The inverse agonist propranolol confers no corticosteroid-sparing activity in mild-to-moderate persistent asthma.

The murine asthma model shows that switching off airway ß2 receptors with an inverse agonist may confer anti-inflammatory effects as well as corticosteroid-sparing activity. We have assessed for any corticosteroid-sparing effects of propranolol, an inverse agonist, added to low-dose inhaled corticosteroid (ICS) compared with higher dose ICS. A randomized double-blind placebo-controlled cross-over trial in mild-to-moderate persistent asthmatic patients was performed. After a run-in (2 weeks) on hydrofluoroalkane-beclometasone dipropionate (HFA-BDP) at 100 µg/day (HFA-BDP100), patients received randomized treatments (4 weeks) with propranolol at 80 mg/day plus HFA-BDP at 100 µg/day compared with placebo plus HFA-BDP at 400 µg/day (HFA-BDP400). Propranolol was up-titrated to 80 mg/day over the initial 2 weeks. Tiotropium was co-administered until 5 days before each histamine challenge (the primary outcome). Sixteen patients completed the study [mean age, 38 years; forced expiratory volume in 1 s (FEV1), 86.4%; histamine provocative concentration causing a 20% fall in FEV1 (PC20), 1.39 mg/ml; ICS dose, 406 µg/day]. Histamine PC20 was unchanged by adding propranolol to HFA-BDP100 compared with baseline (HFA-BDP100) {0.17 doubling dilution (dd) difference [95% confidence interval (CI): -0.58 to 0.92]}, but there was a significant improvement with HFA-BDP400 compared with both baseline [1.05 dd (95% CI: 0.43-1.66); P=0.02], and propranolol+HFA-BDP100 [0.88 dd (95% CI: 0.45-1.30); P=0.006]. Significant improvements were also observed with HFA-BDP400 for exhaled nitric oxide, blood eosinophils, serum eosinophilic cationic protein and asthma quality-of-life questionnaire symptoms compared with propranolol+HFA-BDP100. Salbutamol recovery post-challenge was partially blunted by propranolol (median prolongation 5 min; P=0.002). Domiciliary evening FEV1 also fell with propranolol+HFA-BDP100 [mean reduction from baseline 0.22 litres (95% CI: 0.10-0.34); P=0.012], whereas Asthma Control Questionnaire remained unchanged. In conclusion, the inverse agonist propranolol produced no improvements when given with low-dose ICS, whereas further significant improvements in airway hyper-responsiveness and inflammation were demonstrated with higher dose ICS. Thus, propranolol does not confer corticosteroid-sparing activity in persistent asthma.

Thrombocytosis is associated with increased short and long term mortality after exacerbation of chronic obstructive pulmonary disease: a role for antiplatelet therapy?

INTRODUCTION: Evidence suggests that platelets play a significant role in inflammation in addition to their role in thrombosis. Systemic inflammation is linked to poor short and long term outcomes in COPD. Increased platelet activation has been reported in acute exacerbations of COPD (AECOPD). We investigated whether thrombocytosis is independently associated with poor outcomes following AECOPD. METHODS: An observational cohort study of patients hospitalised with AECOPD was performed. Patients were >40 years with spirometry confirmed COPD admitted between 2009 and 2011. Platelet count was recorded on admission. The primary outcome was 1-year all-cause mortality. Secondary outcomes included inhospital mortality and cardiovascular events. Analyses were conducted using logistic regression after adjustment for confounding variables. RESULTS: 1343 patients (49% male) were included. Median age was 72 years (IQR 63-79 years). 157 (11.7%) had thrombocytosis. Thrombocytosis was associated with both 1-year mortality and inhospital mortality; OR 1.53 (95% CI 1.03 to 2.29, p=0.030) and OR 2.37 (95% CI 1.29 to 4.34, p=0.005), respectively. Cardiovascular hospitalisation was not significantly increased (OR 1.13 (95% CI 0.73 to 1.76, p=0.600)) in patients with thrombocytosis. Aspirin or clopidogrel treatment correlated with a reduction in 1-year mortality (OR 0.63 (95% CI 0.47 to 0.85, p=0.003)) but not inhospital mortality (OR 0.69 (95% CI 0.41 to 1.11, p=0.124)). CONCLUSIONS: After adjustment for confounders thrombocytosis was associated with increased 1-year mortality after exacerbation of COPD. Antiplatelet therapy was associated with significantly lower 1-year mortality and may have a protective role to play in patients with AECOPD.

Proof-of-concept evaluation of trough airway hyper-responsiveness following regular racemic or levosalbutamol in genotype-stratified steroid-treated persistent asthmatic patients.

Asthmatic patients receiving ICSs (inhaled corticosteroids) may take frequent add-on therapy with salbutamol despite on-demand prescription. Frequent salbutamol use can be detrimental in asthma. The isomeric formulation of salbutamol and the B2ADR (ß2 adrenoceptor) 16 genotype may also influence this phenomenon. We performed a randomized, double-blind, placebo-controlled, triple crossover, proof of concept trial comparing 2 weeks of regular therapy with inhaled racemic salbutamol [200 µg q.i.d. (four times daily)], levosalbutamol (100 µg q.i.d.) or placebo on trough methacholine PC20 [provocative concentration causing 20% fall in FEV1 (forced expiratory volume in 1 s)] 6 h post-dose (the primary outcome) in 30 persistent asthmatic patients (15 who were Arg16 homozygous and 15 who were Gly16 homozygous) all receiving ICSs. There was no worsening of AHR (airway hyper-responsiveness) at trough to methacholine after 2 weeks regular exposure to either racemic (P=0.53) or levosalbutamol (P=0.84) compared with placebo, nor between genotypes-as dd (doubling dilution) difference in methacholine PC20 from placebo [salbutamol/Arg16=0.36 dd [95% CI (confidence interval), -0.43, 1.15]; salbutamol/Gly16=0.01 dd (95% CI, -0.47, 0.49); levosalbutamol/Arg16=-0.01 dd (95% CI, -0.89, 0.87); and levosalbutamol/Gly16=0.28 dd (95% CI, -0.22, 0.77)]. Both active treatments improved morning PEF (peak expiratory flow) in Gly16 (P=0.04 overall) but not Arg16 (P=0.50 overall) patients, whereas evening PEF improved in both Gly16 (P<0.001 overall) and Arg16 (P=0.006 overall) patients. In conclusion, the regular exposure to either racemic or levosalbutamol for 2 weeks added to ICSs did not cause worsening of AHR at trough compared with placebo; with no difference seen between B2ADR 16 genotypes.

Effects of intravenous and oral ß-blockade in persistent asthmatics controlled on inhaled corticosteroids.

OBJECTIVE: Despite their benefits in the treatment of cardiovascular disease, ß-blockers are seldom used to treat asthmatics. We assessed the safety and tolerability of acute dosing with esmolol and propranolol in patients with asthma. DESIGN: Post-hoc analysis of a double blind, randomised, placebo controlled trial of ß-blocker use in asthma. PATIENTS: Mild-to-moderate asthmatics on inhaled corticosteroids. INTERVENTIONS: Each participant underwent a 6-8 week dose titration of oral propranolol. A subgroup received an intravenous bolus dose of esmolol (0.5 mg/kg). Measurements were recorded pre- and post-esmolol and first dose exposure to 10 mg, 20 mg, and 80 mg of propranolol. Tiotropium was given concurrently with propranolol. Bronchoconstriction was reflected as a fall in forced expiratory volume in 1 s (FEV1) or increase in total airway resistance at 5 Hz (R5). RESULTS: 12 patients completed the trial. There were no adverse effects on FEV1% or R5% following intravenous esmolol. There were significant reductions at 2 min post-esmolol in heart rate (-4.7 beats/min (bpm), 95% CI -7.9 to -1.3 bpm; p=0.002) and systolic blood pressure (-5.9 mm Hg, 95% CI -11.4 to -0.4 mm Hg; p=0.03). No bronchoconstriction was seen during up titration following the first dose of 10 mg, 20 mg or 80 mg of propranolol in the presence of tiotropium. No difference in the asthma control questionnaire at 80 mg propranolol was seen versus placebo in the presence of tiotropium. CONCLUSIONS: Intravenous esmolol was administered without any adverse effects on pulmonary function in selected, stable, mild-to-moderate asthmatics controlled on inhaled corticosteroids. Tiotropium prevented propranolol induced bronchoconstriction after acute dosing during up-titration to 80 mg with no adverse impact on asthma control.

Randomized placebo-controlled trial to evaluate chronic dosing effects of propranolol in asthma.

RATIONALE: Unblinded studies have shown improvements in airway hyperresponsiveness with chronic nadolol in steroid-naive patients with asthma. OBJECTIVES: To assess the effects of chronic nonselective ß-blockade as add-on to inhaled corticosteroids (ICS) in patients with asthma. METHODS: A double-blind randomized placebo-controlled crossover trial of propranolol in patients with mild-to-moderate asthma receiving ICS was performed. Participants underwent a 6- to 8-week dose titration of propranolol or placebo as tolerated to a maximum of 80 mg per day. Tiotropium was given for the first 4 to 6 weeks of each treatment period. MEASUREMENTS AND MAIN RESULTS: Primary outcome was methacholine challenge. Secondary outcomes included histamine challenge, pulmonary function, mini-asthma quality of life questionnaire (mini-AQLQ), and asthma control questionnaire (ACQ). Eighteen patients completed (mean [SEM]): age, 36 (4) yr; FEV1%, 93 (2); ICS, 440 (66) µg/d. No significant difference was observed in methacholine or histamine challenge after exposure to propranolol versus placebo. For methacholine challenge, the doubling dilution difference was 0.04 (95% confidence interval [CI], -0.56 to 0.63), P = 0.89. Albuterol recovery at 20 minutes after histamine challenge was partially attenuated by propranolol versus placebo: FEV1% mean difference, 5.28 (95% CI, 2.54-8.01), P = 0.001. After chronic ß-blockade there was a small worsening in FEV1 % predicted of 2.4% (95% CI, -0.1 to 4.8), P = 0.055. No difference was found for ACQ or mini-AQLQ. CONCLUSIONS: This is the first placebo-controlled study to assess the effects of chronic nonselective ß-blockade in asthma, showing no significant effect of propranolol compared with placebo on either methacholine or histamine airway hyperresponsiveness and no change in ACQ or AQLQ. Clinical trial registered with www.clinicaltrials.gov (NCT01074853).

Cardiovascular events after clarithromycin use in lower respiratory tract infections: analysis of two prospective cohort studies.

OBJECTIVE: To study the association of clarithromycin with cardiovascular events in the setting of acute exacerbations of chronic obstructive pulmonary disease and community acquired pneumonia. DESIGN: Analysis of two prospectively collected datasets. SETTING: Chronic obstructive pulmonary disease dataset including patients admitted to one of 12 hospitals around the United Kingdom between 2009 and 2011; Edinburgh pneumonia study cohort including patients admitted to NHS Lothian Hospitals between 2005 and 2009. POPULATION: 1343 patients admitted to hospital with acute exacerbations of chronic obstructive pulmonary disease and 1631 patients admitted with community acquired pneumonia. MAIN OUTCOME MEASURES: Hazard ratios for cardiovascular events at one year (defined as hospital admissions with acute coronary syndrome, decompensated cardiac failure, serious arrhythmia, or sudden cardiac death) and admissions for acute coronary syndrome (acute ST elevation myocardial infarction, non-ST elevation myocardial infarction, and unstable angina). Secondary outcomes were all cause and cardiovascular mortality at one year. RESULTS: 268 cardiovascular events occurred in the acute exacerbations of chronic obstructive pulmonary disease cohort and 171 in the community acquired pneumonia cohort over one year. After multivariable adjustment, clarithromycin use in acute exacerbations of chronic obstructive pulmonary disease was associated with an increased risk of cardiovascular events and acute coronary syndrome-hazard ratios 1.50 (95% confidence interval 1.13 to 1.97) and 1.67 (1.04 to 2.68). After multivariable adjustment, clarithromycin use in community acquired pneumonia was associated with increased risk of cardiovascular events (hazard ratio 1.68, 1.18 to 2.38) but not acute coronary syndrome (1.65, 0.97 to 2.80). The association between clarithromycin use and cardiovascular events persisted after matching for the propensity to receive clarithromycin. A significant association was found between clarithromycin use and cardiovascular mortality (adjusted hazard ratio 1.52, 1.02 to 2.26) but not all cause mortality (1.16, 0.90 to 1.51) in acute exacerbations of chronic obstructive pulmonary disease. No association was found between clarithromycin use in community acquired pneumonia and all cause mortality or cardiovascular mortality. Longer durations of clarithromycin use were associated with more cardiovascular events. Use of ß lactam antibiotics or doxycycline was not associated with increased cardiovascular events in patients with acute exacerbations of chronic obstructive pulmonary disease, suggesting an effect specific to clarithromycin. CONCLUSIONS: The use of clarithromycin in the setting of acute exacerbations of chronic obstructive pulmonary disease or community acquired pneumonia may be associated with increased cardiovascular events. These findings require confirmation in other datasets.

Inhaled and systemic corticosteroid response in severe asthma assessed by alveolar nitric oxide: a randomized crossover pilot study of add-on therapy.

AIMS: Alveolar nitric oxide (CA(NO)) is a potential biomarker of small airway inflammation. We investigated effects on CA(NO) of the addition of coarse and fine particle inhaled corticosteroids to standard therapy in severe asthma. METHODS: Severe asthmatics taking ≥1600 µg day(-1) budesonide or equivalent performed a randomized open-label crossover study. Subjects with FEV(1) < 80%, gas trapping and CA(NO) ≥2 ppb entered a 6 week dose-ramp run-in of fluticasone/salmeterol(FPSM) 250/50 µg twice daily for 3 weeks, then 500/50 µg twice daily for 3 weeks. Patients then received additional HFA-beclomethasone diproprionate (BDP) 200 µg twice daily or FP 250 µg twice daily for 3 weeks in a crossover. Participants then received prednisolone(PRED) 25 mg day(-1) for 1 week. Nitric oxide, lung function, mannitol challenge, systemic inflammatory markers and urinary cortisol were measured. RESULTS: Fifteen completed per protocol: mean (SD) age 51 (12) years, FEV(1) 58 (13)% predicted, residual volume 193 (100)% predicted and mannitol(PD10) 177 (2.8) µg. There was no significant difference between FPSM and add-on therapy for CA(NO). FPSM/BDP and FPSM/PRED suppressed broncial flux (Jaw(NO)) and FE(NO) compared with FPSM alone, but there was no significant difference between FPSM/BDP and FPSM/FP. ECP, e-selectin and ICAM-1 were suppressed by FPSM/PRED compared with FPSM and FPSM/FP but not FPSM/BDP. Plasma cortisol was significantly suppressed by FPSM/PRED. CONCLUSION: In severe asthma, CA(NO) is insensitive to changes in dose and delivery of inhaled corticosteroids and is not suppressed by systemic corticosteroids. Additional inhaled HFA-BDP reduced FE(NO) and Jaw(NO) without adrenal suppression. There was a trend to reduction in FE(NO) and Jaw(NO) with additional FP but this did not reach statistical significance. PRED reduced FE(NO) and Jaw(NO) with suppression of systemic inflammatory markers and urinary cortisol.

Bisphosphonate-anchored PEGylation and radiolabeling of superparamagnetic iron oxide: long-circulating nanoparticles for in vivo multimodal (T1 MRI-SPECT) imaging.

The efficient delivery of nanomaterials to specific targets for in vivo biomedical imaging is hindered by rapid sequestration by the reticuloendothelial system (RES) and consequent short circulation times. To overcome these two problems, we have prepared a new stealth PEG polymer conjugate containing a terminal 1,1-bisphosphonate (BP) group for strong and stable binding to the surface of ultrasmall-superparamagnetic oxide nanomaterials (USPIOs). This polymer, PEG(5)-BP, can be used to exchange the hydrophobic surfactants commonly used in the synthesis of USPIOs very efficiently and at room temperature using a simple method in 1 h. The resulting nanoparticles, PEG(5)-BP-USPIOs are stable in water or saline for at least 7 months and display a near-zero ζ-potential at neutral pH. The longitudinal (r(1)) and transverse (r(2)) relaxivities were measured at a clinically relevant magnetic field (3 T), revealing a high r(1) of 9.5 mM(-1) s(-1) and low r(2)/r(1) ratio of 2.97, making these USPIOs attractive as T1-weighted MRI contrast agents at high magnetic fields. The strong T1-effect was demonstrated in vivo, revealing that PEG(5)-BP-USPIOs remain in the bloodstream and enhance its signal 6-fold, allowing the visualization of blood vessels and vascular organs with high spatial definition. Furthermore, the optimal relaxivity properties allow us to inject a dose 4 times lower than with other USPIOs. PEG(5)-BP-USPIOs can also be labeled using a radiolabeled-BP for visualization with single photon emission computed tomography (SPECT), and thus affording dual-modality contrast. The SPECT studies confirmed low RES uptake and long blood circulation times (t(1/2) = 2.97 h). These results demonstrate the potential of PEG(5)-BP-USPIOs for the development of targeted multimodal imaging agents for molecular imaging.

Reconstruction of an extensive peri-orbital defect secondary to mucormycosis in a patient with myelodysplasia.

We present the case of a 68-year old gentleman with previously diagnosed myelodysplastic syndrome with pancytopenia who presented with exophthalmia, rhinorrhea, and ophthalmoplegia. Nasal endoscopy revealed black necrotic lesions. He was diagnosed with rhino-orbital mucormycosis and commenced on intravenous antifungals. Despite this therapy he progressed to have total unilateral loss of visual acuity and cutaneous necrosis. He underwent emergency orbital exenteration and extensive cheek and sinus debridement. Necrotic lesions were found in the orbit, the maxillary and ethmoidal sinuses. He underwent reconstruction of this defect using a free myocutaneous ALT flap with a segment of vastus lateralis. Prior to surgery his anemia and thrombocytopenia were addressed with packed red cell and platelet transfusions as well as preoperative thromboelastography (TEG) to measure functional fibrinogen to platelet ratio. Intraoperative platelet administration was guided by repeated TEG analysis. There were no significant intraoperative or postoperative bleeding complications and both flap and donor site healed unremarkably. Few reports exist in the literature related to free tissue transfer in patients with hematological disorders but low platelet count has been implicated in an increased complication rate.

Sensitivity of impulse oscillometry and spirometry in beta-blocker induced bronchoconstriction and beta-agonist bronchodilatation in asthma.

BACKGROUND: Impulse oscillometry (IOS) provides an alternative method of assessing pulmonary function to conventional spirometry. OBJECTIVE: To compare the sensitivities of IOS and spirometry in assessing bronchoconstriction to propranolol and bronchodilation with salbutamol. METHODS: A post-hoc analysis of a randomized placebo-controlled crossover study was performed. Patients with mild-to-moderate persistent stable asthma taking 1,000 µg/day or less beclomethasone dipropionate equivalent received 10 or 20 mg of oral propranolol followed by histamine challenge, with recovery to nebulized salbutamol (5 mg). Spirometry and IOS were measured before and 2 hours after beta-blocker, post histamine, and 20 minutes post-salbutamol. Pre versus post percent change (95%CI) values were compared, and standardized response means (SRM) were calculated to assess the "signal to noise" of each test. RESULTS: Thirteen participants (mean age, 34 years) completed the protocol. Eleven participants received 20 mg of propranolol; 2 received 10 mg, because this dose caused more than 10% decrease in forced expiratory volume in 1 second (FEV(1)) on the test-dose algorithm. All IOS indices (R5, R5-R20, AX, RF) showed significant worsening of airways resistance or reactance to propranolol. FEV(1) but not FEF25-75 showed significant deterioration after beta-blocker (mean percent change, 4.6% and 6.2%). The magnitude of change was consistently higher for parameters of IOS, with the largest change being observed with R5 and RF (mean percent change, 30.8% and 39.4%). The SRMs for IOS outcomes were better than for spirometry. All measures of lung function showed significant bronchodilator response, with the best SRMs seen in R5 and RF. CONCLUSION: IOS is a more sensitive response outcome than spirometry with respect to bronchoconstriction to oral propranolol and bronchodilatation after salbutamol in patients with mild to moderate asthma.

A case of paraganglioma of the recurrent laryngeal nerve.

Paragangliomas are rare neuroendocrine tumors that derive from the extra-adrenal paraganglia. In the head and neck region, these neoplasms most commonly arise from the carotid body, the vagus nerve, and the jugulotympanic area. We describe the case of an 87-year-old woman with an incidental finding of a clinically, radiologically, and cytologically presumed retrosternal goiter. During a left thyroid lobectomy, she was found to have a mass that originated in the left recurrent laryngeal nerve. The mass was resected, and subsequent histopathologic examination found it to be a paraganglioma. Follow-up evaluation confirmed the expected finding of a left-sided vocal fold palsy. To the best of our knowledge, this is the first reported case of a paraganglioma arising from a recurrent laryngeal nerve.

Is a positive nasal lysine-aspirin challenge test associated with a more severe phenotype of chronic rhinosinusitis and asthma?

BACKGROUND: Current guidelines recommend a greater use of aspirin challenge testing in the diagnosis of aspirin-intolerant rhinosinusitis and asthma, a disorder with high burden of illness and resistance to treatment. The indications for these tests and their clinical significance remain unclear. This study was designed to characterize the phenotype of patients with chronic rhinosinusitis with nasal polyposis (CRSwNP) with or without asthma undergoing a nasal lysine-aspirin (L-ASA) challenge to evaluate which factors strongly predict a positive test. METHODS: Seventy-five patients with CRSwNP underwent nasal challenge with 16 mg (total) of L-ASA after 30 minutes of acclimatization and diluent challenge. A positive challenge was defined as a 25% drop in total nasal volume measured by acoustic rhinometry. RESULTS: Twenty-three (31%) participants gave a history of aspirin intolerance and 38 (51%) had a positive nasal L-ASA challenge. Upper airway measures (CT scan score, olfaction, polyp grading, peak nasal inspiratory flow, nasal symptoms, etc.) and lower airway measures (methacholine provocative concentration required to produce a 20% drop in forced expiratory volume in 1 second, effective special airway resistance, and spirometry) were not significantly worse in patients with a positive aspirin challenge. Test sensitivity was 48%, specificity was 52%, positive predictive value was 29%, and negative predictive value was 68%. A regression analysis identified forced expiratory flow at 25-75% (FEF(25-75)), history of aspirin intolerance, and duration of rhinosinusitis as significant predictors of a positive aspirin challenge. CONCLUSION: A positive response to nasal L-ASA challenge is not associated with a more severe phenotype of CRSwNP with or without asthma. A history of aspirin intolerance, duration of rhinosinusitis, and FEF(25-75) predict a greater response to aspirin.

Effects of extra-fine inhaled and oral corticosteroids on alveolar nitric oxide in COPD.

PURPOSE: Alveolar nitric oxide (CA(NO)) has been suggested as a surrogate marker of distal airway inflammation in COPD. Coarse particle-inhaled corticosteroids (ICS) have been shown not to suppress CA(NO). We evaluated whether extra-fine particle size ICS (HFA-BDP) or systemic oral corticosteroids could suppress CA(NO) in COPD. METHODS: Chronic obstructive pulmonary disease (COPD) patients with a FEV1/FVC ratio <0.7, FEV1 <80% predicted with CA(NO) > 2 ppb underwent a double-blind randomized, controlled, crossover trial with an open-label systemic steroid comparator. After a 2 week steroid washout period, participants were randomized to 3 weeks of 100 mcg of HFA-BDP twice daily and then 3 weeks of 400 mcg of HFA-BDP twice daily, or matched placebos with subsequent crossover. All patients then received 1 week open-label, 25 mg/day of prednisolone. Exhaled nitric oxide, plasma cortisol, and lung function were recorded. CA(NO) was corrected for axial diffusion. RESULTS: In 16 participants, there were no significant differences seen with either dose of HFA-BDP compared with placebo. Oral prednisolone significantly reduced FE(NO) and J'aw(NO) but not CA(NO). Plasma cortisol was significantly suppressed by oral prednisolone only. CONCLUSIONS: Whilst CA(NO) remains a biomarker of interest in COPD, it is not suppressed by systemic or extra-fine particle ICS. CA(NO) is not a useful marker for monitoring response of small airway disease to therapies in COPD. The study was approved by the local Committee on Medical Research Ethics and registered on ClinicalTrials.Gov (NCT 00921921).

A randomized primary care trial of steroid titration against mannitol in persistent asthma: STAMINA trial.

BACKGROUND: We compared titrating inhaled corticosteroid (ICS) against mannitol airway hyperresponsiveness (AHR) or a reference strategy (control) based on symptoms, reliever use, and lung function in primary care. METHODS: One hundred sixty-four patients with persistent asthma were randomized in parallel group fashion following an initial ICS tapering. Subsequent ICS doses (as ciclesonide) were titrated against either the provocative dose of mannitol causing a 10% fall in FEV(1) (PD(10)) (AHR strategy) or a control group (reference strategy) over a 1-year period. RESULTS: One hundred nineteen participants (n = 61 AHR, n = 58 control) completed the study. Time to first mild exacerbation was not significantly different: hazard ratio, 1.29; 95% CI, 0.716-2.31; P = .40. Although there were 27% fewer total number of mild exacerbations over 12 months in AHR vs control groups (n = 84 vs n = 115, P = .03), there was no difference in severe exacerbations (n = 12 vs n = 13). No other significant differences were seen between groups with the exception of mannitol PD(10) and ICS dose. There was a 1.52 (95% CI, 0.61-2.42; P = .001) doubling dose difference in mannitol PD(10) between AHR vs control groups. The final mean daily ciclesonide dose was higher (P < .0001) in AHR vs control groups (514 µg vs 208 µg), with no associated significant suppression of overnight urinary cortisol/creatinine. Significant improvements were seen within the AHR group but not the control group for the provocative concentration of methacholine causing a 20% fall in FEV(1) (P < .05), salivary eosinophilic cationic protein (P < .05), exhaled nitric oxide (P < .05), symptoms (P < .005), and reliever use (P < .001). CONCLUSIONS: Mannitol challenge was well tolerated in a primary care setting. Using mannitol resulted in exposure to a higher dose of ciclesonide, which was associated with equivocal effects on exacerbations without associated adrenal suppression. Large-scale trials using mannitol in patients with more severe disease may now be warranted to further define its role. TRIAL REGISTRATION: ClinicalTrials.gov; No.: NCT01216579; URL: www.clinicaltrials.gov.

Inhaled corticosteroid dose response using domiciliary exhaled nitric oxide in persistent asthma: the FENOtype trial.

BACKGROUND: International guidelines advocate a standard approach to asthma management for all, despite its heterogeneity. "Personalized" treatment of inflammatory asthma phenotypes confers superior benefits. We wished to evaluate dose response to inhaled corticosteroids (ICSs) in patients with asthma with an elevated fractional exhaled nitric oxide (Feno) phenotype using domiciliary measurements. METHODS: We performed a randomized, crossover trial in 21 patients with mild to moderate persistent asthma receiving ICSs with elevated Feno (>30 parts per billion [ppb]) that increased further (>10 ppb) after ICS washout. Patients were randomized to 2 weeks of either fluticasone propionate 50 µg bid (FP100) or 250 µg bid (FP500). The primary outcome was response in diurnal domiciliary Feno levels. Secondary outcomes included mannitol challenge, serum eosinophilic cationic protein (ECP), blood eosinophil count, and asthma control questionnaire. RESULTS: We found significant dose-related reductions of diurnal Feno compared with baseline - morning Feno: baseline = 71 ppb (95% CI, 61-83 ppb); FP100 = 34 ppb (95% CI, 29-40 ppb), P < .001; FP500 = 27 ppb (95% CI, 22-33 ppb), P < .001; and significant dose separation for morning, P < .05, and evening, P < .001. Time-series Feno displayed exponential decay: FP100 R² = 0.913, half-life = 69 h (95% CI, 50-114 h); FP500 R² = 0.966, half-life = 55 h (95% CI, 45-69 h), as well as diurnal variation. The Asthma Control Questionnaire showed significant improvements exceeding the minimal important difference (>0.5) with values in keeping with controlled asthma (<0.75) after each dose: FP100 = 0.48 (95% CI, 0.24-0.71), P = .004; FP500 = 0.37 (95% CI, 0.18-0.57), P = .001. All other secondary inflammatory related outcomes (mannitol, ECP, and eosinophils) showed significant improvements from baseline but no dose separation. CONCLUSIONS: There is a significant dose response of diurnal Feno to ICS in patients with asthma with an elevated Feno phenotype, which translates into well-controlled asthma. Further interventional studies are warranted using domiciliary Feno in this specific phenotype. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT00995657; URL: clinicaltrials.gov.

Fluticasone/Salmeterol combination confers benefits in people with asthma who smoke.

BACKGROUND: Smoking induces airway inflammation and relative resistance to inhaled steroids. The objective of this study was to evaluate the effects on airway hyperresponsiveness of adding salmeterol to fluticasone vs doubling the dose of fluticasone in patients with asthma who smoked and patients with asthma who did not smoke. METHODS: Sixteen patients with mild to moderate persistent asthma who did not smoke and 15 such patients who smoked completed a double-blind, randomized, placebo-controlled crossover study. They received either a fluticasone/salmeterol combination (FP/SM) (125/25 µg) two puffs bid (plus fluticasone placebo), or active fluticasone (250 µg) two puffs bid (plus FP/SM placebo), for 2 weeks each, with baselines after 1-week to 2-week run-in and washout periods. The primary outcome was the change from baseline in the provocative concentration of methacholine required to produce a 20% fall in FEV(1) (PC(20)). RESULTS: In the patients who did not smoke, there were similar improvements in the methacholine PC(20) with the use of fluticasone and FP/SM. The patients who smoked gained a benefit from FP/SM but not fluticasone, amounting to a PC(20) difference of 1.6 doubling dilutions (95% CI, 1.0-2.2), P < .01. The provocative dose of mannitol required to produce a 15% fall in FEV(1) (PD(15)) showed greater improvements with FP/SM than fluticasone in both patients who smoked and did not smoke. Similar differences in airway caliber between those who smoked and did not smoke were observed in FEV(1) and airway resistance. CONCLUSIONS: FP/SM confers greater improvements in airway hyperresponsiveness and airway caliber in patients with asthma who smoke compared with double the dose of fluticasone. We hypothesize that in the presence of relative steroid resistance, the smooth muscle stabilization conferred by salmeterol is of greater clinical importance in patients who smoke than in those who do not smoke. TRIAL REGISTRY: ClinicalTrials.gov: No.: NCT00830505; URL: www.clinicaltrials.gov.

The impact of tiotropium on mortality and exacerbations when added to inhaled corticosteroids and long-acting ß-agonist therapy in COPD.

BACKGROUND: Tiotropium has been shown to improve lung function, quality of life, and exacerbations and reduce mortality when compared with placebo in COPD. It remains unclear whether benefits are seen when tiotropium is used in conjunction with inhaled corticosteroids (ICSs) plus long-acting ß-agonists (LABAs). METHODS: We performed a retrospective cohort study using a National Health Service database of patients with COPD in Tayside, Scotland, between 2001 and 2010 that is linked with databases regarding hospital admissions, pharmacy prescriptions, and death registries. The impact of the addition of tiotropium (Tio) to ICS + LABA therapy on all-cause mortality, hospital admissions for respiratory disease, and emergency oral corticosteroid bursts was evaluated. Adjusted hazard ratios (HRs) were calculated by Cox regression after inclusion of the following covariates: cardiovascular and respiratory disease, diabetes, smoking, age, sex, and deprivation index. RESULTS: A total of 1,857 patients were given ICS + LABA + Tio, and 996 were given ICS + LABA. Mean follow-up was 4.65 years. The adjusted HR for all-cause mortality for ICS + LABA + Tio vs ICS + LABA was 0.65 (95% CI, 0.57-0.75; P < .001). Adjusted HRs for hospital admissions and oral corticosteroid bursts were 0.85 (95% CI, 0.73-0.99; P = .04) and 0.71 (95% CI, 0.63-0.80; P < .001), respectively. CONCLUSIONS: The study suggests that the addition of tiotropium to ICSs and LABA therapy may confer benefits in reducing all-cause mortality, hospital admissions, and oral corticosteroid bursts in patients with COPD. Triple therapy is widely used in the real-life management of COPD, with only limited scientific support. The study supports the use of triple therapy in COPD and provides a platform for randomized controlled trials specifically addressing this topic.

Effects of hydrocortisone on acute ß-adrenoceptor blocker and histamine induced bronchoconstriction.

AIMS: ß-adrenoceptor blockers are avoided in asthma due to concerns of bronchoconstriction. We investigated the safety of acute exposure to propranolol in asthmatics, sequentially challenged with histamine to mimic an asthma exacerbation and evaluated the role of intravenous hydrocortisone in potentiating salbutamol reversibility. METHODS: Persistent atopic asthmatics, requiring ≤ 1000 µg day(-1) budesonide, performed a randomized double-blind placebo-controlled crossover study. Following 10 mg or 20 mg of oral propranolol, patients received 400 mg intravenous hydrocortisone or placebo, followed by histamine challenge with nebulized salbutamol 5 mg and ipratropium 500 µg recovery. RESULTS: Thirteen patients completed per protocol. Hydrocortisone did not potentiate salbutamol recovery post propranolol and histamine challenge vs. placebo (mean difference in FEV(1) 0.04 ml, 95% CI -0.07, 0.15, P= 0.417). ß-adrenoceptor blocker induced bronchoconstriction was demonstrated by spirometry and impulse oscillometry. For the placebo visit, FEV(1) fell 4.7% 2 hours post propranolol (95% CI 1.8, 7.5, P= 0.008) whilst total airway resistance (R5%) increased 31.3% (95% CI 15.6, 47.0, P= 0.04). On both visits FEV(1) % and R5% returned to baseline after salbutamol post histamine. CONCLUSION: Nebulized salbutamol and ipratropium produced a full recovery after propranolol and histamine induced bronchoconstriction, independent of hydrocortisone use. Since the greatest risk of ß-adrenoceptor blockade is after first dose, our findings offer reassurance to those undertaking further evaluation of chronic ß-adrenoceptor blockade as a potential treatment for mild-to-moderate asthma.

Biocompatible inorganic nanoparticles for [18F]-fluoride binding with applications in PET imaging.

A wide selection of insoluble nanoparticulate metal salts was screened for avid binding of [(18)F]-fluoride. Hydroxyapatite and aluminium hydroxide nanoparticles showed particularly avid and stable binding of [(18)F]-fluoride in various biological media. The in vivo behaviour of the [(18)F]-labelled hydroxyapatite and aluminium hydroxide particles was determined by PET-CT imaging in mice. [(18)F]-labelled hydroxyapatite was stable in circulation and when trapped in various tissues (lung embolisation, Subcutaneous and intramuscular), but accumulation in liver via reticuloendothelial clearance was followed by gradual degradation and release of [(18)F]-fluoride (over a period of 4 h) which accumulated in bone. [(18)F]-labelled aluminium hydroxide was also cleared to liver and spleen but degraded slightly even without liver uptake (Subcutaneous and intramuscular). Both materials have properties that are an attractive basis for the design of molecular targeted PET imaging agents labelled with (18)F.

Pharmacokinetic and pharmacodynamic comparison of hydrofluoroalkane and chlorofluorocarbon formulations of budesonide.

AIMS: A hydrofluoroalkane formulation of budesonide pressurized metered-dose inhaler has been developed to replace the existing chlorofluorocarbon one. The aim of this study was to evaluate the pharmacokinetic and pharmacodynamic characteristics of both formulations. METHODS: Systemic bioavailability and bioactivity of both hydrofluoroalkane and chlorofluorocarbon pressurized metered-dose inhaler formulations at 800 µg twice daily was determined during a randomized crossover systemic pharmacokinetic/pharmacodynamic study at steady state in healthy volunteers. Measurements included the following: plasma cortisol AUC(24h) [area under the concentration-time curve (0-24 h)], budesonide AUC(0-12h) and C(max) . Clinical efficacy was determined during a randomized crossover pharmacodynamic study in asthmatic patients receiving 200 µg followed by 800 µg budesonide via chlorofluorocarbon or hydrofluoroalkane pressurized metered-dose inhaler each for 4 weeks. Methacholine PC(20) (primary outcome), exhaled nitric oxide, spirometry, peak expiratory flow and symptoms were evaluated. RESULTS: In the pharmacokinetic study, there were no differences in cortisol, AUC(0-12h) [area under the concentration-time curve (0-12 h)], T(max) (time to maximum concentration) or C(max) (peak serum concentration) between the hydrofluoroalkane and chlorofluorocarbon pressurized metered-dose inhaler. The ratio of budesonide hydrofluoroalkane vs. chlorofluorocarbon pressurized metered-dose inhaler for cortisol AUC(24h) was 1.02 (95% confidence interval 0.93-1.11) and budesonide AUC(0-12h) was 1.03 (90% confidence interval 0.9-1.18). In the asthma pharmacodynamic study, there was a significant dose response (P < 0.0001) for methacholine PC(20) (provocative concentration of methacholine needed to produce a 20% fall in FEV(1) ) with a relative potency ratio of 1.10 (95% confidence interval 0.49-2.66), and no difference at either dose. No significant differences between formulations were seen with the secondary outcome variables. CONCLUSIONS: Hydrofluoroalkane and chlorofluorocarbon formulations of budesonide were therapeutically equivalent in terms of relative lung bioavailability, airway efficacy and systemic effects.