The effect of high-dose fluticasone propionate and budesonide on lung function and asthma exacerbations in patients with severe asthma

AbstractThe purpose of this study was to investigate the comparative efficacy and safety of equal doses of inhaled fluticasone propionate (FP) and inhaled budesonide (BUD) using their respective dry powder inhalers in a population of severe asthmatics requiring high doses of inhaled corticosteroid. This double-blind double-dummy parallel-group study compared the effects of 24 weeks of treatment with FP (2000 μg daily via a Diskhaler® inhaler; Glaxo Wellcome, Evreux, France) and BUD (2000 μg daily via a Turbuhaler® inhaler; Astra Pharmaceuticals, Rijswijka, Netherlands) on lung function and asthma exacerbations in 395 patients with asthma.FP was statistically significantly superior to BUD with respect to the percentage of symptom-free days (P = 0·02), the incidence of days free from rescue bronchodilator usage (P = 0·02) and the distribution of change in peak expiratory flow (PEF) expressed as a percentage of the predicted PEF (P = 0·04). During the treatment period FP was statistically significantly superior to BUD for change in forced expiratory volume in 1 sec (FEV1) at 8, 16 and 24 weeks, change in the median daytime symptom score during weeks 5–16, for incidence of symptomfree days and incidence of days free from rescue bronchodilator usage during weeks 17–24. There was no significant difference between FP and BUD with respect to the number of patients experiencing one or more asthma exacerbation (33·8 and 28·4% of patients, respectively). There was, however, evidence that the exacerbations were clinically less severe in patients treated with FP, in that the time to resolution was quicker (11·0 vs. 14·7 days; P = 0·035), mean duration of all exacerbations (for an individual patient) tended to be shorter (18·5 vs. 23·6 days; P = 0·12), the time off work was reduced (4·2 vs. 7·6 days; P = 0·012) and the lowest PEF recorded during the exacerbation was higher (301 vs. 263 1 min−1; P = 0·07). There were no clinically relevant differences in the safety (serum cortisol levels, markers of bone turnover, adverse events) of FP and BUD at these microgram equivalent doses.The patients recruited into this study, in retrospect, probably had no need for such high doses of inhaled corticosteroid but, irrespective of this, FP at microgram equivalent doses showed evidence of superior efficacy to BUD with respect to lung function and severity of asthma exacerbations without producing any greater adverse systemic effect

Transcriptional signature of human pro-inflammatory TH17 cells identifies reduced IL10 gene expression in multiple sclerosis

We have previously reported the molecular signature of murine pathogenic TH17 cells that induce experimental autoimmune encephalomyelitis (EAE) in animals. Here we show that human peripheral blood IFN-γ+IL-17+ (TH1/17) and IFN-γ−IL-17+ (TH17) CD4+ T cells display distinct transcriptional profiles in high-throughput transcription analyses. Compared to TH17 cells, TH1/17 cells have gene signatures with marked similarity to mouse pathogenic TH17 cells. Assessing 15 representative signature genes in patients with multiple sclerosis, we find that TH1/17 cells have elevated expression of CXCR3 and reduced expression of IFNG, CCL3, CLL4, GZMB, and IL10 compared to healthy controls. Moreover, higher expression of IL10 in TH17 cells is found in clinically stable vs. active patients. Our results define the molecular signature of human pro-inflammatory TH17 cells, which can be used to both identify pathogenic TH17 cells and to measure the effect of treatment on TH17 cells in human autoimmune diseases

Roflumilast in moderate-to-severe chronic obstructive pulmonary disease treated with longacting bronchodilators: two randomised clinical trials

Background Patients with chronic obstructive pulmonary disease (COPD) have few options for treatment. The efficacy and safety of the phosphodiesterase-4 inhibitor roflumilast have been investigated in studies of patients with moderate-to-severe COPD, but not in those concomitantly treated with longacting inhaled bronchodilators. The effect of roflumilast on lung function in patients with COPD that is moderate to severe who are already being treated with salmeterol or tiotropium was investigated. Methods In two double-blind, multicentre studies done in an outpatient setting, after a 4-week run-in, patients older than 40 years with moderate-to-severe COPD were randomly assigned to oral roflumilast 500 mu g or placebo once a day for 24 weeks, in addition to salmeterol (M2-127 study) or tiotropium (M2-128 study). The primary endpoint was change in prebronchodilator forced expiratory volume in 1s (FEV(1)). Analysis was by intention to treat. The studies are registered with ClinicalTrials.gov, number NCT00313209 for M2-127, and NCT00424268 for M2-128. Findings In the salmeterol plus roflumilast trial, 466 patients were assigned to and treated with roflumilast and 467 with placebo; in the tiotropium plus roflumilast trial, 371 patients were assigned to and treated with roflumilast and 372 with placebo. Compared with placebo, roflumilast consistently improved mean prebronchodilator FEV(1) by 49 mL (p<0.0001) in patients treated with salmeterol, and 80 mL (p<0.0001) in those treated with tiotropium. Similar improvement in postbronchodilator FEV(1) was noted in both groups. Furthermore, roflumilast had beneficial effects on other lung function measurements and on selected patient-reported outcomes in both groups. Nausea, diarrhoea, weight loss, and, to a lesser extent, headache were more frequent in patients in the roflumilast groups. These adverse events were associated with increased patient withdrawal. Interpretation Roflumilast improves lung function in patients with COPD treated with salmeterol or tiotropium, and could become an important treatment for these patients

Learning with whom to communicate using relational reinforcement learning

Relational reinforcement learning is a promising direction within reinforcement learning research. It upgrades reinforcement learning techniques using relational representations for states, actions, and learned value functions or policies to allow natural representations and abstractions of complex tasks. Multi-agent systems are characterized by their relational structure and present a good example of a complex task. In this article, we show how relational reinforcement learning could be a useful tool for learning in multi-agent systems. We study this approach in more detail on one important aspect of multi-agent systems, i.e., on learning a communication policy for cooperative systems (e.g., resource distribution). Communication between agents in realistic multi-agent systems can be assumed costly, limited, and unreliable. We perform a number of experiments that highlight the conditions in which relational representations can be beneficial when taking the constraints mentioned above into account.keywordsoptimal policyreinforcement learningaction spacemultiagent systemmarkov decision processthese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves