Cased-based education rounds-the eternal heart of an international training program.

Case-based teaching or "Morning Rounds" have been used in medical education for more than a century and remain a cornerstone for teaching in many training programs. Our Pediatric Critical Care Medicine (PCCM) program was established forty years ago and has retained this form of teaching since its inception. Case-based rounds have consistently had the highest evaluation of all curricula in our program. Here we review the history of how these rounds were introduced in medical education, provide data from the learners' evaluation of these case-based rounds, and discuss the strengths and potential drawbacks of this form of teaching from an educational theories perspective with the hope that they can be used by other Pediatric Critical Care training programs.

Understanding general practitioners' prescribing choices to patients with chronic low back pain: a discrete choice experiment.

BACKGROUND: Although NSAIDs are recommended as a first line analgesic treatment, opioids are very commonly prescribed to patients with low back pain (LBP) despite risks of harms. AIM: This study aimed to determine factors contributing to general practitioners' (GPs') prescribing choices to patients with chronic LBP in a primary care setting. METHOD: This discrete choice experiment (DCE) presented 210 GPs with hypothetical scenarios of a patient with chronic LBP. Participants chose their preferred treatment for each choice set, either the opioid, NSAID or neither. The scenarios varied by two patient attributes; non-specific LBP or LBP with referred leg pain (sciatica) and number of comorbidities. The three treatment attributes also varied, being: the type of opioid or NSAID, degree of pain reduction and number of adverse events. The significance of each attribute in influencing clinical decisions was the primary outcome and the degree to which GPs preferred the alternative based on the number of adverse events or the amount of pain reduction was the secondary outcome. RESULTS: Overall, GPs preferred NSAIDs (45.2%, 95% CI 38.7-51.7%) over opioids (28.8%, 95% CI 23.0-34.7%), however there was no difference between the type of NSAID or opioid preferred. Additionally, the attributes of pain reduction and adverse events did not influence a GP's choice between NSAIDs or opioids for patients with chronic LBP. CONCLUSION: GPs prefer prescribing NSAIDs over opioids for a patient with chronic low back pain regardless of patient factors of comorbidities or the presence of leg pain (i.e. sciatica).

In Vitro Drug Delivery of a Fixed-Dose Combination of Fluticasone Furoate/Umeclidinium/Vilanterol from a Dry Powder Inhaler.

Background: Dry powder inhalers (DPIs) require patients to impart sufficient energy through inhalation to ensure adequate dose emission, medication deaggregation, and resultant particle sizes suitable for lung deposition. There is an ongoing debate regarding the level of inspiratory effort, and therefore inspiratory flow rate, needed for optimal dose delivery from DPIs. Materials and Methods: The delivered dose (DD) and fine particle fraction (FPF) for each component of fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) 100/62.5/25 µg and FF/UMEC/VI 200/62.5/25 µg ELLIPTA DPIs were assessed at flow rates of 30, 60, and 90 L/min. Electronic lung (eLung) (eLung; an electronic breathing simulator) assessments were conducted to replicate inhalation profiles representing a wide range of inhalation parameters and inhaled volumes achieved by patients with chronic obstructive pulmonary disease (COPD) or asthma of all severity levels. Timing and duration of dose emission were assessed using a particle detector located at the entrance of an anatomical throat cast attached to the eLung. Results: During DD assessment, a mean of >80% of the nominal blister content (nbc) was emitted from the ELLIPTA DPI at all flow rates. In Next Generation Impactor assessments, the observed mean DD across flow rates for FF/UMEC/VI 100/62.5/25 µg ranged from 85.9% to 97.0% of nbc and 84.0% to 93.5% for FF/UMEC/VI 200/62.5/25 µg. In eLung assessments, 82.8% to 95.5% of nbc was delivered across the PIF range, 43.5 to 129.9 L/min (COPD), and 85.1% to 92.3% across the PIF range, 67.4 to 129.9 L/min (asthma). The FPF (mass <5 µm; % nbc) for each component was comparable across all flow rates and inhalation profiles. Dose emission timings indicated that near-complete dose emission occurs before reaching PIF. Conclusions: Dose delivery assessments across all flow rates and inhalation profiles indicate that patients with all severity levels of COPD or asthma can achieve the required inspiratory effort for efficient delivery of all components of FF/UMEC/VI from the ELLIPTA DPI. Dose emission profiles suggest rapid and near-complete dose delivery from the ELLIPTA DPI before reaching PIF.

Opioid deprescribing in patients with chronic noncancer pain: a systematic review of international guidelines.

ABSTRACT: In response to the overuse of prescription opioid analgesics, clinical practice guidelines encourage opioid deprescribing (ie, dose reduction or cessation) in patients with chronic noncancer pain. Therefore, this study evaluated and compared international clinical guideline recommendations on opioid deprescribing in patients with chronic noncancer pain. We searched PubMed, EMBASE, PEDro, National Institute for Health and Care Excellence (United Kingdom), and MAGICapp databases from inception to June 4, 2021, with no language or publication restrictions. In addition, we searched the National Guideline Clearinghouse and International Guideline Network databases from inception to December 2018. Two independent reviewers conducted the initial title and abstract screening. After discrepancies were resolved through discussion, 2 independent reviewers conducted the full-text screening of each potentially eligible reference. Four independent reviewers completed the prepiloted, standardized data extraction forms of each included guideline. Extracted information included bibliographical details; strength of recommendations; and the outcomes, such as when and how to deprescribe, managing withdrawal symptoms, additional support, outcome monitoring, and deprescribing with coprescription of sedatives. A narrative synthesis was used to present the results. This study found that clinical practice guidelines agree on when and how to deprescribe opioid analgesics but lack advice on managing a patient's withdrawal symptoms, outcome monitoring, and deprescribing with coprescription of sedatives. Quality assessment of the guidelines suggests that greater discussion on implementation and dissemination is needed.

Opioid deprescribing: Qualitative perspectives from those with chronic non-cancer pain.

AIM: Deprescribing is the systematic process of discontinuing medications when the harms outweigh the benefits. This study aimed to identify barriers and facilitators in people with chronic non-cancer pain when deprescribing opioid analgesics, and their views on resources that assist with deprescribing. METHODS: A purposive sampling strategy was used to recruit 19 adults with chronic non-cancer pain from the community who were, or had been, on long-term opioid therapy. Recruitment continued until thematic saturation was achieved. Semi-structured telephone interviews were conducted. A five-step framework and thematic analysis method identified themes for each study aim. RESULTS: Themes identifying barriers to opioid deprescribing raised challenges of a lack of available alternatives, managing opioid dependency and withdrawal symptoms or inability to function without opioids when in extreme pain. Facilitating themes described the value of support networks, including a trusting doctor-patient relationship and finding individual coping strategies to address deprescribing barriers. We explored a variety of resources from electronic forms such as websites and apps to paper-based or face to face. Participants expressed that whatever the form, resources need to be educational but also simple and engaging. CONCLUSIONS: Most people suffering from chronic non-cancer pain expressed dissatisfaction with being on opioids but most were still unwilling to deprescribe due to insufficient alternatives, a lack of support from their doctors and lack of information about the deprescribing process. Deprescribing can be facilitated by improving supportive networks and strategies and providing simple and positive educational resources.

Do Patients with Acute Low Back Pain in Emergency Departments Have More Severe Symptoms than Those in General Practice? ASystematic Review with Meta-Analysis.

INTRODUCTION: There is a common belief that patients presenting to emergency departments have more severe pain levels and functional limitations than those who are seen in general practice. The aim of this systematic review was to compare pain and disability levels of patients with acute low back pain presenting to general practice vs those presenting to emergency departments. METHODS: Electronic searches were conducted in MEDLINE, EMBASE, and CINAHL from database inception to February 2019. Observational studies including patients with acute non-specific low back pain presenting to emergency departments and/or general practice were eligible. Pain and/or disability scores expressed on a 0-100 scale were the primary outcomes. Risk of bias was evaluated with a validated tool for observational studies, and the overall quality of evidence was assessed with Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Meta-analysis with random effects and meta-regression were used to test for differences between the two settings. RESULTS: We included 12 records reporting results for 10 unique studies with a total of 6,999 participants from general practice (n = 6) and emergency departments (n = 4). There was low-quality evidence (downgraded for indirectness and inconsistency) that patients presenting to emergency departments had higher pain scores than those in general practice, with a mean difference of 17.3 points (95% confidence interval: 8.8 to 25.9 on a 0-100 scale). Similarly, there was low-quality evidence (downgraded for indirectness and inconsistency) that patients presenting to emergency departments had higher disability scores than those in general practice (mean difference: 21.7; 95% confidence interval: 4.6 to 38.7 on a 0-100 scale). CONCLUSION: Patients with acute non-specific low back pain presenting to emergency departments may report higher levels of pain and disability than those seen in general practice.

Barriers, facilitators, and resources to opioid deprescribing in primary care: experiences of general practitioners in Australia.

ABSTRACT: Deprescribing is the systematic process of discontinuing drugs when harms outweigh the benefits. We conducted semistructured telephone interviews with 22 general practitioners (GPs) who had prescribed or deprescribed opioids in patients with chronic noncancer pain within the past 6 months to investigate the barriers and facilitators to deprescribing opioid analgesics in patients with chronic noncancer pain. We also explored GPs' perspectives on the available resources to assist them with opioid deprescribing. Interviews were audio-recorded, transcribed verbatim, and then coded using an iterative process until data saturation reached. The thematic analysis process identified themes, first as concepts, and then refined to overarching themes after the merging of similar subthemes. Themes exploring barriers to deprescribing highlighted the difficulties GPs face while considering patient factors and varying prescribing practices within the confines of the health system. Patient motivation and doctor-patient rapport were central factors to facilitate deprescribing and GPs considered the most important deprescribing resource to be a multidisciplinary network of clinicians to support themselves and their patients. Therefore, although GPs emphasised the importance of deprescribing opioid analgesics, they also expressed many barriers relating to managing complex pain conditions, patient factors, and varying prescribing practices between clinicians. Some of these barriers could be mitigated by GPs having time and resources to educate and build rapport with their patients. This suggests the need for further development of multimodal resources and improved support through the public health system to enable GPs to prioritise patient-centred care.

Peak Inspiratory Flow Rate in COPD: An Analysis of Clinical Trial and Real-World Data.

BACKGROUND: The influence of peak inspiratory flow (PIF) on dose delivery from dry powder inhalers (DPIs) and association with treatment efficacy in patients with chronic obstructive pulmonary disease (COPD) has not been fully determined. In vitro studies have demonstrated adequate dose delivery through ELLIPTA DPI at PIF ≥30 L/min. This analysis of two clinical trials and a real-world population of COPD patients determined spirometric PIF distribution, and explored the relationship between PIF and outcomes in the trials. METHODS: The replicate Phase IV, 12-week, randomized, double-blind 207608/207609 (NCT03478683/NCT03478696) trials evaluated fluticasone furoate/umeclidinium/vilanterol via ELLIPTA DPI versus budesonide/formoterol+tiotropium in COPD patients. This post hoc analysis assessed spirometric PIF distribution at screening and relationship between PIF and lung function outcomes in the pooled 207608/207609 population. Spirometric PIF distributions in a real-world population of COPD patients were evaluated by retrospective analysis of the Kaiser Permanente Northwest (KPNW) database to assess similarities between clinical trial and real-world populations. RESULTS: A total of 1460 (207608/207609) and 3282 (KPNW) patients were included. There was considerable overlap between spirometric PIF distributions for both populations. Overall, 99.7% and 99.8% of the 207608/207609 and KPNW populations, respectively, reported spirometric PIF ≥50 L/min, estimated as equivalent to ELLIPTA PIFR ≥30 L/min. In the 207608/207609 combined analysis, there was no significant interaction between spirometric PIF and treatment for lung function endpoints, indicating treatment effect is independent of PIF. CONCLUSION: Nearly all COPD patients in the 207608/207609 and KPNW populations achieved spirometric PIF values estimated as equivalent to PIFR of ≥30 L/min through the ELLIPTA DPI. Lack of correlation between spirometric PIF at screening and treatment efficacy aligns with consistent dose performance from the ELLIPTA DPI across a wide range of PIFs, achieved by patients with COPD of all severities.

Correction to: Deprescribing Opioids in Chronic Non­cancer Pain: Systematic Review of Randomised Trials.

Page 9, Fig. 2, which originally appeared as.

Clinician and patient beliefs about diagnostic imaging for low back pain: a systematic qualitative evidence synthesis.

OBJECTIVE: Overuse of diagnostic imaging for patients with low back pain remains common. The underlying beliefs about diagnostic imaging that could drive overuse remain unclear. We synthesised qualitative research that has explored clinician, patient or general public beliefs about diagnostic imaging for low back pain. DESIGN: A qualitative evidence synthesis using a thematic analysis. METHODS: We searched MEDLINE, EMBASE, CINAHL, AMED and PsycINFO from inception to 17 June 2019. Qualitative studies that interviewed clinicians, patients and/or general public exploring beliefs about diagnostic imaging for low back pain were included. Four review authors independently extracted data and organised these according to themes and subthemes. We used the Critical Appraisal Skills Programme tool to critically appraise included studies. To assess confidence in review findings, we used the GRADE-Confidence in the Evidence from Reviews of Qualitative Research method. RESULTS: We included 69 qualitative studies with 1747 participants. Key findings included: Patients and clinicians believe diagnostic imaging is an important test to locate the source of low back pain (33 studies, high confidence); patients with chronic low back pain believe pathological findings on diagnostic imaging provide evidence that pain is real (12 studies, moderate confidence); and clinicians ordered diagnostic imaging to reduce the risk of a missed diagnosis that could lead to litigation, and to manage patients' expectations (12 studies, moderate confidence). CONCLUSION: Clinicians and patients can believe that diagnostic imaging is an important tool for locating the source of non-specific low back pain. Patients may underestimate the harms of unnecessary imaging tests. These beliefs could be important targets for intervention. PROSPERO REGISTRATION NUMBER: CRD42017076047.

Deprescribing Opioids in Chronic Non-cancer Pain: Systematic Review of Randomised Trials.

BACKGROUND: Deprescribing, the process of reducing or discontinuing unnecessary or harmful medicines is an essential part of clinical practice. OBJECTIVE: To evaluate the efficacy of interventions designed to deprescribe opioid analgesics for pain relief in patients with chronic non-cancer pain. METHODS: We searched electronic databases, including clinical trial registries, from database inception to 13th January 2020 without restrictions, and conducted citation tracking. Our systematic review included randomised controlled trials (RCTs) evaluating interventions reducing the prescription, or use of opioid analgesics in patients with chronic pain versus control. Inventions could be aimed at the patient, clinician, or both. We excluded trials enrolling patients with cancer or illicit drug use. Two authors independently screened and extracted data. Outcome follow-up timepoints were short (≤ 3 months), intermediate (> 3 but < 12 months) or long (≥ 12 months) term. Primary outcome was the reduction in opioid dose [morphine milligram equivalent (MME) mg/day]. Methodological quality was assessed using the Cochrane Risk of Bias Tool. RESULTS: We included ten patient-focused RCT interventions (n = 835; median 37 participants) and 2 testing clinician-focused interventions (n = 291 clinicians); none at low risk of bias. Patient-focused interventions did not reduce opioid dose in the intermediate term [e.g. dose reduction protocol, mean difference (MD) - 19.9 MME, 95% CI - 107.5 to 67.7], nor did they increase the number of participants who ceased their dose, or increase the risk of serious adverse events or adverse events. One clinician intervention of education plus decision tools versus decision tools alone reduced the number of opioid prescriptions (risk difference (RD) - 0.1, 95% CI - 0.2 to - 0.1), dose (MD - 5.3 MME, 95% CI - 6.2 to - 4.5) and use (RD - 0.1, 95% CI - 0.1 to - 0.0) in the long term. LIMITATIONS: Study heterogeneity prevented meta-analysis. CONCLUSION: The small number of studies and heterogeneity prevented firm conclusions to recommend any one opioid-analgesic-deprescribing strategy in patients with chronic pain. SYSTEMATIC REVIEW REGISTRATION NUMBER: PROSPERO CRD42017068422.

In Vitro Dosing Performance of the ELLIPTA® Dry Powder Inhaler Using Asthma and COPD Patient Inhalation Profiles Replicated with the Electronic Lung (eLung™).

BACKGROUND: To evaluate the in vitro dose delivery characteristics of approved asthma and chronic obstructive pulmonary disease (COPD) therapies delivered via the ELLIPTA(®) dry powder inhaler across inhalation endpoints representative of the target patient population, using the Electronic Lung (eLung™) to replicate inhaler-specific patient inhalation profiles that were previously recorded in vivo. METHODS: Selected profiles, representative of the range of inhalation endpoints achieved by patients with all severities of asthma and COPD, were replicated using the eLung breathing simulator in conjunction with an oropharyngeal cast. A Next Generation Impactor was coupled to the eLung to determine the aerodynamic particle size distribution of the ex-throat dose (ETD) of asthma and COPD therapies delivered via the ELLIPTA inhaler. Delivered dose (DD), ETD, and fine particle dose (FPD; defined as a mass of active substance less than 5 µm) were determined for fluticasone furoate (FF)/vilanterol (VI) 100/25 µg and 200/25 µg (asthma and COPD), umeclidinium (UMEC)/VI 62.5/25 µg (COPD only), FF 100 µg and 200µg monotherapy (asthma only), and UMEC 62.5 µg monotherapy (COPD only). RESULTS: Inhalation profiles replicated by eLung covered a wide range of peak inspiratory flow rates (41.6-136.9 L/min), pressure drops (1.2-13.8 kPa), and inhaled volumes through the inhaler (0.7-4.2L). DD was consistent across the range of patient representative inhalation parameters for all components (FF, VI, and UMEC) of each therapy assessed; although ETD and FPD were also generally consistent, some small variation was observed. Dose delivery was consistent for each of the components, whether delivered as mono- or combination therapy. CONCLUSIONS: The in vitro performance of the ELLIPTA inhaler has been demonstrated for the delivery of FF/VI, UMEC/VI, FF monotherapy, and UMEC monotherapy. Across a range of inspiratory profiles, DD was consistent, while ETD and FPD showed little flow dependency.

The ELLIPTA® Dry Powder Inhaler: Design, Functionality, In Vitro Dosing Performance and Critical Task Compliance by Patients and Caregivers.

Dry powder inhalers (DPIs) are commonly used for the delivery of inhaled medications, and should provide consistent, efficient dosing, be easy to use correctly, and be liked by patients; these attributes can all affect patient compliance and therefore treatment efficacy. The ELLIPTA(®) DPI was developed for the delivery of once-daily therapies for the treatment of asthma and chronic obstructive pulmonary disease. It has moderate resistance to airflow and can hold one or two blister strips, with each blister containing a sealed single dose of medication. Monotherapies can be delivered by the single-strip configuration and, in the two-strip configuration, one dose from each strip can be aerosolized simultaneously to allow combination therapies to be delivered, which enables the formulations for each product to be developed individually, since they are stored separately until the point of administration. There are three principal operating steps to administer a dose: open, inhale, close. This article summarizes the design, functionality, and in vitro dose-delivery characteristics of the ELLIPTA inhaler, and describes the results of human factors validation tests, designed to assess the performance of critical tasks required to use the inhaler. Results from the in vitro studies indicate that the ELLIPTA inhaler performs consistently with respect to in vitro dose delivery characteristics at a range of flow rates that can be achieved by the target population (≥30 L/min) and over its 30-day in-use life. Data from the human factors validation tests demonstrated that almost all participants (≥97%) were able to complete each of the steps required to prepare a dose for inhalation without error. Overall, the ELLIPTA inhaler has a versatile single- or two-strip design that allows it to be used for the delivery of a range of treatment options. It also improves patient ease-of-use when compared with the DISKUS(®) DPI.

Effect of Disease Severity in Asthma and Chronic Obstructive Pulmonary Disease on Inhaler-Specific Inhalation Profiles Through the ELLIPTA® Dry Powder Inhaler.

BACKGROUND: Two studies were undertaken to characterize the maximal effort inhalation profiles of healthy subjects and patients with asthma or chronic obstructive pulmonary disease (COPD) through a moderate-resistance dry powder inhaler (DPI). Correlations between inhaler-specific inhalation characteristics and inhaler-independent lung function parameters were investigated. METHODS: Healthy subjects (n = 15), patients with mild, moderate, or severe asthma (n = 45), and patients with mild, moderate, severe, or very-severe COPD (n = 60) were included in the studies. Inhalation pressure drop versus time profiles were recorded using an instrumented ELLIPTA® DPI or bespoke resistor component with equivalent resistivity. Inhaler-independent lung function assessments included pharyngometry, spirometry, plethysmography, and diffusion. RESULTS: For the inhaler-specific inhalation profiles, the mean maximal effort peak inspiratory flow rates (PIFRs) varied across the subgroups from 65.8-110.6 L/min (range: 41.6-142.9). Peak pressure drop, PIFR, inhaled volume, and average inhalation flow rate (primary endpoints) did not differ markedly between healthy subjects and patients with asthma or mild COPD. Moderate, severe, and very-severe COPD patients demonstrated lower mean peak pressure drops, PIFRs and inhaled volumes, which tended to decrease with increasing COPD severity. Severe and very-severe COPD patients demonstrated shorter mean inhalation times compared with all other participants. Inhaler-independent lung function parameters were consistent with disease severity, and statistically significant (p < 0.05) strong correlations (R > 0.7) with components of the inhaler-specific inhalation profiles were observed in the COPD cohort; correlations in the asthma cohort tended to be weaker. CONCLUSIONS: All participants achieved a maximal effort PIFR ≥ 41.6 L/min through the moderate resistance of the ELLIPTA inhaler. Patients with asthma achieved similar inhalation profiles to healthy subjects, but increasing COPD severity tended to reduce a patient's inhalation capability. Correlation analyses suggest that some lung function parameters may be a useful indicator of ability to inhale efficiently through a moderate-resistance DPI, such as the ELLIPTA inhaler.

The pharmacodynamics, pharmacokinetics, safety and tolerability of inhaled fluticasone furoate and vilanterol administered alone or simultaneously as fluticasone furoate/vilanterol.

PURPOSE: To investigate the potential for systemic pharmacokinetic (PK) and pharmacodynamic (PD) interactions between inhaled fluticasone furoate (FF) and vilanterol (VI) when delivered simultaneously via the ELLIPTA™ dry powder inhaler (DPI). METHODS: Randomized, double-blind, placebo-controlled, crossover study. Healthy subjects (n = 16) received single doses of FF (800 mcg), VI (100 mcg), FF/VI (800/100 mcg), and placebo. Endpoints measured were systemic PD (FF: serum cortisol; VI: heart rate), FF and VI plasma PK (0-48 hours), pharyngometry, inhalation and breath hold profiles and safety assessments. RESULTS: Treatment differences [90% confidence interval (CI)] in weighted mean serum cortisol (0-24 hours) were 12.3% [4.4, 20.9] (FF/VI vs. FF) and for maximum heart rate (0-4 hours) were -1.2 bpm [-4.6, 2.1] (FF/VI vs. VI). When delivered simultaneously, FF and VI systemic exposures were slightly lower (<20%) versus delivery of either agent alone (although this was not a formal bioequivalence study). In vitro simulation of selected inhalation profiles and modeling supported the PK and PD findings. FF/VI, FF and VI were well tolerated with an AE incidence comparable to placebo. CONCLUSIONS: These results suggest there was a slight PK interaction and no PD interactions of concern between inhaled FF and VI when delivered simultaneously via the ELLIPTA DPI in healthy subjects.

Tolerability of fluticasone furoate/vilanterol combination therapy in children aged 5 to 11 years with persistent asthma.

BACKGROUND: Asthma is a chronic disease afflicting millions of children worldwide. Short-acting ß2-agonist reliever medications and inhaled corticosteroid (ICS) maintenance therapies are effective treatments; however, many children remain uncontrolled with short-acting ß2-agonist and ICS treatment, in which case guidelines recommend adding a long-acting ß2-agonist. OBJECTIVE: We sought to investigate the safety profile, tolerability, and pharmacokinetic (PK) and pharmacodynamic (PD) properties of the long-acting ß2-agonist vilanterol (VI) combined with the ICS fluticasone furoate (FF) administered via the ELLIPTA dry powder inhaler (GlaxoSmithKline, London, United Kingdom) in children aged 5 to 11 years with persistent asthma. METHODS: In this randomized, double-blind, repeated-dose, 2-way crossover study, data from 8- to 11-year-old children with asthma were reviewed before those from 5- to 7-year-old children with asthma. Patients received once-daily FF/VI, 100/25 µg, or FF, 100 µg, in the morning for 14 days, followed by a ≥7-day washout period before switching to the other treatment for 14 days; the study duration was ≤11 weeks. Primary end points were adverse events (AEs), clinical laboratory measurements, peak expiratory flow, maximum heart rate, blood pressure, and electrocardiographic parameters. Secondary end points comprised PK (AUC0-4, Cmax) and PD (serum potassium [0-4 hours], serum cortisol [0-12 hours], and glucose [0-4 hours]) parameters on day 14. RESULTS: Twenty-six children were randomized (58% boys; mean age, 8.1 years). No clinically significant changes in the primary end points were observed. Five patients reported 4 and 2 AEs with FF/VI and FF therapy, respectively. After FF/VI or FF treatment, the geometric mean ratios (90% CIs) for FF AUC0-4 (1.02 [0.86-1.22]) and FF Cmax (0.98 [0.65-1.48]) were similar. For serum glucose (0-4 hours) concentration, a difference of 0.50 mM (95% CI, 0.19-0.82 mM) was observed for FF/VI versus FF; no differences were observed for other PD parameters. No AEs were judged to be serious or treatment related. The PK profile of FF did not seem to be altered by VI and was not affected by age or sex. The significance of an increased serum glucose level is difficult to judge as measurements were taken from nonfasted patients. Results can be compared only with active treatment, and the ability to generalize is limited by the small number of patients in this single-center study. CONCLUSIONS: Once-daily repeated dosing of FF/VI, 100/25 µg, using the ELLIPTA dry powder inhaler was as well tolerated as FF, 100 µg, in this small, selected population of 5- to 11-year-old, mostly white/caucasian children with persistent asthma.

Safety, tolerability, pharmacokinetics, and pharmacodynamics of fluticasone furoate, a novel inhaled corticosteroid, in children aged 5-11 years with persistent asthma: A randomized trial.

This multi-center, randomized, double-blind, placebo-controlled, two-way crossover study characterized the safety, tolerability, pharmacokinetics, and pharmacodynamics of fluticasone furoate (FF) in children (5-11 years) with persistent asthma. Twenty-seven children received inhaled FF 100 µg or placebo via the ELLIPTA™ dry powder inhaler once daily for 14 days, with a ≥7 day washout period. Adverse events (AEs) were reported by eight (31%) and four (16%) subjects during FF 100 µg and placebo treatment, respectively. Headache was reported by three subjects during FF 100 µg treatment and by no subjects during placebo treatment, all other AEs were reported by only one subject on either treatment; there were no serious AEs. Following repeat dosing, the arithmetic mean (SD) FF Cmax was 26.71 pg/mL (9.16) at 31 minutes post-dose. Arithmetic mean (SD) FF AUC(0-t) was 121.44 pg h/mL (83.04). Arithmetic mean values for weighted mean (SD) serum cortisol (0-12 hours) on day 14 were 56.49 (16.51) and 67.57 (20.66) ng/mL for FF 100 µg and placebo, respectively. No clinically significant effect of FF on serum cortisol levels was observed. FF was well tolerated. Pharmacokinetic profiles were well defined and did not differ between age groups in the study population, and no clinically significant suppression of serum cortisol was observed.

Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Vilanterol, a Novel Inhaled Long-Acting ß-Agonist, in Children Aged 5-11 Years with Persistent Asthma: A Randomized Trial.

This multi-center, randomized, double-blind, placebo-controlled, two-way crossover study was designed to characterize the safety, tolerability, pharmacokinetic, and pharmacodynamic profile of single and once-daily repeat doses of vilanterol 25 µg in children aged 5-11 years. Twenty-eight children with persistent asthma received a single inhaled dose of vilanterol 25 µg or placebo via the ELLIPTA™ dry powder inhaler (DPI) on Day 1, followed 7 days later by once-daily treatment for 7 days. Nine (33%) subjects reported adverse events (AEs) with vilanterol 25 µg and 6 (23%) with placebo. No serious or drug-related AEs were reported; 3 subjects experienced upper respiratory tract infection (URTI) with vilanterol 25 µg versus none with placebo. Similar pharmacokinetic profiles of vilanterol 25 µg were observed irrespective of age or gender. No clinically relevant changes in heart rate, Fridericia's correction (QTcF), maximum glucose or minimum potassium parameters were observed during treatment with vilanterol 25 µg compared with placebo treatment. Vilanterol was well-tolerated and no long-acting ß2-agonist (LABA)-mediated AEs were observed. The pharmacokinetic profile of vilanterol 25 µg suggests exposure is similar regardless of age or gender in a pediatric population aged 5-11 years.

Pharmacokinetics and pharmacodynamics of intravenous and inhaled fluticasone furoate in healthy Caucasian and East Asian subjects.

AIM: The aim of the study was to evaluate the pharmacokinetics (PK) of inhaled and intravenous (i.v.) fluticasone furoate (FF) in healthy Caucasian, Chinese, Japanese and Korean subjects. METHOD: This was an open label, randomized, two way crossover study in healthy Caucasian, Chinese, Japanese and Korean subjects (n = 20 per group). Inhaled FF (200 µg for 7 days, then 800 µg for 7 days from a dry powder inhaler [DPI]) was administered in one treatment period and i.v.FF (250 µg infusion) in the other. FF PK and serum cortisol (inhaled 200 µg only) were compared between the ethnic groups using analysis of variance. P450 CYP3A4 activity and safety were also assessed. RESULTS: Ethnic differences in i.v. FF PK were accounted for by body weight differences. CYP3A4 activity was similar across the groups. Higher FF systemic exposure was seen following inhaled dosing in Chinese, Japanese and Korean subjects compared with Caucasian subjects. Absolute bioavailability was greater (36%-55%) in all East Asian groups than for Caucasian subjects following inhaled FF 800 µg. Deconvolution analysis suggested inhaled FF resided in the lung of East Asian subjects longer than for Caucasians (time for 90% to be absorbed [t90]: 29.1-30.8 h vs. 21.4 h). In vitro simulation method predicted comparable delivered lung dose across ethnic groups. Serum cortisol weighted mean was similar between Caucasians and Chinese or Koreans, while in Japanese was on average 22% lower than in Caucasians. All FF treatments were safe and well tolerated. CONCLUSION: Modestly higher (<50%) FF systemic exposure seen in East Asian subjects following inhaled dosing was not associated with a clinically significant effect on serum cortisol, suggesting that a clinical dose adjustment in East Asian subjects is not required.

Mercury, selenium and neurochemical biomarkers in different brain regions of migrating common loons from Lake Erie, Canada.

Common loons (Gavia immer) can be exposed to relatively high levels of dietary methylmercury (MeHg) through fish consumption, and several studies have documented MeHg-associated health effects in this species. To further study the neurological risks of MeHg accumulation, migrating loons dying of Type E botulism were collected opportunistically from the Lake Erie shore at Long Point (Ontario, Canada) and relationships between total mercury (THg), selenium (Se), and selected neurochemical receptors and brain enzymes were investigated. THg concentrations were 1-78 µg/g in liver; and 0.3-4 µg/g in the brain (all concentrations reported on a dry weight basis). A significant (p < 0.05) positive correlation was found between THg in liver and THg in 3 subregions of the brain (cerebral cortex: r = 0.433; cerebellum: r = 0.293; brain stem: r = 0.405). THg varied significantly among different brain regions, with the cortex having the highest concentrations. Se levels in the cortex and cerebellum were 1-29 and 1-10 µg/g, respectively, with no significant differences between regions. Se was not measured in brain stem due to insufficient tissue mass. There were molar excesses of Se over mercury (Hg) in both cortex and cerebellum at all Hg concentrations, and a significant positive relationship between THg and the Hg:Se molar ratio (cortex: r = 0.63; cerebellum: r = 0.47). No significant associations were observed between brain THg and the N-methyl-D-aspartic acid (NMDA) receptor concentration, nor between THg and muscarinic cholinergic (mACh) receptor concentration; however, brain THg levels were lower than in previous studies that reported significant Hg-associated changes in neuroreceptor densities. Together with previous studies, the current findings add to our understanding of Hg distribution in the brain of common loons, and the associations between Hg and sub-lethal neurochemical changes in fish-eating wildlife.