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

Low Temperature Intrinsic Defects in X-Irradiated Hydroxyapatite Synthetic Single Crystals

ESR studies of radiation-induced defects have been conducted on synthetic calcium hydroxyapatite single crystals. For a room temperature x-irradiation a major defect (labeled A) was reported to be an O- ion. X irradiation at 6 K shows defect A, trapped atomic hydrogen, and a nonaxial holelike center (labeled I). These new centers are stable at 6 K but anneal near 77 K. Observations at 9 and 35 GHz indicate that the I center is a spin-1/2 defect located in six inequivalent sites. In the ab plane, spectra exhibit an isotropic hyperfine doublet (∼13 G splitting) and an anisotropic doublet (17-27 G splitting) in three symmetry-related sites. For other orientations additional site splitting and forbidden transitions make the spectra very complex. The hyperfine coupling tensor for the anisotropic doublet has diagonal elements -29.5, -19.2, and +3.11 G. The g tensor for this defect has diagonal elements 2.0068, 2.0032, and 2.0148. The sets of directional cosines associated with the minimum g value and the intermediate A value each indicate a direction corresponding approximately to that of the vector from an OH oxygen to a neighboring PO43- oxygen. The model proposed for the I center is a hole trapped by both an OH- and a neighboring PO 43-. The anisotropic doublet is accounted for with 65% of the spin density on OH-. The remaining spin density is on a phosphate oxygen. This creates a PO42- defect with the isotropic coupling arising from hyperfine interaction with the 31P nucleus

Frittage par compression isostatique à chaud (CIC) et spark plasma sintering (SPS) de nanoparticules en carbure de silicium (SiC) synthétisées à échelle pilote par pyrolyse laser

Des nanoparticules en SiC (20 nm) synthétisées par pyrolyse laser à échelle pilote et préalablement compactées à plus de 1 GPa avec ou sans ajouts de frittage (Al2O3 + Y2O3) ont été frittées par Compression Isostatique à Chaud (CIC) et par Spark Plasma Sintering (SPS). Pour les échantillons frittés sans adjonction d'ajouts, des taux de densification de l'ordre de 95 % ont été obtenus par CIC alors que par SPS ils sont inférieurs à 80 %. En présence d'ajouts les deux méthodes ont permis de densifier les matériaux à des valeurs proches de 100 %. Les plus faibles tailles de grains après frittage ont été observées pour les échantillons frittés par CIC (sans ajouts : ~35 nm et avec ajouts : ~100–200 nm) alors que par SPS les tailles de grains se situent typiquement entre 100 nm et 1 μm. Une évaluation des propriétés mécaniques de base a permis de mettre en évidence un optimum de dureté (28 GPa) pour des tailles de domaines monocristallins de 200 nm correspondant aussi à un optimum de ténacité (6,5 MPa m1/2)