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Imperial College preclinical studies guided the desired selectivity profile for long-acting muscarinic receptor antagonists (LAMA). Binding, functional and clinical studies from Imperial laboratories were the first to demonstrate the long duration of tiotropium bromide (Spiriva®) in human tissue, and confirmed its long duration of action in patients and established it as the first-line treatment for chronic obstructive pulmonary disease (COPD). Tiotropium has had a beneficial impact on the management of COPD and is incorporated into the major international treatment guidelines. It improves symptoms, reduces exacerbations and mortality, and provides a cost-effective therapy. Imperial have also produced the first pre-clinical and clinical data for the next LAMA in development (glycopyrrolate, Seebri®), which has recently been marketed. Our profiling of tiotropium has also led to the development of several novel LAMA.
The Centre for Decision Research and Experimental Economics (CeDEx) at Nottingham is a world leader in the development and application of experimental and behavioural economics. CeDEx's research is increasingly influential in affecting the way in which experimental methodology is utilised by public sector agencies (e.g. Department for Environment, Food & Rural Affairs, DEFRA) and in fashioning the public and policy makers' understanding of how human motivations and decision processes affect individual and group behaviour and, in particular, their responses to different policy tools (e.g. incentives, regulation, information, `nudges' etc). The research of the CeDEx group has had broad and diffuse impacts on public decision-making and public debate; through public events, the provision of advice to government departments and regulators, the delivery of training workshops, commissioned research and an active strategy of engagement in public debate.
Hundreds of synthetic chemicals contaminate our food and water. Brunel's research shows harmful cumulative cocktail effects of low levels of contaminants in food and water, previously thought to be safe. The active translation of these results into European chemicals legislation also ensured a sound basis for including multiple chemical exposures in risk assessment. By working with the European Food Safety Authority, we demonstrated a viable approach to grouping chemicals for mixtures risk assessment. Based on our research, a totally new approach to grouping chemicals for mixtures risk assessment has been decided. This will influence maximum residue levels for toxic pesticides in food in Europe leading to better protection of consumers against the increased risks of harm due to multiple pesticide residues present in the majority of food items.
Impact: Health and welfare; policy; the environment; fundamental changes to phthalate use, wider EU and US Endocrine Disrupting Chemical (EDC) regulations and chemical bans.
Significance: Shaped policy, regulation and the potential causal relationship of environmental EDC on male reproductive disorders and testicular dysgenesis syndrome.
Beneficiaries: Governments; chemical and food regulatory agencies; healthcare workers advising and treating pregnant women; pregnant women and their fetuses; males with disorders of sex development; adult males; plastics manufacturers.
Attribution: EDC research was developed and shaped by Prof Richard Sharpe and colleagues at UoE.
Reach: International; Europe, North America.
Genotoxicity (DNA damage) can often induce carcinogenesis. Swansea-led work on `genotoxicity thresholds' reassured 25,000 HIV-infected individuals, who had taken anti-viral tablets (Viracept®) contaminated with the genotoxin ethyl methanesulfonate (EMS).
Before 2008, genotoxicity was assumed to increase with dose, and genotoxic drugs were discarded. Research at Swansea University showed that exposure to low-levels of genotoxins did not pose significant risks to DNA. This concept has now been incorporated into regulatory guidelines; in July 2008 the European Medicines Agency accepted that cancer-risk was not increased for patients who received Viracept® tablets contaminated with a low dose of the genotoxin ethyl methanesulfonate (EMS).
The European Union Cosmetics Directive (adopted in 2003) banned the use of animals for testing cosmetic ingredients and the final deadline for compliance was March 2013. The development of alternative methods of safety assessment was therefore essential to ensure both consumer protection and viability of the cosmetics industry. Our research has focussed on the development of computational alternatives to animal testing, including the identification of structural alerts that have been encoded into computational workflows to support toxicity prediction. These methods have delivered tools to the cosmetics industry in Europe and worldwide to enable them to comply with the directive and develop new products. Our findings have also been used to inform thinking and policy in Europe and to develop a new approach to the safety assessment of cosmetics.
Research at the University of Leeds has underpinned the company Lhasa Ltd. which has made widely available the toxicity prediction software currently known as Derek Nexus. The use of Derek Nexus by large pharmaceutical companies to support drug development is effectively universal. Toxicology prediction software has led to changes in guidelines issued by regulatory authorities and to industry-wide changes to the investigation of the toxicity of trace impurities. These changes have reduced the resources needed for experimental investigation of toxicity, and have increased revenues derived from launched drugs by extending their patent period of exclusivity. Lhasa Ltd. derives income in support of its charitable aims from Derek Nexus , and a related product Meteor Nexus (Meteor) also based on research undertaken in Leeds. The company reported revenues over £5.4M in 2012 and employs 71 highly qualified staff.
The EU REACH regulation 2007 (Registration, Evaluation, Authorisation and restriction of Chemicals) requires producers and importers of chemicals to register them and provide information to ensure their safe use whilst minimising the use of animal testing. When the White Paper on REACH was published in 2001, over 90% of the 100,000+ chemicals in use had few or no toxicological data available. In order to address the deficiency in the ability for companies to comply with these regulations, LJMU has developed a suite of computational tools to predict toxicity of chemicals using only knowledge of chemical structure and properties. These models have been incorporated into predictive software including the OECD (Organisation for Economic Co-operation and Development) QSAR Toolbox which is promoted by the European Chemicals Agency (ECHA), as a useful means to provide information for REACH dossiers and has been taken up by industry internationally for this purpose.
The Cambridge-led Emerging Risk Factors Collaboration (ERFC) is a global consortium involving individual-participant data on 2.5 million participants from 130 cohort studies. The ERFC has helped optimise approaches to cardiovascular disease (CVD) risk assessment by: 1) quantifying the incremental predictive value provided by assessment of risk factors 2) evaluating the independence of associations between risk factors and CVD and 3) addressing uncertainties related to the implementation of screening. ERFC publications on lipids, lipoproteins, and inflammation biomarkers have been cited by 9 guidelines published since 2010, including those of the European Society of Cardiology and the American Heart Association.
Research at the University of Nottingham (UoN) has had influence on development of health policy in the UK and internationally. It is recognised that the risk of diseases related to obesity and insulin resistance, is partly determined by the nutritional environment experienced during early life. Against a background of scepticism researchers at the UoN have generated data that has been critical in demonstrating the biological plausibility of such associations. This has influenced expert panels and non-governmental organisations in framing their current recommendations for nutrition in pregnancy and infancy, which benefit women and children worldwide.