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Purpose: GOLD 2019 proposed a novel treatment decision tool for follow-up based on the predominant trait (exacerbation or dyspnea) of patients, alongside treatment escalation and de-escalation strategies. This study was designed to provide an up-to-date snapshot of patient and disease characteristics, treatment pathways, and healthcare resource use (HRU) in COPD in real life, and comprehensively examine patients considering GOLD 2019 recommendations.Patients and Methods: This mixed design, observational, multicenter (14 pulmonology clinics) study included all patients with a documented COPD diagnosis (excluding asthma-COPD overlap [ACO]) for >12 months, aged >40 years at diagnosis who had a COPD-related hospital visit, spirometry test and blood eosinophil count (BEC) measurement under stable conditions within the 12 months before enrollment between February and December 2020. Data were collected cross-sectionally from patients and retro-spectively from hospital medical records. Results: This study included 522 patients (GOLD group A: 17.2%, B: 46.4%, C: 3.3%, D: 33.1%), of whom 79.5% were highly symptomatic and 36.2% had high risk of exacerbation. Exacerbations (n = 832; 46.6% moderate, 25.5% severe) were experienced by 57.5% of patients in the previous 12 months. Inter-rater agreement between investigators and patients regarding the reason for visit was low (Kappa coefficient: 0.338, p = 0.001). Inhaled treatment was modified in 88 patients at index, mainly due to symptomatic state (31.8%) and exacerbations (27.3%); treatment was escalated (57.9%, mainly switched to LABA+LAMA+ICS), inhaler device and/or active ingredient was changed (36.4%) or treatment was de-escalated (5.7%). 27% had >1 hospital overnight stay over 12 months. Emergency department visits and days with limitation of daily activities were higher in group D (p < 0.001). Conclusion: Despite being on-treatment, many patients with COPD experience persistent symptoms and exacerbations requiring hospital-related HRU. A treatable trait approach and holistic disease management may improve outcomes by deciding the right treatment for the right patient at the right time., GlaxoSmithKline [208435], This study was funded by GlaxoSmithKline (GSK study 208435) . Volkan Eken and Hakan Erkus are GlaxoSmithKline Pharmaceuticals employees and shareholders. The other authors report no other conflicts of interest in this study.

The coronavirus disease 2019 (COVID-19) pandemic has prompted significant changes in patient care in rheumatology and gastroenterology, with clinical guidance issued to manage ongoing therapy while minimising the risk of nosocomial infection for patients and healthcare professionals (HCPs). Subcutaneous (SC) formulations of biologics enable patients to self-administer treatments at home; however, switching between agents may be undesirable. CT-P13 SC is the first SC formulation of infliximab that received regulatory approval and may be termed a biobetter as it offers significant clinical advantages over intravenous (IV) infliximab, including improved pharmacokinetics and a convenient mode of delivery. Potential benefits in terms of reduced immunogenicity have also been suggested. With a new SC formulation, infliximab provides an additional option for dual formulation, which enables patients to transition from IV to SC administration route without changing agent. Before COVID-19, clinical trials supported the efficacy and safety of switching from IV to SC infliximab for patients with rheumatoid arthritis and inflammatory bowel disease (IBD), and SC infliximab may have been selected on the basis of patient and HCP preferences for SC agents. During the pandemic, patients with rheumatic diseases and IBD have successfully switched from IV to SC infliximab, with some clinical benefits and high levels of patient satisfaction. As patients switched to SC therapeutics, the reduction in resource requirements for IV infusion services may have been particularly welcome given the pandemic, facilitating reorganisation and redeployment in overstretched healthcare systems, alongside pharmacoeconomic benefits and a reduction in exposure to nosocomial infection. Telemedicine and contactless healthcare have been pushed to the forefront during the pandemic, and a lasting shift towards remote patient management and community/home-based drug administration is anticipated. SC infliximab supports the implementation of this paradigm for future improvements of healthcare value delivered. The accumulation of real-world data during the pandemic supports the high level of confidence, with patients, physicians, and healthcare systems benefitting from its uptake. ispartof: ADVANCES IN THERAPY vol:39 issue:6 pages:2342-2364 ispartof: location:United States status: published

Problematic severe asthma remains a significant challenge to manage, accounting for the majority of healthcare utilization among children with asthma. The heterogeneity is recognized and the clinical phenotypes of "difficult-to-treat" asthma (DA) and "severe therapy-resistant asthma" (STRA) help to guide management. Recent evidence supports molecular distinctions between these phenotypes and shows poor correlations between peripheral and airway markers of inflammation, especially in STRA. Airway neutrophils in the context of childhood severe asthma have been explored, but their role in disease causation, protection, or as bystanders remain unknown, and thus, treatment implications are unclear. Several novel management strategies, including once-daily maintenance therapy, single-device maintenance and reliever therapy, and novel biological treatments are being increasingly used for DA and STRA. However, pediatric data for efficacy of novel treatments is scarce, and when available, is restricted to adolescents. The aim of this review is to highlight recent advances in objective biomarkers that aid stratification and management of childhood severe asthma and to highlight gaps in pediatric evidence. Specifically, the urgent need for efficacy studies to improve the management of problematic severe asthma in children younger than 12 years.

Objective To evaluate and compare benefits and harms of three biological treatments with different modes of action versus active conventional treatment in patients with early rheumatoid arthritis. Design Investigator initiated, randomised, open label, blinded assessor, multiarm, phase IV study. Setting Twenty nine rheumatology departments in Sweden, Denmark, Norway, Finland, the Netherlands, and Iceland between 2012 and 2018. Participants Patients aged 18 years and older with treatment naive rheumatoid arthritis, symptom duration less than 24 months, moderate to severe disease activity, and rheumatoid factor or anti-citrullinated protein antibody positivity, or increased C reactive protein. Interventions Randomised 1:1:1:1, stratified by country, sex, and anti-citrullinated protein antibody status. All participants started methotrexate combined with (a) active conventional treatment (either prednisolone tapered to 5 mg/day, or sulfasalazine combined with hydroxychloroquine and intra-articular corticosteroids), (b) certolizumab pegol, (c) abatacept, or (d) tocilizumab. Main outcome measures The primary outcome was adjusted clinical disease activity index remission (CDAI≤2.8) at 24 weeks with active conventional treatment as the reference. Key secondary outcomes and analyses included CDAI remission at 12 weeks and over time, other remission criteria, a non-inferiority analysis, and harms. Results 812 patients underwent randomisation. The mean age was 54.3 years (standard deviation 14.7) and 68.8% were women. Baseline disease activity score of 28 joints was 5.0 (standard deviation 1.1). Adjusted 24 week CDAI remission rates were 42.7% (95% confidence interval 36.1% to 49.3%) for active conventional treatment, 46.5% (39.9% to 53.1%) for certolizumab pegol, 52.0% (45.5% to 58.6%) for abatacept, and 42.1% (35.3% to 48.8%) for tocilizumab. Corresponding absolute differences were 3.9% (95% confidence interval −5.5% to 13.2%) for certolizumab pegol, 9.4% (0.1% to 18.7%) for abatacept, and −0.6% (−10.1% to 8.9%) for tocilizumab. Key secondary outcomes showed no major differences among the four treatments. Differences in CDAI remission rates for active conventional treatment versus certolizumab pegol and tocilizumab, but not abatacept, remained within the prespecified non-inferiority margin of 15% (per protocol population). The total number of serious adverse events was 13 (percentage of patients who experienced at least one event 5.6%) for active conventional treatment, 20 (8.4%) for certolizumab pegol, 10 (4.9%) for abatacept, and 10 (4.9%) for tocilizumab. Eleven patients treated with abatacept stopped treatment early compared with 20-23 patients in the other arms. Conclusions All four treatments achieved high remission rates. Higher CDAI remission rate was observed for abatacept versus active conventional treatment, but not for certolizumab pegol or tocilizumab versus active conventional treatment. Other remission rates were similar across treatments. Non-inferiority analysis indicated that active conventional treatment was non-inferior to certolizumab pegol and tocilizumab, but not to abatacept. The results highlight the efficacy and safety of active conventional treatment based on methotrexate combined with corticosteroids, with nominally better results for abatacept, in treatment naive early rheumatoid arthritis. Trial registration EudraCT2011-004720-35, NCT01491815 .

Biologic therapies have changed the outcome of both adult and pediatric patients with Inflammatory Bowel Disease (IBD). In September 2013, the first biosimilar of infliximab was introduced into the pharmaceutical market. In 2015, a first position paper on the use of biosimilars in pediatric IBD was published by the ESPGHAN IBD Porto group. Since then, more data have accumulated for both adults and children demonstrating biosimilars are an effective and safe alternative to the originator. In this updated position statement, we summarize current evidence and provide joint consensus statements regarding the recommended practice of biosimilar use in children with IBD. ispartof: JOURNAL OF PEDIATRIC GASTROENTEROLOGY AND NUTRITION vol:68 issue:1 pages:144-153 ispartof: location:United States status: published

Recently, two "fixed triple" single-inhaler combinations of an inhaled corticosteroid (ICS), a long-acting beta(2)-agonist (LABA), and a long-acting muscarinic antagonist (LAMA) have become available for patients with COPD. This review presents the clinical evidence that led to the approval of these triple therapies, discusses the role of ICS in patients with COPD, and presents data on the relative efficacy of "fixed triple" (ICS/LAMA/LABA) therapy vs LAMA, ICS/LABA, and LAMA/LABA combinations, and summarizes studies in which ICS/LABAs were combined with LAMAs to form "open triple" combinations. Of the five main fixed triple studies completed so far, three evaluated the efficacy and safety of an extrafine formulation of beclometasone dipropionate, formoterol fumarate, and glycopyrronium; the other two studies evaluated fluticasone furoate, vilanterol, and umeclidinium. Overall, compared to LAMA, ICS/LABA, or LAMA/LABA, triple therapy decreased the risk of exacerbations and improved lung function and health status, with a favorable benefit-to-harm ratio. Furthermore, triple therapy showed a promising signal in terms of improved survival. The evidence suggests that triple therapy is the most effective treatment in moderate/severe symptomatic patients with COPD at risk of exacerbations, with marginal if any risk of side effects including pneumonia. Ongoing studies are examining the role of triple therapy in less severe symptomatic patients with COPD and asthma-COPD overlap.

Claus F Vogelmeier,1 Kenneth R Chapman,2 Marc Miravitlles,3 Nicolas Roche,4 Jørgen Vestbo,5 Chau Thach,6 Donald Banerji,6 Robert Fogel,6 Francesco Patalano,7 Petter Olsson,8 Konstantinos Kostikas,7 Jadwiga A Wedzicha9 1Member of the German Center for Lung Research (DZL), Department of Medicine, Pulmonary and Critical Care Medicine, University Medical Center Giessen and Marburg, Philipps-Universität Marburg, Marburg, Germany; 2Asthma and Airway Centre, University Health Network and University of Toronto, Toronto, ON, Canada; 3Pneumology Department, Hospital Universitari Vall d’Hebron, CIBER de Enfermedades Respiratorias (CIBERES), Barcelona, Spain; 4Service de Pneumologie AP-HP, Cochin Hospital, University Paris Descartes (EA2511), Paris, France; 5Institute of Infection, Immunity and Respiratory Medicine, The University of Manchester and Manchester University NHS Foundation Trust, Manchester, UK; 6Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA; 7Novartis Pharma AG, Basel, Switzerland; 8Novartis Sverige AB, Täby, Sweden; 9National Heart and Lung Institute, Imperial College London, London, UK Background: The FLAME study compared once-daily indacaterol/glycopyrronium (IND/GLY) 110/50 µg with twice-daily salmeterol/fluticasone (SFC) 50/500 µg in symptomatic patients with moderate to very severe COPD and a history of exacerbations in the previous year. Methods: This prespecified and post hoc subgroup analysis evaluated treatment efficacy on 1) moderate/severe exacerbations according to prior exacerbation history and treatment, and 2) types of exacerbations according to health care resource utilization (HCRU) during 1-year follow-up. Results: IND/GLY reduced the rate of moderate/severe exacerbations versus SFC in patients with a history of 1 exacerbation (rate ratio [RR]: 0.83, 95% CI: 0.75–0.93), ≥2 exacerbations (RR: 0.85, 95% CI: 0.70–1.03) and ≥2 exacerbations or ≥1 hospitalization in the previous year (RR: 0.86, 95% CI: 0.74–1.00). Prolonged time-to-first exacerbation was observed in all the groups according to exacerbation history. Moderate/severe exacerbations decreased with IND/GLY versus SFC, independent of previous treatment. IND/GLY significantly reduced rates of moderate/severe exacerbations treated with antibiotics (RR: 0.79, 95% CI: 0.67–0.93) and systemic corticosteroids and antibiotics (RR: 0.80, 95% CI: 0.70–0.91); rates of exacerbations treated with systemic corticosteroids alone were comparable (RR: 0.99, 95% CI: 0.80–1.22). Conclusion: Overall, IND/GLY demonstrated consistent beneficial effects versus SFC on moderate/severe exacerbations, independent of prior exacerbation history or treatment. The efficacy of IND/GLY on exacerbation prevention was superior to SFC for exacerbations treated with antibiotics with/without systemic corticosteroids and was similar for exacerbations treated with systemic corticosteroids alone. Keywords: indacaterol/glycopyrronium, salmeterol/fluticasone, LABA/LAMA, LABA/ICS

Recently, two "fixed triple" single-inhaler combinations of an inhaled corticosteroid (ICS), a long-acting beta(2)-agonist (LABA), and a long-acting muscarinic antagonist (LAMA) have become available for patients with COPD. This review presents the clinical evidence that led to the approval of these triple therapies, discusses the role of ICS in patients with COPD, and presents data on the relative efficacy of "fixed triple" (ICS/LAMA/LABA) therapy vs LAMA, ICS/LABA, and LAMA/LABA combinations, and summarizes studies in which ICS/LABAs were combined with LAMAs to form "open triple" combinations. Of the five main fixed triple studies completed so far, three evaluated the efficacy and safety of an extrafine formulation of beclometasone dipropionate, formoterol fumarate, and glycopyrronium; the other two studies evaluated fluticasone furoate, vilanterol, and umeclidinium. Overall, compared to LAMA, ICS/LABA, or LAMA/LABA, triple therapy decreased the risk of exacerbations and improved lung function and health status, with a favorable benefit-to-harm ratio. Furthermore, triple therapy showed a promising signal in terms of improved survival. The evidence suggests that triple therapy is the most effective treatment in moderate/severe symptomatic patients with COPD at risk of exacerbations, with marginal if any risk of side effects including pneumonia. Ongoing studies are examining the role of triple therapy in less severe symptomatic patients with COPD and asthma-COPD overlap.

Contains fulltext : 229046.pdf (Publisher’s version ) (Open Access) BACKGROUND: Fluid accumulation frequently coexists with acute kidney injury (AKI) and is associated with increased risk for AKI progression and mortality. Among septic shock patients, restricted use of resuscitation fluid has been reported to reduce the risk of worsening of AKI. Restrictive fluid therapy, however, has not been studied in the setting of established AKI. Here, we present the protocol and statistical analysis plan of the REstricted fluid therapy VERsus Standard trEatment in Acute Kidney Injury-the REVERSE-AKI trial that compares a restrictive fluid therapy regimen to standard therapy in critically ill patients with AKI. METHODS: REVERSE-AKI is an investigator-initiated, multinational, open-label, randomized, controlled, feasibility pilot trial conducted in seven ICUs in five countries. We aim to randomize 100 critically ill patients with AKI to a restrictive fluid treatment regimen vs standard management. In the restrictive fluid therapy regimen, the daily fluid balance target is neutral or negative. The primary outcome is the cumulative fluid balance assessed after 72 hours from randomization. Secondary outcomes include safety, feasibility, duration, and severity of AKI, and outcome at 90 days (mortality and dialysis dependence). CONCLUSIONS: This is the first multinational trial investigating the feasibility and safety of a restrictive fluid therapy regimen in critically ill patients with AKI. TRIAL REGISTRATION: clinical.trials.gov NCT03251131.

The act of nonmedical switching, defined as switching stable patients who are generally doing well with their current therapy from an originator biologic to its biosimilar, has been endorsed as a reasonable treatment strategy. The safety and efficacy of nonmedical switching have been evaluated in randomized controlled and real-world evidence studies, which have demonstrated that although many patients maintain treatment response after the switch, some patients experience therapy failure, resulting in therapy discontinuation. It has been postulated that the vast majority, if not all, of these treatment failures result from a "nocebo effect", defined as patients' negative expectations toward the therapy change. Reports suggest that the risk of a nocebo effect is higher following a mandated nonmedical switch. Although the nocebo effect is a well-recognized phenomenon in pain studies, evidence is limited in immune-mediated diseases primarily because it is difficult to quantify, especially retrospectively. In spite of this, numerous biosimilar studies in patients with immune-mediated diseases have concluded that nonmedical switching failures are due to a nocebo effect. The objective of this narrative review was to explore the reasons for nonmedical switch failure or discontinuation and the role of the nocebo effect among patients with inflammatory rheumatic and gastrointestinal diseases who switched from an originator biologic to its biosimilar. ispartof: RHEUMATOLOGY AND THERAPY vol:7 issue:1 pages:35-64 ispartof: location:England status: published

Summary Background Whether blood eosinophil counts and exhaled nitric oxide (FeNO) are associated with important outcomes in mild asthma is unclear. In this prespecified subgroup analysis of a previously published open-label clinical trial, we aimed to assess associations between blood eosinophil counts and FeNO with outcomes and response to asthma treatment. Methods In the previously reported 52-week, open-label, randomised controlled trial, people with mild asthma receiving only β agonist reliever inhalers were enrolled at one of 16 clinical trials units in New Zealand, the UK, Italy, or Australia. Eligible participants were randomly assigned (1:1:1, stratified by country), to receive inhalers to take as-needed salbutamol (two inhalations of 100 μg in a pressurised metered dose inhaler), maintenance budesonide (200 μg twice per day by inhaler) plus as-needed salbutamol (two inhalations of 100 μg), or as-needed budesonide–formoterol (one inhalation of 200 μg budesonide and 6μg formoterol by inhaler). The primary outcome was the annual rates of asthma exacerbations per patient, and in this prespecified subgroup analysis, we assessed whether annual exacerbation rates in each treatment group were significantly different depending on levels of blood eosinophil count, FeNO, or a composite score of both. Analyses were done for patients with available biomarker measurements The study was registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12615000999538. Findings 675 participants were enrolled between March 17, 2016, and Aug 29, 2017, of whom 656 had results for blood eosinophil analysis and 668 had results for FeNO. Of the patients who received as-needed salbutamol, the proportion of patients having a severe exacerbation increased progressively with increasing blood eosinophil count (two [4%] of 49 participants with Interpretation In patients with mild asthma, the effects of as-needed budesonide–formoterol on exacerbations are independent of biomarker profile, whereas the benefits of maintenance inhaled budesonide are greater in patients with high blood eosinophil counts than in patients with low counts. Funding AstraZeneca, Health Research Council of New Zealand.

The aim of this paper was to propose key steps for community pharmacist integration into a patient care pathway for chronic obstructive pulmonary disease (COPD) management. A literature search was conducted to identify publications focusing on the role of the community pharmacist in identification and management of COPD. The literature search highlighted evidence supporting an important role for pharmacists at each of the four key steps in the patient care pathway for COPD management. Step 1 (primary prevention): pharmacists are ideally placed to provide information on disease awareness and risk prevention campaigns, and to encourage lifestyle interventions, including smoking cessation. Step 2 (early detection/case finding): pharmacists are often the first point of contact between the patient and the healthcare system and can therefore play an important role in the early identification of patients with COPD. Step 3 (management and ongoing support): pharmacists can assist patients by providing advice and education on dosage, inhaler technique, treatment expectations and the importance of adherence, and by supporting self-management, including recognition and treatment of COPD exacerbations. Step 4 (review and follow-up): pharmacists can play an important role in monitoring adherence and ongoing inhaler technique in patients with COPD. In summary, pharmacists are ideally positioned to play a vital role in all key stages of an integrated COPD patient care pathway from early disease detection to the support of management plans, including advice and counselling regarding medications, inhaler technique and treatment adherence. Areas requiring additional consideration include pharmacist training, increasing awareness of the pharmacist role, administration and reimbursement, and increasing physician-pharmacist collaboration.

Summary Background To date, no studies have assessed the efficacy of single-inhaler triple therapy in asthma. Here we report on two studies that compared the single-inhaler extrafine combination of beclometasone dipropionate (BDP; inhaled corticosteroid), formoterol fumarate (FF; long-acting β2 agonist), and glycopyrronium (G; long-acting muscarinic antagonist) with the combination of BDP with FF. Methods Two parallel-group, double-blind, randomised, active-controlled, phase 3 trials (Triple in Asthma With Uncontrolled Patients on Medium Strength of ICS + LABA [TRIMARAN] and Triple in Asthma High Strength Versus ICS/LABA HS and Tiotropium [TRIGGER]) recruited patients from 171 sites across 16 countries (TRIMARAN), and from 221 sites across 17 countries (TRIGGER). The sites were a mixture of secondary and tertiary care centres and specialised investigation units. Eligible patients were adults (aged 18–75 years) with uncontrolled asthma, a history of one or more exacerbations in the previous year, and previously treated with inhaled corticosteroid (TRIMARAN: medium dose; TRIGGER: high dose) plus a long-acting β2 agonist. Enrolled patients were initially treated with BDP/FF (TRIMARAN: 100 μg BDP and 6 μg FF; TRIGGER: 200 μg BDP and 6 μg FF) for 2 weeks, then randomly assigned to treatment using an interactive response technology system with a balanced block randomisation scheme stratified by country. Patients, investigators, site staff, and sponsor staff were masked to BDP/FF/G and BDP/FF assignment. In TRIMARAN, patients were randomly assigned (1:1) to 52 weeks of BDP/FF/G (100 μg BDP, 6 μg FF, and 10 μg G) or BDP/FF (100 μg BDP and 6 μg FF), two inhalations twice daily. In TRIGGER, patients were randomly assigned (2:2:1) to 52 weeks of BDP/FF/G (200 μg BDP, 6 μg FF, and 10 μg G) or BDP/FF (200 BDP and 6 μg FF), both two inhalations twice daily, or open-label BDP/FF (200 μg BDP and 6 μg FF) two inhalations twice daily plus tiotropium 2·5 μg two inhalations once daily. Coprimary endpoints for both trials (BDP/FF/G vs BDP/FF) were pre-dose forced expiratory volume in 1 s (FEV1) at week 26 and rate of moderate and severe exacerbations over 52 weeks. Safety was assessed in all patients who received at least one dose of study treatment. These trials were registered with ClinicalTrials.gov , NCT02676076 (TRIMARAN), NCT02676089 (TRIGGER). Findings Between Feb 17, 2016, and May 17, 2018, 1155 patients in TRIMARAN were given BDP/FF/G (n=579) or BDP/FF (n=576). Between April 6, 2016, and May 28, 2018, 1437 patients in TRIGGER were given BDP/FF/G (n=573), BDP/FF (n=576), or BDP/FF plus tiotropium (n=288). Compared with the BDP/FF group, week 26 predose FEV1 improved in the BDP/FF/G group by 57 mL (95% CI 15–99; p=0·0080) in TRIMARAN and by 73 mL (26–120; p=0·0025) in TRIGGER, with reductions in the rate of moderate and severe exacerbations of 15% (rate ratio 0·85, 95% CI 0·73–0·99; p=0·033) in TRIMARAN and 12% (0·88, 0·75–1·03; p=0·11) in TRIGGER. Four patients had treatment-related serious adverse events, one in TRIMARAN in the BDP/FF/G group and three in TRIGGER—one in the BDP/FF/G and two in the BDP/FF group. Three patients in the BDP/FF/G group in TRIMARAN and two patients in TRIGGER—one in the BDP/FF/G group and one in the BDP/FF group—had adverse events leading to death. None of the deaths were considered as related to treatment. Interpretation In uncontrolled asthma, addition of a long-acting muscarinic antagonist to inhaled corticosteroid plus long-acting β2-agonist therapy improves lung function and reduces exacerbations. Funding Chiesi Farmaceutici.

The efficacy, safety and positioning of inhaled corticosteroids (ICS) in the treatment of patients with chronic obstructive pulmonary disease (COPD) is much debated, since it can result in clear clinical benefits in some patients ("friend") but can be ineffective or even associated with undesired side effects, e.g. pneumonia, in others ("foe"). After critically reviewing the evidence for and against ICS treatment in patients with COPD, we propose that: 1) ICS should not be used as a single, stand-alone therapy in COPD; 2) patients most likely to benefit from the addition of ICS to long-acting bronchodilators include those with history of multiple or severe exacerbations despite appropriate maintenance bronchodilator use, particularly if blood eosinophils are > 300 cells . mu L-1, and those with a history of and/or concomitant asthma; and 3) the risk of pneumonia in COPD patients using ICS is higher in those with older age, lower body mass index (BMI), greater overall fragility, receiving higher ICS doses and those with blood eosinophils < 100 cells . mu L-1. All these factors must be carefully considered and balanced in any individual COPD patient before adding ICS to her/his maintenance bronchodilator treatment. Further research is needed to clarify some of these issues and firmly establish these recommendations.

BACKGROUNDPatients with chronic obstructive pulmonary disease (COPD) with an eosinophilic phenotype may benefit from treatment with mepolizumab, a monoclonal antibody directed against interleukin-5.METHODSWe performed two phase 3, randomized, placebo-controlled, double-blind, parallel-group trials comparing mepolizumab (100 mg in METREX, 100 or 300 mg in METREO) with placebo, given as a subcutaneous injection every 4 weeks for 52 weeks in patients with COPD who had a history of moderate or severe exacerbations while taking inhaled glucocorticoid-based triple maintenance therapy. In METREX, unselected patients in the modified intention-to-treat population with an eosinophilic phenotype were stratified according to blood eosinophil count (>= 150 per cubic millimeter at screening or >= 300 per cubic millimeter during the previous year). In METREO, all patients had a blood eosinophil count of at least 150 per cubic millimeter at screening or at least 300 per cubic millimeter during the previous year. The primary end point was the annual rate of moderate or severe exacerbations. Safety was also assessed.RESULTSIn METREX, the mean annual rate of moderate or severe exacerbations in the modified intention-to-treat population with an eosinophilic phenotype (462 patients) was 1.40 per year in the mepolizumab group versus 1.71 per year in the placebo group (rate ratio, 0.82; 95% confidence interval [CI], 0.68 to 0.98; adjusted P = 0.04); no significant between-group differences were found in the overall modified intention-to-treat population (836 patients) (rate ratio, 0.98; 95% CI, 0.85 to 1.12; adjusted P>0.99). In METREO, the mean annual rate of moderate or severe exacerbations was 1.19 per year in the 100-mg mepolizumab group, 1.27 per year in the 300-mg mepolizumab group, and 1.49 per year in the placebo group. The rate ratios for exacerbations in the 100-mg and 300-mg mepolizumab groups versus the placebo group were 0.80 (95% CI, 0.65 to 0.98; adjusted P = 0.07) and 0.86 (95% CI, 0.70 to 1.05; adjusted P = 0.14), respectively. A greater effect of mepolizumab, as compared with placebo, on the annual rate of moderate or severe exacerbations was found among patients with higher blood eosinophil counts at screening. The safety profile of mepolizumab was similar to that of placebo.CONCLUSIONSMepolizumab at a dose of 100 mg was associated with a lower annual rate of moderate or severe exacerbations than placebo among patients with COPD and an eosinophilic phenotype. This finding suggests that eosinophilic airway inflammation contributes to COPD exacerbations.

Background Chronic obstructive pulmonary disease (COPD) is a progressive disease and a composite endpoint could be an indicator of treatment effect on disease worsening. This post-hoc analysis assessed whether indacaterol/glycopyrronium (IND/GLY) 110/50 μg once daily reduced the risk of clinically important deterioration (CID) versus salmeterol/fluticasone (SFC) 50/500 μg twice daily in moderate-to-very severe COPD patients from the FLAME study. Methods CID was defined as ≥100 mL decrease in forced expiratory volume in 1 s (FEV1) or ≥ 4-unit increase in St. George’s Respiratory Questionnaire (SGRQ) total score or a moderate-to-severe COPD exacerbation. Changes from baseline in the rate of moderate and severe exacerbations, time to first moderate-to-severe exacerbation, and change from baseline in the SGRQ score, measured after Week 12 up to Week 52, were assessed by presence of early CID (CID+) or absence of CID (CID−) at Week 12. Results IND/GLY significantly delayed the time to CID (hazard ratio [HR] (95% confidence interval [CI]), 0.72 [0.67–0.78]; P

Long acting muscarinic antagonists (LAMA) are currently considered the therapeutic mainstay for patients with COPD and have been shown to improve clinical outcomes including symptoms, exercise capacity and airflow limitation. Irisin , is a newly discovered hormone-like myokine generated by skeletal muscle cells in response to exercise and it is suggested to regulate energy expenditure and exercise capacity. The aim of the present study was to investigate if treatment with LAMA alters serum irisin levels in patients with COPD. Irisin was assessed by ELISA in the serum of 506 patients with COPD, GOLD II-IV, with a smoking history >10 PY, who were included in the PROMISE-COPD cohort. The effect of inhaled LAMA on serum irisin levels was evaluated in a proof-of-concept cohort of 40 COPD patients. Univariate linear regression analysis revealed that there was a significant negative association of irisin with age-adjusted Charlson score (p = 0.003) and a positive association of irisin with 6-min walking distance (6MWD) (p = 0.018) and treatment with LAMA (p = 0.004) but not with LABA or ICS. Multivariate analysis revealed that the association of irisin with LAMA treatment remains significant after adjustment for age-adjusted score and 6MWD. In the proof-of-concept cohort a single inhalation of LAMA stimulated serum irisin levels after 4 h. These findings imply that treatment of COPD patients with LAMA increase circulating irisin, thus explaining some of the beneficial extra-pulmonary effects of these drugs when used in the treatment of COPD.

PURPOSE OF REVIEW: To assess current pharmacological principles used for treatment of nocturia/nocturnal polyuria.RECENT FINDINGS: The pathophysiology of nocturia is often multifactorial, but two main mechanisms have been identified, occurring alone or in combination: low functional bladder capacity and nocturnal polyuria. The multifactorial pathophysiology not only implies several possible targets for therapeutic intervention but also means that it is unlikely that one treatment modality including drugs will be successful in all patients. Drugs approved for the treatment of male LUTS and male and female OAB are known to be far more effective for treatment of the daytime symptoms than for nocturia. Several pharmacological principles have been tested with varying success. The treatment of choice should depend upon the main underlying cause, thus aiming primarily to increase bladder capacity by counteracting detrusor overactivity and/or reducing nocturnal polyuria. Using current available agents, effective, personalized treatment should be designed taking into account gender, co-morbidities, and identified etiological factors. However, there is a medical need for new, approved drugs for treatments for patients with nocturia.

Evidence and guidelines are becoming increasingly clear about imbalance between the risks and benefits of inhaled corticosteroids (ICSs) in patients with COPD. While selected patients may benefit from ICS-containing regimens, ICSs are often inappropriately prescribed with – according to Belgian market research data – up to 70% of patients in current practice receiving ICSs, usually as a fixed combination with a long-acting β2-adrenoreceptor agonist. Studies and recommendations support withdrawal of ICSs in a large group of patients with COPD. However, historical habits appear difficult to change even in the light of recent scientific evidence. We have built a collaborative educational platform with chest physicians and primary care physicians to increase awareness and provide guidance and support in this matter., SCOPUS: re.j, info:eu-repo/semantics/published

Background Inhaled corticosteroids (ICS) are associated with an increased risk of pneumonia in patients with chronic obstructive pulmonary disease (COPD). Other factors such as severity of airflow limitation and concurrent asthma may further raise the possibility of developing pneumonia. This study assessed the risk of pneumonia associated with ICS in patients with COPD. Methods Electronic Medical Record data linked to National Health Registries were collected from COPD patients and matched reference controls in 52 Swedish primary care centers (2000–2014). Levels of ICS treatment (high, low, no ICS) and associated comorbidities were assessed. Patients were categorized by airflow limitation severity. Results A total of 6623 patients with COPD and 48,566 controls were analyzed. Patients with COPD had a more than 4-fold increase in pneumonia versus reference controls (hazard ratio [HR] 4.76, 95% confidence interval [CI]: 4.48–5.06). ICS use increased the risk of pneumonia by 20–30% in patients with COPD with forced expiratory volume in 1 s ≥ 50% versus patients not using ICS. Asthma was an independent risk factor for pneumonia in the COPD population. Multivariate analysis identified independent predictors of pneumonia in the overall population. The highest risk of pneumonia was associated with high dose ICS (HR 1.41, 95% CI: 1.23–1.62). Conclusions Patients with COPD have a greater risk of pneumonia versus reference controls; ICS use and concurrent asthma increased the risk of pneumonia further.

Background: Clinical use of biosimilar infliximab (CT-P13) in inflammatory bowel diseases (IBDs) is based on extrapolation of indication from clinical studies performed in rheumatological diseases. Only few data exist of behaviour of infliximab trough levels (TLs) and anti-drug antibodies (ADAs) during switching.Aim: The objective of this study was to evaluate changes in TLs, ADA formation and disease activity after switching from originator infliximab to biosimilar one.Methods: All our IBD patients receiving maintenance infliximab therapy were switched to biosimilar infliximab. TLs and ADAs were measured before the last originator infusion and before the third biosimilar infusion. Laboratory values, disease activity indices (partial Mayo score and Harvey-Bradshaw index) and demographic data were collected from patient records.Results: A total of 62 patients were included in the final analysis (32 Crohn's disease, 30 ulcerative colitis (UC) or IBD-unclassified). No significant changes in median TLs before (5.5mg/l) and after switching (5.5mg/l, p=.05) occurred in the entire study group or in the Crohn's disease (CD) subgroup (5.75 and 6.5mg/l, p=.68). However, in the subgroup of ulcerative colitis, the change in median TL was significantly different (from 5.2 to 4.25mg/l, p=.019). Two patients developed ADAs after switching. No changes in disease activity were detected during switching and no safety concerns occurred.Conclusions: Switching from originator to biosimilar infliximab resulted in statistically significant differences in infliximab TLs in patients with UC but not in patients with Crohn's disease. The clinical significance for this difference is doubtful and in neither group changes in disease activity occurred.

Rationale: Post hoc analyses suggest that blood eosinophils have potential as a predictive biomarker of inhaled corticosteroid efficacy in the management of chronic obstructive pulmonary disease (COPD). Objectives: We prospectively investigated the value of blood eosinophils as a predictor of responsiveness to an inhaled corticosteroid/long-acting β2-agonist combination versus a long-acting β2-agonist/long-acting muscarinic antagonist combination for exacerbation prevention. Methods: We conducted prespecified analyses of data from the FLAME (Effect of Indacaterol Glycopyronium vs Fluticasone Salmeterol on COPD Exacerbations) study, which compared once-daily long-acting β2-agonist/long-acting muscarinic antagonist indacaterol/glycopyrronium 110/50 μg with twice-daily long-acting β2-agonist/inhaled corticosteroid salmeterol/fluticasone combination 50/500 μg in patients with one or more exacerbations in the preceding year. Subsequent post hoc analyses were conducted to address further cutoffs and endpoints. Measurements and Main Results: We compared treatment efficacy according to blood eosinophil percentage (

Effectiveness, efficacy and safety of biosimilar infliximab (CT-P13) in inflammatory bowel disease (IBD) patients has been shown in previous studies. Limited data exist on health-related quality of life (HRQoL) of switching originator to biosimilar infliximab (IFX) in IBD patients. The objective of this study was to evaluate impact of switching originator to biosimilar IFX on HRQoL, disease activity, and health care costs in IBD maintenance treatment. In this single-center prospective observational study, all IBD patients receiving maintenance IFX therapy were switched to biosimilar IFX. HRQoL was measured using the generic 15D health-related quality of life instrument (15D) utility measurement and the disease-specific Inflammatory Bowel Disease Questionnaire (IBDQ). Crohn Disease Activity Index (CDAI) or Partial Mayo Score (pMayo), and fecal calprotectin (FC) served for evaluation of disease activity. Data were collected at time of switching and 3 and 12 months after switching. Patients' characteristics, clinical background information and costs were collected from patient records and the hospital's electronic database. Fifty-four patients were included in the analysis. No statistically significant changes were observed in 15D, CDAI, pMayo, and FC during 1-year follow-up. IBDQ scores were higher (P = .018) in Crohn disease 3 months after switching than at time of switching. Costs of biosimilar IFX were one-third of costs of originator one. Total costs related to secondary health care (excluding costs of IFX), were similar before and after the onset of biosimilar IFX. HRQoL and disease activity were after switching from originator to biosimilar IFX comparable, but the costs of biosimilar IFX were only one-third of those of the originator one.

Cervical dystonia is the most frequent form of focal dystonia. Symptoms often result in pain and functional disability. Local injections of botulinum neurotoxin are currently the treatment of choice for cervical dystonia. Although this treatment has proven effective and is widely applied worldwide, many issues still remain open in the clinical practice. We performed a systematic review of the literature on botulinum toxin treatment for cervical dystonia based on a question-oriented approach, with the aim to provide practical recommendations for the treating clinicians. Key-questions from the clinical practice were explored. Results suggest that while the beneficial effect of botulinum toxin treatment on different aspects of cervical dystonia is well established, robust evidence is still missing concerning some practical aspects, such as doseequivalence between different formulations, optimal treatment intervals, treatment approaches, and the use of supportive techniques including electromyography (EMG) or ultrasounds. Established strategies to prevent or manage common side effects (including excessive muscle weakness, pain at injection site, dysphagia) and potential contraindications to this treatment (pregnancy and lactation, use of anticoagulants, neurological comorbidities) should also be further explored.

Cervical dystonia (CD) is the most frequent form of focal dystonia. Symptoms often result in pain and functional disability. Local injections of botulinum neurotoxin are currently the treatment of choice for CD. Although this treatment has proven effective and is widely applied worldwide, many issues still remain open in the clinical practice. We performed a systematic review of the literature on botulinum toxin treatment for CD based on a question-oriented approach, with the aim to provide practical recommendations for the treating clinicians. Key questions from the clinical practice were explored. Results suggest that while the beneficial effect of botulinum toxin treatment on different aspects of CD is well established, robust evidence is still missing concerning some practical aspects, such as dose equivalence between different formulations, optimal treatment intervals, treatment approaches, and the use of supportive techniques including electromyography or ultrasounds. Established strategies to prevent or manage common side effects (including excessive muscle weakness, pain at injection site, dysphagia) and potential contraindications to this treatment (pregnancy and lactation, use of anticoagulants, neurological comorbidities) should also be further explored.

BACKGROUND Chronic antiplatelet therapy in the post-acute phase of non-cardioembolic ischemic stroke is limited by the risk of intracranial hemorrhage (ICH) complications. METHODS We developed an ICH risk score based on the PERFORM trial cohort (n = 19,100), which included patients with a non-cardioembolic ischemic stroke or transient ischemic attack, and externally validated this score in one contemporary trial of very similar size and inclusion criteria, the PRoFESS trial (n = 20,332 patients). Outcome was ICH over 2 years. A Cox proportional-hazard regression analysis identified risk factors. Discrimination was quantified with c-statistics and calibration was assessed by comparing predicted and observed ICH risk in PERFORM and PRoFESS. RESULTS ICH occurred within 2 years in 263 (1.4%) patients in PERFORM trial and in 246 (1.2%) patients in PRoFESS trial. A 13-point score based on 9 items (Intracranial-B2LEED3S score - low body mass index, blood pressure, lacune, elderly, Asian ethnicity, coronary artery or cerebrovascular disease history, dual antithrombotic agent or oral anticoagulant, gender) was derived from the PERFORM trial. In PERFORM, the observed 2-year ICH risk varied from 0.75% in low-risk (score ≤2) to 2.44% in high-risk patients (score ≥5) with an acceptable calibration but a low discrimination both in PERFORM (c-statistic 0.64, 95% CI 0.61-0.68) and on external validation in PRoFESS (0.58, 95% CI 0.55-0.62). CONCLUSION The Intracranial-B2LEED3S score helps identify patients who are at a high risk of bleeding. However, other variables need to be identified to improve the score (e.g., microbleeds) (Clinical Trial Registration Information ISRCTN66157730). URL: http://www.isrctn.com/ISRCTN66157730?totalResults=5&pageSize=10&page=1&searchType=basic-search&offset=3&q=&filters=conditionCategory%3ACirculatory+System%2CrecruitmentCountry%3ATaiwan%2CrecruitmentCountry%3AAustria&sort=.

Background: Global Initiative for Chronic Obstructive Lung Disease (GOLD) global strategy (2015) provides guidance for the treatment of chronic obstructive pulmonary disease (COPD) with different first-choice options per GOLD category without specification. Objectives: To evaluate the level of medical experts’ consensus on their preferred first-choice treatment within different COPD categories. Methods: A two-round Delphi Panel consisting of 15 questions was completed by Belgian pulmonologists (n=31) and European (n=10) COPD experts. Results: Good consensus was reached by both expert groups for long-acting bronchodilators instead of short-acting bronchodilators as first-choice treatment in GOLD A. Single bronchodilation with long-acting muscarinic antagonist (LAMA) was preferred over long-acting β2-agonist (LABA) and LABA/LAMA as first-choice treatment in GOLD B and GOLD C. For GOLD D patients based on the forced expiratory volume in 1 second (FEV1), SCOPUS: ar.j, info:eu-repo/semantics/published

Dave Singh,1 Massimo Corradi,2 Monica Spinola,3 Alberto Papi,4 Omar S Usmani,5 Mario Scuri,3 Stefano Petruzzelli,3 Jørgen Vestbo1 1Division of Infection, Immunity and Respiratory Medicine, University of Manchester, Manchester, UK; 2Department of Medicine and Surgery, University of Parma, Parma, Italy; 3Chiesi Farmaceutici SpA, Parma, Italy; 4Department of Medical Sciences, Research Centre on Asthma and COPD, University of Ferrara, Ferrara, Italy; 5National Heart and Lung Institute, Imperial College London, London, UK Abstract: The goals of COPD therapy are to prevent and control symptoms, reduce the frequency and severity of exacerbations, and improve exercise tolerance. The triple combination therapy of inhaled corticosteroids (ICSs), long-acting beta2 agonists (LABAs), and long-acting muscarinic antagonists (LAMAs) has become an option for maintenance treatment of COPD and as a “step-up” therapy from single or double combination treatments. There is evidence that triple combination ICS/LABA/LAMA with different inhalers improves lung function, symptoms, and health status and reduces exacerbations. A new triple fixed-dose combination of extrafine beclomethasone dipropionate (100 µg/puff)/formoterol fumarate (6 µg/puff)/glycopyrronium bromide (12.5 µg/puff) has been developed as a hydrofluoroalkane pressurized metered dose inhaler. Two large pivotal studies showed that this extrafine fixed ICS/LABA/LAMA triple combination is superior to fixed ICS/LABA combined therapy and also superior to the LAMA tiotropium in terms of lung function and exacerbation prevention in COPD patients at risk of exacerbation. This review considers the new information provided by these clinical trials of extrafine triple therapy and the implications for the clinical management of COPD patients. Keywords: COPD, inhaled triple therapy, beclomethasone dipropionate, formoterol fumarate and glycopyrronium bromide

BACKGROUND Most guidelines recommend either a long-acting beta-agonist (LABA) plus an inhaled glucocorticoid or a long-acting muscarinic antagonist (LAMA) as the firstchoice treatment for patients with chronic obstructive pulmonary disease (COPD) who have a high risk of exacerbations. The role of treatment with a LABA–LAMA regimen in these patients is unclear. METHODS We conducted a 52-week, randomized, double-blind, double-dummy, noninferiority trial. Patients who had COPD with a history of at least one exacerbation during the previous year were randomly assigned to receive, by inhalation, either the LABA indacaterol (110 μg) plus the LAMA glycopyrronium (50 μg) once daily or the LABA salmeterol (50 μg) plus the inhaled glucocorticoid fluticasone (500 μg) twice daily. The primary outcome was the annual rate of all COPD exacerbations. RESULTS A total of 1680 patients were assigned to the indacaterol–glycopyrronium group, and 1682 to the salmeterol–fluticasone group. Indacaterol–glycopyrronium showed not only noninferiority but also superiority to salmeterol–fluticasone in reducing the annual rate of all COPD exacerbations; the rate was 11% lower in the indacaterol– glycopyrronium group than in the salmeterol–fluticasone group (3.59 vs. 4.03; rate ratio, 0.89; 95% confidence interval [CI], 0.83 to 0.96; P=0.003). The indacaterol– glycopyrronium group had a longer time to the first exacerbation than did the salmeterol–fluticasone group (71 days [95% CI, 60 to 82] vs. 51 days [95% CI, 46 to 57]; hazard ratio, 0.84 [95% CI, 0.78 to 0.91], representing a 16% lower risk; P

Design Systematic Review. Objective To determine which intervention approaches to manage depression in the workplace have been successful and yielded value for employers in developed economies. Data Sources We searched MEDLINE, EMBASE, CINAHL, Central, PsycINFO, and Business Source Premier up to June 2010 using search terms in four broad areas: work setting, depression, intervention, and work outcomes. Study Selection Two independent reviewers selected potential articles that met the following criteria: working age individuals with mild or moderate depression; interventions or programs that were workplace-based or could be implemented and/or facilitated by the employer; inclusion of a comparator group in the analysis; outcomes of prevention, management, and recurrences of work disability or sickness absence, and work functioning. Methods Two reviewers independently reviewed each article for quality and extracted data using standardised forms. Following guidelines from the GRADE Working Group, the quality of evidence addressing each outcome was graded as high, moderate, low, or very low on the basis of six criteria: study design, risk of bias, consistency, generalisability, data precision, and economic benefit. Using this information and following Cochrane Collaboration guidelines, the findings for each intervention were summarised and key messages were developed. Results We identified ten randomised trials and two non-randomised studies from various countries and jurisdictions that evaluated a wide range of intervention practices. The evidence was graded as "very low" for all outcomes identified. Therefore, no intervention could be recommended. Conclusions To date, there is insufficient quality of evidence to determine which interventions are effective and yield value to manage depression in the workplace.

Design Systematic Review. Objective To determine which intervention approaches to manage depression in the workplace have been successful and yielded value for employers in developed economies. Data Sources We searched MEDLINE, EMBASE, CINAHL, Central, PsycINFO, and Business Source Premier up to June 2010 using search terms in four broad areas: work setting, depression, intervention, and work outcomes. Study Selection Two independent reviewers selected potential articles that met the following criteria: working age individuals with mild or moderate depression; interventions or programs that were workplace-based or could be implemented and/or facilitated by the employer; inclusion of a comparator group in the analysis; outcomes of prevention, management, and recurrences of work disability or sickness absence, and work functioning. Methods Two reviewers independently reviewed each article for quality and extracted data using standardised forms. Following guidelines from the GRADE Working Group, the quality of evidence addressing each outcome was graded as high, moderate, low, or very low on the basis of six criteria: study design, risk of bias, consistency, generalisability, data precision, and economic benefit. Using this information and following Cochrane Collaboration guidelines, the findings for each intervention were summarised and key messages were developed. Results We identified ten randomised trials and two non-randomised studies from various countries and jurisdictions that evaluated a wide range of intervention practices. The evidence was graded as "very low" for all outcomes identified. Therefore, no intervention could be recommended. Conclusions To date, there is insufficient quality of evidence to determine which interventions are effective and yield value to manage depression in the workplace.

Over the past decade, facial cosmetic procedures have become more commonplace ill dentistry and oral and maxillofacial surgery. An increasing number of patients seek minimal invasive procedures. One of the most requested procedures is treatment with botulinum toxin type A (BoNTA). Treatment of dynamic rhytids and lines with BoNTA is effective and produces high rates of improvement with rapid onset and long duration of action (longer than 4 months for some patients) compared with placebo. This paper considers the history and pharmacology of this neurotoxin, and focusses on the literature concerning the treatment of different facial areas with BoNTA. It also presents clinical guidelines on the treatment of glabellar lines, the frontalis muscle, pen-orbital lines, gummy smile and masseter muscle hypertrophy. Knowledge about the mechanisms of action and the ability to use BoNTA as an adjunctive treatment are mandatory for those working in the field of cosmetic facial surgery.

Few randomised controlled trials (RCTs) have been performed in which a second-generation antiepileptic drug (AED) used as monotherapy was compared with placebo or another AED in children (Studies were identified using PubMed (Medline), Embase and the Cochrane Library (January 1990-January 2010). All reports were assessed for methodological quality and results were summarised descriptively.Nine RCTs were included. No difference in efficacy and safety between second-generation AEDs and first-generation AEDs in children was detected. Considerable heterogeneity in study design, inclusion criteria and primary endpoints impaired formal meta-analysis and correct interpretation of results. Follow-up periods were between 2 and 104 weeks; the dosage of the tested AEDs varied between studies, with sometimes use of apparent subtherapeutic dosages; in only two studies the method of randomisation was well described, in only three the power calculations; several studies did not use an intention-to-treat analysis. Although from the available studies first- and second-generation AEDs appear to have similar efficacy and safety in children with epilepsy, these trials are inadequate to provide a sufficient evidence base for decision making. Better trials are needed: AEDs should be studied in optimal paediatric doses, power should be sufficient to detect small but clinically relevant differences, and the follow-up period should be long enough. Most important, primary endpoint to be evaluated should be time to treatment failure or retention rate, since these outcomes combine efficacy and safety. (C) 2010 Elsevier B.V. All rights reserved.

Background: Whether self-monitoring of blood glucose (SMBG) improves glycaemic control in patients with type 2 diabetes mellitus (T2DM) not using insulin is questionable. Our aim was to investigate the effects of SMBG in patients with T2DM who were in persistent moderate glycaemic control whilst not using insulin.Methods: Patients were eligible when between 18 and 70 years of age, with an HbA1c between 7 and 8.5%, using one or two oral blood glucose lowering agents. Forty-one of the anticipated 52 patients were randomly assigned to receive either SMBG added to usual care, or to continue with usual care for one year. A fasting glucose value and three postprandial glucose values were measured twice weekly (including a Saturday or a Sunday). The primary efficacy parameter was HbA1c. Furthermore, health-related quality of life and treatment satisfaction were assessed using the Short-form 36 Health Survey Questionnaire (SF-36), the Type 2 Diabetes Symptom Checklist (DSC-r), the Diabetes Treatment Satisfaction Questionnaire (DTSQ) and the WHO-Wellbeing Index (WHO-5).Results: Change in HbA1c between groups was -0.05% (95% CI: -0.51, 0.41; p=0.507). Also, there were no significant changes between groups on the DTSQ, DSC type 2, WHO-5 or SF-36, except for the SF-36 dimension 'health change' which was lower in the SBMG group (mean difference: -12 (95% CI: -20.9, -3.1).Conclusion: On top of the absence of a clinical benefit, tablet-treated T2DM patients experienced some worsening of their health perception. We therefore argue that the use of SMBG in this patient group is questionable, and its unlimited use and promotion should be reconsidered.

BI 1002494 [(R)-4-{(R)-1-[7-(3,4,5-trimethoxy-phenyl)-[1,6]napthyridin-5-yloxy]-ethyl}pyrrolidin-2-one] is a novel, potent, and selective spleen tyrosine kinase (SYK) inhibitor with sustained plasma exposure after oral administration in rats, which qualifies this molecule as a good in vitro and in vivo tool compound. BI 1002494 exhibits higher potency in inhibiting high-affinity IgE receptor-mediated mast cell and basophil degranulation (IC50 = 115 nM) compared with B-cell receptor-mediated activation of B cells (IC50 = 810 nM). This may be explained by lower kinase potency when the physiologic ligand B-cell linker was used, suggesting that SYK inhibitors may exhibit differential potency depending on the cell type and the respective signal transduction ligand. A 3-fold decrease in potency was observed in rat basophils (IC50 = 323 nM) compared with human basophils, but a similar species potency shift was not observed in B cells. The lower potency in rat basophils was confirmed in both ex vivo inhibition of bronchoconstriction in precision-cut rat lung slices and in reversal of anaphylaxis-driven airway resistance in rats. The different cellular potencies translated into different in vivo efficacy; full efficacy in a rat ovalbumin model (that contains an element of mast cell dependence) was achieved with a trough plasma concentration of 340 nM, whereas full efficacy in a rat collagen-induced arthritis model (that contains an element of B-cell dependence) was achieved with a trough plasma concentration of 1400 nM. Taken together, these data provide a platform from which different estimates of human efficacious exposures can be made according to the relevant cell type for the indication intended to be treated.

OBJECTIVE Mealtime insulin is commonly added to manage hyperglycemia in type 2 diabetes when basal insulin is insufficient. However, this complex regimen is associated with weight gain and hypoglycemia. This study compared the efficacy and safety of exenatide twice daily or mealtime insulin lispro in patients inadequately controlled by insulin glargine and metformin despite up-titration. RESEARCH DESIGN AND METHODS In this 30-week, open-label, multicenter, randomized, noninferiority trial with 12 weeks prior insulin optimization, 627 patients with insufficient postoptimization glycated hemoglobin A1c (HbA1c) were randomized to exenatide (10–20 µg/day) or thrice-daily mealtime lispro titrated to premeal glucose of 5.6–6.0 mmol/L, both added to insulin glargine (mean 61 units/day at randomization) and metformin (mean 2,000 mg/day). RESULTS Randomization HbA1c and fasting glucose (FG) were 8.3% (67 mmol/mol) and 7.1 mmol/L for exenatide and 8.2% (66 mmol/mol) and 7.1 mmol/L for lispro. At 30 weeks postrandomization, mean HbA1c changes were noninferior for exenatide compared with lispro (–1.13 and –1.10%, respectively); treatment differences were –0.04 (95% CI –0.18, 0.11) in per-protocol (n = 510) and –0.03 (95% CI –0.16, 0.11) in intent-to-treat (n = 627) populations. FG was lower with exenatide than lispro (6.5 vs. 7.2 mmol/L; P = 0.002). Weight decreased with exenatide and increased with lispro (−2.5 vs. +2.1 kg; P < 0.001). More patients reported treatment satisfaction and better quality of life with exenatide than lispro, although a larger proportion of patients with exenatide experienced treatment-emergent adverse events. Exenatide resulted in fewer nonnocturnal hypoglycemic episodes but more gastrointestinal adverse events than lispro. CONCLUSIONS Adding exenatide to titrated glargine with metformin resulted in similar glycemic control as adding lispro and was well tolerated. These findings support exenatide as a noninsulin addition for patients failing basal insulin.

Objectives— Incretin-based therapies for the treatment of type 2 diabetes mellitus improve plasma lipid profiles and postprandial lipemia, but their exact mechanism of action remains unclear. Here, we examined the acute effect of the glucagon-like peptide-1 receptor agonist, exenatide, on intestinal and hepatic triglyceride-rich lipoprotein production and clearance in healthy humans. Methods and Results— Fifteen normolipidemic, normoglycemic men underwent 2 studies each (SC 10 μg exenatide versus placebo), 4 to 6 weeks apart, in random order, in which triglyceride-rich lipoprotein particle kinetics were examined with a primed, constant infusion of deuterated leucine and analyzed by multicompartmental modeling under pancreatic clamp conditions. A fed state was maintained during each study by infusing a high-fat, mixed macronutrient, liquid formula at a constant rate directly into the duodenum via a nasoduodenal tube. Exenatide significantly suppressed the plasma concentration and production rate of triglyceride-rich lipoprotein-apolipoprotein B-48, but not of triglyceride-rich lipoprotein-apolipoprotein B-100. Conclusions— These results suggest a possible direct effect of exenatide on intestinal lipoprotein particle production, independent of changes in weight gain and satiety as seen in long-term studies and independent of changes in gastric emptying. This finding expands our understanding of the effects of exenatide in metabolic regulation beyond its primary therapeutic role in regulation of glucose homeostasis. Clinical Trial Registration— URL: http://www.clinicaltrials.gov , NCT01056549.

To test the safety and efficacy of exenatide once weekly (EQW) compared with metformin (MET), pioglitazone (PIO), and sitagliptin (SITA) over 26 weeks, in suboptimally treated (diet and exercise) drug-naive patients with type 2 diabetes. ispartof: Diabetes Care vol:35 issue:2 pages:252-258 ispartof: location:United States status: published

Over the past decade, facial cosmetic procedures have become more commonplace ill dentistry and oral and maxillofacial surgery. An increasing number of patients seek minimal invasive procedures. One of the most requested procedures is treatment with botulinum toxin type A (BoNTA). Treatment of dynamic rhytids and lines with BoNTA is effective and produces high rates of improvement with rapid onset and long duration of action (longer than 4 months for some patients) compared with placebo. This paper considers the history and pharmacology of this neurotoxin, and focusses on the literature concerning the treatment of different facial areas with BoNTA. It also presents clinical guidelines on the treatment of glabellar lines, the frontalis muscle, pen-orbital lines, gummy smile and masseter muscle hypertrophy. Knowledge about the mechanisms of action and the ability to use BoNTA as an adjunctive treatment are mandatory for those working in the field of cosmetic facial surgery.

Background: Whether self-monitoring of blood glucose (SMBG) improves glycaemic control in patients with type 2 diabetes mellitus (T2DM) not using insulin is questionable. Our aim was to investigate the effects of SMBG in patients with T2DM who were in persistent moderate glycaemic control whilst not using insulin. Methods: Patients were eligible when between 18 and 70 years of age, with an HbA1c between 7 and 8.5%, using one or two oral blood glucose lowering agents. Forty-one of the anticipated 52 patients were randomly assigned to receive either SMBG added to usual care, or to continue with usual care for one year. A fasting glucose value and three postprandial glucose values were measured twice weekly (including a Saturday or a Sunday). The primary efficacy parameter was HbA1c. Furthermore, health-related quality of life and treatment satisfaction were assessed using the Short-form 36 Health Survey Questionnaire (SF-36), the Type 2 Diabetes Symptom Checklist (DSC-r), the Diabetes Treatment Satisfaction Questionnaire (DTSQ) and the WHO-Wellbeing Index (WHO-5). Results: Change in HbA1c between groups was -0.05% (95% CI: -0.51, 0.41; p=0.507). Also, there were no significant changes between groups on the DTSQ, DSC type 2, WHO-5 or SF-36, except for the SF-36 dimension 'health change' which was lower in the SBMG group (mean difference: -12 (95% CI: -20.9, -3.1). Conclusion: On top of the absence of a clinical benefit, tablet-treated T2DM patients experienced some worsening of their health perception. We therefore argue that the use of SMBG in this patient group is questionable, and its unlimited use and promotion should be reconsidered.

Background Glucagon-like peptide-1 receptor agonists (GLP-1 RA) added to insulin in type 2 diabetes patients have shown to lower body weight, improve glycaemic control and reduce total daily insulin dose in short term studies, although the individual response greatly varies. Objective To evaluate GLP-1 RA treatment on body weight, glycaemic control and total daily insulin dose in obese, insulin-using type 2 diabetes patients after 2 years follow-up in a real life setting and to explore a possible relation with eating behaviour. Setting The Martini Hospital and the University Medical Center in Groningen in the Netherlands. Methods Eligible patients were at least 18 years of age, were on insulin therapy and obese (BMI > 30 kg/m2), started GLP-1 RA treatment. At baseline eating behaviour was classified according to the validated Dutch Eating Behaviour Questionnaire. A 2 years follow-up was performed. Main outcome measures Body weight, HbA1c and total daily insulin dose. Results 151 Patients started with exenatide or liraglutide. 120 patients completed the 2 years follow-up. From baseline to 2 years, body weight (mean ± SD) changed from 117.9 ± 22.1 to 107.9 ± 22.9 kg (P

Objective: To review current evidence concerning pharmacology of biosimilar candidates to be used in rheumatology. Methods: A PubMed search up to August 2013 was performed using relevant search terms to include all studies assessing pharmacological properties of biosimilar candidates to be used in rheumatology. Data on study characteristics, type of intervention, pharmacokinetics (PK), pharmacodynamics (PD) and bioequivalence ratios was extracted. Results: Of 280 articles screened, 5 fulfilled our inclusion criteria. Two trials, PLANETAS and PLANETRA, compared CT-P13 and infliximab in patients with active ankylosing spondylitis and rheumatoid arthritis, respectively PK bioequivalence was demonstrated in the phase 1 PLANETAS trial by highly comparable area under the curve (AUC) and maximum drug concentrations (Cmax), whose geometric mean ratios fell between the accepted bioequivalence range of 80-125\%. Equivalence in efficacy and safety was demonstrated in the phase 3 PLANETRA trial. Two phase 1 trials comparing etanercept biosimilar candidates TuNEX and HD203 in healthy volunteers showed a high degree of similarity in AUC and Cmax, with respective geometric mean ratios between PK bioequivalence range. The last included trial referred to GP2013, a rituximab biosimilar candidate, which demonstrated PK and PD bioequivalence to reference product in three different dosing regimens in cynomolgus monkeys. Conclusion: Infliximab, etanercept and rituximab biosimilar candidates have demonstrated PK bioequivalence in the trials included in this review. CT-P13 has recently been approved for use in the European market and the remaining biosimilar candidates are currently being tested in patients with rheumatoid arthritis. publishersversion published