Population pharmacokinetic analysis of mycophenolic acid in renal transplant recipients following oral administration of mycophenolate mofetil

Aim To develop a population pharmacokinetic model for mycophenolic acid in adult kidney transplant recipients, quantifying average population pharmacokinetic parameter values, and between- and within-subject variability and to evaluate the influence of covariates on the pharmacokinetic variability. Methods Pharmacokinetic data for mycophenolic acid and covariate information were previously available from 22 patients who underwent kidney transplantation at the Princess Alexandra Hospital. All patients received mycophenolate mofetil 1 g orally twice daily. A total of 557 concentration-time points were available. Data were analysed using the first-order method in NONMEM (version 5 level 1.1) using the G77 FORTRAN compiler. Results The best base model was a two-compartment model with a lag time (apparent oral clearance was 271 h(-1), and apparent volume of the central compartment 981). There was visual evidence of complex absorption and time-dependent clearance processes, but they could not be successfully modelled in this study. Weight was investigated as a covariate, but no significant relationship was determined. Conclusions The complexity in determining the pharmacokinetics of mycophenolic acid is currently underestimated. More complex pharmacokinetic models, though not supported by the limited data collected for this study, may prove useful in the future. The large between-subject and between-occasion variability and the possibility of nonlinear processes associated with the pharmacokinetics of mycophenolic acid raise questions about the value of the use of therapeutic monitoring and limited sampling strategies.

Diffusion modeling of percutaneous absorption kinetics: 3. Variable diffusion and partition coefficients, consequences for stratum corneum depth profiles and desorption kinetics

Stratum corneum (SC) desorption experiments have yielded higher calculated steady-state fluxes than those obtained by epidermal penetration studies. A possible explanation of this result is a variable diffusion or partition coefficient across the SC. We therefore developed the diffusion model for percutaneous penetration and desorption to study the effects of either a variable diffusion coefficient or variable partition coefficient in the SC over the diffusion path length. Steady-state flux, lag time, and mean desorption time were obtained from Laplace domain solutions. Numerical inversion of the Laplace domain solutions was used for simulations of solute concentration-distance and amount penetrated (desorbed)-time profiles. Diffusion and partition coefficients heterogeneity were examined using six different models. The effect of heterogeneity on predicted flux from desorption studies was compared with that obtained in permeation studies. Partition coefficient heterogeneity had a more profound effect on predicted fluxes than diffusion coefficient heterogeneity. Concentration-distance profiles show even larger dependence on heterogeneity, which is consistent with experimental tape-stripping data reported for clobetasol propionate and other solutes. The clobetasol propionate tape-stripping data were most consistent with the partition coefficient decreasing exponentially for half the SC and then becoming a constant for the remaining SC. (C) 2004 Wiley-Liss, Inc.

Endurance exercise, plasma oxidation and cardiovascular risk

Objective-Although physical activity is beneficial to health, people who exercise at high intensities throughout their lifetime may have increased cardiovascular risk. Aerobic exercise increases oxidative stress and may contribute to atherogenesis by augmented oxidation of plasma lipoproteins. The aim of this study was to examine the relationship between aerobic power and markers of oxidative stress, including the susceptibility of plasma to oxidation. Methods and results-Aerobic power was measured in 24 healthy men aged 29 9 years (mean +/- SD). Plasma was analysed from subjects of high aerobic power (HAP; VO(2)max, 64.6 +/- 6.1 ml/kg/min) and lower aerobic power (LAP;VO(2)max, 45.1 +/- 6.3 ml/kg/min) for total antioxidant capacity (TAC), malondialdehyde (MDA) and susceptibility to oxidation. Three measures were used to quantify plasma oxidizability: (1) lag time to conjugated diene formation (lag time); (2) change in absorbance at 234 nm and; (3) slope of the oxidation curve during propagation (slope). The HAP subjects had significantly lowerTAC (1.38 +/- 0.04 versus 1.42 +/- 0.06 TEAC units; P < 0.05), significantly higher change in absorbance (1.55 +/- 0.21 versus 1.36 +/- 0.17 arbitrary units; P < 0.05), but no difference in MDA (P = 0.6), compared to LAP subjects. There was a significant inverse association between TAC and slope (r = -0.49; P < 0.05). Lipoprotein profiles and daily intake of nutrients did not differ between the groups. Conclusions-These findings suggest that people with high aerobic power, due to extreme endurance exercise, have plasma with decreased antioxidant capacity and higher susceptibility to oxidation, which may increase their cardiovascular risk.

Investigation of in vitro transdermal absorption of fentanyl from patches placed on skin samples obtained from various anatomic regions of dogs

Objective-To investigate in vitro transdermal absorption of fentanyl from patches through skin samples obtained from various anatomic regions of dogs. Sample Population-Skin samples from 5 Greyhounds. Procedure-Skin samples from the dogs' thoracic, neck, and groin regions were collected postmortem and frozen. After samples were thawed, circular sections were cut and placed in Franz-type diffusion cells in a water bath (32degreesC). A commercial fentanyl patch, attached to an acetate strip with a circular hole, was applied to each skin sample. Cellulose strips were used as control membranes. Samples of receptor fluid in the diffusion cells were collected at intervals for 48 hours, and fentanyl concentrations were analyzed by use of high-performance liquid chromatography. Results-Mean +/- SD release rate of fentanyl from the patch, defined by its absorption rate through the non-rate-limiting cellulose membrane, was linear during the first 8 hours (2.01 +/- 0.05 pg/cm(2) of cellulose membrane/h) and then decreased. Fentanyl passed through skin from the groin region at a faster rate and with a significantly shorter lag time, compared with findings in neck or thoracic skin samples. Conclusions and Clinical Relevance-In vitro, fentanyl from a patch was absorbed more quickly and to a greater extent through skin collected from the groin region of dogs, compared with skin samples from the thoracic and neck regions. Placement of fentanyl patches in the groin region of dogs may decrease the lag time to achieve analgesia perioperatively; however, in vivo studies are necessary to confirm these findings.

Population pharmacokinetics of itraconazole and its active metabolite hydroxy-itraconazole in paediatric cystic fibrosis and bone marrow transplant patients

Objective: The objective of the study was to characterise the population pharmacokinetic properties of itraconazole and its active metabolite hydroxyitraconazole in a representative paediatric population of cystic fibrosis and bone marrow transplant (BMT) patients and to identify patient characteristics influencing the pharmacokinetics of itraconazole. The ultimate goals were to determine the relative bioavailability between the two oral formulations (capsules vs oral solution) and to optimise dosing regimens in these patients. Methods: All paediatric patients with cystic fibrosis or patients undergoing BMT at The Royal Children's Hospital, Brisbane, QLD, Australia, who were prescribed oral itraconazole for the treatment of allergic bronchopulmonary aspergillosis (cystic fibrosis patients) or for prophylaxis of any fungal infection (BMT patients) were eligible for the study. Blood samples were taken from the recruited patients as per an empirical sampling design either during hospitalisation or during outpatient clinic visits. ltraconazole and hydroxy-itraconazole plasma concentrations were determined by a validated high-performance liquid chromatography assay with fluorometric detection. A nonlinear mixed-effect modelling approach using the NONMEM software to simultaneously describe the pharmacokinetics of itraconazole and its metabolite. Results: A one-compartment model with first-order absorption described the itraconazole data, and the metabolism of the parent drug to hydroxy-itraconazole was described by a first-order rate constant. The metabolite data also showed one-compartment characteristics with linear elimination. For itraconazole the apparent clearance (CLitraconazole) was 35.5 L/hour, the apparent volume of distribution (V-d(itraconazole)) was 672L, the absorption rate constant for the capsule formulation was 0.0901 h(-1) and for the oral solution formulation was 0.96 h-1. The lag time was estimated to be 19.1 minutes and the relative bioavailability between capsules and oral solution (F-rel) was 0.55. For the metabolite, volume of distribution, V-m/(F (.) f(m)), and clearance, CL/(F (.) fm), were 10.6L and 5.28 L/h, respectively. The influence of total bodyweight was significant, added as a covariate on CLitraconazoie/F and V-d(itraconazole)/F (standardised to a 70kg person) using allometric three-quarter power scaling on CLitraconazole/F, which therefore reflected adult values. The unexplained between-subject variability (coefficient of variation %) was 68.7%, 75.8%, 73.4% and 61.1% for CLitraconazoie/F, Vd(itraconazole)/F, CLm/(F (.) fm) and F-rel, respectively. The correlation between random effects of CLitraconazole and Vd((itraconazole)) was 0.69. Conclusion: The developed population pharmacokinetic model adequately described the pharmacokinetics of itraconazole and its active metabolite, hydroxy-itraconazole, in paediatric patients with either cystic fibrosis or undergoing BMT. More appropriate dosing schedules have been developed for the oral solution and the capsules to secure a minimum therapeutic trough plasma concentration of 0.5 mg/L for these patients.

The effects of equine skin preparation on transdermal drug penetration in vitro

An increasing number of formulations are applied to equine skin, yet variable penetration can affect efficacy, or the incidence of adverse effects, or both. To investigate the effects of common methods of skin preparation on transdermal drug penetration in vitro, we clipped, harvested, and froze skin samples from 5 Thoroughbred geldings. Thawed samples were prepared as follows: control (no preparation); cleaned with aqueous chlorhexidine (Aq-C, 0.1% w/v); cleaned with alcoholic chlorhexidine (Al-C, 0.5% w/v); shaved (Sh); or tape-stripped (Ta) with the use of adhesive tape. The samples were then placed in diffusion cells, and 2 g of methylsalicylate (MeSa) gel (Dencorub) was applied to the stratum corneum side. The penetration of MeSa and its analyte, salicylate (Sa), through the skin samples was measured over 10 h. Compared with control skin, significantly more MeSa penetrated through skin prepared with Al-C or Sh (P < 0.01) or with Aq-C or Ta (P < 0.05), and significantly more Sa was recovered in the receptor phase from skin prepared with Aq-C, Al-C, or Sh (P < 0.05) or with Ta (P < 0.01). A significantly higher rate of penetration and shorter lag time were also noted for MeSa with all the prepared skin samples, compared with the control samples. The results show that clinical techniques routinely used to clean or prepare skin can significantly affect the rate and extent of penetration of a topically applied drug. This may result in greater systemic availability of active drug, which could lead to enhanced efficacy and, possibly, a higher incidence of adverse effects.

The influence of excipients on the diffusion of ibuprofen and paracetamol in gastric mucus

The aim of this study was to examine the diffusion of commonly administered analgesics, ibuprofen and paracetamol, through gastric mucus. As ibuprofen and paracetamol are often formulated with alkalising excipients, or are commonly co-administered with antacids that have been demonstrated to alter their absorption, diffusion was also studied in the presence of a range of soluble and insoluble antacids or buffering agents. The effect of pH, which has been demonstrated to modify the properties of mucus, was also studied. Mucus was a significant barrier to diffusion for both drugs, compared to an unstirred aqueous layer with diffusion rates significantly lower in the presence of a mucus barrier for both drugs; ibuprofen diffusion also demonstrated a significant increase in the lag time. Paracetamol diffusion was not significantly affected by addition of any antacid, whereas ibuprofen rates were affected and the diffusion lag time for ibuprofen was significantly reduced in all cases. Isolated increases in pH increased the rate and reduced the lag time for ibuprofen diffusion. It was shown that mucus acts as a passive barrier in the case of paracetamol diffusion, and an interactive barrier to ibuprofen diffusion. Changes in mucus viscosity at different pH values may be responsible for the observed changes in ibuprofen diffusion rate. © 2004 Elsevier B.V. All rights reserved.

Transition metal ion coordination in hydrophilic polymer membranes

The research described within this thesis is concerned with the investigation of transition metal ion complexation within hydrophilic copolymer membranes. The membranes are copolymers of 4-methyl-4'-vinyl-2,2'-bipyridine, the 2-hydroxyethyl ester of 4,4'- dicarboxy-2,2'-bipyridine & bis-(5-vinylsalicylidene)ethylenediamine with 2-hydroxyethyl methacrylate. The effect of the polymer matrix on the formation and properties of transition metal iron complexes has been studied, specifically Cr(III) & Fe(II) salts for the bipyridyl- based copolymer membranes and Co(II), Ni(II) & Cu(II) salts for the salenH2- based copolymer membranes. The concomitant effect of complex formation on the properties of the polymer matrix have also been studied, e.g. on mechanical strength. A detailed body of work into the kinetics and thermodynamics for the formation of Cu(II) complexes in the salenH2- based copolymer membranes has been performed. The rate of complex formation is found to be very slow while the value of K for the equilibrium of complex formation is found to be unexpectedly small and shows a slight anion dependence. These phenomena are explained in terms of the effects of the heterogeneous phase provided by the polymer matrix. The transport of Cr(III) ions across uncomplexed and Cr(III)-pre-complexed bipyridyl-based membranes has been studied. In both cases, no Cr(III) coordination occurs within the time-scale of an experiment. Pre-complexation of the membrane does not lead to a change in the rate of permeation of Cr(III) ions. The transport of Co(II), Ni(II) & Cu(II) ions across salenH2- based membranes shows that there is no detectable lag-time in transport of the ions, despite independent evidence that complex formation within the membranes does occur. Finally, the synthesis of a number of functionalised ligands is described. Although they were found to be non-polymerisable by the methods employed in this research, they remain interesting ligands which provide a startmg pomt for further functionalisation.

Transition metal ion co-ordination in hydrophilic polymer membrane

This thesis is concerned with the investigation of transition metal (TM) ion complexation with hydrophilic membranes composed of copolymers of 4-vinyl pyridine & 4-methyl-4'vinyl- 2,2'-bipyridine with 2-hydroxyethyl methacrylate. The Cu(II), CoCII) & Fe(II) complexes with these coordinating membranes were characterised by a variety of techniques, in order to assess the effect of the polymer on the properties of the complex, and vice versa. A detailed programme of work was instigated into the kinetics of formation for the polymer-bound tris(bipyridyl) iron(II) complex; the rate and extent of complex formation was found to be anion-dependent. This is explained in terms of the influence of the anion on the transport properties and water content of the membrane, the controlling factor in the development of the tris-complex being the equilibrium concentration of Fe(II) in the gel matrix. A series of transport studies were performed with a view to the potential application of complexing hydrogel membranes for aqueous TM ion separations. A number of salts were studied individually and shown to possess a range of permeabilities; the degree of interaction between particular metal-ion:ligand combinations is given by the lag-time observed before steady-state permeation is achieved. However, when two TM salts that individually display different transport properties were studied in combination, they showed similar lag-times & permeabilities, characteristic of the more strongly coordinating metal ion. This 'anti-selective' nature thus renders the membrane systems unsuitable for TM ion separations. Finally, attempts were made to synthesise and immobilise a series of N ,0-donor macrocyclic ligands into hydrogel membranes. Although the functionalisation reactions failed, limited transport data was obtained from membranes in which the ligands were physically entrapped within the polymer matrix.

Firm performance and investment in R&D and intellectual property

This paper analyses the relationship between innovation - proxied by Research and Development (R&D), patent and trade mark activity – and profitability in a panel of Australian firms (1995 to 1998). Special attention is given to assessing the nature of competitive conditions faced by different firms, as the nature of competition is likely to affect the returns to innovation. The hypothesis is that lower levels of competition will imply higher returns to innovation. To allow for a time lag time before any return to innovation, the market value of the firms is used as a proxy for expected future profits. The results give some support for the main hypothesis: the market’s valuation of R&D activity is higher in industries where competition is lower. However, the paper highlights the difficulty in assessing competitive conditions and finds a number of results that challenge the simple hypothesis.

Lichen growth and lichenometry

Lichenometry is one of the most widely used methods available for dating the surface age of various substrata including rock surfaces, boulders, walls, and archaeological remains. It depends on the assumption that if the lag time before colonisation of a substratum by a lichen is known and lichen age can be estimated, then a minimum date can be obtained by measuring the diameter (or another property related to size) of the largest lichen at the site. Lichen age can be determined by variety of methods including calibrating lichen size against surfaces of known age (‘indirect lichenometry’), by constructing a growth rate-size curve from direct measurement of lichen growth (‘direct lichenometry’), using radio-carbon (RC) dating, and from lichen ‘growth rings’. This chapter describes: (1) lichen growth rates and longevity, (2) methods of estimating lichen age, (3) the methodology of lichenometry and (4) applications of lichenometry. Despite its limitations, lichenometry is likely to continue to play an important role in dating a variety of surfaces and also in providing data that contribute to the debate regarding global warming and climate change.

The use of the lichen genus Rhizocarpon in lichenometric dating with special reference to Holocene glacial events

Lichenometry is one of the most widely used methods of dating the surface age of substrata including rock surfaces, boulders, walls, and archaeological remains and has been particularly important in dating late Holocene glacial events. Yellow-green species of the crustose genus Rhizocarpon have been the most useful lichens in lichenometry because of their low growth rates and longevity. This review describes: (1) the biology of the genus Rhizocarpon, (2) growth rates and longevity, (3) environmental growth effects, (4) methods of estimating lichen age, (5) the methodology of lichenometry, (6) applications to dating glacial events, and (7) future research. Lichenometry depends on many assumptions, most critically that if the lag time before colonisation of a substratum is known and lichen age can be estimated, then a minimum surface age date can be obtained by measuring the size of the largest Rhizocarpon thallus. Lichen age can be estimated by calibrating thallus size against surfaces of known age (‘indirect lichenometry’), by constructing a growth rate-size curve from direct measurement of growth (‘direct lichenometry’), using radio-carbon (RC) dating, or from lichen ‘growth rings’. Future research should include a more rigorous investigation of the assumptions of lichenometry, especially whether the largest thallus present at a site is a good indicator of substratum age, and further studies on the establishment, development, growth, senescence, and mortality of Rhizocarpon lichens.

Antimicrobial activity of a chlorhexidine intravascular catheter site gel dressing

Objectives: The antimicrobial efficacy of a chlorhexidine gluconate (CHG) intravascular catheter gel dressing was evaluated against methicillin-resistant Staphylococcus aureus (MRSA) and an extended-spectrum β-lactamase (ESBL)-producing Escherichia coli. Chlorhexidine deposition on the skin surface and release from the gel were determined. Methods: The antimicrobial efficacy was evaluated in in vitro studies following microbial inoculation of the dressing and application of the dressing on the inoculated surface of a silicone membrane and donor skin [with and without a catheter segment and/or 10% (v/v) serum] on diffusion cells. Antimicrobial activity was evaluated for up to 7 days. Chlorhexidine skin surface deposition and release were also determined. Results: MRSA and E. coli were not detectable within 5 min following direct inoculation onto the CHG gel dressing. On the silicone membrane, 3 log and 6 log inocula of MRSA were eradicated within 5 min and 1 h, respectively. Time to kill was prolonged in the presence of serum and a catheter segment. Following inoculation of donor skin with 6 log cfu of MRSA, none was detected after 24 h. Chlorhexidine was released from the gel after a lag time of 30 min and increasing amounts were detected on the donor skin surface over the 48 h test period. The CHG gel dressing retained its antimicrobial activity on the artificial skin for 7 days. Conclusions: The CHG intravascular catheter site gel dressing had detectable antimicrobial activity for up to 7 days, which should suppress bacterial growth on the skin at the catheter insertion site, thereby reducing the risk of infection. © The Author 2011. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.

Análise da influência das provas periciais produzidas por professores da Universidade Federal do Rio Grande do Norte nos processos administrativos oriundos do Ministério Público do RN

Dissertação (mestrado)—Universidade de Brasília, Universidade Federal da Paraíba, Universidade Federal do Rio Grande do Norte, Programa de Pós-Graduação Multiinstitucional e Inter-Regional de Pós-Graduação em Ciências Contábeis, 2016.