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Lung drug deposition study

Haruko Yokoyama, Kanako Ito, Hirokazu Mihashi, Yasuyuki Shiraishi, Risa Takayanagi, Yasuhiko Yamada
The aim of this study was to establish an appropriate inhalation method with a mometasone furoate dry powder inhaler (MF-DPI). Utilizing a tone-based inhalation training device, we investigated the maximum peak inspiratory flow rate time (Tmax PIFR) and peak inspiratory flow rate (PIFR) to determine whether either had an influence on lung deposition with use of an MF-DPI. A low tone indicated a PIFR of 28 L/min and a high tone that of 40 L/min, while 60 L/min was considered to be the standard. We established an inhalation profile in consideration of a human inhalation pattern, in which Tmax PIFR was set at 0...
2016: Biological & Pharmaceutical Bulletin
Ronald Dahl, Alan Kaplan
BACKGROUND: In many countries worldwide, the long-acting anticholinergic drug tiotropium is available as a dry powder formulation delivered by means of the HandiHaler® inhalation device and as an aqueous solution delivered via the Respimat® Soft Mist™ Inhaler. Tiotropium HandiHaler® is a single-dose, dry powder, breath-actuated inhaler that provides delivered doses and lung deposition of tiotropium that are, over a wide range, not influenced by the severity of chronic obstructive pulmonary disease (COPD)...
October 11, 2016: BMC Pulmonary Medicine
Laura Lucarini, Mariaconcetta Durante, Cecilia Lanzi, Alessandro Pini, Giulia Boccalini, Laura Calosi, Flavio Moroni, Emanuela Masini, Guido Mannaioni
Idiopathic pulmonary fibrosis is a severe disease characterized by excessive myofibroblast proliferation, extracellular matrix and fibrils deposition, remodelling of lung parenchyma and pulmonary insufficiency. Drugs able to reduce disease progression are available, but therapeutic results are unsatisfactory; new and safe treatments are urgently needed. Poly(ADP-ribose) polymerases-1 (PARP-1) is an abundant nuclear enzyme involved in key biological processes: DNA repair, gene expression control, and cell survival or death...
October 4, 2016: Journal of Cellular and Molecular Medicine
Shao-Hui Lin, Wei Cui, Gui-Ling Wang, Shuai Meng, Ying-Chun Liu, Hong-Wei Jin, Liang-Ren Zhang, Ying Xie
Albumin-based nanoparticles (NPs) are a promising technology for developing drug-carrier systems, with improved deposition and retention profiles in lungs. Improved understanding of these drug-carrier interactions could lead to better drug-delivery systems. The present study combines computational and experimental methods to gain insights into the mechanism of binding of albuterol sulfate (AS) to bovine serum albumin (BSA) on the molecular level. Molecular dynamics simulation and surface plasmon resonance spectroscopy were used to determine that there are two binding sites on BSA for AS: the first of which is a high-affinity site corresponding to AS1 and the second of which appears to represent the integrated functions of several low-affinity sites corresponding to AS2, AS3, and AS8...
2016: Drug Design, Development and Therapy
Marius Hittinger, Nico Alexander Mell, Hanno Huwer, Brigitta Loretz, Nicole Schneider-Daum, Claus-Michael Lehr
Acute respiratory distress syndrome is linked to inflammatory processes in the human lung. The aim of this study was to mimic in vitro the treatment of lung inflammation by using a cell-based human autologous co-culture model. As a potential trial medication, we developed a pulmonary dry powder formulation loaded with interleukin-10 (IL-10), a potent anti-inflammatory cytokine. The inflammatory immune response was stimulated by lipopolysaccharide. The co-culture was combined with the Pharmaceutical Aerosol Deposition Device on Cell Cultures )PADDOCC), to deposit the IL-10-loaded microparticles on the inflamed co-culture model at the air-liquid interface...
September 2016: Alternatives to Laboratory Animals: ATLA
Marius Hittinger, Julia Janke, Hanno Huwer, Regina Scherließ, Nicole Schneider-Daum, Claus-Michael Lehr
The development of new formulations for pulmonary drug delivery is a challenge on its own. New in vitro models which address the lung are aimed at predicting and optimising the quality, efficacy and safety of inhaled drugs, to facilitate the more rapid translation of such products into the clinic. Reducing the complexity of the in vivo situation requires that such models reproducibly reflect essential physiological factors in vitro. The choice of cell types, culture conditions and the experimental set-up, can affect the outcome and the relevance of a study...
September 2016: Alternatives to Laboratory Animals: ATLA
Jos L J van der Velden, Ying Ye, James D Nolin, Sidra M Hoffman, David G Chapman, Karolyn G Lahue, Sarah Abdalla, Peng Chen, Yong Liu, Brydon Bennett, Nasreen Khalil, Donna Sutherland, William Smith, Gerald Horan, Mahmoud Assaf, Zebulun Horowitz, Rajesh Chopra, Randall M Stevens, Maria Palmisano, Yvonne M W Janssen-Heininger, Peter H Schafer
BACKGROUND: Lung remodeling and pulmonary fibrosis are serious, life-threatening conditions resulting from diseases such as chronic severe asthma and idiopathic pulmonary fibrosis (IPF). Preclinical evidence suggests that JNK enzyme function is required for key steps in the pulmonary fibrotic process. However, a selective JNK inhibitor has not been investigated in translational models of lung fibrosis with clinically relevant biomarkers, or in IPF patients. METHODS: The JNK inhibitor CC-930 was evaluated in the house dust mite-induced fibrotic airway mouse model, in a phase I healthy volunteer pharmacodynamic study, and subsequently in a phase II multicenter study of mild/moderate IPF (n = 28), with a 4-week, placebo-controlled, double-blind, sequential ascending-dose period (50 mg QD, 100 mg QD, 100 mg BID) and a 52-week open-label treatment-extension period...
December 2016: Clinical and Translational Medicine
Árpád Farkas, Ágnes Jókay, Imre Balásházy, Péter Füri, Veronika Müller, Gábor Tomisa, Alpár Horváth
One of the most widespread dry powder fixed combinations used in asthma and chronic obstructive pulmonary disease (COPD) management is Symbicort(®) Turbuhaler(®). The aim of this study was to simulate the deposition distribution of both components of this drug within the airways based on realistic airflow measurements. Breathing parameters of 25 healthy adults (11 females and 14 males) were acquired while inhaling through Turbuhaler(®). Individual specific emitted doses and particle size distributions of Symbicort(®) Turbuhaler(®) were determined...
October 10, 2016: European Journal of Pharmaceutical Sciences
Federico Lavorini, Søren Pedersen, Omar S Usmani
Over the last decade, there is increasing evidence that the small airways, i. e. airways <2 mm in internal diameter, contribute significantly to the pathophysiology and clinical expression of asthma and chronic obstructive pulmonary disease (COPD). The increased interest in small airways is, at least in part, a result of innovation in small-particle aerosol formulations that better target the distal lung and also advanced physiological methods of assessing small airway responses. Increasing the precision of drug deposition may improve targeting of specific diseases or receptor locations, decrease airway drug exposure and side effects, and thereby increase the efficiency and effectiveness of inhaled drug delivery...
August 11, 2016: Chest
Hanpeng Chen, Arcadia Woods, Ben Forbes, Stuart Jones
Nanocarriers can aid therapeutic agent administration to the lung, but controlling drug delivery from these systems after deposition in the airways can be problematic. The aim of this study was to evaluate if chemically mediated shell permeabilisation could help manipulate the rate and extent of nanocarrier drug release. Rifampicin was loaded into lipid shell (loading efficiency 41.0±11.4%, size 50nm) and polymer shell nanocarriers (loading efficiency 25.9±2.3%, size 250nm). The drug release at pH 7.4 (lung epithelial pH) and 4...
September 25, 2016: International Journal of Pharmaceutics
Heino Stass, Johannes Nagelschmitz, Dominik Kappeler, Knut Sommerer, Claudius Kietzig, Boris Weimann
BACKGROUND: Ciprofloxacin dry powder for inhalation (Ciprofloxacin DPI) is in development as long-term intermittent therapy to reduce the frequency of acute exacerbations in noncystic fibrosis bronchiectasis (NCFB) patients with respiratory bacterial pathogens. There is no approved therapy in this indication. Reliable, reproducible lung deposition is a prerequisite for inhaled drugs. METHODS: In this phase I study, six patients with NCFB, six with chronic obstructive pulmonary disease (COPD), and 12 healthy volunteers (HVs), received one dose of (99m)Tc-Ciprofloxacin DPI 32...
July 22, 2016: Journal of Aerosol Medicine and Pulmonary Drug Delivery
Eleonore Fröhlich, Annalisa Mercuri, Shengqian Wu, Sharareh Salar-Behzadi
Modern strategies in drug development employ in silico techniques in the design of compounds as well as estimations of pharmacokinetics, pharmacodynamics and toxicity parameters. The quality of the results depends on software algorithm, data library and input data. Compared to simulations of absorption, distribution, metabolism, excretion, and toxicity of oral drug compounds, relatively few studies report predictions of pharmacokinetics and pharmacodynamics of inhaled substances. For calculation of the drug concentration at the absorption site, the pulmonary epithelium, physiological parameters such as lung surface and distribution volume (lung lining fluid) have to be known...
2016: Frontiers in Pharmacology
Junzi Wu, Gareth R Williams, Christopher Branford-White, Heyu Li, Yan Li, Li-Min Zhu
In this work, we sought to generate sustained-release injectable microspheres loaded with the GLP-1 analogue liraglutide. Using water-in-oil-in-water double emulsion methods, poly(lactic-co-glycolic acid) (PLGA) microspheres loaded with liraglutide were prepared. The microspheres gave sustained drug release over 30days, with cumulative release of up to 90% reached in vitro. The microspheres were further studied in a rat model of diabetes, and their performance compared with a group given daily liraglutide injections...
September 20, 2016: European Journal of Pharmaceutical Sciences
Jatinder Kaur Mukker, Ravi Shankar Prasad Singh, Hartmut Derendorf
Inhaled corticosteroids are used as one of the first-line drug therapy in patients with asthma. However, their long-term use is associated with various oropharyngeal and systemic side and adverse effects. Design of pro-soft drug is one of the strategies, which was adopted in the design of ciclesonide for mitigation of side effects usually observed with the use of inhaled corticosteroids. Ciclesonide, a pro-soft drug, is converted to an active metabolite desisobutyryl-ciclesonide in the lungs. The anti-inflammatory effect of desisobutyryl-ciclesonide is much higher than ciclesonide, and therefore, the local effect of the metabolite is higher with lower systemic side effects...
September 2016: Journal of Pharmaceutical Sciences
Luigino Calzetta, Barbara Rinaldi, Mario Cazzola, Maria Gabriella Matera
The pharmacokinetic (PK) and pharmacodynamic (PD) effects of long-acting β2-agonists and mostly inhaled corticosteroids (ICSs) shape the efficacy and safety of these agents in the treatment of asthma. In fact, the PK and PD characteristics of the drug largely determine the degree of pulmonary targeting Areas covered. In this review, we summarize the PK and PD properties of inhaled fluticasone furoate (FF) and vilanterol trifenatate (VI) and their fixed-dose combination (FDC) for the treatment of asthma Expert opinion...
July 2016: Expert Opinion on Drug Metabolism & Toxicology
Rami Fishler, Josué Sznitman
Quantifying respiratory flow characteristics in the pulmonary acinar depths and how they influence inhaled aerosol transport is critical towards optimizing drug inhalation techniques as well as predicting deposition patterns of potentially toxic airborne particles in the pulmonary alveoli. Here, soft-lithography techniques are used to fabricate complex acinar-like airway structures at the truthful anatomical length-scales that reproduce physiological acinar flow phenomena in an optically accessible system. The microfluidic device features 5 generations of bifurcating alveolated ducts with periodically expanding and contracting walls...
2016: Journal of Visualized Experiments: JoVE
Aateka Patel, A Woods, Yanira Riffo-Vasquez, Anna Babin-Morgan, Marie-Christine Jones, Stuart Jones, Kavitha Sunassee, Stephen Clark, Rafael T M de Rosales, Clive Page, Domenico Spina, Ben Forbes, Lea Ann Dailey
Lipid nanocapsules (LNCs) are semi-rigid spherical capsules with a triglyceride core that present a promising formulation option for the pulmonary delivery of drugs with poor aqueous solubility. Whilst the biodistribution of LNCs of different size has been studied following intravenous administration, the fate of LNCs following pulmonary delivery has not been reported. We investigated quantitatively whether lung inflammation affects the clearance of 50nm lipid nanocapsules, or is exacerbated by their pulmonary administration...
August 10, 2016: Journal of Controlled Release: Official Journal of the Controlled Release Society
Xingqi Wang, Zijun Ouyang, Qian You, Shuai He, Qianqian Meng, Chunhui Hu, Xudong Wu, Yan Shen, Yang Sun, Xuefeng Wu, Qiang Xu
Idiopathic pulmonary fibrosis is a progressive, degenerative and almost irreversible disease. There is hardly an effective cure for lung damage due to pulmonary fibrosis. The purpose of this study was to evaluate the role of obaculactone in an already-assessed model of idiopathic pulmonary fibrosis induced by bleomycin administration. Mice were subjected to intratracheal instillation of bleomycin, and obaculactone was given orally after bleomycin instillation daily for 23days. Treatment with obaculactone ameliorated body weight loss, lung histopathology abnormalities and pulmonary collagen deposition, with a decrease of the inflammatory cell number and the cytokine level in bronchoalveolar lavage fluid...
July 15, 2016: Toxicology and Applied Pharmacology
Renaud Respaud, Denis Marchand, Thibaut Pelat, Kam-Meng Tchou-Wong, Chad J Roy, Christelle Parent, Maria Cabrera, Joël Guillemain, Ronan Mac Loughlin, Eric Levacher, Alexandre Fontayne, Laurence Douziech-Eyrolles, Alexandra Junqua-Moullet, Laurent Guilleminault, Philippe Thullier, Emmanuelle Guillot-Combe, Laurent Vecellio, Nathalie Heuzé-Vourc'h
The high toxicity of ricin and its ease of production have made it a major bioterrorism threat worldwide. There is however no efficient and approved treatment for poisoning by ricin inhalation, although there have been major improvements in diagnosis and therapeutic strategies. We describe the development of an anti-ricin neutralizing monoclonal antibody (IgG 43RCA-G1) and a device for its rapid and effective delivery into the lungs for an application in humans. The antibody is a full-length IgG and binds to the ricin A-chain subunit with a high affinity (KD=53pM)...
July 28, 2016: Journal of Controlled Release: Official Journal of the Controlled Release Society
Balakeshwa Ramaiah, Sree Harsha Nagaraja, Usha Ganganahalli Kapanigowda, Prakash Rao Boggarapu, Rajarajan Subramanian
BACKGROUND: Following administration, the antibiotic travels freely through the body and also accumulates in other parts apart from the infection site. High dosage and repeated ingestion of antibiotics in the treatment of pneumonia leads to undesirable effects and inappropriate disposition of the drug. By way of targeted lung delivery, this study was intended to eliminate inappropriate azithromycin disposition and to achieve higher azithromycin concentration to treat deeper airway infections...
2016: Daru: Journal of Faculty of Pharmacy, Tehran University of Medical Sciences
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