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Pulmonary Drug deposition models

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https://www.readbyqxmd.com/read/28645838/sensitivity-analysis-and-uncertainty-quantification-in-pulmonary-drug-delivery-of-orally-inhaled-pharmaceuticals
#1
Jun Lu, Jinxiang Xi, Joseph E Langenderfer
In spite of widespread use of modeling tools in inhalation dosimetry, it remains difficult to quantify the output uncertainties when subjected to various sources of input variability. This study aimed to develop a computational model that can quantify the input sensitivity and output uncertainty in pulmonary drug delivery by coupling probabilistic analysis package NESSUS with ANSYS Fluent. An image-based mouth-lung model was used to simulate the transport and deposition of drug particles and variability in particle size, density, and inhalation speed were considered...
June 20, 2017: Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28599855/impact-of-droplet-evaporation-rate-on-resulting-in-vitro-performance-parameters-of-pressurized-metered-dose-inhalers
#2
Poonam Sheth, Matthew R Grimes, Stephen W Stein, Paul B Myrdal
Pressurized metered dose inhalers (pMDIs) are widely used for the treatment of pulmonary diseases. The overall efficiency of pMDI drug delivery may be defined by in vitro parameters such as the amount of drug that deposits on the model throat and the proportion of the emitted dose that has particles that are sufficiently small to deposit in the lung (i.e., fine particle fraction, FPF). The study presented examines product performance of ten solution pMDI formulations containing a variety of cosolvents with diverse chemical characteristics by cascade impaction with three inlets (USP induction port, Alberta Idealized Throat, and a large volume chamber)...
June 6, 2017: International Journal of Pharmaceutics
https://www.readbyqxmd.com/read/28578783/biology-and-treatment-of-aggressive-fibromatosis-or-desmoid-tumor
#3
REVIEW
Keith M Skubitz
Aggressive fibromatosis, also known as desmoid-type fibromatosis (DTF) or desmoid tumor, is an uncommon locally invasive tumor. Because of its low incidence and variable behavior, DTF is often first seen by physicians who are not familiar with it, and recent advances in understanding this disease have led to changes in treatment approaches. The Wnt (β-catenin) pathway appears to play a key role in DTF pathogenesis, and recent studies of DTF biology suggest a possible model of DTF pathogenesis. Histologically, DTF shows a poorly circumscribed proliferation of myofibroblast-like cells with variable collagen deposition, similar to the proliferative phase of wound healing, and DTF has been associated with trauma and pregnancy...
June 2017: Mayo Clinic Proceedings
https://www.readbyqxmd.com/read/28507469/lungs-deposition-and-pharmacokinetic-study-of-submicron-budesonide-particles-in-wistar-rats-intended-for-immediate-effect-in-asthma
#4
Abdul Rauf, Aseem Bhatnagar, S S Sisodia, Roop K Khar, Farhan J Ahmad
The purpose of the present investigation was to study the aerosolization, lungs deposition and pharmacokinetic study of inhalable submicron particles of budesonide in male Wistar rats. Submicron particles were prepared by antisolvent nanoprecipitation method and freeze-dried to obtain free flowing powder. The freeze-drying process yielded dry powder with desirable aerodynamic properties for inhalation therapy. An in-house model inhaler was designed to deliver medicine to lungs, optimized at dose level of 10 mg for 30 sec of fluidization...
2017: EXCLI journal
https://www.readbyqxmd.com/read/28463041/effect-of-pressurized-metered-dose-inhaler-spray-characteristics-and-particle-size-distribution-on-drug-delivery-efficiency
#5
Morteza Yousefi, Kiao Inthavong, Jiyuan Tu
BACKGROUND: A key issue in pulmonary drug delivery is improvement of the delivery device for effective and targeted treatment. Pressurized metered dose inhalers (pMDIs) are the most popular aerosol therapy device for treating lung diseases. This article studies the effect of spray characteristics: injection velocity, spray cone angle, particle size distribution (PSD), and its mass median aerodynamic diameter (MMAD) on drug delivery. METHODS: An idealized oral airway geometry, extending from mouth to the main bronchus, was connected to a pMDI device...
May 2, 2017: Journal of Aerosol Medicine and Pulmonary Drug Delivery
https://www.readbyqxmd.com/read/28357073/effect-of-bosentan-is-correlated-with-mmp-9-timp-1-ratio-in-bleomycin-induced-pulmonary-fibrosis
#6
Wan-Li Zuo, Jie-Min Zhao, Ji-Xiong Huang, Wei Zhou, Ze-Hong Lei, Yan-Ming Huang, Yan-Fen Huang, Hai-Gang Li
Pulmonary fibrosis (PF) is a life-threatening non-tumorous disease characterized by progressive fibrosis and worsening lung function. Various drugs, such as bleomycin, can contribute to lung injury and PF, with lung injury potentially occurring in 10% of bleomycin users. Bleomycin is the most commonly used drug in the establishment of an animal model of PF in rats. Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) serve an important role in controlling tissue organization and fibrosis following injury...
February 2017: Biomedical Reports
https://www.readbyqxmd.com/read/28300665/grape-seed-extract-ameliorates-bleomycin-induced-mouse-pulmonary-fibrosis
#7
Qi Liu, Jun-Xia Jiang, Ya-Nan Liu, Ling-Tian Ge, Yan Guan, Wei Zhao, Yong-Liang Jia, Xin-Wei Dong, Yun Sun, Qiang-Min Xie
Pulmonary fibrosis is common in a variety of inflammatory lung diseases, such as interstitial pneumonia, chronic obstructive pulmonary disease, and silicosis. There is currently no effective clinical drug treatment. It has been reported that grape seed extracts (GSE) has extensive pharmacological effects with minimal toxicity. Although it has been found that GSE can improve the lung collagen deposition and fibrosis pathology induced by bleomycin in rat, its effects on pulmonary function, inflammation, growth factors, matrix metalloproteinases and epithelial-mesenchymal transition remain to be researched...
May 5, 2017: Toxicology Letters
https://www.readbyqxmd.com/read/28282577/therapeutic-efficacy-of-a-co-blockade-of-il-13-and-il-25-on-airway-inflammation-and-remodeling-in-a-mouse-model-of-asthma
#8
Fang-Qi Zhang, Xin-Peng Han, Fang Zhang, Xuan Ma, Dong Xiang, Xue-Min Yang, Hai-Feng Ou-Yang, Zhikui Li
Repeated airway inflammation and unremitting remodeling provoke irreversible pulmonary dysfunction and resistance to current drugs in patients with chronic bronchial asthma. Interleukin (IL)-13 and IL-25 play an important role in airway inflammation and remodeling in asthma. We aimed to investigate whether co-inhibiting IL-13 and IL-25 can effectively down-regulate allergen-induced airway inflammation and remodeling in mice. Mice with asthma induced by chronic exposure to ovalbumin (OVA) were given soluble IL-13 receptor α2 (sIL-13R) or soluble IL-25 receptor (sIL-25R) protein alone and in combination to neutralize the bioactivity of IL-13 and IL-25, and relevant airway inflammation and remodeling experiments were performed...
May 2017: International Immunopharmacology
https://www.readbyqxmd.com/read/28161667/aerodynamic-properties-and-in-silico-deposition-of-meloxicam-potassium-incorporated-in-a-carrier-free-dpi-pulmonary-system
#9
Anita Chvatal, Árpád Farkas, Imre Balásházy, Piroska Szabó-Révész, Rita Ambrus
Dry powder inhalers (DPIs) have been among the fastest developing inhaler forms in the past decades. Researches are focusing on the formulation of carrier-free powders to obtain a higher deep-lung deposition and hereby to increase the effectiveness of the medicine. The aim of our study was to prepare a carrier-free dry powder formulation of meloxicam potassium (MP), a novel salt form of meloxicam, using a one-step co-spray drying technology. Different types of excipients were used to modify the crystal structure and to increase aerosolization efficacy...
February 1, 2017: International Journal of Pharmaceutics
https://www.readbyqxmd.com/read/28161666/cellular-internalization-and-transport-of-biodegradable-polyester-dendrimers-on-a-model-of-the-pulmonary-epithelium-and-their-formulation-in-pressurized-metered-dose-inhalers
#10
Rodrigo S Heyder, Qian Zhong, Reinaldo C Bazito, Sandro R P da Rocha
The purpose of this study was to evaluate the effect of generation and surface PEGylation of degradable polyester-based dendrimers nanocarriers on their interactions with an in vitro model of the pulmonary epithelium as well as to assess the ability to formulate such carriers in propellant-based, portable oral-inhalation devices to determine their potential for local and systemic delivery of drugs to and through the lungs. Hydroxyl (-OH) terminated polyester dendrimers of generation 3 and 4 (G3, and G4) were synthesized using a divergent approach...
March 30, 2017: International Journal of Pharmaceutics
https://www.readbyqxmd.com/read/28109773/exploring-polyvinylpyrrolidone-in-the-engineering-of-large-porous-plga-microparticles-via-single-emulsion-method-with-tunable-sustained-release-in-the-lung-in-vitro-and-in-vivo-characterization
#11
Rui Ni, Uwe Muenster, Jing Zhao, Lan Zhang, Eva-Maria Becker-Pelster, Martin Rosenbruch, Shirui Mao
Sustained pulmonary drug delivery is regarded as an effective strategy for local treatment of chronic lung diseases. Despite of the progress made so far, there remains a need for respirable drug loaded porous microparticles, where porosity of the microparticles can be readily engineered during the preparation process, with tunable sustained drug release upon lung deposition. In this work, polyvinyl pyrrolidone (PVP) was used as a novel porogen to engineer PLGA-based large porous particles (LPPs) using single emulsion method, with fine tuning of the porosity, sustained drug release both in vitro and in vivo...
January 18, 2017: Journal of Controlled Release: Official Journal of the Controlled Release Society
https://www.readbyqxmd.com/read/28060543/inhibition-of-the-kca3-1-channel-alleviates-established-pulmonary-fibrosis-in-a-large-animal-model
#12
Louise Organ, Barbara Bacci, Emmanuel Koumoundouros, Wayne G Kimpton, Chrishan S Samuel, Cameron J Nowell, Peter Bradding, Katy M Roach, Glen Westall, Jade Jaffar, Ken J Snibson
Idiopathic pulmonary fibrosis is a chronic progressive disease of increasing prevalence marked by poor prognosis and limited treatment options. Ca2+-activated KCa3.1 potassium channels have been shown to play a key role in the aberrant activation and responses to injury in both epithelial cells and fibroblasts, both considered key drivers in the fibrotic process of IPF. Pharmacological inhibition of IPF-derived fibroblasts is able to somewhat prevent TGF-βand bFGF-dependent profibrotic responses. In the current study, we investigated whether blockade of the KCa3...
January 6, 2017: American Journal of Respiratory Cell and Molecular Biology
https://www.readbyqxmd.com/read/27863742/nanoparticle-transport-and-delivery-in-a-heterogeneous-pulmonary-vasculature
#13
Salman Sohrabi, Shunqiang Wang, Jifu Tan, Jiang Xu, Jie Yang, Yaling Liu
Quantitative understanding of nanoparticles delivery in a complex vascular networks is very challenging because it involves interplay of transport, hydrodynamic force, and multivalent interactions across different scales. Heterogeneous pulmonary network includes up to 16 generations of vessels in its arterial tree. Modeling the complete pulmonary vascular system in 3D is computationally unrealistic. To save computational cost, a model reconstructed from MRI scanned images is cut into an arbitrary pathway consisting of the upper 4-generations...
January 4, 2017: Journal of Biomechanics
https://www.readbyqxmd.com/read/27836120/computationally-efficient-analysis-of-particle-transport-and-deposition-in-a-human-whole-lung-airway-model-part-ii-dry-powder-inhaler-application
#14
Arun V Kolanjiyil, Clement Kleinstreuer, Ruxana T Sadikot
Pulmonary drug delivery is becoming a favored route for administering drugs to treat both lung and systemic diseases. Examples of lung diseases include asthma, cystic fibrosis and chronic obstructive pulmonary disease (COPD) as well as respiratory distress syndrome (ARDS) and pulmonary fibrosis. Special respiratory drugs are administered to the lungs, using an appropriate inhaler device. Next to the pressurized metered-dose inhaler (pMDI), the dry powder inhaler (DPI) is a frequently used device because of the good drug stability and a minimal need for patient coordination...
May 1, 2017: Computers in Biology and Medicine
https://www.readbyqxmd.com/read/27774309/microparticulate-nanoparticulate-powders-of-a-novel-nrf2-activator-and-an-aerosol-performance-enhancer-for-pulmonary-delivery-targeting-the-lung-nrf2-keap-1-pathway
#15
Priya Muralidharan, Don Hayes, Stephen M Black, Heidi M Mansour
This systematic and comprehensive study reports for the first time on the successful rational design of advanced inhalable therapeutic dry powders containing dimethyl fumarate, a first-in-class Nrf2 activator drug to treat pulmonary inflammation, using particle engineering design technology for targeted delivery to the lungs as advanced spray dried (SD) one-component DPIs. In addition, two-component co-spray dried (co-SD) DMF:D-Man DPIs with high drug loading were successfully designed for targeted lung delivery as advanced DPIs using organic solution advanced spray drying in closed mode...
2016: Molecular Systems Design & Engineering
https://www.readbyqxmd.com/read/27740878/predicting-exposure-after-oral-inhalation-of-the-selective-glucocorticoid-receptor-modulator-azd5423-based-on-dose-deposition-pattern-and-mechanistic-modeling-of-pulmonary-disposition
#16
Per Bäckman, Ulrika Tehler, Bo Olsson
BACKGROUND: Exposure following oral inhalation depends on the deposition pattern of the inhaled aerosol, the extent and rate of oral and pulmonary absorption, as well as systemic distribution and clearance. For lipophilic inhaled compounds with low water solubility and high permeability, the extent and rate of pulmonary absorption can be assumed dependent on deposition pattern as well as dissolution rate. MATERIALS AND METHODS: A mechanistic model of airway deposition, mucociliary clearance, dissolution, absorption, and dissipation was applied to simulate systemic exposure of the novel selective glucocorticoid receptor modulator, AZD5423, when dosed to healthy volunteers using two different nebulizers and two different dry powder inhalers in combination with two different primary particle size distributions...
April 2017: Journal of Aerosol Medicine and Pulmonary Drug Delivery
https://www.readbyqxmd.com/read/27704718/hydamtiq-a-selective-parp-1-inhibitor-improves-bleomycin-induced-lung-fibrosis-by-dampening-the-tgf-%C3%AE-smad-signalling-pathway
#17
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...
February 2017: Journal of Cellular and Molecular Medicine
https://www.readbyqxmd.com/read/27685186/autologous-co-culture-of-primary-human-alveolar-macrophages-and-epithelial-cells-for-investigating-aerosol-medicines-part-ii-evaluation-of-il-10-loaded-microparticles-for-the-treatment-of-lung-inflammation
#18
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
https://www.readbyqxmd.com/read/27685185/autologous-co-culture-of-primary-human-alveolar-macrophages-and-epithelial-cells-for-investigating-aerosol-medicines-part-i-model-characterisation
#19
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
https://www.readbyqxmd.com/read/27590145/jnk-inhibition-reduces-lung-remodeling-and-pulmonary-fibrotic-systemic-markers
#20
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
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