Optimized Aerosol Delivery to a Mechanically Ventilated Rodent

MacLoughlin, Ronan; Higgins, Brendan D.; Laffey, John G.; O’Brien, Timothy

doi:10.1089/jamp.2008.0717

Cited by 37 publications

(43 citation statements)

References 26 publications

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“…The nebulizer performance characteristics, measured using laser diffraction (Spraytec, Malvern Instruments, Malvern, UK) as previously described [18], are outlined in terms of average input droplet size (lm volumetric median diameter, VMD) and aerosol output rate (mL/ min) ( Table 1).…”

Section: Nebulizersmentioning

confidence: 99%

In Vitro Determination of the Main Effects in the Design of High-Flow Nasal Therapy Systems with Respect to Aerosol Performance

et al. 2018

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Introduction: The use of concurrent aerosol delivery during high-flow nasal therapy (HFNT) may be exploited to facilitate the delivery of a variety of prescribed medications for inhalation. Until now, a systematic approach to determine the conditions required to yield an optimal emitted dose has not been reported. The aim of this study was to establish the effects of gas flow rate, input droplet size, and nebulizer position on the amount of aerosol exiting the nasal cannula during HFNT and thus becoming available for inhalation. Methods: Testing was completed according to a factorial statistical design of experiments (DOE) approach. Emitted dose was characterized with a vibrating mesh nebulizer (Aerogen Solo, Aerogen Ltd) for an adult model of HFNT at three clinically relevant gas flow rates, using three nebulizers producing varying input droplet sizes and placed at two different nebulizer positions.

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Section: Nebulizersmentioning

confidence: 99%

In Vitro Determination of the Main Effects in the Design of High-Flow Nasal Therapy Systems with Respect to Aerosol Performance

et al. 2018

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“…Radioactive labeling allows for regional dosimetry via X-ray tomography (CT), PET and SPECT, but not for determination of the bioactivity of the substances. On the other hand, fluorescent substances including nanoparticles have been widely used for preclinical dosimetry studies both in vitro and in vivo [7,8] and numerous fluorescent probes are available for studying the bioactivity of drugs in terms of activation/deactivation of complex biological processes in living animals. Consequently, using innovative preclinical strategies of optical imaging has allowed in vivo real-time insight not only in genomics and proteomics ([9] and references 1-6 herein), but also in disease state of animal models such as the size of cancer lesions or of a remodeled bone [10].…”

Section: Introductionmentioning

confidence: 99%

Quantitative detection of drug dose and spatial distribution in the lung revealed by Cryoslicing Imaging

Barapatre

Symvoulidis

Möller

et al. 2015

Journal of Pharmaceutical and Biomedical Analysis

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Administration of drugs via inhalation is an attractive route for pulmonary and systemic drug delivery. The therapeutic outcome of inhalation therapy depends not only on the dose of the lung-delivered drug, but also on its bioactivity and regional distribution. Fluorescence imaging has the potential to monitor these aspects already during preclinical development of inhaled drugs, but quantitative methods of analysis are lacking. In this proof-of-concept study, we demonstrate that Cryoslicing Imaging allows for 3D quantitative fluorescence imaging on ex vivo murine lungs. Known amounts of fluorescent substance (nanoparticles or fluorophore-drug conjugate) were instilled in the lungs of mice. The excised lungs were measured by Cryoslicing Imaging. Herein, white light and fluorescence images are obtained from the face of a gradually sliced frozen organ block. A quantitative representation of the fluorescence intensity throughout the lung was inferred from the images by accounting for instrument noise, tissue autofluorescence and out-of-plane fluorescence. Importantly, the out-of-plane fluorescence correction is based on the experimentally determined effective light attenuation coefficient of frozen murine lung tissue (10.0 ± 0.6 cm(-1) at 716 nm). The linear correlation between pulmonary total fluorescence intensity and pulmonary fluorophore dose indicates the validity of this method and allows direct fluorophore dose assessment. The pulmonary dose of a fluorescence-labeled drug (FcγR-Alexa750) could be assessed with an estimated accuracy of 9% and the limit of detection in ng regime. Hence, Cryoslicing Imaging can be used for quantitative assessment of dose and 3D distribution of fluorescence-labeled drugs or drug carriers in the lungs of mice.

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“…This is achieved through the combined use of a low flow rate and low residual volume breath-actuated vibrating mesh nebulizer, generating a small droplet size appropriate for alveolar deposition. 32 …”

Section: Key Findingsmentioning

confidence: 99%

Aerosol-Mediated Delivery of AAV2/6-IκBα Attenuates Lipopolysaccharide-Induced Acute Lung Injury in Rats

MacLoughlin

Higgins²,

Devaney³

et al. 2015

Human Gene Therapy

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Inhibition of the proinflammatory transcription factor NF-jB has previously been shown to attenuate the inflammatory response in tissue after injury. However, the feasibility and efficacy of aerosolized adeno-associated viral (AAV) vector-delivered transgenes to inhibit the NF-jB pathway are less clear. Initial studies optimized the AAV vector for delivery of transgenes to the pulmonary epithelium. The effect of repeated nebulization on the integrity and transduction efficacy of the AAV vector was then examined. Subsequent in vivo studies examined the efficacy of aerosolized rAAV2/6 overexpressing the NF-jB inhibitor IjBa in a rodent endotoxin-induced lung injury model. Initial in vitro investigations indicated that rAAV2/6 was the most effective vector to transduce the lung epithelium, and maintained its integrity and transduction efficacy after repeated nebulization. In our in vivo studies, animals that received aerosolized rAAV2/6-IjBa demonstrated a significant increase in total IjBa levels in lung tissue relative to null vector-treated animals. Aerosolized rAAV2/6-IjBa attenuated endotoxin-induced bronchoalveolar lavage-detected neutrophilia, interleukin-6 and cytokine-induced neutrophil chemoattractant-1 levels, as well as total protein content, and decreased histologic indices of injury. These results demonstrate that aerosolized AAV vectors encoding human IjBa significantly attenuate endotoxin-mediated lung injury and may be a potential therapeutic candidate in the treatment of acute lung injury.

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Optimized Aerosol Delivery to a Mechanically Ventilated Rodent

Cited by 37 publications

References 26 publications

In Vitro Determination of the Main Effects in the Design of High-Flow Nasal Therapy Systems with Respect to Aerosol Performance

In Vitro Determination of the Main Effects in the Design of High-Flow Nasal Therapy Systems with Respect to Aerosol Performance

Quantitative detection of drug dose and spatial distribution in the lung revealed by Cryoslicing Imaging

Aerosol-Mediated Delivery of AAV2/6-IκBα Attenuates Lipopolysaccharide-Induced Acute Lung Injury in Rats

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