Voltammetric behaviour of drug molecules as a predictor of metabolic liabilities

© 2020 by the authors. Licensee MDPI, Basel, Switzerland. Electron transfer plays a vital role in drug metabolism and underlying toxicity mechanisms. Currently, pharmaceutical research relies on pharmacokinetics (PK) and absorption, distribution, metabolism, elimination and toxicity (ADMET) measurements to understand and predict drug reactions in the body. Metabolic stability (and toxicity) prediction in the early phases of the drug discovery and development process is key in identifying a suitable lead compound for optimisation. Voltammetric methods have the potential to overcome the significant barrier of new drug failure rates, by giving insight into phase I metabolism events which can have a direct bearing on the stability and toxicity of the parent drug being dosed. Herein, we report for the first time a data-mining investigation into the voltammetric behaviour of reported drug molecules and their correlation with metabolic stability (indirectly measured via t1/2), as a potential predictor of drug stability/toxicity in vivo. We observed an inverse relationship between oxidation potential and drug stability. Furthermore, we selected and prepared short-(2 h) drug molecules to prospectively survey the relationship between oxidation potential and stability

Global Capital Market Volatility and the Developing Countries: Lessons from the East Asian Crisis

Summary The emerging global economy is characterised by the virtually free movement of capital, while labour is still essentially confined to the nation state. The East Asian crisis has revealed the extent to which international financial ‘architecture’ does not yet correspond to this reality – let alone resolve its inconsistencies. The consequent public action problem is analysed in this article by first addressing the global causes of emerging market volatility and the failure of international financial institutions (such as the IMF) to contain it. The current attempt to extend multilateral bank regulation towards emerging markets is shown to suffer from severe limitations, as do proposals for mutual regulatory recognition and a global credit insurance system. The prospects for establishing a binding set of rules for global investment, with logical consequences for both multilateral capital taxation and international debt resolution, are improving, but remain problematic due to the ‘missing institutions’ required to create an orderly global capital market. The article concludes with an unexpected implication for the concept of citizenship itself

"More money for health - more health for the money": a human resources for health perspective

<p>Abstract</p> <p>Background</p> <p>At the MDG Summit in September 2010, the UN Secretary-General launched the Global Strategy for Women's and Children's Health. Central within the Global Strategy are the ambitions of "more money for health" and "more health for the money". These aim to leverage more resources for health financing whilst simultaneously generating more results from existing resources - core tenets of public expenditure management and governance. This paper considers these ambitions from a human resources for health (HRH) perspective.</p> <p>Methods</p> <p>Using data from the UK Department for International Development (DFID) we set out to quantify and qualify the British government's contributions on HRH in developing countries and to establish a baseline.. To determine whether activities and financing could be included in the categorisation of 'HRH strengthening' we adopted the Agenda for Global Action on HRH and a WHO approach to the 'working lifespan' of health workers as our guiding frameworks. To establish a baseline we reviewed available data on Official Development Assistance (ODA) and country reports, undertook a new survey of HRH programming and sought information from multilateral partners.</p> <p>Results</p> <p>In financial year 2008/9 DFID spent £901 million on direct 'aid to health'. Due to the nature of the Creditor Reporting System (CRS) of the Organisation for Economic Co-operation and Development (OECD) it is not feasible to directly report on HRH spending. We therefore employed a process of imputed percentages supported by detailed assessment in twelve countries. This followed the model adopted by the G8 to estimate ODA on maternal, newborn and child health. Using the G8's model, and cognisant of its limitations, we concluded that UK 'aid to health' on HRH strengthening is approximately 25%.</p> <p>Conclusions</p> <p>In quantifying DFID's disbursements on HRH we encountered the constraints of the current CRS framework. This limits standardised measurement of ODA on HRH. This is a governance issue that will benefit from further analysis within more comprehensive programmes of workforce science, surveillance and strategic intelligence. The Commission on Information and Accountability for Women's and Children's Health may present an opportunity to partially address the limitations in reporting on ODA for HRH and present solutions to establish a global baseline.</p

Multiplexing siRNAs to compress RNAi-based screen size in human cells

Here we describe a novel strategy using multiplexes of synthetic small interfering RNAs (siRNAs) corresponding to multiple gene targets in order to compress RNA interference (RNAi) screen size. Before investigating the practical use of this strategy, we first characterized the gene-specific RNAi induced by a large subset (258 siRNAs, 129 genes) of the entire siRNA library used in this study (∼800 siRNAs, ∼400 genes). We next demonstrated that multiplexed siRNAs could silence at least six genes to the same degree as when the genes were targeted individually. The entire library was then used in a screen in which randomly multiplexed siRNAs were assayed for their affect on cell viability. Using this strategy, several gene targets that influenced the viability of a breast cancer cell line were identified. This study suggests that the screening of randomly multiplexed siRNAs may provide an important avenue towards the identification of candidate gene targets for downstream functional analyses and may also be useful for the rapid identification of positive controls for use in novel assay systems. This approach is likely to be especially applicable where assay costs or platform limitations are prohibitive

Initial Comparisons between the Advanced Technology Development Gen 2 Baseline Cells and Variant C Cells

The Advanced Technology Development Program is testing a second generation of lithium-ion cells, consisting of a baseline and three variant chemistries. The cathode composition of the Variant C chemistry was altered with an increase to the aluminum dopant and a decrease to the cobalt dopant to explore the impact on performance. However, it resulted in a 20% drop in rated capacity. Also, the Variant C average power fade is higher, but capacity fade is higher for the Baseline cell chemistry. Initial results indicate that the Variant C chemistry will reach end of life sooner than the Baseline chemistry