A Randomised, Placebo-Controlled, Dose-Finding Study Of AZD9668, An Oral Inhibitor of Neutrophil Elastase, in Patients with Chronic Obstructive Pulmonary Disease Treated with Tiotropium

2012 ◽  
Vol 9 (2) ◽  
pp. 111-120 ◽  
Author(s):  
Claus Vogelmeier ◽  
Teresita O. Aquino ◽  
Christopher D. O'Brien ◽  
John Perrett ◽  
Kulasiri A. Gunawardena
Keyword(s):  
Chronic Obstructive Pulmonary Disease ◽  
Pulmonary Disease ◽  
Neutrophil Elastase ◽  
Dose Finding ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Finding Study ◽  
Dose Finding Study

scholarly journals Glycopyrrolate/eFlow CS: The First Nebulized Long-Acting Muscarinic Antagonist Approved to Treat Chronic Obstructive Pulmonary Disease

2018 ◽  
Vol 53 (3) ◽  
pp. 285-293 ◽  
Author(s):  
Roy A. Pleasants
Keyword(s):  
Chronic Obstructive Pulmonary Disease ◽  
Pulmonary Disease ◽  
Data Extraction ◽  
Treatment Options ◽  
Dose Finding ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Muscarinic Antagonist ◽  
Patient Reported ◽  
Long Acting

Objective: To review the pharmacology, efficacy, and safety of the first nebulized long-acting muscarinic antagonist (LAMA), glycopyrrolate (GLY)/eFlow closed system (CS) nebulizer, approved for maintenance treatment of chronic obstructive pulmonary disease (COPD). Data Sources: A PubMed search was conducted (January 2000 to July 2018) using the following terms/phrases: nebulized glycopyrrolate, inhalation devices in COPD, long-acting muscarinic antagonists COPD, and COPD survey. Retrieved articles were reviewed to identify additional references. Study Selection and Data Extraction: Primary and review articles on GLY/eFlow CS and other treatment options for patients with COPD were selected. Data Synthesis: Guidelines recommend the use of LAMAs, alone or in combination with long-acting β2-agonists, as maintenance therapy for the majority of patients with COPD. With the range of different devices and bronchodilators now available, treatment can be tailored based on individual needs. The eFlow CS nebulizer delivers GLY rapidly over a 2- to 3-minute period and provides bronchodilation within 30 minutes, lasting 12 hours. Phase 2 dose-finding and phase 3 studies demonstrated sustained statistically significant and clinically important improvements in pulmonary function and patient-reported outcomes with GLY/eFlow CS. Relevance to Patient Care and Clinical Practice: GLY/eFlow CS provides a novel, portable, efficient, and rapid drug delivery system. Conclusions: The recently approved GLY/eFlow CS drug-device combination provides a viable treatment option for patients with COPD, particularly those with conditions that may impair proper use of traditional handheld inhalers.

scholarly journals α-1-Antitrypsin variants and the proteinase/antiproteinase imbalance in chronic obstructive pulmonary disease

2015 ◽  
Vol 308 (2) ◽  
pp. L179-L190 ◽  
Author(s):  
Nicola J. Sinden ◽  
Michael J. Baker ◽  
David J. Smith ◽  
Jan-Ulrich Kreft ◽  
Timothy R. Dafforn ◽  
...  
Keyword(s):  
Chronic Obstructive Pulmonary Disease ◽  
Pulmonary Disease ◽  
Proteolytic Activity ◽  
Neutrophil Elastase ◽  
Point Mutations ◽  
Chronic Obstructive ◽  
Proteinase 3 ◽  
Serine Proteinases ◽  
Obstructive Pulmonary Disease ◽  
Reaction Diffusion Model

The excessive activities of the serine proteinases neutrophil elastase and proteinase 3 are associated with tissue damage in chronic obstructive pulmonary disease. Reduced concentrations and/or inhibitory efficiency of the main circulating serine proteinase inhibitor α-1-antitrypsin result from point mutations in its gene. In addition, α-2-macroglobulin competes with α-1-antitrypsin for proteinases, and the α-2-macroglobulin-sequestered enzyme can retain its catalytic activity. We have studied how serine proteinases partition between these inhibitors and the effects of α-1-antitrypsin mutations on this partitioning. Subsequently, we have developed a three-dimensional reaction-diffusion model to describe events occurring in the lung interstitium when serine proteinases diffuse from the neutrophil azurophil granule following degranulation and subsequently bind to either α-1-antitrypsin or α-2-macroglobulin. We found that the proteinases remained uninhibited on the order of 0.1 s after release and diffused on the order of 10 μm into the tissue before becoming sequestered. We have shown that proteinases sequestered to α-2-macroglobulin retain their proteolytic activity and that neutrophil elastase complexes with α-2-macroglobulin are able to degrade elastin. Although neutrophil elastase is implicated in the pathophysiology of emphysema, our results highlight a potentially important role for proteinase 3 because of its greater concentration in azurophil granules, its reduced association rate constant with all α-1-antitrypsin variants studied here, its greater diffusion distance, time spent uninhibited following degranulation, and its greater propensity to partition to α-2-macroglobulin where it retains proteolytic activity.

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