Long-term safety of tiotropium/olodaterol Respimat® in patients with moderate-to-very severe COPD and renal impairment in the TONADO® studies

Introduction: The safety, lung function efficacy, and symptomatic benefits of combined tiotropium and olodaterol in patients with COPD were established in the 1-year TONADO (R) studies (NCT01431274; NCT01431287). As tiotropium is predominantly excreted by the kidneys, the long-term safety profile of tiotropium/olodaterol was investigated in patients with renal impairment in a prespecified safety analysis of the TONADO studies. Methods: These were 2 replicate, randomized, double-blind, parallel-group, 52-week Phase III studies that assessed tiotropium/olodaterol compared with tiotropium or olodaterol alone (all via Respimat (R)) in patients with moderate-to-very severe COPD. In this analysis, renal impairment was defined as mild (creatinine clearance [CLcr] 60-89 mL/min), moderate (CLcr 30-59 mL/min) or severe (CLcr 15-29 mL/min). Adverse events (AEs) were pooled from both studies. Results: Of 3,041 patients included in this analysis, 1,333 (43.8%) had mild, 404 (13.3%) had moderate, and 5 (0.2%) had severe renal impairment; these were distributed equally between treatment groups. Almost one-quarter of all treated patients (23.4%) had a history of cardiac disorder, 45.6% had hypertension, and 13.3% had glucose metabolism disorders, including diabetes. AEs with olodaterol, tiotropium, and tiotropium/olodaterol occurred in 75.1%, 70.8%, and 72.0% of patients with no renal impairment, 75.7%, 74.0%, and 73.3% with mild renal impairment, and 84.3%, 79.5%, and 79.7% with moderate renal impairment, respectively. There was no notable effect of renal impairment on the proportion of patients with an AE, and no differences were observed between tiotropium/olodaterol versus the monocomponents. There was no difference in the incidence of major adverse cardiac events, renal and urinary tract AEs, or potential anticholinergic effects with increasing severity of renal impairment. Conclusion: Over half the patients enrolled in the TONADO studies had renal impairment, and there was a high level of pre-existing cardiovascular comorbidity. The safety and tolerability of tiotropium/olodaterol is comparable to the monocomponents, irrespective of the level of renal impairment

Dose counter performance of mometasone furoate/formoterol inhalers in subjects with asthma or COPD

BACKGROUND: Consistent delivery of medication to treat asthma and chronic obstructive pulmonary disease (COPD) is critical for disease control. Dose tracking may eliminate the possibility of sub-therapeutic dosing. This study evaluated the overall performance, including accuracy and ruggedness, of the mometasone furoate/formoterol (MF/F) metered-dose inhaler (MDI) with an integrated numerical dose-counting mechanism in adolescent and adult subjects (aged ≥ 12 y) with persistent asthma or COPD. METHODS: In a phase III, open-label, single-arm, multicenter study, subjects demonstrating at least 90% compliance with MF/F during the screening period received twice daily MF/F MDI 100/10 μg with the integrated dose counter for 4 weeks. Accuracy and ruggedness of the dose counter were assessed by the overall discrepancy rate of subject-recorded actuations versus subject-recorded dose counter readings. Discrepancy rates for Counterstrip™, a manual counting method, were evaluated for reference. Compliance and ergonomic safety were also assessed. RESULTS: The 233 subjects who used ≥ 90% of labeled actuations were included in the primary analysis. Of 26,317 total actuations, 33 dose counter discrepancies occurred (rate = 0.13/100 actuations), of which 13 were due to undercounting. In comparison, the Counterstrip discrepancy rate was 10-fold higher (1.34/100 actuations). Compliance with medication use, Counterstrip use, and e-diary recordings were all high (>98%). No new repetitive strain injuries or exacerbations of preexisting ergonomic injuries of the finger, hand, or arm were reported. CONCLUSIONS: The MF/F MDI dose counter was accurate and rugged in subjects with asthma or COPD. No new repetitive strain injuries or exacerbations of existing ergonomic injuries were associated with inhaler use. CLINICAL TRIAL REGISTRATION NUMBER: ClinicalTrials.gov identifier = NCT00604500

Influence of C-159T SNP of the CD14 gene promoter on lung function in smokers

CD14, a co-receptor for endotoxin, plays a significant role in the inflammatory response to this environmentally important pollutant. The C-159T single nucleotide polymorphism (SNP) in the CD14 gene promoter is reported to affect expression of CD14, with TT homozygous persons having higher CD14 expression. This SNP has been linked to pathogenesis of asthma and with cardiovascular diseases in smokers. We hypothesize that CD14 also plays a role in development of COPD in smokers who are exposed to inhaled endotoxin by cigarette smoking and to endotoxin released from Gram-negative microbes colonizing their airways. To assess the effect of the C-159T SNP of the CD14 gene promoter on lung function and GOLD score in smokers with COPD, we recruited 246 smokers with COPD with a range of 10–156 pack-year smoking exposures. We found that the C-159T single gene polymorphism of the CD14 gene promoter may play a role in modulating severity of obstructive impairment in smokers with COPD: The TT genotype was associated with lower lung function in smokers with a moderate smoking history. However, the CC genotype was associated with decreased lung function in heavy smokers (>56 pack-years). The result on CC genotype in risk for COPD is analogous with the effect of this genotype in risk for asthma. CD14 may be a factor in the pathophysiology of COPD, as it is in asthma and smoking-related cardiovascular diseases

Complementary and Alternative Medicine (CAM) Attitudes and Competencies of Nursing Students and Faculty: Results of Integrating CAM Into the Nursing Curriculum

As part of the National Center for Complementary and Alternative Medicine (CAM) R25 Education Grant Program, a faculty development program for integrating CAM into the nursing curriculum was instituted in 2003-2006. The Integrating CAM program comprised a number of elements; the primary strategy included a series of 4-week didactic and experiential summer CAM “camps,” attended by a total of 27 faculty members. Camps were designed to influence faculty integration of CAM material into course offerings. The Integrating CAM program was evaluated via a series of faculty and student surveys regarding CAM competencies, attitudes, and perceptions. For more than half of the faculty (out of the 43 who responded), the program yielded a moderate-to-strong influence on incorporation of CAM material into course content; and moderate-to-great increases in both enthusiasm for CAM and perceived CAM knowledge gains. Students at all levels (undergraduate, masters, doctoral; n = 184) reported that their courses contained CAM content; for 70% of students, their CAM knowledge increased; for 50% of students, level of CAM interest increased. Self-reported student CAM competencies were significantly greater in 2006-2007 (n = 191) than in 2003-2004 (n = 143). Results support the strategy of broadly infusing the nursing curriculum with CAM content via faculty development

Bi-fluorescent Staphylococcus aureus infection enables single-cell analysis of intracellular killing in vivo

Techniques for studying the clearance of bacterial infections are critical for advances in understanding disease states, immune cell effector functions, and novel antimicrobial therapeutics. Intracellular killing of Staphylococcus aureus by neutrophils can be monitored using a S. aureus strain stably expressing GFP, a fluorophore that is quenched when exposed to the reactive oxygen species (ROS) present in the phagolysosome. Here, we expand upon this method by developing a bi-fluorescent S. aureus killing assay for use in vivo. Conjugating S. aureus with a stable secondary fluorescent marker enables the separation of infected cell samples into three populations: cells that have not engaged in phagocytosis, cells that have engulfed and killed S. aureus, and cells that have viable internalized S. aureus. We identified ATTO647N-NHS Ester as a favorable dye conjugate for generating bi-fluorescent S. aureus due to its stability over time and invariant signal within the neutrophil phagolysosome. To resolve the in vivo utility of ATTO647N/GFP bi-fluorescent S. aureus, we evaluated neutrophil function in a murine model of chronic granulomatous disease (CGD) known to have impaired clearance of S. aureus infection. Analysis of bronchoalveolar lavage (BAL) from animals subjected to pulmonary infection with bi-fluorescent S. aureus demonstrated differences in neutrophil antimicrobial function consistent with the established phenotype of CGD

Imaging and quantification of spreading and trapping of carbon dioxide in saline aquifers using meter-scale laboratory experiments

The role of capillary forces during buoyant migrati on of CO2 is critical towards plume immobilization within the post-injection phase of a geological carbon sequestration operation. However, the inherent heterogeneity of the subsurface makes it very challenging to evaluate the effects of capillary forces on the storage capacity of these formations and to assess in-situ plume evolution. To overcome the lack of accurate and continuous observations at the field scale and to mimic vertical migration and entrapment of realistic CO2 plumes in the presence of a background hydraulic gradient, we conducted two unique long-te rm experiments in a 2.44 m × 0.5 m tank. X-ray attenuation allowed measuring the evolution of a CO2-surrogate fluid saturation, thus providing direct insight into capillarity- and buoyancy-domin ated flow processes occurring under successive drainage and imbibition conditions. The comparison of saturation distributions between two experimental campaigns suggests that layered-type h eterogeneity plays an important role on non- wetting phase (NWP) migration and trapping, because it leads to (i) longer displacement times (3.6 months vs. 24 days) to reach stable trapping c onditions, (ii) limited vertical migration of the plume (with center of mass at 39% vs. 55% of aquife r thickness), and (iii) immobilization of a larger fraction of injected NWP mass (67.2% vs. 51. 5% of injected volume) as compared to the homogenous scenario. While these observations confirm once more the role of geological heterogeneity in controlling buoyant flows in the s ubsurface, they also highlight the importance of characterizing it at scales that are below seismic resolution (1-10 m)

Safety profile and clinical activity of multiple subcutaneous doses of MEDI-528, a humanized anti-interleukin-9 monoclonal antibody, in two randomized phase 2a studies in subjects with asthma

<p>Abstract</p> <p>Background</p> <p>Interleukin-9 (IL-9)-targeted therapies may offer a novel approach for treating asthmatics. Two randomized placebo-controlled studies were conducted to assess the safety profile and potential efficacy of multiple subcutaneous doses of MEDI-528, a humanized anti-IL-9 monoclonal antibody, in asthmatics.</p> <p>Methods</p> <p>Study 1: adults (18-65 years) with mild asthma received MEDI-528 (0.3, 1, 3 mg/kg) or placebo subcutaneously twice weekly for 4 weeks. Study 2: adults (18-50 years) with stable, mild to moderate asthma and exercise-induced bronchoconstriction received 50 mg MEDI-528 or placebo subcutaneously twice weekly for 4 weeks. Adverse events (AEs), pharmacokinetics (PK), immunogenicity, asthma control (including asthma exacerbations), and exercise challenge test were evaluated in study 1, study 2, or both.</p> <p>Results</p> <p>In study 1 (N = 36), MEDI-528 showed linear serum PK; no anti-MEDI-528 antibodies were detected. Asthma control: 1/27 MEDI-528-treated subjects had 1 asthma exacerbation, and 2/9 placebo-treated subjects had a total of 4 asthma exacerbations (one considered a serious AE). In study 2, MEDI-528 (n = 7) elicited a trend in the reduction in mean maximum decrease in FEV₁post-exercise compared to placebo (n = 2) (-6.49% MEDI-528 vs -12.60% placebo; -1.40% vs -20.10%; -5.04% vs -15.20% at study days 28, 56, and 150, respectively). Study 2 was halted prematurely due to a serious AE in an asymptomatic MEDI-528-treated subject who had an abnormal brain magnetic resonance imaging that was found to be an artifact on further evaluation.</p> <p>Conclusions</p> <p>In these studies, MEDI-528 showed an acceptable safety profile and findings suggestive of clinical activity that support continued study in subjects with mild to moderate asthma.</p> <p>Trial registration</p> <p>ClinicalTrials (NCT): <a href="http://www.clinicaltrials.gov/ct2/show/NCT00507130">NCT00507130</a> and ClinicalTrials (NCT): <a href="http://www.clinicaltrials.gov/ct2/show/NCT00590720">NCT00590720</a></p

Profiling the bronchodilator effects of the novel ultra-long-acting β-agonist indacaterol against established treatments in chronic obstructive pulmonary disease

Indacaterol is a novel, inhaled, ultra-long-acting β 2 -agonist providing 24-h bronchodilation with once-daily (od) dosing for maintenance use in patients with chronic obstructive pulmonary disease (COPD). This article reviews the bronchodilator properties of indacaterol compared with other treatments used in COPD. Data from five published placebo-controlled studies were reviewed. Two 14-day crossover studies, the first comparing indacaterol 300 µg od with salmeterol 50 µg twice daily (bid), the second comparing indacaterol 150 µg and 300 µg od with tiotropium 18 µg od, assessed forced expiratory volume in 1 s (FEV 1 ) at 24 h postdose (trough). Third, a 14-day crossover study evaluated trough FEV 1 following indacaterol 300 µg dosed morning or evening compared with salmeterol 50 µg bid. Fourth, a single-dose study of indacaterol 150 and 300 µg measured FEV 1 at 5 min postdose compared with salmeterol/fluticasone 50/500 µg and salbutamol 200 µg. Finally, data from a 1-year study with indacaterol 300 µg and formoterol 12 µg bid were examined to determine whether bronchodilation was maintained long term. In the first two studies, indacaterol increased trough FEV 1 after 14 days by a statistically significant and clinically relevant margin over placebo; indacaterol had a greater effect than salmeterol and a similar effect to tiotropium. In the third study, indacaterol had the same effect on trough FEV 1 whether dosed in the morning or evening. In the fourth study, the onset of the bronchodilator effect of indacaterol was similar to that of salbutamol. In the fifth study, the bronchodilator effect of indacaterol on trough FEV 1 was maintained at a significant and clinically relevant level over 52 weeks, whereas the bronchodilator effect of formoterol diminished over time. To conclude, indacaterol is a highly effective bronchodilator that is superior to or at least as effective as other available long-acting bronchodilators for COPD