IPS brochure 2015 by Nicola Tingley

Institute of Pharmaceutical Science

From molecules to medicine

Welcome to the Institute of Pharmaceutical Science at King’s College London The notion of producing a snapshot of our research activity arose from the preparation in 2013 of the Impact Statements for the Research Excellence Framework 2014 (REF 2014) exercise. This booklet provides for the nonspecialist an overview of the breadth and depth of our work in a way accessible to a wide audience. Then, in December 2014, the results of the REF 2014 evaluation exercise were published. They showed that 91% of our research measured collectively by output, impact and environment, were ranked as either world-leading or internationally excellent within the REF Unit of Assessment 3 category (Allied Health Professions, Dentistry, Nursing and Pharmacy) to which IPS had contributed. Overall this analysis showed that, based on ‘Power’, a factor taking into account both the quality of research as well as the number of researchers assessed, King’s College London was ranked first in the UK out of the 83 universities which made returns within the Unit of Assessment 3 category. I hope you enjoy reading these brief accounts of our research activities. Please do not hesitate to contact me or the named Principal Investigators for more information.

January 2015 Professor Peter Hylands Head, Institute of Pharmaceutical Science Faculty of Life Sciences & Medicine www.kcl.ac.uk/ips

Cover Image Courtesy of Dr Khuloud Al-Jamal and Mr Izzat Suffian. The image won first place in the Innovation category of the Engineering and Physical Sciences Research Council Science Photo Competition 2013. It depicts a pioneering new drug delivery system. The lung cancer cells (green) are captured in the process of taking up carbon nanotube nanoneedles (gold) that, one day, may be used to deliver targeted drug therapies, minimising harmful side effects.

Contents

1. Starting with the basics

The elastic behaviour of worm-like micelles Advanced warning and potential treatment for Alzheimer’s disease When is an insult not an insult? Perfecting the taste sensation Understanding the superbug Using chaotic mathematics for our chaotic body systems Neutrons help scientists fight problem infections

5 6 7 8 9 10 11

2. Drug discovery

Targeting transcription factors in the fight against cancer Hope on the horizon for asthma and COPD Understanding chronic cough may lead to much-needed help Gastrin inhibitors: a new angle on some age-old problems Iron chelation: not just for those with beta-thalassemia Living better with Parkinson’s disease

13 15 16 17 18 19

3. Drug formulation and development

Targeted drug delivery through the use of nanomedicines Designing drugs to save lives Challenges in developing novel inhaled medicines Getting past a barrier to better deliver medicines Image guided drug delivery: targeted treatments for cancer Exploring the safety of nanomedicines Dial-up medicine gets personal

21 22 23 24 25 26 27

4. Natural medicines

At one with nature under the sun Using science to explore tradition Using tradition to tackle fibrosis

29 30 31

5. From bench to bedside

Is simplifying drug regimes always better? The treatment’s been prescribed, so why isn’t the patient responding properly? Children are not just half-size adults Perfecting prescribing through naturalistic research

33 34 35 36

6. Science in action

Helping teenagers take science into space Keeping hazardous drivers off the roads The complexities of assessing drug-driving Beating those cheating

39 40 41 42

Starting with the basics

1. Starting with the basics

The elastic behaviour of wormlike micelles

ext time you squirt your shower gel into your hand, look at it a bit more closely. ‘The rheology of shower gel is very complicated,’ says Dr Cécile Dreiss, ‘it needs to be squeezable from the bottle but not flow off your hand and then be spreadable when applied to the body.’ These properties are linked to the formulation of the shower gel components and how they interact together and organise themselves at the very small scale to give a specific elastic and viscous behaviour to the product. This is mostly thanks to wormlike micelles: elongated, flexible aggregates of surfactants which, by entangling like a dish of spaghetti, give a very elastic behaviour to materials. They are used in fields as diverse as personal care products to oil-well recovery and are of great interest to Dr Dreiss and her team. Rheology, the study of flow and deformation of matter, helps to understand how compounds are assembled, how they interact at the nanometre level and how that correlates with their properties. To study such properties, one technique Dr Dreiss uses is small-angle neutron scattering that probes the structure of matter at a very small scale and gives far better resolution then conventional light scattering techniques. A current focus for Dr Dreiss is looking at cyclodextrins, ring-shaped compounds widely used in the pharmaceutical industry to solubilise drugs. ‘They can interact with a number of molecules as they will encapsulate most hydrophobic molecules that can fit into their cavity,’ Dr Dreiss explains. As such, she is seeing if she can use cyclodextins to modulate the assembly of wormlike micelles. ‘This has a huge impact on their rheology,’ says Dr Dreiss, ‘cyclodextrins will snatch surfactants from micelles so you can modulate micelle assembly and kill off their elastic properties just by playing with the composition. At the moment I’m having lots of fun combining different compounds to see what happens, but,’ she continues, ‘more importantly, going from something that’s completely liquid to something that’s very elastic and gel-like has applications in drug delivery. For instance, you could inject something as a liquid that then forms a gel-like compound in the body and use it as a depot.’ Who knows what’s next for both drug delivery and the composition of your shower gel.

Cyclodextrins will snatch surfactants from micelles so you can modulate micelle assembly and kill off their elastic properties just by playing with the composition

Illustration of wormlike micelles

About the researcher https://kclpure.kcl.ac.uk/portal/cecile.dreiss.html

1. Starting with the basics

Advanced warning and potential treatment for Alzheimer’s disease

M It is hoped that the fruit of all these efforts will be the development of a test that could spot potential Alzheimer’s disease before symptoms even occur

If you have a downregulation of cerebrospinal fluid production, you are making your brain more vulnerable to the accumulation of toxic compounds

odern medicine has pushed life expectancy up and up and while many are enjoying a healthy older age, conditions such as Alzheimer’s disease loom large for those who are living longer. Current therapies for Alzheimer’s disease alleviate some symptoms but do little for progression. This may partly be because treatment is given only when symptoms manifest. But what if we could tell prior to this if someone was going to develop Alzheimer’s disease? Dr Legido-Quigley’s group is trying to find a biochemical signature of the metabolism implicated in the development of Alzheimer’s disease so that it can be diagnosed at the pre-symptomatic stage, maybe 20 years before onset. As an analytical chemist she uses metabolomics (non-targeted, small-molecule analysis), quantitation and fingerprinting to analyse molecules in biofluids and tissues, utilising refined high-performance liquid chromatography and mass spectrometry methods. Dr Legido-Quigley and her team, who work in collaboration with the Institute of Psychiatry and the National Institutes of Health in the United States (US), have access to samples from people at all stages of dementia, as well as healthy controls. In one study they found a decrease of the lipid phosphatidylcholine in plasma samples from people with pre-Alzheimer’s. As the enzymes that break down lipids have been directly associated with Alzheimer’s disease, changes in phosphatidylcholine could indicate pathological changes elsewhere in the metabolic pathway. They are also using genome-wide association to try and find new Alzheimer’s-associated genes in plasma. Another project involves 1,500 plasma and urine samples from people with Alzheimer’s disease, those with mild cognitive impairment (both those who go on to develop Alzheimer’s disease and those who don’t) and controls. It is hoped that the fruit of all these efforts will be the development of a test that could spot potential Alzheimer’s disease before symptoms even occur. Dr Jane Preston’s work is focused on the production of proteins that circulate in the cerebrospinal fluid (CSF). She explains how ‘you need an adequate flow of CSF to act as a drainage pathway for metabolites and toxins. If you have a downregulation of CSF production, you are making your brain more vulnerable to the accumulation of toxic compounds because you are reducing the flow of fluids through the ventricular system. Toxic accumulation can include amyloid peptide that is associated with Alzheimer’s pathology. Dr Preston’s work revealed two things that could potentially make an older, healthy brain more susceptible to the accumulation of amyloid peptides, without invoking a pathology. The first is a biochemical one. ‘Although overall the levels of proteins rose,’ says Dr Preston, ‘synthesis of some key proteins, such as transthyretin that binds amyloid and prevents it from depositing, decreased.’ The second is a physical one. ‘Historically,’ explains Dr Preston ‘one looks for toxins in the CSF that indicate that the bloodbrain barrier (BBB) has broken down. But we found that you don’t need a broken BBB to accumulate proteins in CSF, the fluid just needs to slow down its flow rate.’ This work encouraged clinical colleagues at Rhode Island Hospital in the US to carry out studies in people with dementia where they attempted to speed up CSF flow in ventricles with a shunt, as you would do with hydrocephalus. After a year, there was stabilising of dementia symptoms. ‘It is invasive,’ says Dr Preston, ‘but it’s drug free and is based on the premise that if you can just increase the circulation of CSF, you can reduce toxic build up.’ There is now interest from small biotech companies to investigate pharmacological means to speed up CSF production for mild cognitive impairment and even perhaps dementia.

About the researcher

https://kclpure.kcl.ac.uk/portal/cristina.legido_quigley.html

1. Starting with the basics

When is an insult not an insult?

arkinson’s disease affects around one in every 500 people. While medication to help control symptoms means those with this neurological disorder can live life more easily for a while, limited knowledge of the underlying pathology means there are still no drugs that actually stop it from developing or progressing. Parkinson’s disease is primarily caused by the death of dopaminergic neurons in the substantia nigra. These are particularly sensitive to dysfunctions in energy metabolism because of the highly oxidising environment they inhabit. Dr Richard Parsons explains how in his work ‘I look at energy regulation and how vitamin B3 (in the form of nicotinamide) fits into that.’ Nicotinamide is a precursor for the coenzyme nicotinamide adenine dinucleotide (NADH), which is intimately involved in energy metabolism. Nicotinamide is metabolised by nicotinamide N-methyl transferase (NNMT) and is a part of adenosine triphosphate (ATP) production and synapse formation. ‘Originally people thought this enzyme was just involved in regulating vitamin B3 and in drug metabolism, but my research has found that it is fundamental to the very functioning and survival of neurons. It’s involved in not only energy metabolism but cell survival and communication and may also be involved developmentally and in the stress response.’ Dr Parsons became interested in NNMT’s role in Parkinson’s disease when he showed it to be highly upregulated in the brain in this condition. ‘At first we thought that NNMT actually caused Parkinson’s disease. As such, we overexpressed it in an in-vitro model and expected the cells to be harmed, but it had the opposite effect.’ In fact, NNMT appears to be neuroprotective. ‘Using the SH-SY5Y neuroblastoma cell line,’ he explains, ‘we have now teased apart that NNMT increases ATP through sirtuins.’ These proteins are involved in longevity and are the same ones induced during calorie restriction. Knowing that there is potentially a therapy to protect vulnerable dopaminergic neurons in Parkinson’s disease, his team, along with collaborators from both King’s, such as Dr Sarah Salvage, and with Professor David Dexter at Imperial College London, are moving on to work in vivo using gene therapy to see if NNMT has an effect in the substantia nigra. ‘We want to test it against Parkinson’s disease models,’ he says, ‘to see what effect it has. Does it protect neurons or encourage growth? Ultimately,’ he continues, ‘we are looking at potential targets for drugs and gene therapy.’

Ultimately we are looking at potential targets for drugs and gene therapy for Parkinson’s disease

a a n

n a

Immunohistochemical localization of NNMT protein in the substantia nigra of a control (top) and Parkinson’s disease (above) subject typical of the expression observed; n = neuron cell body; d = dendritic process; a = axonal process; magniﬁcation, 3400X scale bar = 25 nm

About the researcher https://kclpure.kcl.ac.uk/portal/richard.parsons.html

1. Starting with the basics

Perfecting the taste sensation You can have a chocolate bar with really good quality cocoa solids, but a horrible taste and gritty feel if the amorphous ratio isn’t well controlled

r Paul Royall and his group have a major interest in the structure of lactose, a large component of milk, and how that structure can affect the properties of one of the most essential things in life: a good bar of chocolate. ‘There are various forms of lactose that will greatly influence the sensory properties of chocolate,’ says Dr Royall, ‘for instance, we can slowly crystallise it to form nice regular-shaped molecules or we can spray- or freeze-dry it to create an unstable, disordered, amorphous arrangement. For chocolate, the ratio of amorphous to crystalline lactose will have an influence on how it tastes and how it feels in the mouth. You can have a chocolate bar with really good quality cocoa solids, but a horrible taste and gritty feel if the amorphous ratio isn’t well controlled.’ A lot of the work of Dr Royall and his team has been on the ratio between the alpha form of lactose, which appears as large ‘tomahawks,’ and the needle-like beta form. ‘You need to know how much of each form there is when you want to crystallise things,’ he explains. ‘Chocolate will taste different according to how much of each form you have,’ says Dr Royall, ‘the beta form is about 50 times more soluble in water than the alpha monohydrate form and if you put it on the end of your tongue it will taste a lot sweeter.’ In confectionery, knowing this ratio is useful; by making it taste sweeter you can use less lactose when manufacturing. Dr Royall’s group uses a variety of techniques to measure lactose forms including a very old one: optical polarimetry. ‘Because the forms are chiral, the forms will rotate the light in a different way. When characterising solutions of lactose with optical polarimetry, the way the light’s rotated will change as a function of time. If I make up a solution of lactose, it starts off as all alpha and slowly converts to beta, eventually producing an equilibrium between the two forms. It happens at a different rate according to temperature, a finding essential for the manufacture of chocolate from different sources of milk.’ This knowledge is not only applicable to confectionery though. They are also looking at how the different forms of lactose help when making medications. ‘If I make a tablet containing the tomahawk form, it’s quite a nice formulation; if I make it out of the other form, it’s needlelike and can break in a different way. However the needle-like beta form will go into a solution a lot quicker than the tomahawk one, which may be a big help when making a medication that needs to rapidly dissolve.’ Knowledge such as this will mean in the future, more medications can be tailored to our drug delivery needs.

Top: Alpha lactose ‘tomahawk’ Above: Beta lactose ‘needle’

About the researcher

https://kclpure.kcl.ac.uk/portal/paul.royall.html

1. Starting with the basics

Understanding the superbug Dr Richard Harvey changing a sample on the D16 neutron diffractometer at the Institut Laue Langevin in Grenoble, France

ethicillin-resistant Staphylococcus aureus (MRSA) is a huge concern in the healthcare industry. While there are a number of measures in place that have greatly limited its spread in recent years, understanding how MRSA acts in the environment it finds itself in is a vital part of hopefully one day eliminating its threat all together. Dr Richard Harvey uses his roots in microbiology to see what can be solved using techniques such as neutron scattering to look at the physical mechanisms of drug resistance in bacteria on an atomic scale. ‘We’re concentrating on changes that occur in MRSA in response to weak acid conditions,’ he explains. These conditions can be found where MRSA resides in the body such as on the skin and inside the nose. ‘It seems,’ he continues, ‘that changes in pH make the bacteria better adapted to their environment and confer resistance to both the body’s defence and some antibiotics.’ Staphylococci membranes are hard to study as the lipids they have evolved to enable this response to pH are not very stable. One such membrane phospholipid that appears to play a key role in neutralising the plasma membrane in response to cationic threats (a mechanism thought to be involved in drug resistance) is lysylphosphatidylglycerol (LPG). The adaptability of the membrane is part of their survival mechanism, both for colonising human surfaces and to live inside host cells. Dr Harvey explains that ‘people have tried to study these bacteria with biophysical means but at the end of the experiment their samples have degraded.’ As such, a big part of his research has been in synthesising stable analogues of the lipids to use in biophysical experiments. ‘We’ve shown how the membrane changes in response to pH and how those changes affect interactions with drugs.’ One such change they have found is that the lipid bilayer structure alters according to pH. Dr Harvey and his team are ultimately trying to find out the evolutionary role of LPG. ‘While it might play a part in MRSA’s colonisation of people and animals, is there a more ancient role in terms of defence in their native environment? Is it upregulated in lower pH conditions? We need to find out if these conditions are ones in which you’d find bacteria under stress from other things like antibiotics in the environment.’

We’ve shown how the membrane changes in response to pH and how those changes affect interactions with drugs

About the researcher https://kclpure.kcl.ac.uk/portal/richard.d.harvey.html

1. Starting with the basics

Using chaotic mathematics for our chaotic body systems

D Using this novel mathematical approach, we can see clear changes in the earliest stages of sepsis, which are not otherwise detectable from the blood pressure signal

A data image created by applying Attractor Reconstruction analysis to a mouse blood pressure trace obtained by Dr Nandi’s lab

r Manasi Nandi, an integrative pharmacologist, uses animal systems to validate new drug targets, prior to going into humans. Her group’s expertise is in monitoring the cardiovascular system in small mammals. ‘We use radiotelemetry to measure blood pressure in freely roaming mice or rats using implanted transmitters,’ she explains. ‘The system is great because animals are left undisturbed in their own cages and we can visualise the data in another room. This means it very much fits into the 3Rs ethos (reduce, replace, refine) by minimising animal stress.’ They have developed an additional way to visualise the very small blood vessels that supply blood to vital organs like the liver. ‘This technique is very sensitive,’ says Dr Nandi, ‘it gives us much more information about how much a disease has advanced, above and beyond what we currently measure’. At the moment, they are particularly focused on septic shock, something affecting millions of people a year, up to half of whom die because of it. While there is a clear need to develop new treatments for critically ill patients in which the syndrome has progressed, evidence has shown that early diagnosis and the provision of rapid interventional treatment, is more likely to save lives. ‘Conventionally, when we induce septic shock in animals and then look at what happens to the cardiovascular system, we take five minute snapshots of blood pressure data every hour, recording the heart rate and the systolic and diastolic blood pressures,’ explains Dr Nandi, ‘but there’s so much more going on in the waveform and we felt we may be missing something by doing only this. As such, they are trying to find ways to look at all of the data and subtleties that may be hidden in the waveforms, to fully understand what is happening in the early stages of septic shock. This project is a joint collaboration with Dr Mark Christie at King’s and Dr Philip Aston, a mathematician, based at the University of Surrey. Dr Aston has written coding based on the mathematics of chaos that converts blood pressure data into a three dimensional signal. This is then rotated to give an ‘Attractor’ with a visually striking triangular shape (as illustrated). ‘From this we can derive numerous parameters relating to the Attractor, which changes colour and shape in response to subtle changes in blood pressure,’ says Dr Nandi. ‘Using this novel mathematical approach, we can see clear changes in the earliest stages of sepsis, which are not otherwise detectable from the blood pressure signal. The preliminary results are telling us that the system goes from being variable and chaotic in the healthy state to becoming more synchronised very rapidly after the onset of sepsis.’ This is of vital importance, by the time shock is detected it is often too late to initiate life-saving treatment. By finding an early warning system for septic shock it is hoped that many lives will be saved.

About the researcher

https://kclpure.kcl.ac.uk/portal/manasi.nandi.html

1. Starting with the basics

Neutrons help scientists fight problem infections Molecular model of a fungal cell membrane showing how the drug, amphotericin B (blue), complexes with ergosterol molecules (yellow) and inserts between the phospholipid molecules (red, grey and yellow)

mphotericin has been used for almost half a century to treat a variety of infections caused by fungi, ranging from common diseases such as thrush and ringworm to more serious fungal conditions that affect people with AIDS and those undergoing chemotherapy. Lately, however, there are increasing numbers of people with fungal infections that do not respond to amphotericin and there is now a desperate hunt to find new drugs that can be used to treat patients infected with these amphotericin-resistant fungi. Sadly though, the design of these new drugs will not be straightforward because very little is known about how amphotericin works. For this reason, Professor Jayne Lawrence and Dr David Barlow are working to find out more about the drug’s mechanism of action with the hope then to determine how best to design new and improved versions for treating amphotericinresistant infections. ‘I take care of the laboratory work,’ says Professor Lawrence, ‘while David carries out the computer analyses of the data. We use the technique of neutron diffraction to look at how the drug interacts differently with the cholesterol-containing membranes that surround human cells and the ergosterolcontaining membranes that surround fungal cells.’ Dr Barlow takes up the story: ‘What we effectively do is use the neutron diffractometer like a very powerful ‘microscope’ to see how the molecules are arranged inside the cell membranes.’ ‘Our results,’ says Professor Lawrence, ‘provide the first direct evidence that amphotericin associates with ergosterol, forming pores that span the fungal cell membrane, making the cells leaky so that they eventually die.’ This knowledge, alongside the results of their further experiments looking at human cell membranes, will hopefully lead to the development of new anti-fungal drugs that can be used in place of amphotericin.

What we effectively do is use the neutron diffractiometer like a very powerful microscope

About the researchers https://kclpure.kcl.ac.uk/portal/jayne.lawrence.html https://kclpure.kcl.ac.uk/portal/dave.barlow.html

Drug discovery

2. Drug discovery

Targeting transcription factors in the fight against cancer

ven with current treatments, the prognosis for many cancers is still poor and there is a large unmet clinical need for novel anticancer drugs. With his colleague, Dr Khondaker Rahman, Professor David Thurston’s laboratory focuses on the design, synthesis and evaluation of novel anticancer agents that work by inhibiting the transcription factors that are up-regulated in many tumour types. They achieve this through methods including high throughput screening, molecular modelling and medicinal chemistry. For their current research, Professor Thurston and Dr Rahman are searching for new types of anticancer drugs that work by blocking transcription factors from interacting with their cognate DNA sequences. Their latest molecule, KMR-28-39, targets the NFkB-binding site of DNA as this transcription factor is over-expressed in many tumour types. ‘We are finding high growth inhibition of pancreatic and breast tumour cells at very low, almost femtomolar, concentrations of KMR-28-39, which is highly unusual,’ reports Professor Thurston. ‘Preliminary experiments suggest that this agent should have low toxicity in humans so we are now undertaking pre-clinical studies with the hope of progressing KMR-28-39 to Phase I clinical trials.’ Ultimately, this drug could be used to treat any tumours that over-express NFkB and the team hopes to follow the same strategy for other transcription factors and tumour types. ‘If we find a tumour type that has a particular transcription factor up-regulated,’ says Professor Thurston, ‘we could design our molecules to target that particular transcription factor and DNA sequence.’ To help with this, they have developed high-throughput, robotics-based assays for transcription factor inhibitor screening. After making the transcription factor protein in their laboratory, they add a FRET label to it, along with a partner label to a fragment of DNA containing the transcription factor recognition site. ‘We know that when the transcription factor is bound to its DNA recognition site, the two FRET labels come close together and we obtain a specific signal,’ explains Professor Thurston, ‘so in the highthroughput screen, if a novel molecule binds to either the DNA or protein, it will block the interaction of the two and cause a detectable change in the FRET signal. Using this approach, we have been able to screen libraries of novel molecules of up to 100,000 in size, with larger screens planned.’ This work is carried out in collaboration with the German company European ScreeningPort who have robotic screening systems and large compound libraries of diverse structures. ‘We make the protein and develop the assay at King’s, then send the protein and assay protocol to Germany where they set up the assay in high-throughput mode,’ says Professor Thurston. ‘We have a screening cascade in place whereby if we get a ‘hit’, we then move into the secondary phase where we carry out biophysical experiments to confirm disruption of the transcription factor/DNA complex and cellular experiments to ensure that the hits have biological activity. For promising molecules, it’s then back to the King’s laboratories for further medicinal chemistry and molecular modeling studies (with Dr Paul Jackson) to make analogues of the hit compounds and learn more about structure–activity relationships. The ultimate goal is to pick the best lead compound and then progress it towards clinical trials where it can benefit cancer patients.’

The ultimate goal is to pick the best lead compound and then progress it towards clinical trials where it can benefit cancer patients

Molecular model by Dr Paul Jackson showing inhibition of binding of NFkB transcription factor (yellow) to its DNA binding sequence by KMR-28-39. Imidazole group of KMR-28-39 prevents Lys 145 from interacting with DNA minor groove.

continued over...

2. Drug discovery

Molecular model showing PPA-64, an efflux pump inhibitor developed by Dr Rahman’s group, binding to the drug binding pocket of MexB efflux pump (pdb id 3W9J)

Multidrug resistant pathogens have emerged as a major concern for public health, highlighted in a series of high level publications from the Chief Medical Officer, Department of Health, Centres for Disease Control (CDC) and World Health Organisation. There are particular concerns about the emergence of a number of Gram-negative pathogens and tuberculosis strains, for which there are dwindling treatment options and few novel compounds in late stage development. Dr Khondaker Miraz Rahman uses his training as a synthetic medicinal chemist to develop novel drug-like chemical scaffolds as anti-infective agents and carry out mechanistic studies to understand their molecular and cellular mechanisms of action. ‘We are designing and developing drug-like molecules by direct screening of antimicrobial efficacy against clinical isolates of pathogens. We believe this approach is likely to become the new paradigm and places a greater emphasis on identification of novel molecules by phenotypic screening as a target-based approach has largely failed to deliver any new antibiotic in the last two decade’ he explains. ‘We are trying to tackle all the key pitfalls of antibiotic drug discovery upfront to maximise the possibilities of success at the translational level’ he continues. The Institute of Pharmaceutical Science has recently established a strategic partnership with Public Health England to develop new therapies to treat multiple drug-resistant pathogens. Dr Rahman is working with Public Health England to develop novel classes of compounds with antimicrobial activity against multidrug resistant (MDR) Gram-negative pathogens and MDR tuberculosis. An ongoing collaboration with Dr Mark Sutton’s group at Public Health England has identified four novel chemical scaffolds that have shown promising antimicrobial activity against multidrug resistant isolates of Gram-negative pathogens Klebsiella pneumoniae and Acinetobacter baumannii as well as broad-spectrum activity against a range of other pathogens such as MRSA. The collaboration has enabled a detailed analysis of the structure-activity relationship of these compounds, some of which show very low minimum inhibitory concentrations, are rapidly bactericidal and do not appear to induce resistance in studies carried out to date. A number of lead molecules are being further characterised with the intention of evaluating their effectiveness in in-vivo infection models and potentially progressing to commercial development. In addition to developing antimicrobial agents, Dr Rahman’s research group is also developing new type of efflux pump inhibitors to tackle antimicrobial resistance in MDR Gram-negative pathogens. His team along with his collaborators at Public Health England and University of Cambridge is using in-silico prediction methods to explore the range of available scaffolds that might be compatible with developing inhibitors for RND type efflux pumps that are prevalent in many drug resistant pathogens including Pseudomonas aeruginosa.

About the researchers

https://kclpure.kcl.ac.uk/portal/david.thurston.html https://kclpure.kcl.ac.uk/portal/k.miraz.rahman.html

2. Drug discovery

Hope on the horizon for asthma and COPD

espiratory inflammatory diseases are a huge and growing concern. Worldwide, asthma affects around 300 million people and chronic obstructive pulmonary disease (COPD) is the sixth leading cause of death. While effective, current treatments with combinations of glucocorticosteroid and long-acting beta-2 agonist inhalers have safety concerns for some patients. To overcome both these safety factors and the need for multiple medications, Professor Clive Page and Dr Domenico Spina discovered, developed and have now taken to clinical trial a new class of therapeutic agent for asthma and COPD in the form of RPL554, an inhaled phosphodiesterase (PDE) 3/4 inhibitor. ‘We set about trying to find a drug that had two separate biological activities,’ recalls Professor Page, ‘you need both acute treatment of bronchospasm to relax airway smooth muscle and longer-term treatment to reduce inflammation.’ It was known that the isoenzyme PDE3 is involved in regulation of airway smooth muscle function and that PDE4 is the predominant PDE isoenzyme in inflammatory cells. ‘As such,’ says Professor Page, ‘we needed a drug that targeted both PDE3 and PDE4.’ A literature search identified that such a drug, trequensin, had been used in the cardiovascular field but had not been developed further due to safety concerns in these patients. Another problem, specific to PDE4 inhibitors, is that while they had been shown to have beneficial effects in asthma, nausea as a side-effect limited their use. Finding a PDE3/4 inhibitor that didn’t cause these side-effects was key and steered Professor Page and Dr Spina to develop what eventually became RPL554. The team also worked to produce inhalable analogues of suitable compounds and carried out pre-clinical studies on animal models of lung inflammation they developed specifically for this task. The discovery of RPL554 led Professor Page to form Verona Pharma plc in 2006. To date, more than £11 million has been raised to allow Verona Pharma to develop a suitable aerosolised formulation of RPL554 for use as a medication in a single inhaler. Following completion of toxicological studies in 2008, a Phase I/ IIa clinical trial was carried out at the Centre for Human Drug Research at Leiden in the Netherlands. They were delighted when they successfully showed that in people with asthma and COPD at the dose of RPL554 that bronchodilated patients, it was also an anti-inflammatory. This dual activity of RPL554 makes it unique amongst drugs being developed for the treatment of respiratory diseases. They also demonstrated that RPL554 had a good safety profile, with no evidence of adverse cardiovascular, emetic or gastrointestinal side effects. Further studies with both healthy control and patient populations mean this drug should soon be making its way to helping people with asthma and COPD live more easily with their sometimes life-limiting health conditions.

You need both acute treatment of bronchospasm to relax airway smooth muscle and longer-term treatment to reduce inflammation

The dual activity of RPL554 makes it unique amongst drugs being developed for the treatment of respiratory diseases

About the researchers https://kclpure.kcl.ac.uk/portal/clive.page.html https://kclpure.kcl.ac.uk/portal/domenico.spina.html

2. Drug discovery

Understanding chronic cough may lead to much-needed help

We don’t really have drugs for chronic cough. Over the counter remedies don’t work for these people so it’s a huge clinical unmet need

CGRP

TRPV1

cough is annoying even if you only have it for a day or two. But for some people this annoyance becomes a part of their daily life for months or even years. Dr Domenico Spina works to try and understand what causes this hyper-tussive cough. ‘There’s something different about these patients,’ he says, ‘if you treat them with morphine, it will suppress the cough but it doesn’t change their sensitivity to applied stimulants such as citric acid.’ He is also exploring how to treat it. ‘We don’t really have drugs for this. Over the counter remedies don’t work for these people so it’s a huge clinical unmet need.’ The mechanism behind chronic coughing has yet to be completely understood but it is known that there is an increase in expression of proteins like transient receptor potential vanilloid 1 (TRPV1 , aka the capsaicin receptor) in idiopathic cough and elevation of neurotrophic factors in people with chronic cough as part of idiopathic pulmonary fibrosis. These point to potential targets for new anti-tussive drugs that Dr Spina’s team are exploring. ‘We have in-vitro assays where you take just the vagus nerve and electrically excite it or we work with guinea-pig isolated main bronchi’ explains Dr Spina. ‘Here you can measure conduction and report the action potentials along C- and Ad fibres. It appears that proteins are expressed along the length of the vagus nerve and in peripheral terminals as these can be measured even if there is no cell body. We can hopefully use this to screen molecules.’ They have also taken their investigations into animal studies to try and develop means of testing potential agents. ‘There is no meaningful model for chronic cough,’ says Dr Spina ‘so we’re trying to find a good one.’ Much development work in other areas of science uses mice as you can easily knock genes in or out. ‘The problem is,’ says Dr Spina, ‘mice don’t cough.’ As such, they have had to turn to guineapig and rabbit models and are concentrating on a fairly non-invasive approach. ‘What’s great about the way the experiments are designed is that we can use them as their own controls and crossovers so we make sure we limit the number we have to use, in line with the ‘3Rs’ (reduce, replace, refine).’ With these models, they are hoping to develop inhaled medications with a peripheral mode of action. ‘This way,’ says Dr Spina, ‘there are less CNS sideeffects and it’s easier to get the drug into clinical trials and then helping people as soon as possible.’ MERGED

Confocal image of immunohistochemical staining for calcitonin gene related peptide (CGRP) and transient receptor potential vanilloid 1 (TRPV1) in trachea epithelium

About the researcher

https://kclpure.kcl.ac.uk/portal/domenico.spina.html

2. Drug discovery

Gastrin inhibitors: a new angle on some age-old problems

he late Professor Sir James Black, a Nobel Prize recipient, carried out several decades of successful research in the field of gastrointestinal physiology and pharmacology. One great achievement was the discovery of H2 receptor antagonists for the treatment of gastric ulcers. However, while these antagonists are useful, stopping treatment can cause symptom relapse. Research into the causes of this observation led to the discovery by the Black group that the hormone gastrin can regulate acid secretion and the growth of certain gastrointestinal tumours. As such, they concentrated their efforts on searching for novel gastrin antagonists. Cholecystokinin (CCK) and gastrin are closely related peptide hormones: gastrin can activate the CCK receptor CCK2, found on enterochromaffin cells in the gastrointestinal tract. This knowledge led to the discovery by the Black group of a variety of compounds that act as antagonists at CCK2 receptors. Based on this work, and in collaboration with or built upon by pharmaceutical companies, a number of gastrin antagonists have progressed through the necessary regulatory toxicology, Phase I clinical studies to assess safety. There are now several in clinical development for the treatment of gastric acid-related disorders and for gastric and pancreatic cancer. For instance, the Black group has worked with the pharmaceutical company Yamanouchi on their novel CCK2 antagonist netezepide that affects development of gastric tumours. Consistent with this molecule being active as a gastrin antagonist, it has recently been shown to cause a dose-dependent sustained increase in gastric pH in healthy volunteers and is now moving into Phase II studies.

A number of gastrin antagonists are now in clinical development for the treatment of gastric acid related disorders and for gastric and pancreatic cancer

The stomach. Engraving, 1686 Image courtesy of the Wellcome Library, London

About the researcher http://www.kcl.ac.uk/aboutkings/history/famouspeople/sirjamesblack.aspx

2. Drug discovery

Iron chelation: not just for those with beta-thalassaemia We designed the compound so that it can enter into cells and scavenge iron and then the iron complex can escape out through membranes

ver 60,000 people a year are born with beta-thalassaemia. While blood transfusion therapy is life-saving for those affected, it leads to iron buildup, necessitating chelation as a countermeasure. Research carried out by Professor Robert Hider and Dr Sukhi Bansal brought about a new class of therapeutic agent in the form of deferiprone. Licensed in Europe since 1995, in combination with desferoxamine, deferiprone is currently the most efficient method of chelation-based iron removal. Deferiprone also has a unique aspect to it. ‘We designed the compound so that it can enter into cells and scavenge iron and then the iron complex can escape out through membranes,’ says Professor Hider. This gives deferiprone an advantage over similar chelators as heart failure due to iron overload is the predominant cause of death in those with beta-thalassemia major. This advantage was behind gaining FDA approval in 2011. Although deferiprone has been licensed in Europe for nearly a decade, Professor Hider and his team continue to further develop this drug. ‘Around one per cent of people given deferiprone develop reversible agranulocytosis,’ he explains; ‘we want to design this property out of the molecule.’ As such, King’s is collaborating with researchers at Zhejiang University in Hangzhou, a leading Chinese centre for pharmaceutical science. This collaborative effort has identified a lead compound that is soon to go into clinical trial in China. With heart failure a major concern, monitoring of iron levels is essential for people undergoing repeated blood transfusions and accompanying iron chelation. Monitoring is equally as essential for those undergoing iron-replacement therapy for conditions such as iron-deficiency anaemia. Such monitoring can be carried out through analysis of levels of hepcidin, a peptide hormone involved in regulating plasma iron load. Clinical analysis of hepcidin is through mass spectrometry and a highly important development in the use of this was the synthesis by Dr Bansal’s team of a reliable internal standard in the form of a synthetic hepcidin. Important also was the refinement of the method of analysis itself. This research has led to the development of an assay that has both high rates of recovery from biological matrices and is highly reproducible. This assay has been widely adopted by hospital clinicians and the international pharmaceutical industry. Iron overload can also be determined through levels of non transferrin-bound iron and the team have additionally developed and patented a fluorescence-based flow cytometry method for quantification of this marker that is being utilised in clinical trials. Further, deferiprone is proving to be useful beyond the disease area it was originally designed for. Professor Hider explains how ‘many forms of neurodegeneration, including Friedreich’s ataxia and Parkinson’s disease, may have part of their progression caused by elevated iron in critical cells. We are currently developing analogues of deferiprone that cross the blood-brain-barrier more effectively and are targeted to the mitochondria where additional iron deposition occurs.’ Chelation therapy provides a novel approach for the treatment of these devastating conditions and investigation has now been brought to the clinical trial phase in those with Friedreich’s ataxia, Parkinson’s disease and pantothenate kinase-associated neurodegeneration. These studies are run by, or are in collaboration with Imperial College London and ApoPharma, the manufacturers of deferiprone, and are already showing very encouraging results.

About the researchers

Professor Robert Hider: http://bit.ly/1uuXcHJ https://kclpure.kcl.ac.uk/portal/sukhi.bansal.html

Running head

Living better with Parkinson’s disease

n the early 1980s, while attempting to synthesise an opioid for recreational use, a groups of drug addicts inadvertently made a neurotoxin called MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine). Many of those who injected this compound rapidly developed acute and severe symptoms similar to Parkinson’s disease due to the destruction of dopaminergic neurons in the substantia nigra. While it was tragic for those affected, the fact that levodopa treatment helped alleviate the symptoms meant that this unfortunate accident brought to light a toxin that could be used to produce a model with pathology very similar to Parkinson’s disease. Building on this finding, Professor Peter Jenner and Dr Sarah Rose found that a MPTP-treated marmoset model was particular reflective of the damage shown in humans with Parkinson’s disease. This model is now used to mimic both early and late stage Parkinson’s disease. Importantly, the MPTP model reflects all the motor symptoms of Parkinson’s disease and responds to all drugs used to treat the disease. The gold-standard treatment for Parkinson’s symptoms is dopamine replacement therapy with levodopa, but while effective, abnormal involuntary movement (dyskinesia) is a debilitating side-effect of long term use. Dyskinesia is also expressed in the MPTP models of Parkinson’s disease after chronic L-DOPA treatment. ‘Thanks to the MPTP model,’ reports Dr Rose, ‘we now know to give much lower doses of L-DOPA and to use combination treatments to achieve a much better control of motor disability, thus reducing the severity of the dyskinesia.’ ‘Since finding the MPTP model,’ says Dr Rose ‘it has been used in the development of every Parkinson’s drug currently on the market. Of these,’ she continues, ‘King’s has tested about 80% of them.’ The model was vital for the development of the dopamine agonist rotigotine as a transdermal patch (Neupro®) and for sustained and extended release preparations of the dopamine agonists ropinirole (Requip XL®) and pramipexole (Mirapexin ER®). It helped in examination of the use of levodopa combined with the COMT inhibitor entacapone for the treatment of ‘wearing off’ in Parkinson’s disease and early monotherapy in the form of Stalevo® and Comtess®/Comtan®. Because of findings such as these, many with Parkinson’s disease can now live a reasonably independent life over a long period of time. This model also formed the basis of Professor Jenner’s spin-out drug-discovery company Proximagen Ltd. Since its launch, it has become one of the UK’s leading Biotech companies and in 2012 it was bought by its US partner Upsher-Smith Laboratories for $357m. Meanwhile, the work at King’s on Parkinson’s disease continues. ‘While we are still searching for drugs that don’t produce any dyskinesia while treating the disease,’ says Dr Rose, ‘we are also looking at other problems associated with Parkinson’s disease such as gut and bladder dysfunction, sleep problems and cognitive decline.’ Symptoms such as constipation and disturbed sleep can appear before motor changes and contribute greatly to quality of life issues. ‘In addition, we don’t have any drugs that successfully treat the underlying pathology of Parkinson’s disease and, with an aim to slow the progression of the disease, we are using cell culture and animal models to look at various strategies to prevent the neurons from dying.’

Since finding the MPTP model, it has been used in the development of every Parkinson’s drug currently on the market

Myenteric ganglion in a model of Parkinson’s disease Triple immunofluorescence staining for HuC/D neurons (blue), nNOS neurons (red) and TH fibres (green) on the myenteric plexus of the distal ileum Magnification 20X

About the researchers https://kclpure.kcl.ac.uk/portal/sarah.salvage.html https://kclpure.kcl.ac.uk/portal/peter.jenner.html

Drug formulation and development

3. Drug formulation and development

Targeted drug delivery through the use of nanomedicines

r Khuloud Al-Jamal says ‘when you give someone a small molecule, it will distribute everywhere. I work on developing nanoscale carriers to deliver drugs or biologics to specific targets in the body.’ These carriers, developed to suit the need, include polymers, liposomes (bio-compatible lipid carriers), carbon-based materials (such as nanotubes or graphene) and hyperbranched carriers such as dendrimers. ‘We also utilise biomimetics such as viral particles,’ says Dr Al-Jamal ‘where you strip the virus of its envelope, then load core proteins with useful nucleic acids to replace viral genome.’ The work Dr Al-Jamal and her team do is in the field of theranostics where you diagnose a condition and deliver a therapy at the same time. ‘You put a specific tag on the carrier that recognises a specific receptor, for instance in a tumour cell,’ explains Dr Al-Jamal, ‘then you can image the carrier to see where it is the body and get it to release the drug when needed.’ Their latest work involves polymeric nanocapsules with an oily core. The size and surface coating of the structure allows them to escape macrophage clearance; the polymeric wall, protects them against enzymatic degradation and prolongs blood circulation time; the oily core means they can load the carriers with water-insoluble drug molecules that could not otherwise be injected. Some of their ground-breaking work has been in cancer. To get the nanocarriers to the tumour cells they use passive targeting. ‘You work with the fact that you can get a lot more to tumour cells as they have leakier blood vessels with enhanced permeation for particles that then get trapped as there is no lymphatic drainage in a tumour,’ explains Dr Al-Jamal. But while you can use passive targeting to reach the tumour, you need active targeting to get into the cells. ‘To achieve this,’ says Dr Al-Jamal, ‘we put a folic acid label on the nanoparticles as cancer cells express folate receptors to a great extent. They then engulf the particles and they are taken inside the cell.’ To visualise them, Dr Al-Jamal explains how ‘we put together a dual-imaging contrast agent made of iron oxide and radioactive probes so we were able to see them with MRI and nuclear imaging.’ They have also engineered into the nanoparticles a remarkable property: they are magneto-responsive. ‘Once the particles have been injected, you can apply a magnet where they are needed and the nanocarrier accumulation will be even higher.’ This also holds the advantage that by just targeting the tumour, you get less toxicity from the drug in other parts of the body, so you can use higher doses. Their current research is with the water-insoluble compound curcumin, a natural anti-inflammatory and anti-cancer agent that has previously proven hard to get to the right target. But that is not all, Dr Al-Jamal explains that ‘you can also use this system to safely deliver biologics, which are very sensitive and can be destroyed by enzymes, and radionuclides for radiotherapy, which means you can deliver targeted radiation just to the tumour area.’

Electron microscope image of lung cancer cells (green) captured in the process of taking up carbon nanotube needles (gold)

They have engineered into the nanoparticles a remarkable property: they are magnetoresponsive

About the researcher https://kclpure.kcl.ac.uk/portal/khuloud.al-jamal.html

3. Drug formulation and development

Designing drugs to save lives

S Once we’ve found the right approach with these drugs, we can use the mechanisms to assess other drugs that need to cross the blood brain barrier

pread by the bite of a Tsetse fly, African trypanosomiasis is caused by a parasitic protozoan. While colloquially known as ‘sleeping sickness,’ this is actually only a final stage symptom. The disease has two distinct stages: in Stage 1 the parasite is confined to the blood and lymphatic system; in Stage 2 it enters the brain. Currently, drugs that don’t cross the blood-brain-barrier (BBB) are used in Stage 1. The BBB-crossing drugs needed for Stage 2 may work, but they are much more toxic. In fact, one of them, melarsoprol, kills 1-in-20 of those it is meant to cure; however, without treatment, the disease is fatal, so it’s a chance that must be taken. To study this neglected disease, Dr Sarah Thomas has assembled and led a multidisciplinary team of experts from King’s and other organisations including the London School of Hygiene and Tropical Medicine. ‘I’m particularly interested in finding out how molecules move across the BBB,’ she says. This line of work has led her to discover how another drug given for Stage 2 trypanosomiasis, nifurtimox, crosses the BBB using several membrane transporters. ‘Ultimately we are hoping to take a reasonably safe Stage 1 drug and engineer it so that it can cross the BBB and be used at Stage 2’ says Dr Thomas. ‘This improves not only efficacy and safety, but also the logistics of only one drug being needed for both stages, a bonus as many of those affected by trypanosomiasis live in remote communities.’ Dr Thomas realised that one way of improving how this drug crossed the BBB was to combine it with nanotechnology. ‘We’re targeting transporters by inhibiting efflux, as opposed to enhancing delivery directly.’ As such, she is working with people like Dr Cécile Dreiss who is trying to understand how different polymers assemble into micelles and how this can be used to enhance BBB transit. ‘We are using an iterative approach’ explains Dr Thomas ‘so as to find which element of nanotechnology formulations improves targeted delivery. Once we’ve found the right approach with these drugs, we can use the mechanisms to assess other drugs that need to cross the BBB or need to avoid the brain to reduce side effects.’

Brain: posterior view. Colour lithograph by Brocades Great Britain Ltd. Image courtesy of the Wellcome Library, London

About the researcher

https://kclpure.kcl.ac.uk/portal/sarah.thomas.html

3. Drug formulation and development

Challenges in developing novel inhaled medicines

r Ben Forbes leads a group addressing the clinical need for safety in the design of novel inhaled medicines. For example, while inhaled nanoparticles can be formulated as promising drug carriers with low toxicity, their surface properties may lead to non-specific adverse effects. ‘We are trying to understand the mechanisms by which adverse effects of inhaling particles occur,’ says Dr Forbes. ‘We’ve developed methods to test the hypothesis that adversity is linked to surface hydrophobicity and have found that rather than a linear relationship, there appears to be a threshold above which surface hydrophobicity causes problems.’ Understanding such properties is invaluable as it means that these findings can be used to develop nanoparticles that exploit the therapeutic opportunities that these systems offer, while avoiding any of the adverse effects that inhaling particles may bring. ‘So far our nanomedicine project has concentrated on evaluating the safety of nanocarriers in-vivo, but we are now looking at the fate and drug delivery potential of the particles we’ve discerned to be safe in healthy and diseased lungs using imaging.’ Dr Forbes also leads a scientific network – ‘Drugs in the Lungs’ – that brings together academic, industrial and regulatory scientists to explore how barriers to the development of novel inhaled medicines may be overcome. One work-stream of the Drugs in the Lungs Network involves interpretation of the finding that alveolar macrophages are increased in number or appear ‘foamy’ in inhalation toxicology studies (as illustrated). ‘The problem is,’ explains Dr Forbes, ‘the safety implications of inducing foaminess in macrophages are poorly understood. Is it an adverse effect or a normal adaptive response to a poorly-soluble particle, similar to a harmless injection-site reaction?’ This is a problematic and urgent question to answer at the moment as it’s holding up the development of inhaled medicines. The good news is that the collaborative approach advocated by the Drugs in the Lungs Network that is necessary to address this question is now being supported in the form of a King’s-led £1m academia-industry research consortium coordinated by the National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3R).

We are trying to understand the mechanisms by which adverse effects of inhaling particles occur

Electron micrograph of a macrophage displaying druginduced vacuolated ‘foamy’ morphology

About the researcher https://kclpure.kcl.ac.uk/portal/ben.forbes.html

3. Drug formulation and development

Getting past a barrier to better deliver medicines This is an attractive approach for drug companies who already have the data needed for the drug to reach the market as this can be used to form a new product using a novel drug delivery approach

We’ve developed our own in-vitro experimental set-up that can test compounds applied to the skin at various different pressures

r Stuart Jones and his group concentrate on developing technologies to deliver active ingredients contained in medicines to where they should be in the body. One of their focuses is drug delivery via the skin, a barrier through which many active agents cannot pass effectively without a little help from the formulation chassis that delivers the drug. Anything that enters the skin does so via passive transport and Dr Jones is developing new ways to control and boost this process. ‘One way to achieve this,’ he explains, ‘is to add a negative counter-ion or nanoparticle to a product that contains a positively-charged drug molecule in order to produce a complex on the skin’s surface. By transiently forming these complexes we can temporarily change the drug’s properties so it can enter the skin. Then, when it enters the tissue, the delivery system’s effect is diminished and it displays the same pharmacological activity as the original medicine.’ This is an attractive approach for drug companies who already have the data needed for the drug to reach the market as this can be used to form a new product using a novel drug delivery approach without having to go through the regulations needed if it was a whole new compound. One application of these dynamic complexes is for topically-applied local anaesthetics. Currently these take around 30 minutes to work, which can be a long period if you’re a child waiting to receive an intravenous infusion in the Accident and Emergency department. Dr Jones hopes that by controlling the entry of the drug molecules into the skin, anaesthesia can be achieved within five minutes. He and his team are also looking at how the entry of compounds into the skin can be changed by the application of different barometric pressures. Dr Jones explains how ‘we’ve developed our own in-vitro experimental set-up that can test compounds applied to the skin at various different pressures. The preliminary results show that if you apply suction to the skin, the compound enters the barrier more quickly. This could help a drug to work better or may lead to a new means of delivering drugs that have not been previously applied to the skin.’ The hope is to develop a technology that will lead to practical applications. ‘We are focused on making products that can be used by real people,’ says Dr Jones, ‘as such the team generate patented technologies and working products as well as research papers.’

About the researcher

https://kclpure.kcl.ac.uk/portal/stuart.jones.html

3. Drug formulation and development

Image guided drug delivery: targeted treatments for cancer

r Maya Thanou focuses her research on how nanoparticles can be used in the clinical setting. For her work, her team uses 100-140nm theranostic nanoparticles (theranostics being ways to simultaneous diagnose and treat) in the form of liposomes that carry an imaging probe for MRI and/or optical imaging. ‘Following intravenous administration,’ explains Dr Thanou, ‘the nanoparticles accumulate in the tumour and we then use imaging that allows us to see the labels for the drug and the particle at the same time.’ In their current studies they are using novel imaging probes to view theranostic liposomes carrying anti-cancer drugs. The nanoparticles are stable when inside the body at a temperature of around 37°c , ‘but then,’ explains Dr Thanou ‘upon imaging we apply Focused Ultrasound to the area the signal is coming from. After only a few minutes of treatment, the temperature is raised by only a few degrees and the liposomes burst, releasing the drug.’ This method means the drug is released only to the area of the tumour. The added advantage is that once the Focused Ultrasound has been applied it draws in more circulating liposomes. ‘By attracting the particles into the tumour,’ says Dr Thanou, ‘you maximise the dose tight where it is needed. Using imaging (either MRI or optical) we can then track the kinetics and release of the particles. As liposomes label the tumours for a number of days we can also use them to monitor the effect on the tumour’s size.’ Using the clinical technique of MRIguided Focused Ultrasound (MRgFUS, a clinically used technique) means we can treat tumours at any depth in the body. While so far this work has been done in rodent models, Dr Thanou explains that ‘as we are able to image with the sort of MRI that is clinically available, as soon as the nanoparticles are fully developed they will be ready to be clinically trialed. Image guided drug delivery is a very elegant way to treat cancer.’ Dr Thanou’s team is also looking at practical considerations such as how long a treatment would be. ‘Timing is an important variable because you can’t have the patient waiting there for ages to be imaged. We are aiming it so the patient can come back two hours after the initial injection to have the MRgFUS treatment. With optical imaging though,’ continues Dr Thanou, ‘we realised we can develop theranostic nanoparticles for image guided treatment for tumours within 2cm from the surface. This can be cheap and easy to apply using handheld optical scanners. In this case the patient doesn’t need protection against radiation and there isn’t a huge cost like with MRI. Things like skin cancer, oral cancer or even small breast tumours may be one day imaged and treated in the GP’s surgery.’

Image guided drug delivery is a very elegant way to treat cancer

Accumulation of the liposome nanoparticles monitored by the near-IR signal at: 40 min (A), 4 h (B), 24 h (C)

About the researcher https://kclpure.kcl.ac.uk/portal/maya.thanou.html

3. Drug formulation and development

Exploring the safety of nanomedicines

U We’ve made fluorescent semiconducting polymer nanoparticles with the hope of developing them for use in diagnostic tests

sing nanoparticles as a vehicle to deliver a new medication in the right concentration to the right location in the lung at the right time may have many advantages over traditional inhaled medicines. Dr Lea Ann Dailey should know as she has carried out a large amount of research on this subject. ‘People want to create nanoparticles for therapeutic use,’ she explains, ‘however, research in the air pollution and occupational health sectors shows inhaling some types of nanoparticles can cause unwanted side effects such as chronic inflammation and fibrosis in the lung. We need to know if the nanomedicines cause any side effects, either by themselves or with the attached therapy.’ ‘Our group is unique,’ says Dr Dailey, ‘in that we are taking methods from the new field of nanotoxicology and applying them to nanoparticles made from biomaterials to find out which are safe for medicinal use or, if they do cause side effects, how this relates to the physical and chemical properties of the material.’ With funding from the UK’s National Centre for the Replacement, Refinement and Reduction of Animals in Research, they are currently doing nanotoxicity studies in the lung using CT and MRI scans to see signs of inflammation and fibrosis development after nanomedicine use, such funding means this research is designed to improve animal welfare and dramatically reduce the number used in a typical toxicology study. In collaboration with Mark Green from the Imaging Sciences Division at King’s, Dr Dailey is also looking at the safety profiles of fluorescent semiconducting polymer nanoparticles (see illustration) first developed for use in flat screen monitors. ‘We’ve made them with the hope of developing them for use in diagnostic tests. For instance you might be able to inject them into the body to light up cancer cells.’ So far, their work has involved seeing how the nanoparticles interact with different cells in the body. ‘We’re excited to see how bright and stable these new materials are when we let them interact with cells. This makes them more useful than many other fluorescence-based imaging agents out on the market.’

Macrophage cells labelled with fluorescent semiconducting polymer nanoparticles

About the researchers

https://kclpure.kcl.ac.uk/portal/lea_ann.dailey.html

3. Drug formulation and development

Dial-up medicine gets personal

rofessor Gino Martini asks ‘If I can dial up exactly what I want from a coffee machine, then why can’t I do that with the tablet I have to take?’ While initially trained and registered as a community pharmacist, Professor Martini went on to do a PhD in drug delivery and has spent the past 20 years as an industrial pharmacist. Working first in formulation design, then as a manager and eventually a Senior Director means he has a unique role at King’s as a Professor of Pharmaceutical Innovation. Professor Martini’s particular focus is on personalised medicine. ‘Currently the pharmaceutical industry has to gear its supply chain to the average patient because producing individualised treatment would just be too complicated and expensive. But I want to see if we can customise medications at the point of dispensing.’ As such, Professor Martini came up with the idea of a ‘build your own’ polypill. ‘I’m looking at ways of customising formulations on an individual basis. I’m exploring how you can click the building blocks of different drugs together in a simple way.’ To enable this, they are using a revolutionary machine called the Gamlen Tablet Press. ‘It’s about the size of a shoebox and weighs around 15kgs so is very portable,’ explains Professor Martini. ‘With it, you can technically make a tablet to exact patient requirements.’ For instance, you can deliver a tablet with exactly the right dose according to a patient’s weight and, if appropriate, combine it with other medications they may need. Professor Martini is also working with Professor Jayne Lawrence and together they have set up a research group around designing formulations for older patients. ‘It’s an unmet medical need,’ says Professor Martini. ‘Around 25% of elderly patients over the age of 80 can’t swallow properly, yet we’re still manufacturing pills as if they’re all being taken by fully-functional adults. Clearly, research is needed to design delivery systems, formulations and dosage forms for elderly patients.’ As such, they are looking at a wide variety of microemulsions that can allow a medication to disperse slowly in the mouth. ‘We’re looking at how to characterise the solutions. We use small-angle neutron scattering to look at the inter-molecular attractions. Once you understand a system from a pure research point of view, and understand how it operates and behaves, then you can start modifying it accordingly.’

Once you understand a system from a pure research point of view, and understand how it operates and behaves, then you can start modifying it accordingly

Gamlen tablet press

About the researcher https://kclpure.kcl.ac.uk/portal/luigi.martini.html

Natural medicines

4. Natural medicines

At one with nature under the sun

ooking out across the ocean after a day’s work aboard an Australian ship, Dr Paul Long felt himself burning in the afternoon sun. But, he observed, the corals slowly emerging from the ebbing tide were not suffering the same fate. With a background in natural products discovery, which attempts to find small molecules or compounds from nature with medicinal or industrial applications, Dr Long was one of the best-placed researchers to answer the question of how corals were protected. He suspected that it was not the coral itself producing the sunscreen, but symbiotic micro-organisms. This wasn’t just an educated guess; Dr Long was the first person to clone a biosynthetic pathway from a microbial symbiant of an invertebrate, proving they were the source of a compound that is now being investigated as an anti-cancer agent. Dr Long’s observation regarding corals led to five years of work in which he and his team have mostly used proteomics to elucidate coral’s sun-screening compound. Not only have they indeed traced it to a symbiotic micro-organism, but they have also found the compound present in nearly all marine life. These findings are about to result in the commercialisation of a completely new type of sunscreen. ‘All current commercial sunscreens are made of synthetic products that don’t biodegrade,’ explains Dr Long. ‘They can be toxic to the environment and there is question as to what they are doing to a person when applied to the skin. Our compound is unique in that it is completely natural and biodegradable.’ Luckily, as collecting it from these specific micro-organisms may have been difficult, the compound is also found in a type of edible seaweed, meaning they already know it is a product that is safe for both people and the environment. Dr Long has a ‘hands-on’ approach and regularly goes on ocean expeditions. This field work has led to a number of other findings. For instance, an observation by Dr Long that many of the proteins found in the coral samples were similar to toxins found in jelly-fish led him to a collaboration with the University of São Paulo in Brazil, where Dr Long has recently been appointed International Visiting Research Professor. Surprisingly, when trying to find exactly what was in the jellyfish sting, he discovered that nobody really knew. With the help of stinging cells from an Atlantic jellyfish, analysed at the Proteomics Unit at King’s, Dr Long’s team became the first to describe the composition of jellyfish venom. ‘On the back of this,’ he says ‘we are now looking at whether we can use jelly fish sting medicinally. We know that venom from other animals can be used for pain control, anti-infectives and anti-coagulants, so there are lots of potential applications. At the moment we are particularly interested in whether we can take a toxin from the jellyfish sting and use it as a cream-based alternative to Botox and the needles needed for its application.’ In another collaboration, with the School of Dentistry at Guy’s, Dr Long’s group also have a compound found in sponges in pre-clinical development as a possible medication for bone diseases. The possibility of extracting useful compounds from marine-life are, it seems, widespread.

Dr Paul Long collecting a sponge specimen at the Great Barrier Reef

Our compound is unique in that it is completely natural and biodegradable

About the researcher https://kclpure.kcl.ac.uk/portal/paul.long.html

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4. Natural medicines

Using science to explore tradition

F This unique computer database enables users to obtain and utilise information to further drug discovery

T. Green, The universal herbal. Citrus, Colchicum, Cistus ladaniferus and Coffea arabica. Image courtesy of the Wellcome Library, London

or millennia, medicinal plants have been used to treat medical conditions and more recently the use of such plants has been growing commercially, especially among people with chronic illnesses who can’t find a suitable treatment with Western medicine. But while many university pharmacy departments have discontinued research into medicinal plant compounds, King’s academics continue such investigations. One such researcher, Dr Qihe Xu tells how ‘although we have 1,500 herbal medicinal products approved in Europe, and there are many more unregistered herbals as functional food or alternative medicines, clinicians often discourage their patients from using these products as they know little about them.’ ‘If you want to understand how medicinal plants work or how they cause problems,’ says Dr Xu, ‘you need to understand which kind of compounds are involved.’ The resurgence in interest in medicinal plants has, in the United States, led to the Food and Drug Administration granting licenses to a handful of medications based on plant extracts with more than one ingredient. ‘This is a huge step forward from approval of single compounds,’ says Professor Peter Hylands, Head of the Institute of Pharmaceutical Science, ‘because it’s often the case that a medicinal plant has multiple active compounds that work by different mechanisms.’ However, although it is of great importance to look at all of the active ingredients in a plant, this does, according to Professor Hylands ‘cause one hell of an analytical problem.’ He explains that ‘if you have two or more different biologically active compounds that have different mechanisms and potentially act synergistically, this causes a really difficult analytical problem.’ To tackle this problem, Professor Hylands’ team has looked to metabolomics, utilising techniques such as mass spectrometry, high-performance liquid chromatography and high-field nuclear magnetic resonance spectroscopy to create profiles of plant extracts. ‘Metabolomics,’ says Professor Hylands, ‘is non-directed; it allows standardisation without knowing what the active compound is. You measure everything and look for consistency. Standardisation is vitally important because if you want to generate a robust evidence base through clinical trials, you have to know what you’re testing and for that you need to standardise the compounds.’ Such metabolomic standardisation processes are now being adopted by Chinese pharmacopoeia and in recent years King’s has spearheaded the study of Traditional Chinese Medicine (TCM). ‘Many of the herbs and combinations prescribed by TCM practitioners are backed by centuries of use,’ says Dr Xu, ‘but scientific evidence is often lacking.’ These observations spurred the development of a database of TCM constituents – Chem-TCM – launched in November 2011 by Professor Hylands, Dr David Barlow, Dr Thomas Ehrman and the US company TimTec LLC. This database incorporates all available chemical, botanical, pharmacological and toxicological data for more than 12,000 TCM constituents. This unique computer database enables users to obtain and utilise information to further drug discovery. Professor Hylands and Dr Xu are also championing the utility of a scientific approach to study TCM by being Directors of the Good Practice in Traditional Chinese Medicine Research Association. Launched in 2012, it stemmed from a 2009 European Union Framework 7 grant of €1 million and a King’s-led project involving more than 150 scientists, clinicians and TCM practitioners from 13 European Union Member States and six non-EU countries including five leading Chinese TCM institutions. Professor Hylands hopes that the Association will inform and influence best practice and harmonise research into the safety and efficacy of TCM.

About the researchers

https://kclpure.kcl.ac.uk/portal/peter.2.hylands.html https://kclpure.kcl.ac.uk/portal/qihe.xu.html

4. Natural medicines

Using tradition to tackle fibrosis

or many with renal failure, treatments such as dialysis and transplantation give a few more years. However, as quality of life is severely compromised, prevention remains a priority. ‘Kidneys can fail due to fibrosis, a scarring pathological condition,’ reports Dr Qihe Xu, ‘however, we have no medications that can reverse or even halt this.’ As such, Dr Xu is looking at Traditional Chinese Medicine (TCM) approaches to find anti-fibrotic activities. Dr Xu, who is a clinician turned scientist, originally trained in Western Medicine and specialised in nephrology. ‘I came to the UK to research molecular medicine; when I started I had no thought that the TCM practices everyone has to learn at medical school in China would ever be a part of my research.’ ‘In contemporary pharmacological research,’ says Dr Xu, ‘you look at specific molecular targets that go wrong and try to fix these one by one. But fibrosis is multifactorial and we currently have no drug that can combat it alone. Our efforts to find an anti-fibrotic medication may have failed because we were focusing on ‘one drug, one target’ mechanisms.’ ‘In TCM,’ says Dr Xu, ‘the activity of many of the individual ingredients is not necessarily very high. TCM practitioners do not believe that dramatic changes are the best thing for the body, instead they try and find ways to modulate the system. Dr Xu has proposed a new strategy whereby first novel disease models are developed; next, traditional knowledge-based solutions are found and optimised, and only then do they find out how working compounds have achieved results. Dr Xu turned to TCM to implement this strategy as it most often uses combinations of ingredients brought together to work in harmony with the whole body system as opposed to single medications that work on only one target. To find potential solutions to trial using this system, Dr Xu’s team first worked with a high-throughput cellular model of fibrosis and tested anything they found reported as anti-fibrotic, whether it was a plant-derived compound, an extract of a medicinal plant or a TCM herbal formula. They found anti-fibrotic properties in 16 herbal formulae, 11 individual herbs and five active compounds. The most potent anti-fibrotic properties came from Salvia miltiorrhiza Bunge root, an ingredient found in around a third of the anti-fibrotic formulae they tested. However, a very small number of plants recommended by TCM practitioners for fibrotic diseases were actually found to be pro-fibrotic. As at least one profibrotic compound is known to cause renal fibrosis and end-stage kidney failure, identification of the active compounds underlying these pro-fibrotic activities is vital. Further development toward finding an anti-fibrotic medication will involve an animal model of fibrosis that can distinguish between compounds that are anti-fibrotic, pro-fibrotic, or have no effect. ‘The model is independent of inflammation,’ says Dr Xu, ‘which is important as while we have a lot of medications to tackle inflammation (often the inciting factor of fibrosis), we have none that tackles fibrosis itself.’ With clinical trials in view, they are currently combining three herbs in different ways to find a best-fit in cellular and animal models. ‘The great thing about using TCM ingredients is that many have been used in people for centuries so the ones we are trying we already know to be safe in patients,’ concludes Dr Xu.

The most potent antifibrotic properties came from Salvia miltiorrhiza Bunge root, an ingredient found in around a third of the anti-fibrotic formulae they tested

About the researcher https://kclpure.kcl.ac.uk/portal/qihe.xu.html

From bench to bedside

5. From bench to bedside

Is simplifying drug regimes always better?

n their research into medication adherence, Dr Vivian Auyeung and Dr Jignesh Patel have recently focused their attention on to novel oral anticoagulant therapies (NOACs). Currently, many needing anticoagulation treatment are prescribed warfarin. As this drug exhibits large inter-patient variability, people taking warfarin require regular monitoring at an anticoagulation clinic such as the one Dr Patel contributes to at King’s College Hospital NHS Foundation Trust (KCH). ‘The beauty of this though,’ says Dr Patel ‘is that when someone comes into the anticoagulation clinic they get to ask questions about their illness and treatment and we are able to provide ongoing support with their warfarin therapy.’ With the advent of NOACs, patients do not need nearly as much monitoring. ‘This is great from a convenience perspective,’ says Dr Auyeung, ‘but this creates an interesting scenario. It may be that because they don’t have that ongoing support, they don’t think their illness is as serious anymore, which will influence whether or not they adhere to their treatment.’ As such, Dr Auyeung and Dr Patel are now looking at illness perception and therapy beliefs of those switched from warfarin to NOACs. Dr Patel is also interested in how NOACs are best prescribed. ‘They’re licensed as a ‘one-size fits all’ medication but we’re not sure this is completely true for ‘real-world’ patients. We’re looking at whether we need to individualise treatments to minimise toxicity, especially for frail elderly patients.’ Both Dr Patel and Dr Auyeung are also involved in other aspects of patient care. For instance, Dr Patel leads the King’s Anticoagulation Reference Centre, a joint initiative between the Institute of Pharmaceutical Science and KCH (under Professor Roopen Arya) that acts as a hub for anticoagulationspecific expertise and information. ‘Here we have clinical and research experience mixing real-world and lab-based research into practice.’ For example, with Professor Bob Flanagan, Director of the Toxicology Unit at KCH, they’ve developed an assay that can quantify any of the NOACs using mass spectrometry. This is useful when, for example, an unconscious patient comes into Accident and Emergency and there is a need to know if they are on anticoagulant therapy and which kind. Dr Auyeung, a psychologist, also works with King’s Health Partners, especially those at St Thomas’ Hospital. ‘I’m interested in how patients think about their medicine and what they do with them once they get home. When a patient leaves hospital they should know what their medication is called, how to take it and what the side effects may be, but we found an information gap as nobody was sure who was supposed to be giving this information. The doctors? The pharmacists? The nurses?’ Spotting this problem led to a change in practice. Patients on cardiac wards at St Thomas’ now get a leaflet when they are admitted titled ‘Questions about your medicines.’ This gives them a range of questions other people have asked, lets them know who to speak to about their medication and provides them with a way of writing down questions specific to them. ‘This really empowers them to ask about their medicines,’ explains Dr Auyeung.

It may be that because people don’t have ongoing support, they don’t think their illness is as serious anymore, which will influence whether or not they adhere to their treatment

About the researchers https://kclpure.kcl.ac.uk/portal/jig.patel.html https://kclpure.kcl.ac.uk/portal/vivian.auyeung.html

5. From bench to bedside

The treatment’s been prescribed... so why isn’t the patient responding properly? Patients need to understand the longterm efficacy and value of their treatment, as opposed to only shortterm gains and goals

rofessor John Weinman, an expert in treatment adherence, tells how ‘the vast majority of medical problems seen in the NHS are long-term conditions where patients need to manage themselves to maintain their current level of health and/or prevent negative outcomes. However,’ continues Professor Weinman, ‘for many years, there has been evidence that this is problematic.’ In fact, backed-up by a World Health Organisation report, Professor Weinman estimates that ‘approaching half of those with long term health problems do not adhere to treatment.’ When looking into the problem, Professor Weinman and his group realised that it wasn’t just a case of practical issues. ‘Even if we provide reminders, simplify the regimen or deliver treatment to a patient’s home, for some, non-adherence still exists. Instead,’ he continues, ‘the key issues are around the patient’s beliefs about their illness and their treatment.’ As such, his team’s research, aided by development of their Illness Perception Questionnaire, looks fundamentally at how the pattern and profile of beliefs the patient has about their illness and treatment have important impacts on their level of motivation and engagement. ‘The great thing about beliefs though,’ says Weinman, ‘is that they are modifiable. Patients need to understand the long-term efficacy and value of their treatment, as opposed to only short-term gains and goals.’ To aid in adherence, Professor Weinman’s team has developed brief, focused interventions that help patients find different ways to think about their illness and use treatment more effectively. A study with people recovering from a first time heart attack showed that just three 20 minute sessions resulted in improved recovery and self-management. Another successful intervention provided personally tailored text messages to people with asthma that challenged the way the receiver thought about their illness and treatment. A further success, with people taking bisphosphonates for osteoporosis, used a cognitively-based, brief intervention delivered by phone to unravel unhelpful beliefs and then link new ones to more effective medicines use behaviours. One huge outcome of this work has been Prof Weinman’s collaboration with Atlantis Healthcare, a leading worldwide commercial provider of patient adherence and support programmes. Atlantis Healthcare delivers programmes across 51 disease states including Alzheimer’s disease, cancer, diabetes, erectile dysfunction, hearing loss, hepatitis C, incontinence and pain. The Managing Director of Atlantis Healthcare UK says that: ‘our distinctiveness and acclaimed success is highly dependent on the rigorous and proven approaches pioneered by Professor Weinman and his colleagues over the past 15 years.’ Professor Weinman continues his work into ways to combat non-adherence. He is the joint principal investigator on a huge worldwide study in collaboration with the pharmaceutical company AbbVie that is looking at illness and treatment beliefs in relation to adherence in almost 8,000 people with rheumatoid arthritis, psoriasis or irritable bowel disease. This is the largest ever study to investigate all these factors and has been conducted in over 30 different countries around the world. ‘The data collection has been completed,’ explains Professor Weinman, ‘and the results will provide important insights into the nature and possible different reasons for non-adherence across these countries and will provide a powerful basis for developing adherence support programmes on a global scale.’

About the researcher

https://kclpure.kcl.ac.uk/portal/john.weinman.html

5. From bench to bedside

Children are not just half-sized adults

r Paul Long is a founding member of a UK research network called Improving Children’s Antibiotic Prescribing (iCAP). ‘If you look at penicillin,’ he explains ‘prescribing is based on four age bands. A 12–18 year old, regardless of any other factors, will get half the adult dose, a 6–12 year old gets half of that, a 1–5 year old half again and below one, they will get what now amounts to 1/16th of the adult dose.’ The group were puzzled by the rationale behind this and found that the guidance dates back to 1963. ‘We found that one of the main reasons why it was put in place was simply that liquid dispensing spoons were crafted to have 5mls on one side and a half measure of 2.5mls on the other. There really was no scientific reason for it. What was also hugely interesting,’ he continues, ‘is that in the original guidance there was detailing of the average weight for a child in each band. We realised that children are now a lot heavier so while this halving of dose may have been fine for the average-size child of the 1960, in real terms, the average-size child of nowadays is getting a lower dose than they would have had 50 years ago.’ The iCAP team is currently focused on best prescribing practices in Primary Care. ‘One thing we found out,’ explains Dr Long, ‘is that GPs do not know these details and in fact they tend to play safe and put children in an age band lower than they should be. This is particularly the case for otitis media, an ear infection that is the most common reason a child will receive antibiotics from their GP. There is actually clear guidance in the UK regarding dose to give in terms of weight – it should be at least 40mg/kg – but by iCAP’s calculations, currently only children under one get the required dose, all other children up to the age of about 15 only get around a third they’re supposed to. This is worrying as there may be children having to repeatedly go back to the GP or even be hospitalised because they are not getting enough of an antibiotic to treat their infection.’ This is also troubling as under-dosing could be one of the things driving antibiotic resistance. As such, iCAP are trying to look into the behaviour of GPs and why they are under-dosing. Have they learnt that most children get better so they are being very cautious while being shown to treat? Do they worry that giving higher doses will increase the amount of adverse events? What are the barriers and drivers of weight-based prescribing? Ultimately they aim to answer these questions so that GPs will have a much clearer idea of how to correctly prescribe antibiotics and children will get the treatment they best need.

There may be children having to repeatedly go back or even be hospitalised because they are not getting enough of an antibiotic to treat their infection

Pewter dosing spoon. Image courtesy of the Wellcome Library, London

About the researcher https://kclpure.kcl.ac.uk/portal/paul.long.html

5. From bench to bedside

Perfecting prescribing through naturalistic research

M While there are other guides to prescribing of psychotropic medications, The Maudsley Prescribing Guidelines are the most fully evidence-based

ental illness is a growing global problem affecting over a billion people at some point in their lives. While lifetime risk of severe mental illness (schizophrenia and bipolar affective disorder) is 2.5%, for depression and anxiety this figure is around 20%. Drug therapy is the mainstay of treatment but prescribing is complex and optimal prescribing is hard to achieve. While clinical trials assess the efficacy and safety of medications in a discrete group of patients under defined circumstances, more naturalistic studies beyond these trials are needed to extend practical prescribing knowledge. Professor David Taylor and his team, who concentrate on the use of psychotropic medications and are based in the Pharmacy department at the South London and Maudsley NHS Foundation Trust (SLaM), are at the forefront of this pharmacoepidemiological type of research. ‘Akin to Phase IV analysis,’ he explains, ‘we look at what the benefits or otherwise drugs provide when introduced to clinical practice.’ Alongside these naturalistic studies, Professor Taylor’s group have published a number of summations of clinical outcomes in the form of meta-analyses. Their work is provoked by enquiries received through the National Centre for Medicines Information in Mental Health, operated by Professor Taylor’s group. ‘We base our research on the questions people ask our service with regard to prescribing psychiatric drugs,’ says Professor Taylor. ‘If we can’t find an answer in the literature we are in place to do the appropriate research.’ He explains how ‘we really have an ideal situation at King’s. At SLaM we have expertise amongst pharmacists working in psychiatry as well as internationally-recognised experts in psychiatry practice; next door, at the Institute of Psychiatry, we have worldrenowned researchers.’ With such a huge database, along with more direct resources available in the surrounding community, study protocols can be varied according to need. Published papers include showing which antipsychotics are most commonly prescribed, singularly or in combination; detailing the potential side effects of psychotropic medications and producing dosing guides using data from therapeutic drug monitoring. ‘This approach has generated a huge amount of original results contained within over 200 papers over the last 20 years’ says Professor Taylor. ‘The usefulness of what we’ve done is reflected in that as a body of work our papers have nearly 5,000 citations.’ One major publication their research helps inform the content of is the Maudsley Prescribing Guidelines, authored by Professor Taylor along with other SLaM staff and King’s academics. Now in its 11th edition, The Guidelines have been in continuous production for twenty years. Updated every two years, they’ve sold over 200,000 copies in nine languages and also come in electronic and iPad versions. ‘The original intention was to provide up to date answers on almost any question in clinical psychopharmacology,’ explains Professor Taylor. ‘As we’ve tried to achieve that, the book’s got bigger and bigger.’ While there are other guides to prescribing of psychotropic medications, these are the most fully evidence-based and are widely regarded as the leading clinical reference for all those involved in prescribing for mental illness.

About the researcher

https://kclpure.kcl.ac.uk/portal/david.taylor.html

6. Science in action

Helping teenagers take science into space

t’s 18:07 hours, January 9th, 2014: Seven British teenagers stare in excitement at a live feed of a rocket taking off from NASA’s Wallops Island Launch Centre in the United States. Sitting alongside them are King’s academics and staff including Dr Julie Keeble, Professor Steve Harridge, Zoe Gaffen and Francesca Slattery. The teenagers are there because they, along with five others, won a competition when taking part in the International Space School Educational Trust’s (ISSET) Mission Discovery Programme at King’s in 2012. They competed alongside around 250 other 14–18 year olds, some of whom gained sponsored places, recruited from all over the UK through ISSET and as part of King’s Widening Participation Programme work with the local community. The annual Mission Discovery Programme takes place over a week and involves a mix of lectures and practical workshops by biomedical scientists at King’s about the science of microgravity, Skype link-ups with NASA physiologists and face-to-face chats with NASA representatives, who in 2012 included Ken Ham, a Space Shuttle Commander, and Michelle Ham, a NASA trainer and ISSET’s US Director. Following this, the students split into teams and competed to design an experiment that could be carried out to the ISS. ‘In the first year the winning experiment aimed to look at the effectiveness of ampicillin in inhibiting e-coli growth in microgravity’ explains Dr Keeble. ‘Antibiotics are considered to be less effective in space but very little research has been done to show this. In terms of long term missions especially, this could be very important.’ The second experiment chosen involved seeing how slime mould grows. This single-celled organism is famed for the ability of its plasmodia to find the shortest possible connections between complex networks. ‘On earth it really only spreads in ‘two dimensions’,’ says Dr Keeble, ‘but the students questioned how it would grow in space. Would it move out into ‘three dimensions’ and so possibly be able to help solve complex wiring problems?’ Once the winners were chosen, Dr Keeble worked with the students and other King’s scientists to make sure the protocols were manageable. She then travelled to Houston to liaise with the company NanoRacks who specialise in helping people carry out research on the ISS. ‘There are a lot of technical requirements to be considered for the experiments,’ explains Dr Keeble, ‘they have to fit into a defined space; have to be stored in the cold for transport, but initiated at room temperature; have to be behind two levels of containment, so are hard to manipulate, and have to run with very little input from the astronauts except for taking pictures. Also, if anything is new to NASA it needs to have a complete safety profile drawn up.’ The next round of winning experiments include looking at whether daphnia reproduce sexually or asexually in space, finding out the effect of plant steroids on their growth in micro-gravity and looking at food degradation by saprophytes. While these experiments hope to produce useable results, ‘ultimately,’ says Dr Keeble ‘the Mission Discovery Programme is there to inspire the kids and increase their aspirations to think that they can do more than they could possibly realise before they took part.’

The Mission Discovery Programme is there to inspire the kids and increase their aspirations

The rocket containing experiments designed by Mission Discovery Programme teenage participants takes off from a NASA launch pad

About the researcher https://kclpure.kcl.ac.uk/portal/julie.keeble.html

6. Science in action

Keeping hazardous drivers off the roads, helping re-license those who have reformed

A The %CDT test has now been approved as the sole biomarker for use in re-assessing high risk driving offenders

round 40,000 people a year in the UK strive to get their licence back from the Driver and Vehicle Licensing Agency (DVLA) having lost it through repeated drink-driving offences. To be able to do so, these ‘High Risk Offenders’ (HROs) must pass a medical assessment to demonstrate they are alcohol free. Historically, this assessment relied on four or five blood biomarkers but concerns raised about the specificity and sensitivity of these tests led to the Department for Transport (DfT) providing funding to Dr Kim Wolff in the late 2000s to identify a better marker of alcohol consumption. The biomarker they investigated – carbohydrate deficient transferrin (CDT) – had been shown to be a much more specific marker of changes made to the body by continuous alcohol consumption compared to the then current panel of tests whose performance can be confounded by non-alcoholic liver disease. Problems also arose because a positive test result could also be obtained in certain medical conditions. Dr Wolff led the first investigation of CDT in a UK population. ‘This was valuable research,’ she says, ‘as government departments are keen that results are contextualised to the British public.’ ‘What was unique about our study,’ reports Dr Wolff ‘was that we integrated a scientific approach to assessing alcohol consumption with the practical need of keeping high-risk drivers off the roads.’ She reports how ‘our research enabled us to look at how well biomarkers could identify those who continued to drink and to separate them out from a general population who weren’t drinking in a problematic way.’ In detailing the study, Dr Wolff discusses how ‘we recruited a wide spectrum of subjects, from social drinkers right through to those who had been hospitalised due to chronic alcohol dependence. It also included people with conditions that may confound the currently-used biomarkers including liver disease, diabetes and obesity.’ Thanks to the research of Dr Wolff and her team, the DfT concluded in their 2010 Road Safety Report that ‘CDT is reliable enough on its own to support a diagnosis of alcohol dependence, harmful or hazardous use and has the advantage that common medications seem to have no influence on the performance of this biomarker.’ As a member of the Secretary of State for Transport’s Honorary Medical Advisory Panel on Alcohol, Drugs and Substance Misuse and Driving (HMAP), Dr Wolff presented her research to the DVLA and, after a short trial period in 2012–13, the %CDT test has now been approved as the sole biomarker for use in re-assessing HROs. ‘What is great,’ says Dr Wolff ‘is that the research works at both ends of the spectrum. The DVLA is more confident in releasing previous drivers who were harmful back to driving and they are much more assured of those that are not given back a licence to drive.’ The Chair of HMAP confirms that ‘this more accurate test has resulted in quicker decisions, fewer appeals against licensing decisions, a greater ethos of evaluation and more research.’ But this is not the end of the relationship between King’s and the DVLA, Dr Wolff highlights how they are ‘continuing to improve the sensitivity of the test by looking at other variables such as pregnancy, prescribed medication and young drinkers.’

About the researcher

https://kclpure.kcl.ac.uk/portal/kim.wolff.html

6. Science in action

The complexities of assessing drug-driving

ear of roadside testing for drunk-driving has radically helped cut the number of accidents due to someone getting behind the wheel when over the limit. Currently though, there are no such standard procedures for those whose choice of intoxicant isn’t alcohol or for whom a prescribed drug may have an unintended adverse effect. ‘The public awareness about the risk of drug driving is quite poor,’ says Dr Kim Wolff, ‘I don’t think people recognise that drugs are as dangerous as alcohol in terms of their ability to impair driver safety.’ In light of this, and in response to the North Report on Drink and Drug Driving Law (2010), a Department for Transport expert panel chaired by Dr Wolff produced the 2013 ‘Driving Under the Influence of Drugs’ report. This review concentrated on substances covered under the Misuse of Drugs Act 1971 including opiates, cocaine, amphetamines, cannabis, ecstasy (MDMA), methadone and benzodiazepines. Similar to the way in which alcohol thresholds are used, the report utilised what is known scientifically about these drugs to suggest threshold limits when it comes to prosecution. However, as some of these drugs are either illegal or used beyond how they are prescribed, many have called for a zero tolerance approach. To find what sits best with the majority, the UK Government has recently put out a public consultation on the matter. In addition, as part of an expert committee commissioned by the Home Office, Dr Wolff is currently helping the UK Government to look at all of the complexities surrounding implementation of new legislation on drugdriving. This includes debate around what technology is best to use and whether or not to test and measure at the roadside. The new legislation is scheduled to become law in the spring of 2015. ‘A key finding that came out of our research was that prescribed medications such as sleeping tablets, strong analgesics and anxiolytics can also cause impairment in driving,’ says Dr Wolff. This has led to a discussion as to who is responsible for driver safety. Although the driver must ultimately make the decision about his/her fitness to drive, the prescribing physician or manufacturer also needs to bear responsibility for making sure the patient is fully aware of the consequences of driving under the influence of certain medications. As such, Dr Wolff is helping the UK government to draw-up guidelines to aid healthcare professionals, including clinicians and pharmacists in giving appropriate advice about drugs and driving.

I don’t think people recognise that drugs are as dangerous as alcohol in terms of their ability to impair driver safety

Image courtesy of the Wellcome Library, London About the researcher https://kclpure.kcl.ac.uk/portal/kim.wolff.html

6. Science in action

Beating those cheating In collaboration with GlaxoSmithKline, the Drug Control Centre delivered all of the antidoping analysis at the London 2012 Olympic and Paralympic Games

Image courtesy of the Wellcome Library, London

hen mass spectator endurance sports such as cycling became the rage in Europe in the 1800s, so did the ‘any means necessary’ tactics to win. Opium, cocaine, amphetamines and nitroglycerine could all be found at some point in the athlete’s kit or trainer’s bag. Modern science has brought more sophisticated methods to help the drive to win including the use of anabolic steroids, erythropoietin and human growth hormone. Matching the development of performance-enhancing substances is the need to test for those that are banned. At the forefront of this branch of science are Professor David Cowan and his team at the Drug Control Centre (DCC).The DCC was the first human sports drugtesting laboratory established outside of an Olympic Games and is still the only accredited anti-doping laboratory in the UK. The DCC has developed a myriad of tests for detecting performance-enhancing substances, the majority of which involve the use of mass spectrometry. They first applied their expertise in finding the hormone human chorionic gonadotropin (hCG) to UK cycling’s Milk Race in the 1980s. Their findings that a number of the winners tested positive led to the International Olympic Committee adding hCG to their list of banned substances. The DCC have since developed tests for many other substances including the anabolic steroid 5α-dihydrotestosterone and several stimulants. Additionally the DCC works to refine testing, for instance by tweaking how the hormone nandrolone is detected they can distinguish those misusing it for competitive gain and those using oral contraceptives containing norethisterone, which may give rise to a suspicious result. ‘Before this,’ says Professor Cowan ‘there may have been both people cheating and beating the test and those who were falsely accused.’ One feature that distinguishes the DCC is the scale of their research, for example, the nandrolone study involved a group of over 1,200 female volunteers. Due to their expertise, the DCC has a long-term relationship with the International Olympic Committee, starting with Sarajevo in 1984, and with the Commonwealth Games. A highlight for the DCC is that in collaboration with GlaxoSmithKline (GSK), they delivered all of the anti-doping analysis at the London 2012 Olympic and Paralympic Games. This operation was characterised by unprecedented scale, speed and accuracy. ‘We really changed the approach here,’ recalls Professor Cowan, ‘we made sure we put a great amount of scientific innovation into drug testing and used it as an opportunity to re-evaluate and refine our methods so they could be successfully up-scaled.’ Testing was delivered from the state-of-the-art Anti-Doping Science Centre (ADSC). Working around the clock throughout both the Olympics and Paralympics they analysed more than 6,250 samples in accordance with the highest possible standard of accreditation for analytical work. One renowned success was that using the new biomarker test developed by the DCC and the University of Southampton they identified for the first time the administration of recombinant human growth hormone in two athletes. The DCC/GSK partnership also ran the public outreach programme ‘Scientists in Sport’ that shared the science behind drug testing with schools and the community. The DCC is now working with those setting up a similar laboratory in Rio de Janeiro for the 2016 Olympic and Paralympic Games. The latest highlight is their work with UK Anti-Doping, with whom they are pioneering ‘athlete biological passports’ that provide long term data an athlete can carry with them wherever they train and compete.

About the researcher

https://kclpure.kcl.ac.uk/portal/david.a.cowan.html

Institute of Pharmaceutical Science Faculty of Life Sciences & Medicine 5th Floor Franklin-Wilkins Building Kingâ&#x20AC;&#x2122;s College London 150 Stamford Street London, SE1 9NH Tel: +44 (0) 20 7848 4295 www.kcl.ac.uk/ips Additional copies of this publication are available from the Institute of Pharmaceutical Scienceâ&#x20AC;&#x2122;s Divisional Manager This publication is also available online at: www.kcl.ac.uk/ips Written by Dr Eleanor Roberts