Thomas A. Robertson
University of South Australia
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Advanced Drug Delivery Reviews | 2011
Tarl W. Prow; Jeffrey E. Grice; Lynlee L. Lin; Rokhaya Faye; Margaret K. Butler; Wolfgang Becker; Elisabeth M. T. Wurm; Corinne Yoong; Thomas A. Robertson; H. Peter Soyer; Michael S. Roberts
Skin is a widely used route of delivery for local and systemic drugs and is potentially a route for their delivery as nanoparticles. The skin provides a natural physical barrier against particle penetration, but there are opportunities to deliver therapeutic nanoparticles, especially in diseased skin and to the openings of hair follicles. Whilst nanoparticle drug delivery has been touted as an enabling technology, its potential in treating local skin and systemic diseases has yet to be realised. Most drug delivery particle technologies are based on lipid carriers, i.e. solid lipid nanoparticles and nanoemulsions of around 300 nm in diameter, which are now considered microparticles. Metal nanoparticles are now recognized for seemingly small drug-like characteristics, i.e. antimicrobial activity and skin cancer prevention. We present our unpublished clinical data on nanoparticle penetration and previously published reports that support the hypothesis that nanoparticles >10nm in diameter are unlikely to penetrate through the stratum corneum into viable human skin but will accumulate in the hair follicle openings, especially after massage. However, significant uptake does occur after damage and in certain diseased skin. Current chemistry limits both atom by atom construction of complex particulates and delineating their molecular interactions within biological systems. In this review we discuss the skin as a nanoparticle barrier, recent work in the field of nanoparticle drug delivery to the skin, and future directions currently being explored.
Journal of Antimicrobial Chemotherapy | 2009
Jason A. Roberts; Carl M. J. Kirkpatrick; Michael S. Roberts; Thomas A. Robertson; Andrew J. Dalley; Jeffrey Lipman
OBJECTIVES To compare the plasma and subcutaneous tissue concentration-time profiles of meropenem administered by intermittent bolus dosing or continuous infusion to critically ill patients with sepsis and without renal dysfunction, and to use population pharmacokinetic modelling and Monte Carlo simulations to assess the cumulative fraction of response (CFR) against Gram-negative pathogens likely to be encountered in critical care units. PATIENTS AND METHODS We randomized 10 patients with sepsis to receive meropenem by intermittent bolus administration (n = 5; 1 g 8 hourly) or an equal dose administered by continuous infusion (n = 5). Serial subcutaneous tissue concentrations were determined using microdialysis and compared with plasma data for first-dose and steady-state pharmacokinetics. Population pharmacokinetic modelling of plasma data and Monte Carlo simulations were then undertaken with NONMEM. RESULTS It was found that continuous infusion maintains higher median trough concentrations, in both plasma (intermittent bolus 0 versus infusion 7 mg/L) and subcutaneous tissue (0 versus 4 mg/L). All simulated intermittent bolus, extended and continuous infusion dosing achieved 100% of pharmacodynamic targets against most Gram-negative pathogens. Superior obtainment of pharmacodynamic targets was achieved using administration by extended or continuous infusion against less susceptible Pseudomonas aeruginosa and Acinetobacter species. CONCLUSIONS This is the first study to compare the relative concentration-time data of bolus and continuous administration of meropenem at the subcutaneous tissue and plasma levels. We found that the administration of meropenem by continuous infusion maintains higher concentrations in subcutaneous tissue and plasma than by intermittent bolus dosing. Administration by extended or continuous infusion will achieve superior CFR against less-susceptible organisms in patients without renal dysfunction.
Critical Care Medicine | 2009
Jason A. Roberts; Michael S. Roberts; Thomas A. Robertson; Andrew J. Dalley; Jeffrey Lipman
Objective:To describe a pharmacokinetic model of piperacillin concentrations in plasma and subcutaneous tissue when administered by bolus dosing and continuous infusion in critically ill patients with sepsis on days 1 and 2 of antibiotic therapy and to compare results against previous results for piperacillin from a cohort of patients with septic shock. Design:Prospective randomized controlled trial. Setting:Eighteen-bed intensive care unit at 918-bed tertiary referral hospital. Patients:Thirteen critically ill adult patients with known or suspected sepsis in whom the treating physician deemed piperacillin–tazobactam appropriate therapy were conveniently sampled. Interventions:Patients were randomized to receive different daily doses of piperacillin–tazobactam by bolus dosing or continuous infusion (continuous infusion—six patients; bolus dosing—seven patients). Serial plasma and tissue concentrations were determined on days 1 and 2 of treatment. Tissue concentrations of piperacillin were determined using a subcutaneously inserted microdialysis catheter. Separate pharmacokinetic models were developed for both bolus and continuous dosing. Measurements and Main Results:This is the first known article to report concurrent plasma and subcutaneous tissue concentrations of a β-lactam antibiotic administered by bolus and continuous dosing in critically ill patients with sepsis. With a 25% lower piperacillin dose administered to the continuous infusion group, the infusion group had statistically significantly higher median plasma concentrations than the bolus group on day 2 (16.6 vs. 4.9 mg/L; p = 0.007). There was a trend to higher median plasma concentrations on day 1 in the bolus dosing group (8.9 vs. 4.9 mg/L; p = 0.078). Median tissue concentrations were not statistically different on day 1 (infusion group 2.4 mg/L vs. bolus group 2.2 mg/L; p = 0.48) and day 2 (infusion group 5.2 mg/L vs. bolus group 0.8 mg/L; p = 0.45). A two-compartment pharmacokinetic model was found to describe the data best. Tissue pharmacodynamic targets were achieved more successfully with infusion dosing. Conclusions:Patients with sepsis do not seem to have the same level of impairment of tissue distribution as described for patients with septic shock. A 25% lower dose of piperacillin administered by continuous infusion seems to maintain higher trough concentrations compared with standard bolus dosing. It is likely that the clinical advantages of continuous infusion are most likely to be evident when treating pathogens with high minimum inhibitory concentration, although without therapeutic drug monitoring and subsequent dose adjustment, infusions may never achieve target concentrations of organisms with very high minimum inhibitory concentrations in a small number of patients.
European Journal of Pharmaceutics and Biopharmaceutics | 2011
Michael S. Roberts; Yuri Dancik; Tarl W. Prow; Camilla A. Thorling; Lynlee L. Lin; Jeffrey E. Grice; Thomas A. Robertson; Karsten König; Wolfgang Becker
New multiphoton and confocal microscope technologies and fluorescence lifetime imaging techniques are now being used to non-invasively image, in space (three dimensions),in time, in spectra, in lifetime and in fluorescence anisotropy (total of 7 dimensions), fluorescent molecules in in situ and in vivo biological tissue, including skin. The process involves scanning a 2D area and measuring fluorescence at a given tissue depth below the surface after excitation by a laser beam with a wavelength within the one-photon or two-photon absorption band of the fluorophores followed by the stacking together of a series of 2D images from different depths to reconstruct the full spatial structure of the sample. Our aim in this work is to describe the principles, opportunities, limitations and applications of this new technology and its application in defining skin morphology, disease and skin penetration in vitro and in vivo by drugs, chemicals and nanoparticles. A key emphasis is in the use of fluorescence lifetime imaging to add additional specificity and quantitation to the detection of the various exogenous chemicals and nanoparticles that may be applied to the skin as well as endogenous fluorescent species in the skin. Examples given include equipment configuration; components in skin autofluorescence in various skin strata; imaging and quantification of coexisting drugs and their metabolites; skin pH; nanoparticle zinc oxide skin penetration; liposome delivery of drugs to deeper tissues; and observations in skin ageing and in various skin diseases.
Journal of Biophotonics | 2008
Michael S. Roberts; Matthew J. Roberts; Thomas A. Robertson; Washington Y. Sanchez; Camilla A. Thorling; Yuhong Zou; Xin Zhao; Wolfgang Becker; Andrei V. Zvyagin
Multiphoton tomography was used to examine xenobiotic transport in vivo. We used the photochemical properties of zinc oxide and fluorescein and multiphoton tomography to study their transport in the skin and in the rat liver in vivo. Zinc oxide nanoparticles were visualised in human skin using the photoluminescence properties of zinc oxide and either a selective emission wavelength band pass filter or a filter with fluorescence lifetime imaging (FLIM). Zinc oxide nanoparticles (30 nm) did not penetrate into human skin in vitro and in vivo and this was validated by scanning electron microscopy with X-ray photoelectron spectroscopy. Fluorescein was measured in the liver using FLIM. Fluorescein is rapidly extracted from the blood into the liver cells and then transported into the bile. It is suggested that multiphoton tomography may be of particular use in defining in vivo 4D (in both space and time) pharmacokinetics.
Journal of Antimicrobial Chemotherapy | 2014
Gloria Wong; Alexander Brinkman; Russell J. Benefield; Mieke Carlier; Jan J. De Waele; Najoua El Helali; Otto R. Frey; Stéphan Juergen Harbarth; Angela Huttner; Brett C. McWhinney; Benoit Misset; Federico Pea; Judit Preisenberger; Michael S. Roberts; Thomas A. Robertson; Anka C. Roehr; Fekade Bruck Sime; Fabio Silvio Taccone; Jacobus P.J. Ungerer; Jeffrey Lipman; Jason A. Roberts
OBJECTIVES Emerging evidence supports the use of therapeutic drug monitoring (TDM) of β-lactams for intensive care unit (ICU) patients to optimize drug exposure, although limited detail is available on how sites run this service in practice. This multicentre survey study was performed to describe the various approaches used for β-lactam TDM in ICUs. METHODS A questionnaire survey was developed to describe various aspects relating to the conduct of β-lactam TDM in an ICU setting. Data sought included: β-lactams chosen for TDM, inclusion criteria for selecting patients, blood sampling strategy, analytical methods, pharmacokinetic (PK)/pharmacodynamic (PD) targets and dose adjustment strategies. RESULTS Nine ICUs were included in this survey. Respondents were either ICU or infectious disease physicians, pharmacists or clinical pharmacologists. Piperacillin (co-formulated with tazobactam) and meropenem (100% of units surveyed) were the β-lactams most commonly subject to TDM, followed by ceftazidime (78%), ceftriaxone (43%) and cefazolin (43%). Different chromatographic and microbiological methods were used for assay of β-lactam concentrations in blood and other biological fluids (e.g. CSF). There was significant variation in the PK/PD targets (100% fT>MIC up to 100% fT>4×MIC) and dose adjustment strategies used by each of the sites. CONCLUSIONS Large variations were found in the type of β-lactams tested, the patients selected for TDM and drug assay methods. Significant variation observed in the PK/PD targets and dose adjustment strategies used supports the need for further studies that robustly define PK/PD targets for ICU patients to ensure a greater consistency of practice for dose adjustment strategies for optimizing β-lactam dosing with TDM.
PLOS ONE | 2009
Fahim Mohamed; Indika Gawarammana; Thomas A. Robertson; Michael S. Roberts; Chathura Palangasinghe; Shukry Zawahir; Shaluka Jayamanne; Jaganathan Kandasamy; Michael Eddleston; Nicholas A. Buckley; Andrew H. Dawson; Darren M. Roberts
Background Deliberate self-poisoning with older pesticides such as organophosphorus compounds are commonly fatal and a serious public health problem in the developing world. The clinical consequences of self-poisoning with newer pesticides are not well described. Such information may help to improve clinical management and inform pesticide regulators of their relative toxicity. This study reports the clinical outcomes and toxicokinetics of the neonicotinoid insecticide imidacloprid following acute self-poisoning in humans. Methodology/Principal Findings Demographic and clinical data were prospectively recorded in patients with imidacloprid exposure in three hospitals in Sri Lanka. Blood samples were collected when possible for quantification of imidacloprid concentration. There were 68 patients (61 self-ingestions and 7 dermal exposures) with exposure to imidacloprid. Of the self-poisoning patients, the median time to presentation was 4 hours (IQR 2.3–6.0) and median amount ingested was 15 mL (IQR 10–50 mL). Most patients only developed mild symptoms such as nausea, vomiting, headache and diarrhoea. One patient developed respiratory failure needing mechanical ventilation while another was admitted to intensive care due to prolonged sedation. There were no deaths. Median admission imidacloprid concentration was 10.58 ng/L; IQR: 3.84–15.58 ng/L, Range: 0.02–51.25 ng/L. Changes in the concentration of imidacloprid in serial blood samples were consistent with prolonged absorption and/or saturable elimination. Conclusions Imidacloprid generally demonstrates low human lethality even in large ingestions. Respiratory failure and reduced level of consciousness were the most serious complications, but these were uncommon. Substitution of imidacloprid for organophosphorus compounds in areas where the incidence of self-poisoning is high may help reduce deaths from self-poisoning.
European Journal of Pharmaceutics and Biopharmaceutics | 2009
Farnaz Monajjemzadeh; Davoud Hassanzadeh; Hadi Valizadeh; Mohammad Reza Siahi-Shadbad; Javid Shahbazi Mojarrad; Thomas A. Robertson; Michael S. Roberts
This study documents drug-excipient incompatibility studies of acyclovir in physical mixtures with lactose and in different tablet brands. Differential scanning calorimetry (DSC) was initially used to assess compatibility of mixtures. The Fourier-transform infrared (FTIR) spectrum was also compared with the spectra of pure drug and excipient. Although DSC results indicated incompatibility with lactose, FTIR spectra were mostly unmodified due to overlapping peaks. Samples of isothermally stressed physical mixture were stored at 95 degrees C for 24 h. The residual drug was monitored using a validated high-performance liquid chromatography (HPLC) assay and data fitting to solid-state kinetic models was performed. The drug loss kinetics followed a diffusion model. The aqueous mixture of drug and excipient was heated in order to prepare an adduct mixture. HPLC analysis revealed one extra peak that was fractionated and subsequently injected into the liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) system. The MRM (Multiple Reaction Monitoring) chromatograms characterized the peak with molecular mass corresponding to an acyclovir-lactose Maillard reaction product. The presence of lactose in commercial tablets was checked using a new TLC method. Overall, the incompatibility of acyclovir with lactose was successfully evaluated using a combination of thermal methods and LC-MS/MS.
Journal of Chromatography B | 2014
Fekade Bruck Sime; Michael S. Roberts; Jason A. Roberts; Thomas A. Robertson
There is strong evidence in literature supporting the benefit of monitoring plasma concentrations of β-lactam antibiotics in the critically ill to ensure appropriateness of dosing. The objective of this work was to develop a method for the simultaneous determination of total concentrations piperacillin, benzylpenicillin, flucloxacillin, meropenem, ertapenem, cephazolin and ceftazidime in human plasma. Sample preparation involved protein precipitation with acetonitrile containing 0.1% formic acid and subsequent dilution of supernatant with 0.1% formic acid in water. Chromatographic separation was achieved on a reversed phase column (C18, 2.6 μm, 2.1 × 50 mm) via gradient elution using water and acetonitrile, each containing 0.1% formic acid, as mobile phase. Tandem mass spectrometry (MSMS) analysis was performed, after electrospray ionization in the positive mode, with multiple reaction monitoring (MRM). The method is accurate with the inter-day and intra-day accuracies of quality control samples (QCs) ranging from 95 to 107% and 95 to 108%, respectively. It is also precise with intra-day and inter-day coefficient of variations ranging from 4 to 12% and 5 to 14%, respectively. The lower limit of quantification was 0.1 μg/mL for each antibiotic except flucloxacillin (0.25 μg/mL). Recovery was greater than 96% for all analytes except for ertapenem (78%). Coefficients of variation for the matrix effect were less than 10% over the six batches of plasma. Analytes were stable over three freeze-thaw cycles, and for reasonable hours on the bench top as well as post-preparation. This novel liquid chromatography tandem mass spectrometry method proved accurate, precise and applicable for therapeutic drug monitoring and pharmacokinetic studies of the selected β-lactam antibiotics.
Current Drug Metabolism | 2009
Peng Li; Guangji Wang; Thomas A. Robertson; Michael S. Roberts
Drug transporters expressed on the hepatocyte membrane play an important role in hepatic drug disposition. In the last two decades, systematic research has resulted in a better understanding of the diversity, expression and substrate specificities of drug transporters in the liver. Here we review recent studies on the role of transporters in drug-drug interactions and disease states such as cirrhosis. We conclude the review by considering techniques and model systems used to study hepatic transporters, including the latest technological developments such as multiphoton microscopy.