Relationships of tacrolimus pharmacokinetic measures and adverse outcomes in stable adult liver transplant recipients

Alternative measures to trough concentrations [non-trough concentrations and limited area under the concentration-time curve (AUC)] have been shown to better predict tacrolimus AUC. The aim of this study was to determine if these are also better predictors of adverse outcomes in long term liver transplant recipients. The associations between tacrolimus trough concentrations (C-0), non-trough concentrations (C-1, C-2, C-4, C-6/8), and AUC(0-12) and the occurrence of hypertension, hyperkalaemia, hyperglycaemia and nephrotoxicity were assessed in 34 clinically stable liver transplant patients. The most common adverse outcome was hypertension, prevalence of 36%. Hyperkalaemia and hyperglycaemia had a prevalence of 21% and 13%, respectively. A sequential population pharmacokinetic/pharmacodynamic approach was implemented. No significant association between predicted C-0, C-1, C-2, C-4, C-6/8 or AUC(0-12) and adverse effects could be found. Tacrolimus concentrations and AUC measures were in the same range in patients with and without adverse effects. Measures reported to provide benefit, preventing graft rejection and minimizing acute adverse effects in the early post-transplant period, were not able to predict adverse effects in stable adult liver recipients whose trough concentrations were maintained in the notional target range.

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.

Odour pollution problems within the district of the Wrekin council

This thesis is concerned with various aspects of Air Pollution due to smell, the impact it has on communities exposed to it, the means by which it may be controlled and the manner in which a local authority may investigate the problems it causes. The approach is a practical one drawing on examples occurring within a Local Authority's experience and for that reason the research is anecdotal and is not a comprehensive treatise on the full range of options available. Odour Pollution is not yet a well organised discipline and might be considered esoteric as it is necessary to incorporate elements of science and the humanities. It has been necessary to range widely across a number of aspects of the subject so that discussion is often restricted but many references have been included to enable a reader to pursue a particular point in greater depth. In a `fuzzy' subject there is often a yawning gap separating theory and practice, thus case studies have been used to illustrate the interplay of various disciplines in resolution of a problem. The essence of any science is observation and measurement. Observation has been made of the spread of odour pollution through a community and also of relevant meterological data so that a mathematical model could be constructed and its predictions checked. It has been used to explore the results of some options for odour control. Measurements of odour perception and human behaviour seldom have the precision and accuracy of the physical sciences. However methods of social research enabled individual perception of odour pollution to be quantified and an insight gained into reaction of a community exposed to it. Odours have four attributes that can be measured and together provide a complete description of its perception. No objective techniques of measurement have yet been developed but in this thesis simple, structured procedures of subjective assessment have been improvised and their use enabled the functioning of the components of an odour control system to be assessed. Such data enabled the action of the system to be communicated using terms that are understood by a non specialist audience.

A study in the reduction of efficiency of nitrogen oxide removal catalysts for automobiles

Automotive catalysts are the most effective short-term answer to air pollution from automobiles. Since strict control of exhaust emissions is, or will be,covered by legislation in most developed countries in the world, catalytic devices will be increasingly fitted to cars. There is consequently an urgent need for the development of catalysts that will not compete for scarce precious metal resources. A number of problems have already been identified in connection with base metal catalysts but quantitative investigations are lacking. The base metal reduction catalysts developed by Imperial Chemical Industries Limited, catalysts and Chemical Group, in collaboration with the Air Pollution Control Laboratory, B L Cars Limited for automotive emission control, are susceptible to de-activation by three major mechanisms. These are: physical loss of the wash-coat (a high surface area coating which supports the active species), aggregation of the active species and poisoning by fuel and engine oil additives. This thesis is especially concerned with the first two of these and attempts to indicate the relative magnitude .of their effect on the activity of. the catalysts. Aggregation of the active species or sintering, as it is loosely called, was studied by using impregnated granules to overcome effects due to the loss of the wash-coat. Samples were aged in a synthetic exhaust gas, free from poisons, and metal crystallite sizes were measured by scanning-electron microscopy. The increase in particle size was correlated with the loss in catalytic activity. In order to maintain a link with the real conditions of service a number of monolithic catalysts were tested in an engine-dynamometer and several previously tested endurance catalysts were examined. A mechanism is proposed for the break-up and subsequent 10s.5 of the wash-coat and suggestions for improved resistance to loss of the' coating and active species are proposed.

Effects of metformin on BRIN-BD11 beta-cell insulin secretory desensitization induced by prolonged exposure to sulphonylureas

Aims: Prolonged exposure of pancreatic beta-cells in vitro to the sulphonylureas tolbutamide and glibenclamide induces subsequent desensitization of insulinotropic pathways. Clinically, the insulin-sensitizing biguanide drug metformin is often administered alongside sulphonylurea as antidiabetic therapy. The present study examines the functional effects of metformin (200 µM) on tolbutamide- and glibenclamide-induced desensitisation. Methods: Acute and prolonged (18 h) effects of exposure to tolbutamide and glibenclamide alone, or in the presence of metformin, were examined in insulin-secreting BRIN-BD11 cells. Results: In acute 20 min incubations at 1.1 mM glucose, metformin increased (1.2-1.7-fold; p <0.001) the insulin-releasing actions of tolbutamide and glibenclamide. At 16.7 mM glucose, metformin significantly enhanced glibenclamide-induced insulin release at all concentrations (50-400 µM) examined, but tolbutamide-stimulated insulin secretion was only augmented at higher concentrations (300-400 µM). Exposure for 18 h to 100 µM tolbutamide or glibenclamide significantly impaired insulin release in response to glucose and a broad range of insulin secretagogues. Concomitant culture with metformin (200 µM) prevented or partially reversed many of the adverse effects on K channel dependent and independent insulinotropic pathways. Beneficial effects of metformin were also observed in cells exposed to glibenclamide for 18 h with significant improvements in the insulin secretory responsiveness to alanine, GLP-1 and sulphonylureas. The decrease of viable cell numbers observed with glibenclamide was reversed by co-culture with metformin, but cellular insulin content was depressed. Conclusions: The results suggest that metformin can prevent the aspects of sulphonylurea-induced beta-cell desensitization. © 2010 Blackwell Publishing Ltd.

Interpreting adverse signals in diabetes drug development programs

Detection and interpretation of adverse signals during preclinical and clinical stages of drug development inform the benefit-risk assessment that determines suitability for use in real-world situations. This review considers some recent signals associated with diabetes therapies, illustrating the difficulties in ascribing causality and evaluating absolute risk, predictability, prevention, and containment. Individual clinical trials are necessarily restricted for patient selection, number, and duration; they can introduce allocation and ascertainment bias and they often rely on biomarkers to estimate long-term clinical outcomes. In diabetes, the risk perspective is inevitably confounded by emergent comorbid conditions and potential interactions that limit therapeutic choice, hence the need for new therapies and better use of existing therapies to address the consequences of protracted glucotoxicity. However, for some therapies, the adverse effects may take several years to emerge, and it is evident that faint initial signals under trial conditions cannot be expected to foretell all eventualities. Thus, as information and experience accumulate with time, it should be accepted that benefit-risk deliberations will be refined, and adjustments to prescribing indications may become appropriate. © 2013 by the American Diabetes Association.

A comparison of the effects of ocular preservatives on mammalian and microbial ATP and glutathione levels

The aim of this study was to investigate the mechanism of action of the preservative sodium chlorite (NaClO2), and the relationship with intracellular glutathione depletion. A detailed comparison of the dose responses of two cultured ocular epithelial cell types and four species of microorganism was carried out, and comparisons were also made with the quaternary ammonium compound benzalkonium chloride (BAK), and the oxidant hydrogen peroxide (H2O2). The viability of mammalian and microbial cells was assessed in the same way, by the measurement of intracellular ATP using a bioluminescence method. Intracellular total glutathione was measured by reaction with 5,5'-dithiobis-2-nitrobenzoic acid in a glutathione reductase-dependent recycling assay. BAK and H2O2 caused complete toxicity to conjunctival and corneal epithelial cells at similar to25 ppm, in contrast to NaClO2 , where >100 ppm was required. The fungi Candida albicans and Alternaria alternata had a higher resistance to NaClO2 than the bacteria Staphyloccus aureus and Pseudomonas aeruginosa , but the bacteria were extremely resistant to H2O2 NaClO2 caused substantial depletion of intracellular glutathione in all cell types, at concentrations ranging from <10 ppm in Pseudomonas , 25-100 ppm in epithelial cells, to >500 ppm in fungal cells. The mechanisms of cytotoxicity of NaClO2 , H2O2 and BAK all appeared to differ. NaClO2 was found to have the best balance of high antibacterial toxicity with low ocular toxicity. The lower toxicity of NaClO2 to the ocular cells, compared with BAK and H2O2 , is in agreement with fewer reported adverse effects of application in the eye.

Low-emission vehicle adoption in a UK local authority fleet:economic barriers and air quality benefits

Local air quality was one of the main stimulants for low carbon vehicle development during the 1990s. Issues of national fuel security and global air quality (climate change) have added pressure for their development, stimulating schemes to facilitate their deployment in the UK. In this case study, Coventry City Council aimed to adopt an in-house fleet of electric and hybrid-electric vehicles to replace business mileage paid for in employee's private vehicles. This study made comparisons between the proposed vehicle technologies, in terms of costs and air quality, over projected scenarios of typical use. The study found that under 2009 conditions, the electric and hybrid fleet could not compete on cost with the current business model because of untested assumptions, but certain emissions were significantly reduced >50%. Climate change gas emissions were most drastically reduced where electric vehicles were adopted because the electricity supply was generated by renewable energy sources. The study identified the key cost barriers and benefits to adoption of low-emission vehicles in current conditions in the Coventry fleet. Low-emission vehicles achieved significant air pollution-associated health cost and atmospheric emission reductions per vehicle, and widespread adoption in cities could deliver significant change. © The Author 2011. Published by Oxford University Press. All rights reserved.

What one hand giveth the other taketh away:some unpredicted effects of enantiomers in psychopharmacology

It is well known that many medicines are a mixture of two enantiomers, or mirror-image molecules. Two enantiomers occur when a molecule has a single chiral centre and the two mirror images, called S or L (left handed) and R or D (right handed), are usually found in equal amounts in the parent (racemic) mixture. While for many compounds used in clinical practice the active moiety is found in one of the two enantiomers with the other being seen as an unnecessary and redundant component of the racemic mixture, the difference between enantiomers can mean a difference between therapeutic and adverse effects, as well as in beneficial pharmacological effect and potency. © 2010 The Author(s).

Disorienting Dilemmas: Their Effects on Learners, Impact on Performance, and Implications for Adult Educators

Disorienting dilemmas induced by adult educators have varied and often adverse effects on learners. Although this may lead to transformative learning, it can have both positive and negative impacts on their performance. Adult educators need to be wary in their efforts to foster and facilitate transformative learning.

The effects and extent of 1,1,1-trichloroethane vapor concentration exposure on workers during solvent vapor degreasing

This study attempted to determine if an excessive amount of 1,1,1 - Trichloroethane was released into the air, the acute effects of exposure and the cause(s) of excessive use. The types of degreasing equipments which were tested in this study are straight vapor and the vapor spray machines. The instruments utilized to obtain the data for this study are Gastech Haline Detector, Organic Vapor Monitor Badge and Personal Sampling Pump. Readings were taken on three different tanks. The data accumulated by this study were obtained during actual cleaning operation. During testing, increased exposure was detected due to exceeding the rate of removal, downward drafts were blowing right over the top of a degreaser and, in some cases, poor general ventilation caused solvent vapor to be blown out of the tank and into the workers' breathing zone, affecting excessive vapor drag out and solvent loss. The results show that, since the characteristics of solvent 1,1,1 - Trichloroethane are well suited to vapor degreasing requirements, by using proper procedures and maintenance, 1,1,1 - Trichloroethane emission during vapor degreasing can be controlled at levels well below the industrial hygiene standard established by OSHA for safe and healthful conditions.

Os efeitos das queimadas na Amazônia em nível celular e molecular

The Amazon holds over half of the planet's remaining tropical forests and comprises the largest biodiversity in the world, accounting for approximately 60 % of the Brazilian territory. However, deforestation fires in the region causes serious problems to exposed human. The aim of this study was to evaluate the chemical compounds as well as the cellular and molecular effects after exposure to organic material extracted from particulate matter less than 10 µm (PM10) in the Amazon region. As for the chemical composition, n-alkanes analysis showed a prevalence of anthropogenic influence during the fires in the region. In addition, there was a predominance of monosaccharides from biomass burning markers. Also, the Polycyclic Aromatic Hydrocarbons (PAH) and their derivatives have also been identified in samples collected in the Amazon. By using the PAH concentrations was possible to calculate the BaP-equivalent and it was found that the dibenz(a) anthracene contributes with 83% to potential carcinogenic risk. As for the potential mutagenic risk, the benzo (a) pyrene is the HPA that has a major contribution in this analysis. It may be noted that the retene was the most abundant PAH. This compound was genotoxic and cause death by necrosis in the human lung cells. In biological tests, the data showed that organic PM10 is capable of causing genetic damage in both plant cells and in human lung cells. This damage cause an arrest in the G1 phase of the cell cycle exposed, increasing the expression of p53 and p21. Additionally, the PM10 caused cell death by apoptosis, increasing the foci of histone - H2AX. Given these results, it is important to emphasize the reduction and better control of biomass burning in the Amazon region thus improving the quality of health of the population being exposed. As clearly stated recently by the World Health Organization, the reduction of air pollution could save millions of lives annually.

Tree heights and diameters of Switzerland's Sanasilva forests

Measurements of tree heights and crown sizes are essential in long-term monitoring of spatially distributed forests to assess the health of forests over time. In Switzerland, in 1994 and 1997, more than 4'500 trees have been recorded in a 8x8 km plot within the Sanasilva Inventory, which comprises the Swiss Level I sites of the International Co-operative Programme on Assessment and Monitoring of Air Pollution Effects on Forests' (ICP Forests). Tree heights and crown sizes were measured for the dominant and co-dominant trees (n = 1,723), resulting in a data set from 171 plots in Switzerland, spreading over a broad range of climatic gradient and forest characteristics (species recorded = 20). Average tree height was 22.1 m, average DBH 34.6 cm and crown diameter 6.5 m. The data set presented here is open to use and shall foster research in allometric equation modelling.

The Effect of Slum Redevelopment on Child Health Outcomes: Evidence from Mumbai

As the population of urban poor living in slums increases, governments are trying to relocate people into government-provided free housing. Slum redevelopment affects every part of a household’s livelihood, but most importantly the health and wellbeing of younger generations. This paper investigates the effect of slum redevelopment schemes on child stunting levels. Data was collected in forty-one buildings under the slum-redevelopment program in Mumbai. The study demonstrates through a fixed effect regression analysis that an additional year of living in the building is associated with an increase in the height-for-age Z-score by 0.124 standard deviations. Possible explanations include an improvement in the overall hygienic environment, sanitation conditions, indoor air pollution, and access to health and water facilities. However, anecdotal evidence suggests that water contamination, loss of livelihood and increased expenses could worsen health outcomes for residents. This study prompts more research on the health effects of slum redevelopment projects, which are becoming increasingly common in the rapidly urbanizing developing world.