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The Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT; Co-Chairman, Professor Sever) was an investigator designed and led multinational study in which different blood pressure-lowering and lipid-lowering treatment strategies were investigated in an attempt to define optimal programmes for intervention to prevent cardiovascular disease in hypertensive subjects. The outcomes of both the antihypertensive arm and the lipid arm of the trial defined the benefits of more contemporary treatments for hypertensive subjects, including calcium channel blockers, angiotensin converting enzyme inhibitors and statins, which have been incorporated into national and international guidelines (including NICE), and have impacted on current clinical practice in the prevention of cardiovascular disease worldwide.
Novel work undertaken at this centre has demonstrated that vitamin B2 (riboflavin) can significantly decrease BP, specifically in people with a common genetic variant affecting the folate-metabolising enzyme MTHFR. The extent of BP-lowering demonstrated is as good as that expected from BP-lowering drugs and much better than that found with common dietary approaches and furthermore, the effect is independent of concurrent BP-lowering drugs. These findings offer a simple, cost-effective targeted treatment for the management of BP in this genetically at-risk group. The global prevalence of this genetic variant is 10% but can be as high as 32% in other countries such as Mexico and Northern China.
Pulmonary arterial hypertension (PAH) is a fatal disease that typically affects women in their childbearing years. Professor Wilkins led a research team at Imperial College that identified phosphodiesterase type 5 (PDE5) as a drug target in the lungs of patients with PAH. Imperial validated the target in cell and animal models and demonstrated proof in patients that Sildenafil, a PDE5 inhibitor, was an effective treatment for PAH. Professor Wilkins conducted a clinical study to compare the effect of oral Sildenafil with Bosentan, the only other available oral therapy for PAH at the time. This study was the first, and remains the only, head-to-head study of two treatments for PAH. Sildenafil demonstrated comparable efficacy, had a greater effect on reducing cardiac mass (an integrated measure of heart work) and was well tolerated.
Sildenafil is now the most commonly prescribed drug for PAH. It is the most cost-effective, as judged by a technology appraisal initiated by NICE. National and international guidelines recommend Sildenafil as a first line treatment for patients in functional classes II and III pulmonary hypertension. Worldwide sales of sildenafil (Revatio®) for the management of PAH were $500m in 2010. With the expiration of the patent the cost of treatment will fall further.
As a result of University of Sheffield research in 1995-2002, a new gold standard treatment for major bleeding on warfarin has been established, ensuring the more effective treatment of tens of thousands of patients requiring emergency anticoagulation reversal each year in the UK alone. The treatment, using prothrombin complex concentrate (PCC) was demonstrated to be superior to fresh frozen plasma (FFP), the standard alternative at the time, and two PCCs have now been licensed for this indication in the UK.
UK and international guidelines now recommend PCC over FFP.
Research on Congenital Adrenal Hyperplasia (CAH) at the University of Sheffield has resulted in both health and commercial impacts. The research has led to a new drug treatment, Chronocort®, being developed for CAH. Chronocort® has been tested in CAH patients with the positive outcome of improved disease control.
Commercial impact arose from the creation of a spin-out company, Diurnal Ltd, in 2004 which has raised investment of £3.8M since 2008, including £0.4M from pharmaceutical industry sources, and (as an SME partner) a €5.6M Framework 7 grant to develop a paediatric treatment for CAH. Diurnal has created five new jobs and has contracts with six UK companies worth £2.7M.
Malignant pleural mesothelioma (MPM) is a treatable but incurable cancer that originates in the cells lining the lungs. Over 14,000 people worldwide are diagnosed annually with MPM. Antifolates are often used in cancer therapy, but side effects are a major issue. A retrospective analysis of cancer trials and phase 1 trial of MPM patients, carried out by Newcastle in collaboration with Eli Lilly Pharmaceuticals, determined that plasma homocysteine levels were a good predictor of drug toxicity in cancer patients treated with the antifolate pemetrexed, and that this drug was well tolerated by patients with low homocysteine levels. It was also determined that pemetrexed treatment should be supplemented with vitamin B12 as well as folic acid, to reduce drug toxicity. Ultimately, this permitted the continued development of pemetrexed, which otherwise would have been too toxic for clinical use. It is now the only licensed drug for MPM treatment in combination with platinum-based chemotherapy.
Research at UCL firmly established tacrolimus as the optimal calcineurin inhibitor to use in immunosuppressive regimens following liver transplantation. Compared to ciclosporin its use improved graft survival by 6% and patient survival by 7%. Assuming 550 liver transplants per year in the UK since 2008, we can estimate that, with 90% of patients treated with tacrolimus and 10% ciclosporin, tacrolimus-based immunosuppression has resulted in 165 grafts and 192 lives being saved during the period 2008-13.
Congenital myasthenic syndromes (CMS) are inherited neuromuscular disorders caused by defects at neuromuscular junctions, which are often a result of acetylcholine receptor gene mutations. A subset of CMS patients (around 14% in the US and Europe) have limb-girdle myasthenia (LGM). This disease can be highly disabling with symptoms including increasing weakness of skeletal muscles. As a result of collaborative work between Newcastle and Oxford, it was determined that many LGM patients have a mutation of the Dok-7 gene (unrelated to the acetylholine receptor), and do not, therefore, respond to standard CMS treatments. Since then, a number of additional mutations have been discovered, and genetic testing is now available for the majority of known LGM-causative genes. Crucially, Dok-7 patients, and those with other non-receptor related mutations, can now be diagnosed accurately and treated effectively, with ephedrine and salbutamol (in the US, albuterol). This significantly improves these patients' quality of life by enabling them to walk and breathe unassisted.
Research at the UCL Institute of Ophthalmology over the last 15 years has developed new treatments for management of uveitis and its sight-threatening complications, which have subsequently become standard practice. Our work, in previously untreatable disease, has allowed restoration of vision in many patients and prevention of further visual loss in others. Many patients have been able to reduce systemic medication, limiting adverse effects of treatment.
Every year in the UK, 150,000 heart attacks are caused by coronary artery occlusion (blockage); worldwide, the figure is 17 million, according to the World Health Organization (WHO). Since 1993, the Leicester Interventional Cardiology group has been at the forefront of research to determine how best to manage such patients. Its findings have been incorporated into official UK (2008), European (2008, 2012) and US (2008) guidelines and have helped to change the way coronary heart disease and heart attacks are treated, with the number of patients treated with primary angioplasty doubling between 2008 and 2011. By guiding service provision, supporting industrial innovation and informing clinical practice, the Unit has contributed to improved healthcare and outcomes for thousands of heart patients. Overall, one-month mortality according to European figures has fallen from 15% to 4% between 2008 and 2013.