ORCID Profile
0000-0003-1946-8984
Current Organisation
University of South Australia
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Publisher: Springer Science and Business Media LLC
Date: 14-07-2016
Publisher: Springer Science and Business Media LLC
Date: 20-05-2009
Publisher: Elsevier BV
Date: 05-2011
DOI: 10.1016/J.ADDR.2011.01.012
Abstract: 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 We present our unpublished clinical data on nanoparticle penetration and previously published reports that support the hypothesis that nanoparticles 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.
Publisher: American Society for Microbiology
Date: 02-2016
DOI: 10.1128/AAC.02461-15
Abstract: The objective of the study was to describe the subcutaneous interstitial fluid (ISF) pharmacokinetics of fluconazole in critically ill patients with sepsis. This prospective observational study was conducted at two tertiary intensive care units in Australia. Serial fluconazole concentrations were measured over 24 h in plasma and subcutaneous ISF using microdialysis. The concentrations in plasma and microdialysate were measured using a validated high-performance liquid chromatography system with electrospray mass spectrometer detector method. Noncompartmental pharmacokinetic analysis was performed. Twelve critically ill patients with sepsis were enrolled. The mean in vivo fluconazole recovery rates ± standard deviation (SD) for microdialysis were 51.4% ± 16.1% with a mean (±SD) fluconazole ISF penetration ratio of 0.52 ± 0.30 (coefficient of variation, 58%). The median free plasma area under the concentration-time curve from 0 to 24 h (AUC 0–24 ) was significantly higher than the median ISF AUC 0–24 (340.4 versus 141.1 mg · h/liter P = 0.004). There was no statistical difference in median fluconazole ISF penetration between patients receiving and not receiving vasopressors (median, 0.28 versus 0.78 P = 0.106). Both minimum and the maximum concentrations of drug in serum ( C max and C min ) showed a significant correlation with the fluconazole plasma exposure ( C max , R 2 = 0.86, P 0.0001 C min , R 2 = 0.75, P 0.001). Our data suggest that fluconazole was distributed variably, but incompletely, from plasma into subcutaneous interstitial fluid in this cohort of critically ill patients with sepsis. Given the variability of fluconazole interstitial fluid exposures and lack of clinically identifiable factors by which to recognize patients with reduced distribution/exposure, we suggest higher than standard doses to ensure that drug exposure is adequate at the site of infection.
Publisher: Springer Science and Business Media LLC
Date: 25-05-2017
Publisher: Springer Science and Business Media LLC
Date: 30-06-2011
DOI: 10.1007/S11095-011-0515-5
Abstract: There is a lack of relevant, non-animal alternatives for assessing exposure and toxicity of nanoparticle-containing cosmetics, e.g. sunscreens. Our goal was to evaluate timecorrelated single photon counting (TCSPC) for simultaneous monitoring of zinc oxide nanoparticles (ZnO-NP) and the metabolic state of volunteer skin. We separated the fluorescence lifetime signatures of endogenous fluorophore signals (i.e. nicotinamide adenine dinucleotide phosphate, NAD(P)H and keratin) and the ZnO-NP signal using advanced TCSPC to simultaneously determine ZnO-NP penetration profiles and NAD(P)H changes in subjects with altered barrier function, including tape-stripped skin and in psoriasis or atopic dermatitis lesions. We detected no ZnO-NP penetration into viable human skin in any group. ZnO-NP signal was significantly increased (p < 0.01) on the surface of tape-stripped and lesional skin after 4 and 2 h of treatment, respectively. Free NAD(P)H signal significantly increased in tape-stripped viable epidermis treated for 4 h of ZnO-NP compared to vehicle control. No significant NAD(P)H changes were noted in the lesional study. TCSPC techniques enabled simultaneous, real-time quantification of ZnO-NP concentration and NAD(P)H via non-invasive imaging in the stratum corneum and viable epidermis of volunteers.
Publisher: Elsevier BV
Date: 04-2011
DOI: 10.1016/J.EJPB.2010.12.023
Abstract: 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 s le. 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. Ex les 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.
Publisher: Oxford University Press (OUP)
Date: 16-01-2014
DOI: 10.1093/JAC/DKT523
Abstract: 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. 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 s ling strategy, analytical methods, pharmacokinetic (PK) harmacodynamic (PD) targets and dose adjustment strategies. 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. 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.
Publisher: Springer Science and Business Media LLC
Date: 13-11-2018
Publisher: Elsevier BV
Date: 06-2014
DOI: 10.1016/J.JCHROMB.2014.04.029
Abstract: 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. S le 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 s les (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.
Publisher: MDPI AG
Date: 02-08-2013
DOI: 10.3390/CELLS2030591
Publisher: Elsevier BV
Date: 02-2015
DOI: 10.1016/J.IJANTIMICAG.2014.08.013
Abstract: Fluconazole is a widely used antifungal agent in critically ill patients. It is predominantly (60-80%) excreted unchanged in urine. Sustained low-efficiency diafiltration (SLED-f) is increasingly being utilised in critically ill patients because of its practical advantages over continuous renal replacement therapy. To date, the effect of SLED-f on fluconazole pharmacokinetics and dosing has not been studied. The objective of this study was to describe the pharmacokinetics of fluconazole in critically ill patients with acute kidney injury receiving SLED-f and to compare this with other forms of renal replacement therapy. Serial blood s les were collected at pre- and post-filter ports within the SLED-f circuit during SLED-f and from an arterial catheter before and after SLED-f from three patients during one session. Fluconazole concentrations were measured using a validated chromatography method. Median clearance (CL) and 24-h area under the concentration-time curve (AUC0-24) were 2.1L/h and 152 mg·h/L, respectively, whilst receiving SLED-f. Moreover, 72% of fluconazole was cleared by a single SLED-f session (6h) compared with previous reports of 33-38% clearance by a 4-h intermittent haemodialysis session. CL and AUC0-24 were comparable with previous observations in a pre-dilution mode of continuous venovenous haemodiafiltration. The observed rebound concentration of fluconazole post SLED-f was 200mg daily are likely to be required to achieve the PK/PD target for common pathogens because of significant fluconazole clearance by SLED-f.
Publisher: SAGE Publications
Date: 2013
DOI: 10.4137/SART.S8108
Abstract: Tobacco smoking remains the single most preventable cause of morbidity and mortality in developed countries and poses a significant threat across developing countries where tobacco use prevalence is increasing. Nicotine dependence is a chronic disease often requiring multiple attempts to quit repeated interventions with pharmacotherapeutic aids have become more popular as part of cessation therapies. First-line medications of known efficacy in the general population include varenicline tartrate, bupropion hydrochloride, nicotine replacement therapy products, or a combination thereof. However, less is known about the use of these products in marginalized groups such as the indigenous, those with mental illnesses, youth, and pregnant or breastfeeding women. Despite the efficacy and safety of these first line pharmacotherapies, many smokers continue to relapse and alternative pharmacotherapies and cessation options are required. Thus, the aim of this review is to summarize the existing and developing pharmacotherapeutic and other options for smoking cessation, to identify gaps in current clinical practice, and to provide recommendations for future evaluations and research.
Publisher: Public Library of Science (PLoS)
Date: 08-04-2009
Publisher: Japanese Society for the Study of Xenobiotics
Date: 2010
DOI: 10.2133/DMPK.DMPK-10-RG-031
Abstract: This study aims to investigate hepatic pharmacokinetics of the four most common drugs (metoprolol, omeprazole, spironolactone, and furosemide) given to patients undergoing liver transplantation before surgery. The investigation was carried out in CCl(4)-induced fibrotic perfused rat livers and the results were compared to those in normal rat liver. Drug outflow fraction-time profiles were obtained after bolus injection into a single-pass-perfused normal or fibrotic rat liver. The pharmacokinetic parameters were estimated using previously developed barrier-limited and space-distributed models. The results showed a marked increase in the liver fibrosis index for CCl(4)-treated rats compared to controls (p<0.05). The extraction ratios (E) for all drugs were significantly lower (p<0.05) in fibrotic than in normal livers and the decrease in E was consistent with the decrease in intrinsic clearance and permeability-surface area product. In addition, other than for furosemide, the mean transit times for all drugs were significantly longer (p<0.01) in the fibrotic livers than in normal livers. Pharmacokinetic model and stepwise regression analyses suggest that these differences arise from a reduction in both the transport of drugs across the basolateral membrane and their metabolic clearance and were in a manner similar to those previously found for another group of drugs.
Publisher: American Society for Microbiology
Date: 06-2011
DOI: 10.1128/AAC.00416-10
Abstract: This work sought to define how pancreatitis affected antibiotic distribution in a perfused rat pancreas model. The distribution kinetics of four antibiotics were examined in control animals and animals with pancreatitis. Meropenem and piperacillin distributed into the extracellular space, and their distribution kinetics were unaffected by pancreatitis. In contrast, in pancreatic cells from animals with pancreatitis, ciprofloxacin showed a reduced uptake and clindamycin showed a reduced distribution.
Publisher: Oxford University Press (OUP)
Date: 27-04-2009
DOI: 10.1093/JAC/DKP139
Abstract: 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. 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. 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. 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.
Publisher: Springer Science and Business Media LLC
Date: 14-08-2021
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2009
Publisher: Future Medicine Ltd
Date: 02-2013
DOI: 10.2217/LMT.12.55
Abstract: SUMMARY Worldwide, lung cancer contributes to over 1.4 million deaths per year. Smoking cessation is strongly recommended in clinical practice guidelines for lung cancer management, yet evidence suggests a translational gap between evidence and practice. There are significant health benefits following smoking cessation even after a short period of time. Long-term implications for lung cancer patients include improvements in quality of life, reductions in postoperative complications and reductions in 12-month mortality. Evidence suggests that combining pharmacotherapy, in particular varenicline tartrate (varenicline), with cognitive and behavioral interventions offers the best opportunity for successful long-term abstinence. This review summarizes the latest evidence for smoking cessation interventions in lung cancer patients, identifies gaps in current clinical practice and highlights priority areas for future research.
Publisher: Bentham Science Publishers Ltd.
Date: 06-2009
DOI: 10.2174/138920009788898037
Abstract: 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 ersity, 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.
Publisher: American Society for Microbiology
Date: 06-2014
DOI: 10.1128/AAC.02340-14
Abstract: This study assessed the pharmacokinetics and dosing adequacy of piperacillin in febrile neutropenic patients after the first dose. Pharmacokinetic analysis was performed using noncompartmental methods. We observed an elevated volume of distribution (29.7 ± 8.0 liters [mean ± standard deviation]) and clearance (20.2 ± 7.5 liters/h) compared to data from other patient populations. Antibiotic exposure did not consistently result in therapeutic targets. We conclude that alternative dosing strategies guided by therapeutic drug monitoring may be required to optimize exposure.
Publisher: SPIE-Intl Soc Optical Eng
Date: 2011
DOI: 10.1117/1.3614473
Abstract: Multiphoton microscopy has been shown to be a useful tool in studying drug distribution in biological tissues. In addition, fluorescence lifetime imaging provides information about the structure and dynamics of fluorophores based on their fluorescence lifetimes. Fluorescein, a commonly used fluorescent probe, is metabolized within liver cells to fluorescein mono-glucuronide, which is also fluorescent. Fluorescein and its glucuronide have similar excitation and emission spectra, but different fluorescence lifetimes. In this study, we employed multiphoton fluorescence lifetime imaging to study the distribution and metabolism of fluorescein and its metabolite in vivo in rat liver. Fluorescence lifetime values in vitro were used to interpret in vivo data. Our results show that the mean fluorescence lifetimes of fluorescein and its metabolite decrease over time after injection of fluorescein in three different regions of the liver. In conclusion, we have demonstrated a novel method to study a fluorescent compound and metabolite in vivo using multiphoton fluorescence lifetime imaging.
Publisher: Springer Science and Business Media LLC
Date: 02-2012
DOI: 10.1007/S11095-012-0690-Z
Abstract: To explore how liver damage arising from cardio-hepatic syndromes in RHF affect the hepatic pharmacokinetics of basic drugs. The hepatic pharmacokinetics of five selected basic drugs with different physicochemical properties were studied in IPRL from control rats and rats with RHF. Hepatic pharmacokinetic modelling was performed with a two-phase physiologically-based organ pharmacokinetic model with the vascular space and dispersion evaluated with the MID technique. The liver damage arising from RHF was assessed by changes in liver biochemistry and histopathology. The expression of various CYP isoforms was evaluated by real-time RT-PCR analysis. Four of the five basic drugs had a significantly lower E in RHF rat livers compared to the control rat livers. Hepatic pharmacokinetic analysis showed that both the CL int and PS were significantly decreased in the RHF rat livers. Stepwise regression analysis showed that the alterations in the pharmacokinetic parameters (E, CL int and PS) can be correlated to the observed histopathological changes (NI, CYP concentration and FI) as well as to the lipophilicity of the basic drugs (logP app). Serious hepatocellular necrosis and fibrosis induced by RHF affects both hepatic microsomal activity and hepatocyte wall permeability, leading to significant impairment in the hepatic pharmacokinetics of basic drugs.
Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)
Date: 18-01-2011
Abstract: The hepatic pharmacokinetics of five selected cationic drugs (propranolol, labetalol, metoprolol, antipyrine, and atenolol) was studied in the liver from control rats and from those with high-fat emulsion-induced nonalcoholic steatohepatitis (NASH). Studies were undertaken using an in situ-perfused rat liver and multiple indicator dilution, and outflow data were analyzed with a physiologically based organ pharmacokinetic model. Hepatic extraction (E) was significantly lower in the NASH model, and lipophilicity was the main solute structural determinant of the observed differences in intrinsic elimination clearance (CL(int)) and permeability-surface area product (PS) with pK(a) defining the extent of sequestration in the liver [apparent distribution ratio (K(v))]. The main pathophysiological determinants were liver fibrosis, leading to a decreased PS, liver fat causing an increase in K(v), and an increase in both total liver cytochrome P450 (P450) concentration and P450 isoform expression for Cyp3a2 and Cyp2d2, causing an increase CL(int) in NASH rat livers compared with control livers. Changes in hepatic pharmacokinetics (PS, K(v), CL(int), and E ratio) as a result of NASH were related to the physicochemical properties of drugs (lipophilicity or pK(a)) and hepatic histopathological changes (fibrosis index, steatosis index, and P450 concentration) by stepwise regression analysis. Thus, it appears that in NASH, counteracting mechanisms to facilitate hepatic removal are created in NASH-induced P450 expression, whereas NASH-induced fibrosis and steatohepatitis inhibit E by decreasing hepatocyte permeability through fibrosis and hepatic sequestration.
Location: United States of America
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Tom Robertson.