Improved lung function and patient-reported outcomes with co-suspension delivery technology glycopyrrolate/formoterol fumarate metered dose inhaler in COPD:a randomized Phase III study conducted in Asia, Europe, and the USA

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Photoreduction of Shewanella oneidensis Extracellular Cytochromes by Organic Chromophores and Dye-Sensitized TiO2.

The transfer of photoenergized electrons from extracellular photosensitizers across a bacterial cell envelope to drive intracellular chemical transformations represents an attractive way to harness nature's catalytic machinery for solar-assisted chemical synthesis. In $\textit{Shewanella oneidensis}$ MR-1 (MR-1), trans-outer-membrane electron transfer is performed by the extracellular cytochromes MtrC and OmcA acting together with the outer-membrane-spanning porin$\cdot$cytochrome complex (MtrAB). Here we demonstrate photoreduction of solutions of MtrC, OmcA, and the MtrCAB complex by soluble photosensitizers: namely, eosin Y, fluorescein, proflavine, flavin, and adenine dinucleotide, as well as by riboflavin and flavin mononucleotide, two compounds secreted by MR-1. We show photoreduction of MtrC and OmcA adsorbed on Ru$^{\text{II}}$-dye-sensitized TiO$_2$ nanoparticles and that these protein-coated particles perform photocatalytic reduction of solutions of MtrC, OmcA, and MtrCAB. These findings provide a framework for informed development of strategies for using the outer-membrane-associated cytochromes of MR-1 for solar-driven microbial synthesis in natural and engineered bacteria.This work was supported by the UK Biotechnology and Biological Sciences Research Council (grants BB/K009753/1, BB/K010220/1, BB/K009885/1, and BB/K00929X/1), the Engineering and Physical Sciences Research Council (EP/M001989/1, PhD studentship 1307196 to E.V.A.), a Royal Society Leverhulme Trust Senior Research Fellowship to J.N.B., the Christian Doppler Research Association, and OMV group

A Decaheme Cytochrome as a Molecular Electron Conduit in Dye-Sensitized Photoanodes.

In nature, charge recombination in light-harvesting reaction centers is minimized by efficient charge separation. Here, it is aimed to mimic this by coupling dye-sensitized TiO2 nanocrystals to a decaheme protein, MtrC from Shewanella oneidensis MR-1, where the 10 hemes of MtrC form a ≈7-nm-long molecular wire between the TiO2 and the underlying electrode. The system is assembled by forming a densely packed MtrC film on an ultra-flat gold electrode, followed by the adsorption of approximately 7 nm TiO2 nanocrystals that are modified with a phosphonated bipyridine Ru(II) dye (RuP). The step-by-step construction of the MtrC/TiO2 system is monitored with (photo)electrochemistry, quartz-crystal microbalance with dissipation (QCM-D), and atomic force microscopy (AFM). Photocurrents are dependent on the redox state of the MtrC, confirming that electrons are transferred from the TiO2 nanocrystals to the surface via the MtrC conduit. In other words, in these TiO2/MtrC hybrid photodiodes, MtrC traps the conduction-band electrons from TiO2 before transferring them to the electrode, creating a photobioelectrochemical system in which a redox protein is used to mimic the efficient charge separation found in biological photosystems.This work was supported by the BBSRC (grants BB/K009753/1, BB/K010220/1, and BB/K009885/1), the EPSRC (EP/H00338X/2; PhD studentship to Emma Ainsworth), the Christian Doppler Research Association and the OMV Group. The authors appreciate Dr. Liang Shi (PNNL) and Dr. Marcus Edwards (UEA) for providing the S. oneidensis strain and the protocol allowing for purification of MtrC.This is the final published version of the article. It was originally published in Advanced Functional Materials (Hwang ET, Sheikh K, Orchard KL, Hojo D, Radu V, Lee C-Y, Ainsworth E, Lockwood C, Gross MA, Adschiri T, Reisner E, Butt JN, Jeuken LJC, Advanced Functional Materials 2015, 25, 2308–2315, doi: 10.1002/adfm.201404541) http://dx.doi.org/10.1002/adfm.201404541

Dose-response to inhaled glycopyrrolate delivered with a novel Co-Suspension™ Delivery Technology metered dose inhaler (MDI) in patients with moderate-to-severe COPD

This study forms part of the first complete characterization of the dose-response curve for glycopyrrolate (GP) delivered using Co-Suspension™ Delivery Technology via a metered dose inhaler (MDI). We examined the lower GP MDI dose range to determine an optimal dose for patients with moderate-to-severe chronic obstructive pulmonary disease (COPD)

A randomized, seven-day study to assess the efficacy and safety of a glycopyrrolate/formoterol fumarate fixed-dose combination metered dose inhaler using novel Co-Suspension™ Delivery Technology in patients with moderate-to-very severe chronic obstructive pulmonary disease

Abstract Background Long-acting muscarinic antagonist/long-acting β 2 -agonist combinations are recommended for patients whose chronic obstructive pulmonary disease (COPD) is not managed with monotherapy. We assessed the efficacy and safety of glycopyrrolate (GP)/formoterol fumarate (FF) fixed-dose combination delivered via a Co-Suspension™ Delivery Technology-based metered dose inhaler (MDI) (GFF MDI). Methods This was a Phase IIb randomized, multicenter, placebo-controlled, double-blind, chronic-dosing (7 days), crossover study in patients with moderate-to-very severe COPD (NCT01085045). Treatments included GFF MDI twice daily (BID) (GP/FF 72/9.6 μg or 36/9.6 μg), GP MDI 36 μg BID, FF MDI 7.2 and 9.6 μg BID, placebo MDI, and open-label formoterol dry powder inhaler (FF DPI) 12 μg BID or tiotropium DPI 18 μg once daily. The primary endpoint was forced expiratory volume in 1 s area under the curve from 0 to 12 h (FEV 1 AUC 0–12 ) on Day 7 relative to baseline FEV 1 . Secondary endpoints included pharmacokinetics and safety. Results GFF MDI 72/9.6 μg or 36/9.6 μg led to statistically significant improvements in FEV 1 AUC 0–12 after 7 days’ treatment versus monocomponent MDIs, placebo MDI, tiotropium, or FF DPI (p ≤ 0.0002). GFF MDI 36/9.6 μg was non-inferior to GFF MDI 72/9.6 μg and monocomponent MDIs were non-inferior to open-label comparators. Pharmacokinetic results showed glycopyrrolate and formoterol exposure were decreased following administration via fixed-dose combination versus monocomponent MDIs; however, this was not clinically meaningful. GFF MDI was well tolerated. Conclusions GFF MDI 72/9.6 μg and 36/9.6 μg BID improve lung function and are well tolerated in patients with moderate-to-very severe COPD. Trial registration ClinicalTrials.gov NCT01085045. Registered 9 March 2010

Evaluation of Fetuses in the Preventive IVIG Therapy for Congenital Heart Block (PITCH) study

The recurrence rate of anti-SSA/Ro associated congenital heart block (CHB) is 17%. Reversal of 3rd degree block has never been achieved. Based on potential reduction of maternal autoantibody titers as well as fetal inflammatory responses, IVIG was evaluated as a preventative therapy for CHB

A phase IIb randomized, chronic-dosing, incomplete block, cross-over study of glycopyrronium, delivered via metered dose inhaler, compared with a placebo and an active control in patients with moderate-to-severe COPD

Abstract Background Long-acting muscarinic antagonist (LAMA) and long-acting β2-agonist (LABA) bronchodilators are key to the pharmacologic treatment of chronic obstructive pulmonary disease (COPD). This Phase IIb study investigated the safety and efficacy of four doses of the LAMA glycopyrronium (GP) delivered using co-suspension delivery technology via metered dose inhaler (MDI). The study was part of a wider clinical trial program performed to determine the optimal dose of GP MDI, the LABA formoterol fumarate dihydrate (FF) MDI, and glycopyrronium/formoterol fumarate dihydrate (GFF) MDI fixed-dose combination to be taken forward into Phase III studies. Methods In this randomized, double-blind, 7-day chronic-dosing, three-period incomplete block, cross-over study, patients with moderate-to-severe COPD received two of the four doses of GP MDI (28.8 μg, 14.4 μg, 7.2 μg, and 3.6 μg) twice daily (BID), and either placebo MDI BID or open-label ipratropium MDI 34 μg four times daily. The primary efficacy endpoint was forced expiratory volume in 1 s (FEV1) area under the curve from 0 to 12 h (AUC0–12) relative to baseline on Day 7. Secondary and exploratory efficacy endpoints were assessed on Days 1 and 7. Safety and tolerability were evaluated throughout the study. Results All GP MDI treatments were superior to placebo MDI for the primary efficacy endpoint (all p < 0.0001). However, only GP MDI 28.8 μg and 14.4 μg demonstrated statistical superiority to placebo MDI for all secondary efficacy endpoints analyzed in this study, with the exception of GP MDI 14.4 μg versus placebo MDI for the proportion of patients achieving ≥12% improvement in FEV1. No nominally significant differences were observed between GP MDI 28.8 μg and GP MDI 14.4 μg for any of the endpoints. All doses of GP MDI were well tolerated, with no unexpected safety findings. Conclusions This study indicated that there was no advantage of GP MDI 28.8 μg compared with GP MDI 14.4 μg. It therefore added to the evidence from the Phase I/II clinical trial program, which identified GP MDI 14.4 μg as the most appropriate dose for use in the Phase III clinical studies. Trial registration ClinicalTrials.gov (NCT01350128). Registered May 09, 2011