Heart Lung Center
      Londinium, England, United Kingdom
  • 2001
    • Komfo Anokye Teaching Hospital
      Coomassie, Ashanti, Ghana
  • 1999
    • The University of Edinburgh
      Edinburgh, Scotland, United Kingdom
  • 1994
    • Papworth Hospital NHS Foundation Trust
      Papworth, England, United Kingdom
  • 1991
    • University of Nottingham
      Nottigham, England, United Kingdom