HIV-1 sub-type C chimaeric VLPs boost cellular immune responses in mice

Several approaches have been explored to eradicate HIV; however, a multigene vaccine appears to be the best option, given their proven potential to elicit broad, effective responses in animal models. The Pr55 Gagprotein is an excellent vaccine candidate in its own right, given that it can assemble into large, enveloped, virus-like particles (VLPs) which are highly immunogenic, and can moreover be used as a scaffold for the presentation of other large non-structural HIV antigens. In this study, we evaluated the potential of two novel chimaeric HIV-1 Pr55 Gag-based VLP constructs - C-terminal fusions with reverse transcriptase and a Tat::Nef fusion protein, designated GagRT and GagTN respectively - to enhance a cellular response in mice when used as boost components in two types of heterologous prime-boost vaccine strategies. A vaccine regimen consisting of a DNA prime and chimaeric HIV-1 VLP boosts in mice induced strong, broad cellular immune responses at an optimum dose of 100 ng VLPs. The enhanced cellular responses induced by the DNA prime-VLP boost were two- to three-fold greater than two DNA vaccinations. Moreover, a mixture of GagRT and GagTN VLPs also boosted antigen-specific CD8+ and CD4+ T-cell responses, while VLP vaccinations only induced predominantly robust Gag CD4+ T-cell responses. The results demonstrate the promising potential of these chimaeric VLPs as vaccine candidates against HIV-1. © 2010 Pillay et al; licensee BioMed Central Ltd.

Acepromazine pharmacokinetics: A forensic perspective

Acepromazine (ACP) is a useful therapeutic drug, but is a prohibited substance in competition horses. The illicit use of ACP is difficult to detect due to its rapid metabolism, so this study investigated the ACP metabolite 2-(1-hydroxyethyl)promazine sulphoxide (HEPS) as a potential forensic marker. Acepromazine maleate, equivalent to 30 mg of ACP, was given IV to 12 racing-bred geldings. Blood and urine were collected for 7 days post-administration and analysed for ACP and HEPS by liquid chromatography–mass spectrometry (LC–MS). Acepromazine was quantifiable in plasma for up to 3 h with little reaching the urine unmodified. Similar to previous studies, there was wide variation in the distribution and metabolism of ACP. The metabolite HEPS was quantifiable for up to 24 h in plasma and 144 h in urine. The metabolism of ACP to HEPS was fast and erratic, so the early phase of the HEPS emergence could not be modelled directly, but was assumed to be similar to the rate of disappearance of ACP. However, the relationship between peak plasma HEPS and the y-intercept of the kinetic model was strong (P = 0.001, r2 = 0.72), allowing accurate determination of the formation pharmacokinetics of HEPS. Due to its rapid metabolism, testing of forensic samples for the parent drug is redundant with IV administration. The relatively long half-life of HEPS and its stable behaviour beyond the initial phase make it a valuable indicator of ACP use, and by determining the urine-to-plasma concentration ratios for HEPS, the approximate dose of ACP administration may be estimated.

The effect of alcohol and drug consumption on academic performance : a treatment effect evaluation

It is often argued that consumption of alcohol, tobacco and drugs is detrimental to the cognitive abilities of teenagers. In order to disentangle a possible causal effect of these substances use from a self-selection bias, we control for pupils previous performance and for their previous rate of progression applying a DiDiD strategy. Using the NELS 1988 panel dataset, we find that the effects of alcohol and tobacco on test scores disappear once the selection bias is controlled for (this does not preclude long term detrimental effects). However, we find reliable evidence that heavy use of drugs (marijuana and cocaine) has direct detrimental effects on educational achievements. Hence, our results may have significant policy implications.

ASAP ECMO : antibiotic, sedative and analgesic pharmacokinetics during extracorporeal membrane oxygenation : a multi-centre study to optimise drug therapy during ECMO

BACKGROUND: Given the expanding scope of extracorporeal membrane oxygenation (ECMO) and its variable impact on drug pharmacokinetics as observed in neonatal studies, it is imperative that the effects of the device on the drugs commonly prescribed in the intensive care unit (ICU) are further investigated. Currently, there are no data to confirm the appropriateness of standard drug dosing in adult patients on ECMO. Ineffective drug regimens in these critically ill patients can seriously worsen patient outcomes. This study was designed to describe the pharmacokinetics of the commonly used antibiotic, analgesic and sedative drugs in adult patients receiving ECMO. METHODS: This is a multi-centre, open-label, descriptive pharmacokinetic (PK) study. Eligible patients will be adults treated with ECMO for severe cardiac and/or respiratory failure at five Intensive Care Units in Australia and New Zealand. Patients will receive the study drugs as part of their routine management. Blood samples will be taken from indwelling catheters to investigate plasma concentrations of several antibiotics (ceftriaxone, meropenem, vancomycin, ciprofloxacin, gentamicin, piperacillin-tazobactum, ticarcillin-clavulunate, linezolid, fluconazole, voriconazole, caspofungin, oseltamivir), sedatives and analgesics (midazolam, morphine, fentanyl, propofol, dexmedetomidine, thiopentone). The PK of each drug will be characterised to determine the variability of PK in these patients and to develop dosing guidelines for prescription during ECMO. DISCUSSION: The evidence-based dosing algorithms generated from this analysis can be evaluated in later clinical studies. This knowledge is vitally important for optimising pharmacotherapy in these most severely ill patients to maximise the opportunity for therapeutic success and minimise the risk of therapeutic failure

Drug abusers perceptions of their parents.

Many clinicians in the area of drug addiction believe that emotional problems arise from particular styles of parenting. To investigate this link, 63 young male and female addicts who had sought treatment completed the Parental Bonding Instrument which tapped their perceptions of their relationship with each parent. Addicts reported early parental experiences differing from those of a control group. Drug abusers judged their parents as cold, indifferent, controlling and intrusive. In addition, these perceptions were shared by male and female addicts. These results, together with previous research suggest that these perceptions might well point to a general risk factor for the development of a broad range of psychological and psychiatric disorders. In addition, the issue of family factors in the design and implementation of drug treatment programs needs to be addressed.

An analytical method for assessing stage-specific drug activity in Plasmodium vivax malaria : implications for ex vivo drug susceptibility testing

The emergence of highly chloroquine (CQ) resistant P. vivax in Southeast Asia has created an urgent need for an improved understanding of the mechanisms of drug resistance in these parasites, the development of robust tools for defining the spread of resistance, and the discovery of new antimalarial agents. The ex vivo Schizont Maturation Test (SMT), originally developed for the study of P. falciparum, has been modified for P. vivax. We retrospectively analysed the results from 760 parasite isolates assessed by the modified SMT to investigate the relationship between parasite growth dynamics and parasite susceptibility to antimalarial drugs. Previous observations of the stage-specific activity of CQ against P. vivax were confirmed, and shown to have profound consequences for interpretation of the assay. Using a nonlinear model we show increased duration of the assay and a higher proportion of ring stages in the initial blood sample were associated with decreased effective concentration (EC50) values of CQ, and identify a threshold where these associations no longer hold. Thus, starting composition of parasites in the SMT and duration of the assay can have a profound effect on the calculated EC50 for CQ. Our findings indicate that EC50 values from assays with a duration less than 34 hours do not truly reflect the sensitivity of the parasite to CQ, nor an assay where the proportion of ring stage parasites at the start of the assay does not exceed 66%. Application of this threshold modelling approach suggests that similar issues may occur for susceptibility testing of amodiaquine and mefloquine. The statistical methodology which has been developed also provides a novel means of detecting stage-specific drug activity for new antimalarials.

Dry powder inhaler formulations : effect of carrier size on the drug dispersion

Background: The size of the carrier influences drug aerosolization from a dry powder inhaler (DPI) formulation. Lactose particles with irregular shape and rough surface in a variety of sizes are additionally used as carriers; however, contradictory reports exist regarding the effect of carrier size on the dispersion of drug. We examined the influence of the spherical particle size of the biodegradable polylactide-co-glycolide (PLGA) carrier on the aerosolization of a model drug, salbutamol sulphate (SS). Methods: Four different sizes (20-150 µm) of polymer carriers were fabricated using solvent evaporation technique and the dispersion of SS from these carriers was measured by a Twin Stage Impinger (TSI). The size and morphological properties of polymer carriers were determined by laser diffraction and SEM, respectively. Results: The FPF was found to increase from 5.6% to 21.3% with increasing carrier sizeup to150 µm. Conclusions: The aerosolization of drug increased linearly with the size of polymer carriers. For a fixed mass of drug particles in a formulation, the mass of drug particles per unit area of carriers is higher in formulations containing the larger carriers, which leads to an increase in the dispersion of drug due to the increased mechanical forces occurred between the carriers and the device walls.

The development of a Monte Carlo system to verify radiotherapy treatment dose calculations

Recent advances in the planning and delivery of radiotherapy treatments have resulted in improvements in the accuracy and precision with which therapeutic radiation can be administered. As the complexity of the treatments increases it becomes more difficult to predict the dose distribution in the patient accurately. Monte Carlo methods have the potential to improve the accuracy of the dose calculations and are increasingly being recognised as the “gold standard” for predicting dose deposition in the patient. In this study, software has been developed that enables the transfer of treatment plan information from the treatment planning system to a Monte Carlo dose calculation engine. A database of commissioned linear accelerator models (Elekta Precise and Varian 2100CD at various energies) has been developed using the EGSnrc/BEAMnrc Monte Carlo suite. Planned beam descriptions and CT images can be exported from the treatment planning system using the DICOM framework. The information in these files is combined with an appropriate linear accelerator model to allow the accurate calculation of the radiation field incident on a modelled patient geometry. The Monte Carlo dose calculation results are combined according to the monitor units specified in the exported plan. The result is a 3D dose distribution that could be used to verify treatment planning system calculations. The software, MCDTK (Monte Carlo Dicom ToolKit), has been developed in the Java programming language and produces BEAMnrc and DOSXYZnrc input files, ready for submission on a high-performance computing cluster. The code has been tested with the Eclipse (Varian Medical Systems), Oncentra MasterPlan (Nucletron B.V.) and Pinnacle3 (Philips Medical Systems) planning systems. In this study the software was validated against measurements in homogenous and heterogeneous phantoms. Monte Carlo models are commissioned through comparison with quality assurance measurements made using a large square field incident on a homogenous volume of water. This study aims to provide a valuable confirmation that Monte Carlo calculations match experimental measurements for complex fields and heterogeneous media.

Nanotechnology in the targeted drug delivery for bone diseases and bone regeneration

Nanotechnology is a vigorous research area and one of its important applications is in biomedical sciences. Among biomedical applications, targeted drug delivery is one of the most extensively studied subjects. Nanostructured particles and scaffolds have been widely studied for increasing treatment efficacy and specificity of present treatment approaches. Similarly, this technique has been used for treating bone diseases including bone regeneration. In this review, we have summarized and highlighted the recent advancement of nanostructured particles and scaffolds for the treatment of cancer bone metastasis, osteosarcoma, bone infections and inflammatory diseases, osteoarthritis, as well as for bone regeneration. Nanoparticles used to deliver deoxyribonucleic acid and ribonucleic acid molecules to specific bone sites for gene therapies are also included. The investigation of the implications of nanoparticles in bone diseases have just begun, and has already shown some promising potential. Further studies have to be conducted, aimed specifically at assessing targeted delivery and bioactive scaffolds to further improve their efficacy before they can be used clinically

I know, but I don’t care : how awareness of Queensland’s drug driving testing methods impact upon perceptions of deterrence and offending behaviours

An increasing body of research is highlighting the involvement of illicit drugs in many road fatalities. Deterrence theory has been a core conceptual framework underpinning traffic enforcement as well as interventions designed to reduce road fatalities. Essentially the effectiveness of deterrence-based approaches is predicated on perceptions of certainty, severity, and swiftness of apprehension. However, much less is known about how the awareness of legal sanctions can impact upon the effectiveness of deterrence mechanisms and whether promoting such detection methods can increase the deterrent effect. Nevertheless, the implicit assumption is that individuals aware of the legal sanctions will be more deterred. This study seeks to explore how awareness of the testing method impacts upon the effectiveness of deterrence-based interventions and intentions to drug drive again in the future. In total, 161 participants who reported drug driving in the previous six months took part in the current study. The results show that awareness of testing had a small effect upon increasing perceptions of the certainty of apprehension and severity of punishment. However, awareness was not a significant predictor of intentions to drug drive again in the future. Importantly, higher levels of drug use were a significant predictor of intentions to drug drive in the future. Whilst awareness does have a small effect on deterrence variables, the influence of levels of drug use seems to reduce any deterrent effect.

Synthesis of an erodible biomimetic hydrogel for drug delivery using native chemical ligation

Hydrogels are hydrophilic, three dimensional polymers that imbibe large quantities of water while remaining insoluble in aqueous solutions due to chemical or physical cross-linking. The polymers swell in water or biological fluids, immobilizing the bioactive agent, leading to drug release in a well-defined specific manner. Thus the hydrogels’ elastic properties, swellability and biocompatibility make them excellent formulations for drug delivery. Currently, many drug potencies and therapeutic effects are limited or otherwise reduced because of the partial degradation that occurs before the administered drug reaches the desired site of action. On the other hand, sustained release medications release drugs continually, rather than providing relief of symptoms and protection solely when necessary. In fact, it would be much better if drugs could be administered in a manner that precisely matches physiological needs at desired times and at the desired site (site specific targeting). There is therefore an unmet need to develop controlled drug delivery systems especially for delivery of peptide and protein bound drugs. The purpose of this project is to produce hydrogels for structural drug delivery and time-dependent sustained release of drugs (bioactive agents). We use an innovative polymerisation strategy based on native chemical ligation (NCL) to covalently cross-link polymers to form hydrogels. When mixed in aqueous solution, four armed (polyethylene glycol) amine (PEG-4A) end functionalised with thioester and four branched Nterminal cysteine peptide dendrimers spontaneously conjugated to produce biomimetic hydrogels. These hydrogels showed superior resistance to shear stress compared to an equivalent PEG macromonomer system and were shown to be proteolytically degradable with concomitant release of a model payload molecule. This is the first report of a peptide dendrimers/PEG macromonomer approach to hydrogel production and opens up the prospect of facile hydrogel synthesis together with tailored payload release.

Advanced Bioactive Inorganic Materials for Bone Regeneration and Drug Delivery

Bioceramics play an important role in repairing and regenerating bone defects. Annually, more than 500,000 bone graft procedures are performed in the United states and approximately 2.2 million are conducted worldwide. The estimated cost of these procedures approaches $2.5billion per year. Around 60% of the bone graft substitutes available on the market involve bioceramics. It is reported that bioceramics in the world market increase by 9% per year. For this reason, the research of bioceramics has been one of the most active areas during, the past several years. Considering the significant importance of bioceramics, our goal was to compile this book to review the latest research advances in the field of bioceramics. The text also summarizes our work during the past 10 years in an effort to share innovative concepts, design of bioceramisc, and methods for material synthesis and drug delivery. We anticipate that this text will provide some useful information and guidance in the bioceramics field for biomedical engineering researchers and material scientists. Information on novel mesoporous bioactive glasses and silicate-based ceramics for bone regeneration and drug delivery are presented. Mesoporous bioactive glasses have shown multifunctional characteristics of bone regeneration and drug delivery due to their special mesopore structures,whereas silicated-based bioceramics, as typical third-generation biomaterials,possess significant osteostimulation properties. Silica nanospheres with a core-shell structure and specific properties for controllable drug delivery have been carefully reviewed-a variety of advanced synthetic strategies have been developed to construct functional mesoporous silica nanoparticles with a core-shell structure, including hollow, magnetic, or luminescent, and other multifunctional core-shell mesoporous silica nanoparticles. In addition, multifunctional drug delivery systems based on these nanoparticles have been designed and optimized to deliver the drugs into the targeted organs or cells,with a controllable release fashioned by virtue of various internal and external triggers. The novel 3D-printing technique to prepare advanced bioceramic scaffolds for bone tissue engineering applications has been highlighted, including the preparation, mechanical strength, and biological properties of 3D-printed porous scaffolds of calcium phosphate cement and silicate bioceramics. Three-dimensional printing techniques offer improved large-pore structure and mechanical strength. In addition , biomimetic preparation and controllable crystal growth as well as biomineralization of bioceramics are summarized, showing the latest research progress in this area. Finally, inorganic and organic composite materials are reviewed for bone regeneration and gene delivery. Bioactive inorganic and organic composite materials offer unique biological, electrical, and mechanical properties for designing excellent bone regeneration or gene delivery systems. It is our sincere hope that this book will updated the reader as to the research progress of bioceramics and their applications in bone repair and regeneration. It will be the best reward to all the contributors of this book if their efforts herein in some way help reader in any part of their study, research, and career development.

Factors associated with suboptimal adherence to antiretroviral therapy in Viet Nam: A cross-sectional study using audio computer-assisted self-interview (ACASI)

Background: Optimal adherence to antiretroviral therapy (ART) is necessary for people living with HIV/AIDS (PLHIV). There have been relatively few systematic analyses of factors that promote or inhibit adherence to antiretroviral therapy among PLHIV in Asia. This study assessed ART adherence and examined factors associated with suboptimal adherence in northern Viet Nam. Methods: Data from 615 PLHIV on ART in two urban and three rural outpatient clinics were collected by medical record extraction and from patient interviews using audio computer-assisted self-interview (ACASI). Results: The prevalence of suboptimal adherence was estimated to be 24.9% via a visual analogue scale (VAS) of past-month dose-missing and 29.1% using a modified Adult AIDS Clinical Trial Group scale for on-time dose-taking in the past 4 days. Factors significantly associated with the more conservative VAS score were: depression (p < 0.001), side-effect experiences (p < 0.001), heavy alcohol use (p = 0.001), chance health locus of control (p = 0.003), low perceived quality of information from care providers (p = 0.04) and low social connectedness (p = 0.03). Illicit drug use alone was not significantly associated with suboptimal adherence, but interacted with heavy alcohol use to reduce adherence (p < 0.001). Conclusions: This is the largest survey of ART adherence yet reported from Asia and the first in a developing country to use the ACASI method in this context. The evidence strongly indicates that ART services in Viet Nam should include screening and treatment for depression, linkage with alcohol and/or drug dependence treatment, and counselling to address the belief that chance or luck determines health outcomes.