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.

D-amino acid residue in a defensin-like peptide from platypus venom: effect on structure and chromatographic properties

The recent discovery that the natriuretic peptide OvCNPb (Ornithorhynchus venom C-type natriuretic peptide B) from platypus (Ornithorynchus anatinus) venom contains a D-amino acid residue suggested that other D-amino-acid-containing peptides might be present in the venom. In the present study, we show that DLP-2 (defensin-like peptide-2), a 42-amino-acid residue polypeptide in the platypus venom, also contains a D-amino acid residue, D-methionine, at position 2, while DLP-4, which has an identical amino acid sequence, has all amino acids in the L-form. These findings were supported further by the detection of isomerase activity in the platypus gland venom extract that converts DLP-4 into DLP-2. In the light of this new information, the tertiary structure of DLP-2 was recalculated using a new structural template with D-Met(2). The structure of DLP-4 was also determined in order to evaluate the effect of a D-amino acid at position 2 on the structure and possibly to explain the large retention time difference observed for the two molecules in reverse-phase HPLC. The solution structures of the DLP-2 and DLP-4 are very similar to each other and to the earlier reported structure of DLP-2, which assumed that all amino acids were in the L-form. Our results suggest that the incorporation of the D-amino acid at position 2 has minimal effect on the overall fold in solution.

Comparative Analysis of Structural and Morphological Properties of Large-Pore Periodic Mesoporous Organosilicas and Pure Silicas

A systematic study on the structural properties and external morphologies of large-pore mesoporous organosilicas synthesized using triblock copolymer EO20PO70EO20 as a template under low-acid conditions was carried out. By employing the characterization techniques of SAXS, FE-SEM, and physical adsorption of N-2 in combination with alpha(s)-plot method, the structural properties and external morphologies of large-pore mesoporous organosilicas were critically examined and compared with that of their pure-silica counterparts synthesized under similar conditions. It has been observed that unlike mesoporous pure silicas, the structural and morphological properties of mesoporous organosilicas are highly acid-sensitive. High-quality mesoporous organosilicas can only be obtained from synthesis gels with the molar ratios of HCl/H2O between 7.08 x 10(-4) and 6.33 x 10(-3), whereas mesoporous pure silicas with well-ordered structure can be obtained in a wider range of acid concentration. Simply by adjusting the HCl/H2O molar ratios, the micro-, meso-, and macroporosities of the organosilica materials can be finely tuned without obvious effect on their structural order. Such a behavior is closely related to their acid-controlled morphological evolution: from necklacelike fibers to cobweb-supported pearl-like particles and to nanosized particulates.

Titanium phosphate for Fuel Cell Proton Conduction Membranes

Environmental issues due to increases in emissions of air pollutants and greenhouse gases are driving the development of clean energy delivery technologies such as fuel cells. Low temperature Proton Exchange Membrane Fuel Cells (PEMFC) use hydrogen as a fuel and their only emission is water. While significant advances have been made in recent years, a major limitation of the current technology is the cost and materials limitations of the proton conduction membrane. The proton exchange membrane performs three critical functions in the PEMFC membrane electrode assembly (MEA): (i) conduction of protons with minimal resistance from the anode (where they are generated from hydrogen) to the cathode (where they combine with oxygen and electrons, from the external circuit or load), (ii) providing electrical insulation between the anode and cathode to prevent shorting, and (iii) providing a gas impermeable barrier to prevent mixing of the fuel (hydrogen) and oxidant. The PFSA (perfluorosulphonic acid) family of membranes is currently the best developed proton conduction membrane commercially available, but these materials are limited to operation below 100oC (typically 80oC, or lower) due to the thermochemical limitations of this polymer. For both mobile and stationary applications, fuel cell companies require more durable, cost effective membrane technologies capable of delivering enhanced performance at higher temperatures (typically 120oC, or higher. This is driving research into a wide range of novel organic and inorganic materials with the potential to be good proton conductors and form coherent membranes. There are several research efforts recently reported in the literature employing inorganic nanomaterials. These include functionalised silica phosphates [1,2], fullerene [3] titania phosphates [4], zirconium pyrophosphate [5]. This work addresses the functionalisation of titania particles with phosphoric acid. Proton conductivity measurements are given together with structural properties.

Thermal Cycling Stability of Silica Membranes for Gas Separation

Hydrogen is being seen as an alternative energy carrier to conventional hydrocarbons to reduce greenhouse gas emissions. High efficiency separation technologies to remove hydrogen from the greenhouse gas, carbon dioxide, are therefore in growing demand. Traditional thermodynamic separation systems utilise distillation, absorption and adsorption, but are limited in efficiency at compact scales. Molecular sieve silica (MSS) membranes can perform this separation as they have high permselectivity of hydrogen to carbon dioxide, but their stability under thermal cycling is not well reported. In this work we exposed a standard MSS membrane and a carbonised template MSS (CTMSS) membrane to thermal cycling from 100 to 450°C. The standard MSS and carbonised template CTMSS membranes both showed permselectivity of helium to nitrogen dropping from around 10 to 6 in the first set of cycles, remaining stable until the last test. The permselectivity drop was due to small micropore collapse, which occurred via structure movement during cycling. Simulating single stage membrane separation with a 50:50 molar feed of H2:CO2, H2 exiting the permeate stream would start at 79% and stabilise at 67%. Higher selectivity membranes showed less of a purity drop, indicating the margin at which to design a stable membrane separation unit for CO2 capture.

Nanocomposite Nafion-Silica membranes for direct methanol fuel cells

Commercially available proton exchange membranes such as Nafion do not meet the requirements for high power density direct methanol fuel cells, partly due to their high methanol permeability. The aim of this work is to develop a new class of high-proton conductivity membranes, with thermal and mechanical stability similar to Nafion and reduced methanol permeability. Nanocomposite membranes were produced by the in-situ sol-gel synthesis of silicon dioxide particles in preformed Nafion membranes. Microstructural modification of Nafion membranes with silica nanoparticles was shown in this work to reduce methanol crossover from 7.48x10-6 cm2s^-1 for pure Nafion® to 2.86 x10-6 cm2s^-1 for nanocomposite nafion membranes (Methanol 50% (v/v) solution, 75 degrees C). Best results were achieved with a silica composition of 2.6% (w/w). We propose that silica inhibits the conduction of methanol through Nafion by blocking sites necessary for methanol diffusion through the polymer electrolyte membrane. Effects of surface chemistry, nanoparticle formation and interactions with Nafion matrix are further addressed.

Molecular sieve silica membranes for H2/CO separation

Efficient separation of fuel gas (H2) from other gases in reformed gas mixtures is becoming increasingly important in the development of alternative energy systems. A highly efficient and new technology available for these separations is molecular sieve silica (MSS) membranes derived from tetraethyl-orthosilicate (TEOS). A permeation model is developed from an analogous electronic system and compared to transport theory to determine permeation, selectivity and apparent activation of energy based on experimental values. Experimental results for high quality membranes show single gas permselectivity peaking at 57 for H2/CO at 150°C with a H2 permeation of 5.14 x 10^-8 mol.m^-2.s^-1.Pa^-1. Higher permeance was also achieved, but at the expense of selectivity. This is the case for low quality membranes with peak H2 permeation at 1.78 x 10-7 mol.m-2.s-1.Pa-1 at 22°C and H2/CO permselectivity of 4.5. High quality membranes are characterised with positive apparent activation energy while the low quality membranes have negative values. The model had a good fit of r-squared of 0.99-1.00 using the experimental data.

Molecular Sieve Silica (MSS) Membranes for Gas Separation and Reaction Processes

Weakly branched silica films formed by the two-step sol-gel process allow for the formation of high selectivity membranes for gas separation. 29Si NMR and gas permeation showed that reduced crosslinking leads to He/CH4 selectivity improvement from 300 to 1000. Applied in membrane reactor for cyclohexane conversion to benzene, conversions were achieved at 14 fold higher than a conventional reactor at 250°C. Hydrothermal stability studies showed that carbon templating of silica is required for hydrothermally stable membranes. From our work it was shown that with correct application of chemistry, practical membrane systems can be built to suit gas separation (e. g. hydrogen fuel) and reactor systems.

Hydrothermal stable templated molecular sieve silica (TMSS) membranes for gas separation

In this work we compare the hydrothermal stability performance of a Templated Molecular Sieve Silica (TMSS) membrane against a standard, non-templated Molecular Sieve Silica (MSS) membrane. The tests were carried under dry and wet (steam) conditions for single gas (He, H2, CO and CO2) at 1-2 atm membrane pressure drop at 200oC. Single gas TMSS membrane H2, permeance and H2/CO permselectivity was found to be 2.05 x 10-8 mols.m-2.s-1.Pa-1 and 15, respectively. The MSS membrane showed similar selectivity, but increased overall flux. He permeance through membranes decayed at a rate of 4-5 x 10-10 mols.m-2.s-1.Pa-1 per day regardless of membrane ambience (dry or wet). Although H2/CO permselectivity of the TMSS membrane slightly improved from 15 to 18 after steam testing, the MSS membrane resulted in significant reduction from 16 to 8.3. In addition, membrane regeneration after more than 50 days resulted in the TMSS membrane reverting to its original permeation levels while no significant improvements were observed for the MSS membra ne. Results showed that the TMSS membrane had enhanced hydrothermal stability and regeneration ability.

Hydrothermal Stability of Modified Silica Membranes for Gas Separation

A new class of hybrid molecular sieve silica (MSS) membranes is developed and tested against standard and organic templated membranes. The hybrid membrane is synthesized by the standard sol-gel process, integrating a template (methyltriethoxysilane - MTES) and a C6 surfactant (triethylhexylammonium bromide) into the silica film matrix. After hydro treatment under a relative humidity of 96% for 50h, the hybrid membrane shows no changes in its gas separation capabilities or energy of mobility. The structural characteristics and integrity of the hybrid membrane are retained due to a high concentration of organophilic functional groups and alkoxides observed using 29 Si NMR. In contrast, the structural integrity of the membranes prepared with non-templated films deteriorated during the hydro treatment due to a large percentage of silanol groups (Si-OH) which react with water. The hybrid membranes underwent a decrease in the H2/CO2 selectivity of only 1% whereas for the non-templated membrane a 21% decrease was observed. The transport mechanism of the hybrid membranes is activated as permeation increased with temperature. The activation energy for the permeation of H2 is positive while negative for CO2. The H2 permeation obtained was 3x 10 -8 mol.m -2 .s -1 .Pa -1 and permselectivities for H2/CO2 and H2/N2 varied between 1-7 and 31-34, respectively.

Hydrothermal Stability Analysis of Carbonised Template Molecular Sieve Silica Membranes

For fuel cell CO clean up application, the presence of water with silica membranes greatly reduces their selectivity to CO. We show results of a new functional carbonised template membrane of around 13nm thickness which offered hydrothermal stability with no compromise to the membrane’s H2/CO permselectivity of 16. Lost permeance was also regenerated.

Hydrostability and Scaling Up Molecular Sieve Silica (MSS) Membranes for H2/CO Separation in Fuel Cell Systems

MSS membranes are a good candidate for CO cleanup in fuel cell fuel processing systems due to their ability to selectively permeate H2 over CO via molecular sieving. Successfully scaled up tubular membranes were stable under dry conditions to 400°C with H2 permeance as high as 2 x 10-6 mol.m-2.s^-1.Pa^-1 at 200 degrees C and H2/CO selectivity up to 6.4, indicating molecular sieving was the dominant mechanism. A novel carbonised template molecular sieve silica (CTMSS) technology gave the scaled up membranes resilience in hydrothermal conditions up to 400 degrees C in 34% steam and synthetic reformate, which is required for use in fuel cell CO cleanup systems.

Bcl-2 in endothelial cells is increased by vitamin E and alpha-lipoic acid supplementation but not exercise training

Atherosclerotic plaque contains apoptotic endothelial cells with oxidative stress implicated in this process. Vitamin E and a-lipoic acid are a potent antioxidant combination with the potential to prevent endothelial apoptosis. Regular exercise is known to increase myocardial protection, however, little research has investigated the effects of exercise on the endothelium. The purpose of these studies was to investigate the effects of antioxidant supplementation and/or exercise training on proteins that regulate apoptosis in endothelial cells. Male rats received a control or antioxidant-supplemented diet (vitamin E and alpha-lipoic acid) and were assigned to sedentary or exercise-trained groups for 14 weeks. Left ventricular endothelial cells (LVECs) were isolated and levels of the anti-apoptotic protein Bcl-2 and the pro-apoptotic protein Bax were measured. Antioxidant supplementation caused a fourfold increase in Bcl-2 (P < 0.05) with no change in Bax (P > 0.05). Bcl-2:Bax was increased sixfold with antioxidant supplementation compared to non-supplemented animals (P < 0.05). Exercise training had no significant effect on Bcl-2, Bax or Bcl-2:Bax either alone or combined with antioxidant supplementation (P > 0.05) compared to non-supplemented animals. However, Bax was significantly lower (P < 0.05) in the supplemented trained group compared to non-supplemented trained animals. Cultured bovine endothelial cells incubated for 24 h with vitamin E and/or a-lipoic acid showed the combination of the two antioxidants increased Bcl-2 to a greater extent than cells incubated with the vehicle alone. In summary, vitamin E and a-lipoic acid increase endothelial cell Bcl-2, which may provide increased protection against apoptosis. (c) 2005 Elsevier Ltd. All rights reserved

Hydrochemistry, mineralogy and sulphur isotope geochemistry of acid mine drainage at the Mt Morgan mine environment, Queensland, Australia

Mineralogical, hydrochemical and S isotope data were used to constrain hydrogeochemical processes that produce acid mine drainage from sulfidic waste at the historic Mount Morgan Au–Cu mine, and the factors controlling the concentration of SO4 and environmentally hazardous metals in the nearby Dee River in Queensland, Australia. Some highly contaminated acid waters, with metal contents up to hundreds of orders of magnitude greater than the Australia–New Zealand environmental standards, by-pass the water management system at the site and drain into the adjacent Dee River. Mine drainage precipitates at Mt. Morgan were classified into 4 major groups and were identified as hydrous sulfates and hydroxides of Fe and Al with various contents of other metals. These minerals contain adsorbed or mineralogically bound metals that are released into the water system after rainfall events. Sulfate in open pit water and collection sumps generally has a narrow range of S isotope compositions (δ34S = 1.8–3.7‰) that is comparable to the orebody sulfides and makes S isotopes useful for tracing SO4 back to its source. The higher δ34S values for No. 2 Mill Diesel sump may be attributed to a difference in the source. Dissolved SO4 in the river above the mine influence and 20 km downstream show distinctive heavier isotope compositions (δ34S = 5.4–6.8‰). The Dee River downstream of the mine is enriched in 34S (δ34S = 2.8–5.4‰) compared with mine drainage possibly as a result of bacterial SO4 reduction in the weir pools, and in the water bodies within the river channel. The SO4 and metals attenuate downstream by a combination of dilution with the receiving waters, SO4 reduction, and the precipitation of Fe and Al sulfates and hydroxides. It is suggested here that in subtropical Queensland, with distinct wet and dry seasons, temporary reducing environments in the river play an important role in S isotope systematics