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      Drug Design, Development and Therapy (submit here)

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      Deposition and transport of linezolid mediated by a synthetic surfactant Synsurf ® within a pressurized metered dose inhaler: a Calu-3 model

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          Abstract

          Background

          Previous studies in our laboratory demonstrated that a synthetic peptide containing lung surfactant enhances the permeability of chemical compounds through bronchial epithelium. The purpose of this study was to test two formulations of Synsurf ® combined with linezolid as respirable compounds using a pressurized metered dose inhaler (pMDI).

          Methods

          Aerosolization efficiency of the surfactant-drug microparticles onto Calu-3 monolayers as an air interface culture was analyzed using a Next Generation Impactor™.

          Results

          The delivered particles and drug dose showed a high dependency from the preparation that was aerosolized. Scanning electron microscopy imaging allowed for visualization of the deposited particles, establishing them as liposomal-type structures (diameter 500 nm to 2 μm) with filamentous features.

          Conclusion

          The different surfactant drug combinations allow for an evaluation of the significance of the experimental model system, as well as assessment of the formulations providing a possible noninvasive, site-specific, delivery model via pMDI.

          Most cited references29

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          Post hoc power analysis: an idea whose time has passed?

          Using a hypothetical scenario typifying the experience that authors have when submitting manuscripts that report results of negative clinical trials, the pitfalls of a post hoc analysis are illustrated. We used the same scenario to explain how confidence intervals are used in interpreting results of clinical trials. We showed that confidence intervals better inform readers about the possibility of an inadequate sample size than do post hoc power calculations.
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            Current perspectives in pulmonary surfactant--inhibition, enhancement and evaluation.

            Pulmonary surfactant (PS) is a complicated mixture of approximately 90% lipids and 10% proteins. It plays an important role in maintaining normal respiratory mechanics by reducing alveolar surface tension to near-zero values. Supplementing exogenous surfactant to newborns suffering from respiratory distress syndrome (RDS), a leading cause of perinatal mortality, has completely altered neonatal care in industrialized countries. Surfactant therapy has also been applied to the acute respiratory distress syndrome (ARDS) but with only limited success. Biophysical studies suggest that surfactant inhibition is partially responsible for this unsatisfactory performance. This paper reviews the biophysical properties of functional and dysfunctional PS. The biophysical properties of PS are further limited to surface activity, i.e., properties related to highly dynamic and very low surface tensions. Three main perspectives are reviewed. (1) How does PS permit both rapid adsorption and the ability to reach very low surface tensions? (2) How is PS inactivated by different inhibitory substances and how can this inhibition be counteracted? A recent research focus of using water-soluble polymers as additives to enhance the surface activity of clinical PS and to overcome inhibition is extensively discussed. (3) Which in vivo, in situ, and in vitro methods are available for evaluating the surface activity of PS and what are their relative merits? A better understanding of the biophysical properties of functional and dysfunctional PS is important for the further development of surfactant therapy, especially for its potential application in ARDS.
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              Biofilm penetration, triggered release and in vivo activity of inhaled liposomal amikacin in chronic Pseudomonas aeruginosa lung infections.

              Chronic infections of Pseudomonas aeruginosa in the lungs of cystic fibrosis patients are intractable antibiotic targets because of their biofilm mode of growth. We have investigated the biofilm penetration, mechanism of drug release and in vivo antimicrobial activity of a unique nanoscale liposomal formulation of amikacin designed specifically for nebulization and inhaled delivery. Penetration of fluorescently labelled liposomes into sputum or P. aeruginosa (PA3064) biofilms was monitored by a filter assay and by epifluorescence or confocal scanning laser microscopy. Amikacin release in vitro and rat lung levels after inhalation of nebulized material were measured by fluorescence polarization immunoassay. A 14 day agar bead model of chronic Pseudomonas lung infection in rats was used to assess the efficacy of liposomal amikacin versus free aminoglycosides in the reduction of bacterial count. Fluorescent liposomes penetrated readily into biofilms and infected mucus, whereas larger (1 microm) fluorescent beads did not. Amikacin release from liposomes was mediated by sputum or Pseudomonas biofilm supernatants. Rhamnolipids were implicated as the major releasing factors in these supernatants, active at one rhamnolipid per several hundred lipids within the liposomes. Inhaled liposomal amikacin was released in a slow, sustained manner in normal rat lungs and was orders of magnitude more efficacious than inhaled free amikacin in infected lungs. Penetration of biofilm and targeted, sustained release from liposomes can explain the superior in vivo efficacy of inhaled liposomal amikacin versus free drug observed in a 14 day infection model. Inhaled liposomal amikacin may represent an important therapy for chronic lung infections.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                1177-8881
                2018
                04 May 2018
                : 12
                : 1107-1118
                Affiliations
                [1 ]Division of Clinical Pharmacology, Department of Medicine, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, South Africa
                [2 ]Department of Pediatrics, Tygerberg Children’s Hospital, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, South Africa
                Author notes
                Correspondence: Lyné van Rensburg, Division of Clinical Pharmacology, Department of Medicine, Faculty of Medicine and Health Sciences, Stellenbosch University, Francie van Zijl Drive, Tygerberg 7505, South Africa, Tel +27 21 938 9344, Email lyne@ 123456sun.ac.za
                Article
                dddt-12-1107
                10.2147/DDDT.S147035
                5942168
                c097438e-9cbd-4172-8999-60a545d4c63f
                © 2018 van Rensburg et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

                History
                Categories
                Original Research

                Pharmacology & Pharmaceutical medicine
                calu-3,pmdi,linezolid,delivery vehicle,pulmonary surfactant,aerosolized particles

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