Lung Retention by Lysosomal Trapping of Inhaled Drugs Can Be Predicted  In Vitro  With Lung Slices

Mucus is the first biological component inhaled drugs encounter on their journey towards their pharmacological target in the upper airways. Yet, how mucus may influence drug disposition and efficacy in the lungs has been essentially overlooked. In this study, a simple in vitro system was developed to investigate the factors promoting drug interactions with airway mucus in physiologically relevant conditions. Thin layers of porcine tracheal mucus were prepared in Transwell® inserts and initially, the diffusion of various fluorescent dyes across those layers was monitored over time. A deposition system featuring a MicroSprayer® aerosolizer was optimized to reproducibly deliver liquid aerosols to multiple air-facing layers and then exploited to compare the impact of airway mucus on the transport of inhaled bronchodilators. Both the dyes and drugs tested were distinctly hindered by mucus with high logP compounds being the most affected. The diffusion rate of the bronchodilators across the layers was in the order: ipratropium ≈ glycopyronnium > formoterol > salbutamol > indacaterol, suggesting hydrophobicity plays an important role in their binding to mucus but is not the unique parameter involved. Testing of larger series of compounds would nevertheless be necessary to better understand the interactions of inhaled drugs with airway mucus.

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A 3D Human Airway Model Enables Prediction of Respiratory Toxicity of Inhaled Drugs In Vitro

Toxicological Sciences ◽

10.1093/toxsci/kfx255 ◽

2017 ◽

Vol 162 (1) ◽

pp. 301-308 ◽

Cited By ~ 23

Author(s):

Kinga Balogh Sivars ◽

Ulf Sivars ◽

Ellinor Hornberg ◽

Hui Zhang ◽

Lena Brändén ◽

...

Keyword(s):

Inhaled Drugs ◽

Human Airway ◽

Airway Model ◽

Respiratory Toxicity

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Prediction of Efficacious Inhalation Lung Doses via the Use of In Silico Lung Retention Quantitative Structure-Activity Relationship Models and In Vitro Potency Screens

Drug Metabolism and Disposition ◽

10.1124/dmd.110.034462 ◽

2010 ◽

Vol 38 (12) ◽

pp. 2218-2225 ◽

Cited By ~ 14

Author(s):

Anne Cooper ◽

Tim Potter ◽

Tim Luker

Keyword(s):

In Silico ◽

Quantitative Structure Activity Relationship ◽

Structure Activity Relationship ◽

Activity Relationship ◽

Quantitative Structure ◽

Structure Activity ◽

Lung Retention

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Preclinical Development of Orally Inhaled Drugs (OIDs)—Are Animal Models Predictive or Shall We Move Towards In Vitro Non-Animal Models?

Animals ◽

10.3390/ani10081259 ◽

2020 ◽

Vol 10 (8) ◽

pp. 1259 ◽

Cited By ~ 1

Author(s):

Dania Movia ◽

Adriele Prina-Mello

Keyword(s):

Animal Models ◽

Respiratory Diseases ◽

Drug Market ◽

Rapid Onset ◽

Attrition Rate ◽

Systemic Diseases ◽

Preclinical Development ◽

Inhaled Drugs ◽

Drug Candidates

Respiratory diseases constitute a huge burden in our society, and the global respiratory drug market currently grows at an annual rate between 4% and 6%. Inhalation is the preferred administration method for treating respiratory diseases, as it: (i) delivers the drug directly at the site of action, resulting in a rapid onset; (ii) is painless, thus improving patients’ compliance; and (iii) avoids first-pass metabolism reducing systemic side effects. Inhalation occurs through the mouth, with the drug generally exerting its therapeutic action in the lungs. In the most recent years, orally inhaled drugs (OIDs) have found application also in the treatment of systemic diseases. OIDs development, however, currently suffers of an overall attrition rate of around 70%, meaning that seven out of 10 new drug candidates fail to reach the clinic. Our commentary focuses on the reasons behind the poor OIDs translation into clinical products for the treatment of respiratory and systemic diseases, with particular emphasis on the parameters affecting the predictive value of animal preclinical tests. We then review the current advances in overcoming the limitation of animal animal-based studies through the development and adoption of in vitro, cell-based new approach methodologies (NAMs).

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Searching for physiologically relevant in vitro dissolution techniques for orally inhaled drugs

International Journal of Pharmaceutics ◽

10.1016/j.ijpharm.2018.11.072 ◽

2019 ◽

Vol 556 ◽

pp. 45-56 ◽

Cited By ~ 7

Author(s):

Snezana Radivojev ◽

Sarah Zellnitz ◽

Amrit Paudel ◽

Eleonore Fröhlich

Keyword(s):

In Vitro Dissolution ◽

Inhaled Drugs

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Ultrastructural Investigations of the Contractile Filaments of Amoebae

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100050950 ◽

1974 ◽

Vol 32 ◽

pp. 188-189

Author(s):

P.L. Moore

Keyword(s):

Cytoplasmic Streaming ◽

Three Dimensional ◽

Freeze Fracture ◽

Amoeboid Movement ◽

Different Types ◽

Chemical Conditions ◽

Complete Interpretation

Previous freeze fracture results on the intact giant, amoeba Chaos carolinensis indicated the presence of a fibrillar arrangement of filaments within the cytoplasm. A complete interpretation of the three dimensional ultrastructure of these structures, and their possible role in amoeboid movement was not possible, since comparable results could not be obtained with conventional fixation of intact amoebae. Progress in interpreting the freeze fracture images of amoebae required a more thorough understanding of the different types of filaments present in amoebae, and of the ways in which they could be organized while remaining functional.The recent development of a calcium sensitive, demembranated, amoeboid model of Chaos carolinensis has made it possible to achieve a better understanding of such functional arrangements of amoeboid filaments. In these models the motility of demembranated cytoplasm can be controlled in vitro, and the chemical conditions necessary for contractility, and cytoplasmic streaming can be investigated. It is clear from these studies that “fibrils” exist in amoeboid models, and that they are capable of contracting along their length under conditions similar to those which cause contraction in vertebrate muscles.

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In Vitro Induction of Crystals of MT Protein by Vinblastine-Colcemid in Mouse Spermatids

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100050676 ◽

1974 ◽

Vol 32 ◽

pp. 132-133

Author(s):

John J. Wolosewick ◽

John H. D. Bryan

Keyword(s):

Endoplasmic Reticulum ◽

Smooth Endoplasmic Reticulum ◽

Nuclear Ring ◽

Rough Er ◽

Distal Direction ◽

In Vitro Induction

Early in spermiogenesis the manchette is rapidly assembled in a distal direction from the nuclear-ring-densities. The association of vesicles of smooth endoplasmic reticulum (SER) and the manchette microtubules (MTS) has been reported. In the mouse, osmophilic densities at the distal ends of the manchette are the organizing centers (MTOCS), and are associated with the SER. Rapid MT assembly and the lack of rough ER suggests that there is an existing pool of MT protein. Colcemid potentiates the reaction of vinblastine with tubulin and was used in this investigation to detect this protein.

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