Vilanterol and fluticasone furoate for asthma.

BACKGROUND: Vilanterol (VI) is a long-acting beta2-agonist (LABA) that binds to the beta2-adrenoceptor on the airway smooth muscle, producing bronchodilation. LABA therapy, which is well established in adults as part of the British Thoracic Society (BTS) Guidelines for the Management of Asthma, leads to improvement in symptoms and lung function and reduction in exacerbations. At present, the commonly used LABAs licensed for use in asthma management (formoterol and salmeterol) require twice-daily administration, whereas VI is a once-daily therapy.Fluticasone furoate (FF) is an inhaled corticosteroid (ICS), and ICS therapy is recommended by the BTS asthma guidelines. ICSs, the mainstay of asthma treatment, lead to a reduction in both airway inflammation and airway hyper-responsiveness. Regular use leads to improvement in symptoms and lung function. ICSs are currently recommended as 'preventer' therapy for patients who use a 'reliever' medication (e.g. short-acting beta2 agonist (SABA), salbutamol) three or more times per week. Most of the commonly used ICS treatments are twice-daily medications, although two once-daily products are currently licensed (ciclesonide and mometasone).At the present time, only one once-daily ICS/LABA combination (FF/VI) is available, and several other combination inhalers are recommended for twice-daily administration. OBJECTIVES: To compare effects of VI and FF in combination versus placebo, or versus other ICSs and/or LABAs, on acute exacerbations and on health-related quality of life (HRQoL) in adults and children with chronic asthma. SEARCH METHODS: We searched the Cochrane Airways Group Register of trials, clinical trial registries, manufacturers' websites and reference lists of included studies up to June 2016. SELECTION CRITERIA: We included randomised controlled trials (RCTs) of adults and children with a diagnosis of asthma. Included studies compared VI and FF combined versus placebo, or versus other ICSs and/or LABAs. Our primary outcomes were health-related quality of life, severe asthma exacerbation, as defined by hospital admissions or treatment with a course of oral corticosteroids, and serious adverse events. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and analysed outcomes using a fixed-effect model. We used standard Cochrane methods. MAIN RESULTS: We identified 14 studies that met our inclusion criteria, with a total of 6641 randomised participants, of whom 5638 completed the study. All studies lasted between two and 78 weeks and showed good methodological quality overall.We included 10 comparisons in this review, seven for which the dose of VI and FF was 100/25 mcg (VI/FF 100/25 mcg vs placebo; VI/FF 100/25 mcg vs same dose of FF; VI/FF 100/25 mcg vs same dose of VI; VI/FF 100/25 mcg vs fluticasone propionate (FP) 500 mcg twice-daily; VI/FF 100/25 mcg vs fluticasone propionate/salmeterol (FP/SAL) 250/50 mcg twice-daily; VI/FF 100/25 mcg vs FP/SAL 250/25 mcg twice-daily; FF/VI 100/25 vs FP/SAL500/50) and three for which the dose of VI and FF was 200/25 mcg (VI/FF 200/25 mcg vs placebo; VI/FF 200/25 mcg vs FP 500 mcg; VI/FF 200/25 mcg vs same dose of FF).We found very few opportunities to combine results from the 14 included studies in meta-analyses. We tabulated the data for our pre-specified primary outcomes. In particular, we found insufficient information to assess whether once-daily VI/FF was better or worse than twice-daily FP/SAL in terms of efficacy or safety.Only one of the 14 studies looked at health-related quality of life when comparing VI and FF 100/25 mcg versus placebo and identified a significant advantage of VI/FF 100/25 mcg (mean difference (MD) 0.30, 95% confidence interval (CI) 0.14 to 0.46; 329 participants); we recognised this as moderate-quality evidence. Only two studies compared VI/FF 100/25 mcg versus placebo with respect to exacerbations; both studies reported no exacerbations in either treatment arm. Five studies (VI/FF 100/25 mcg vs placebo) sought information on serious adverse events; all five studies reported no serious adverse events in the VI/FF 100/25 mcg or placebo arms. We found no comparison relevant to our primary outcomes for VI/FF at a higher dose (200/25 mcg) versus placebo.The small number of studies contributing to each comparison precludes the opportunity to draw robust conclusions for clinical practice. These studies were not of sufficient duration to allow conclusions about long-term side effects. AUTHORS' CONCLUSIONS: Some evidence suggests clear advantages for VI/FF, in combination, compared with placebo, particularly for forced expiratory volume in one second (FEV1) and peak expiratory flow; however, the variety of questions addressed in the included studies did not allow review authors to draw firm conclusions. Information was insufficient for assessment of whether once-daily VI/FF was better or worse than twice-daily FP/SAL in terms of efficacy or safety. It is clear that more research is required to reduce the uncertainties that surround interpretation of these studies. It will be necessary for these findings to be replicated in other work before more robust conclusions are revealed. Only five of the 13 included studies provided data on health-related quality of life, and only six recorded asthma exacerbations. Only one study focused on paediatric patients, so no conclusions can be drawn for the paediatric population. More research is needed, particularly in the primary outcome areas selected for this review, so that we can draw firmer conclusions in the next update of this review.

Mepolizumab versus placebo for asthma.

BACKGROUND: Mepolizumab is a human monoclonal antibody against interleukin-5 (IL-5), the main cytokine involved in the activation of eosinophils, which in turn causes airway inflammation. Recent studies have suggested these agents may have a role in reducing exacerbations and improving health-related quality of life (HRQoL). There are no recommendations for the use of mepolizumab in adults or children in the recent update of the BTS/SIGN guidelines (BTS/SIGN 2014). OBJECTIVES: To compare the effects of mepolizumab with placebo on exacerbations and HRQoL in adults and children with chronic asthma. SEARCH METHODS: We searched the Cochrane Airways Group Register (CAGR) of trials, clinical trial registries, manufacturers' websites and the reference lists of included studies. Searches were conducted in November 2013 and updated in November 2014. SELECTION CRITERIA: We included randomised controlled trials comparing mepolizumab versus placebo in adults and children with asthma. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data and analysed outcomes using a random-effects model. We used standard methods expected by The Cochrane Collaboration. MAIN RESULTS: Eight studies on 1707 participants met the inclusion criteria. Only two studies included children (over 12 years of age), but they did not report separate findings for the adolescents. Seven studies involved intravenous mepolizumab alone; one included a subcutaneous arm. There was heterogeneity in the severity and clinical pattern of asthma among the participants in the eight studies, varying from mild to moderate atopic asthma, to persistent asthma and eosinophilic asthma with recurrent exacerbations. Selection bias was a concern in several of the studies included in this review.Four trials compared intravenous mepolizumab to placebo in relation to HRQoL. Two studies measured scores from the Asthma Quality of Life Questionnaire (AQLQ), which showed a non-significant difference between mepolizumab and placebo (mean difference (MD) 0.21, 95% confidence interval (CI) - 0.01 to 0.44; participants = 682), in the direction favouring mepolizumab. The third study used the St. George's Respiratory Questionnaire (SGRQ) and found a significant difference between mepolizumab and placebo (MD 6.40, 95% CI 3.15 to 9.65; participants = 576), which indicated a clinically important benefit favouring mepolizumab. A fourth study noted that there was no significant difference but did not provide any data. The two studies in people with eosinophilic asthma showed a reduction in clinically significant exacerbation rates (Risk Ratio 0.52, 95% CI 0.43 to 0.64; participants = 690). However, an analysis of four studies that were not confined to people with eosinophilic asthma indicated considerable heterogeneity and no significant difference in people with one or more exacerbations between mepolizumab and placebo using a random-effects model (Risk Ratio 0.67, 95% CI 0.34 to 1.31; participants = 468; I(2) = 59%).The analysis of serious adverse events indicated a significant difference favouring mepolizumab (Risk ratio 0.49, 95% CI 0.30 to 0.80; participants = 1441; studies = 5; I(2) = 0%). It was not possible to combine the results for adverse events, and we deemed the quality of this evidence to be low.A single study compared subcutaneous mepolizumab to placebo in 385 adults with severe eosinophilic asthma and found an improvement in HRQoL scores and a reduction in asthma exacerbations, including exacerbations requiring admission to hospital. AUTHORS' CONCLUSIONS: It is not possible to draw firm conclusions from this review with respect to the role of mepolizumab in patients with asthma. Our confidence in the results of this review are limited by the fact that the intravenous route is not currently licensed for mepolizumab, and the evidence for the currently licenced subcutaneous route is limited to a single study in participants with severe eosinophilic asthma.The currently available studies provide evidence that mepolizumab can lead to an improvement in health-related quality of life scores and reduce asthma exacerbations in people with severe eosinophilic asthma.Further research is needed to clarify which subgroups of patients with asthma could potentially benefit from this treatment. Dosage, ideal dosing regimens and duration of treatment need to be clarified, as the studies included in this review differed in their protocols. There are no studies reporting results from children, so we cannot comment on treatment for this age group. At the present time, larger studies using licenced treatment regimens are required to establish the role of mepolizumab in the treatment of severe asthma.

Identifying appropriate candidates for long-acting antiretroviral therapy: findings from a survey of health care providers in the ATLAS-2M trial.

INTRODUCTION: Recent results from Phase 3 clinical trials with cabotegravir (CAB) and rilpivirine (RPV) long-acting (LA) have shown that a monthly regimen is non-inferior to daily oral antiretroviral therapy (ART). Additional insights are necessary to prepare for LA ART roll-out, including identifying the appropriate patients. METHODS: Within the ATLAS-2M trial, an online survey was administered to 329 health care providers (HCPs) in 13 countries. Multivariate logistic regression was conducted to identify factors associated with providers considering a greater proportion of patients as appropriate LA ART candidates. RESULTS: Forty-seven percent of HCPs believed that "some" patients (25-50%) would be appropriate while nearly one-quarter of HCPs (23%) felt that "many" patients (more than 50%) would be appropriate candidates for LA ART. Providers in the African region had a greater odds of identifying a greater proportion of their patients as appropriate candidates (AOR 8.97; p < 0.001) vs. other regions. Nurses/physician assistants and research staff/pharmacists had a higher odds of perceiving a greater proportion of their patients as appropriate candidates vs. physicians, respectively (AOR 3.42 p < 0.001; AOR 2.48; p = 0.19). Providers who had experience transitioning patients from LA to oral ART had a higher odds of reporting that more of their patients would be appropriate candidates (AOR 1.64; p = 0.008) vs. those without experience. CONCLUSION: A significant proportion of providers reported that many of their patients would be appropriate candidates for LA ART. To optimize roll-out after regulatory approval, it is important to support providers with tools to help identify patients who would most benefit from this option.

Long-Acting Injectable Cabotegravir + Rilpivirine for HIV Maintenance Therapy: Week 48 Pooled Analysis of Phase 3 ATLAS and FLAIR Trials.

BACKGROUND: Long-acting (LA) injectable regimens are a potential therapeutic option in people living with HIV-1. SETTING: ATLAS (NCT02951052) and FLAIR (NCT02938520) were 2 randomized, open-label, multicenter, multinational phase 3 studies. METHODS: Adult participants with virologic suppression (plasma HIV-1 RNA <50 copies/mL) were randomized (1:1) to continue with their current antiretroviral regimen (CAR) or switch to the long-acting (LA) regimen of cabotegravir (CAB) and rilpivirine (RPV). In the LA arm, participants initially received oral CAB + RPV once-daily for 4 weeks to assess individual safety and tolerability, before starting monthly injectable therapy. The primary endpoint of this combined analysis was antiviral efficacy at week 48 (FDA Snapshot algorithm: noninferiority margin of 4% for HIV-1 RNA ≥50 copies/mL). Safety, tolerability, and confirmed virologic failure (2 consecutive plasma HIV-1 RNA ≥200 copies/mL) were secondary endpoints. RESULTS: The pooled intention-to-treat exposed population included 591 participants in each arm [28% women (sex at birth), 19% aged ≥50 years]. Noninferiority criteria at week 48 were met for the primary (HIV-1 RNA ≥50 copies/mL) and key secondary (HIV-1 RNA <50 copies/mL) efficacy endpoints. Seven individuals in each arm (1.2%) developed confirmed virologic failure; 6/7 (LA) and 3/7 (CAR) had resistance-associated mutations. Most LA recipients (83%) experienced injection site reactions, which decreased in incidence over time. Injection site reactions led to the withdrawal of 6 (1%) participants. The serious adverse event rate was 4% in each arm. CONCLUSION: This combined analysis demonstrates monthly injections of CAB + RPV LA were noninferior to daily oral CAR for maintaining HIV-1 suppression.

Arrhythmogenic mutation-linked defects in ryanodine receptor autoregulation reveal a novel mechanism of Ca2+ release channel dysfunction.

Arrhythmogenic cardiac ryanodine receptor (RyR2) mutations are associated with stress-induced malignant tachycardia, frequently leading to sudden cardiac death (SCD). The causative mechanisms of RyR2 Ca2+ release dysregulation are complex and remain controversial. We investigated the functional impact of clinically-severe RyR2 mutations occurring in the central domain, and the C-terminal I domain, a key locus of RyR2 autoregulation, on interdomain interactions and Ca2+ release in living cells. Using high-resolution confocal microscopy and fluorescence resonance energy transfer (FRET) analysis of interaction between fusion proteins corresponding to amino- (N-) and carboxyl- (C-) terminal RyR2 domains, we determined that in resting cells, RyR2 interdomain interaction remained unaltered after introduction of SCD-linked mutations and normal Ca2+ regulation was maintained. In contrast, after channel activation, the abnormal Ca2+ release via mutant RyR2 was intrinsically linked to altered interdomain interaction that was equivalent with all mutations and exhibited threshold characteristics (caffeine >2.5 mmol/L; Ca2+ >150 nmol/L). Noise analysis revealed that I domain mutations introduced a distinct pattern of conformational instability in Ca2+ handling and interdomain interaction after channel activation that was absent in signals obtained from the central domain mutation. I domain-linked channel instability also occurred in intact RyR2 expressed in CHO cells and in HL-1 cardiomyocytes. These new insights highlight a critical role for mutation-linked defects in channel autoregulation, and may contribute to a molecular explanation for the augmented Ca2+ release following RyR2 channel activation. Our findings also suggest that the mutational locus may be an important mechanistic determinant of Ca2+ release channel dysfunction in arrhythmia and SCD.

Ryanodine receptor regulation by intramolecular interaction between cytoplasmic and transmembrane domains.

Ryanodine receptors (RyR) function as Ca(2+) channels that regulate Ca(2+) release from intracellular stores to control a diverse array of cellular processes. The massive cytoplasmic domain of RyR is believed to be responsible for regulating channel function. We investigated interaction between the transmembrane Ca(2+)-releasing pore and a panel of cytoplasmic domains of the human cardiac RyR in living cells. Expression of eGFP-tagged RyR constructs encoding distinct transmembrane topological models profoundly altered intracellular Ca(2+) handling and was refractory to modulation by ryanodine, FKBP12.6 and caffeine. The impact of coexpressing dsRed-tagged cytoplasmic domains of RyR2 on intracellular Ca(2+) phenotype was assessed using confocal microscopy coupled with parallel determination of in situ protein: protein interaction using fluorescence resonance energy transfer (FRET). Dynamic interactions between RyR cytoplasmic and transmembrane domains were mediated by amino acids 3722-4610 (Interacting or "I"-domain) which critically modulated intracellular Ca(2+) handling and restored RyR sensitivity to caffeine activation. These results provide compelling evidence that specific interaction between cytoplasmic and transmembrane domains is an important mechanism in the intrinsic modulation of RyR Ca(2+) release channels.

Treatment dilemmas in a young man presenting with narcolepsy and psychotic symptoms.

Psychotic features can be present in both narcolepsy and psychosis, which can result in challenges in diagnosis and management. The prevalence of both conditions is low and the reports in young people are scarce. Our report illustrates the relevance of a thorough differential diagnosis as well as the need to explore treatment avenues based on the evidence available for both narcolepsy and psychosis symptoms to try and maximise the therapeutic impact.