Browsing by Author "Van Zyl, Johann M."

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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
    (Dove Medical Press, 2018) Van Rensburg, Lyne; Van Zyl, Johann M.; Smith, Johan
    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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    The effect of a peptide-containing synthetic lung surfactant on gas exchange and lung mechanics in a rabbit model of surfactant depletion
    (Dovepress, 2013-03) Van Zyl, Johann M.; Smith, Johan; Hawtrey, Arthur
    Background: Currently, a new generation of synthetic pulmonary surfactants is being developed that may eventually replace animal-derived surfactants used in the treatment of respiratory distress syndrome. Enlightened by this, we prepared a synthetic peptide-containing surfactant (Synsurf) consisting of phospholipids and poly-l-lysine electrostatically bonded to poly-l-glutamic acid. Our objective in this study was to investigate if bronchoalveolar lavage (BAL)-induced acute lung injury and surfactant deficiency with accompanying hypoxemia and increased alveolar and physiological dead space is restored to its prelavage condition by surfactant replacement with Synsurf, a generic prepared Exosurf, and a generic Exosurf containing Ca²⁺. Methods: Twelve adult New Zealand white rabbits receiving conventional mechanical ventilation underwent repeated BAL to create acute lung injury and surfactant-deficient lung disease. Synthetic surfactants were then administered and their effects assessed at specified time points over 5 hours. The variables assessed before and after lavage and surfactant treatment included alveolar and physiological dead space, dead space/tidal volume ratio, arterial end-tidal carbon dioxide tension (PCO₂) difference (mainstream capnography), arterial blood gas analysis, calculated shunt, and oxygen ratios. Results: BAL led to acute lung injury characterized by an increasing arterial PCO₂ and a simultaneous increase of alveolar and physiological dead space/tidal volume ratio with no intergroup differences. Arterial end-tidal PCO₂ and dead space/tidal volume ratio correlated in the Synsurf, generic Exosurf and generic Exosurf containing Ca²⁺ groups. A significant and sustained improvement in systemic oxygenation occurred from time point 180 minutes onward in animals treated with Synsurf compared to the other two groups (P ˂ 0.001). A statistically significant decrease in pulmonary shunt (P ˂ 0.001) was found for the Synsurf-treated group of animals, as well as radiographic improvement in three out of four animals in that group. Conclusion: In general, surfactant-replacement therapy in the animals did not fully restore the lung to its prelavage condition. However, our data show that the formulated surfactant Synsurf improves oxygenation by lowering pulmonary shunt.
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    The effect of certain N-tritylated phenylalanine conjugates of amino-adenosine-3',5'-cyclic monophosphate on moloney murine leukaemia virus reverse transcriptase activity
    (Academy of Science of South Africa (ASSAf), 2010-07) Van Zyl, Johann M.; Ariatti, Mario; Hawtrey, Arthur O.
    Moloney murine leukaemia virus M-MuLV) is a member of the retrovirus family. Its cloned reverse transcriptase RT), similarly to HIV type 1 reverse transcriptase HIV-1 RT), exhibits DNA-polymerase and ribonuclease H RNase H) activities capable of converting the single-stranded retroviral RNA genome into double-stranded DNA. The latter is then integrated into the host chromosome during viral infection. M-MuLV RT is, therefore, an attractive enzyme to help understand mutations in HIV-1 RT and its use in inhibition studies can help facilitate new drug designs. In this study, conjugates consisting of N-trityl derivatives of p-fluoro, p-nitro and p-iodo-DL-phenylalanine were coupled to 8-6-aminohexyl) amino-adenosine-3',5'-cyclic monophosphate and examined for their effect on DNA synthesis by M-MuLV RT. Synthesis was studied in a system containing poly rA).oligo dpT)15 as a template-primer with [ 3H] dTTP. The iodo-derivative, N-trityl-p-iodo-DL-phenylalanine-8-6- aminohexyl) amino-adenosine-3',5'-cyclic monophosphate was found to be a very active inhibitor of the RT enzyme IC50 = 1 μM), while the p-nitro IC50 = 45 μM) and p-fluoro IC50 = 65 μM) were weak inhibitors. Further work will be aimed at determining the mode of binding of the N-tritylated conjugates and also of various substituted amino acids and short peptides to M-MuLV RT to elucidate the mechanisms of inhibition. © 2010. The Authors.
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    Surfactant treatment before first breath for respiratory distress syndrome in preterm lambs : comparison of a peptide-containing synthetic lung surfactant with porcine-derived surfactant
    (Dovepress, 2013-08) Van Zyl, Johann M.; Smith, Johan
    Background: In a recent study utilizing a saline-lavaged adult rabbit model, we described a significant improvement in systemic oxygenation and pulmonary shunt after the instillation of a novel synthetic peptide-containing surfactant, Synsurf. Respiratory distress syndrome in the preterm lamb more closely resembles that of the human infant, as their blood gas, pH values, and lung mechanics deteriorate dramatically from birth despite ventilator support. Moreover, premature lambs have lungs which are mechanically unstable, with the advantage of being able to measure multiple variables over extended periods. Our objective in this study was to investigate if Synsurf leads to improved systemic oxygenation, lung mechanics, and histology in comparison to the commercially available porcine-derived lung surfactant Curosurf® when administered before first breath in a preterm lamb model. Materials and methods: A Cesarean section was performed under general anesthesia on 18 time-dated pregnant Dohne Merino ewes at 129–130 days gestation. The premature lambs were delivered and ventilated with an expiratory tidal volume of 6–8 mL/kg for the first 30 minutes and thereafter at 8–10 mL/kg. In a randomized controlled trial, the two surfactants tested were Synsurf and Curosurf®, both at a dose of 100 mg/kg phospholipids (1,2-dipalmitoyl-L-α-phosphatidylcholine; 90% in Synsurf, 40% in Curosurf®). A control group of animals was treated with normal saline. Measurements of physiological variables, blood gases, and lung mechanics were made before and after surfactant and saline replacement and at 15, 30, 45, 60, 90, 120, 180, 240 and 300 minutes after treatment. The study continued for 5 hours. Results: Surfactant treatment led to a significant improvement in oxygenation within 30 minutes, with the Synsurf group and the Curosurf® group having significantly higher ratios between arterial partial pressure of oxygen/fraction of inspired oxygen (PaO₂/FiO₂; P = 0.021) compared to that of the control (saline-treated) animals. Dynamic compliance improved in the three groups over time, with no intergroup differences. All of the surfactant-treated animals survived, and one in the saline group died before the study ended. Histology between groups was not different, showing mild–moderate injury patterns. Discussion: Treatment with surfactants before first breath clearly resulted in improved systemic oxygenation within 30 minutes of instillation. Both Synsurf- and Curosurf®-treated animals experienced similar and more sustained improvement in oxygenation and decreased calculated shunt compared to saline-treated animals.