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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.

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          Most cited references 29

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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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            Pulmonary drug delivery. Part II: the role of inhalant delivery devices and drug formulations in therapeutic effectiveness of aerosolized medications.

            Research in the area of pulmonary drug delivery has gathered momentum in the last several years, with increased interest in using the lung as a means of delivering drugs systemically. Advances in device technology have led to the development of more efficient delivery systems capable of delivering larger doses and finer particles into the lung. As more efficient pulmonary delivery devices and sophisticated formulations become available, physicians and health professionals will have a choice of a wide variety of device and formulation combinations that will target specific cells or regions of the lung, avoid the lung's clearance mechanisms and be retained within the lung for longer periods. It is now recognized that it is not enough just to have inhalation therapy available for prescribing; physicians and other healthcare providers need a basic understanding of aerosol science, inhaled formulations, delivery devices, and bioequivalence of products to prescribe these therapies optimally.
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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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                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
                © 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.

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                Original Research

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