Download From molecules to medicine Institute of Pharmaceutical

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
4
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
12
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
20
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
28
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
32
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
38
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
3
1.
Starting with
the basics
1. Starting with the basics
The elastic behaviour
of wormlike micelles
N
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
5
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
6
https://kclpure.kcl.ac.uk/portal/cristina.legido_quigley.html
1. Starting with the basics
When is an insult not an insult?
P
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
d
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
7
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
D
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
8
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
M
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
9
7
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
10
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)
A
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
11
2.
Drug
discovery
2. Drug discovery
Targeting transcription factors
in the fight against cancer
E
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...
13
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
14
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
R
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
15
2. Drug discovery
Understanding chronic cough
may lead to much-needed help
A
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
16
https://kclpure.kcl.ac.uk/portal/domenico.spina.html
2. Drug discovery
Gastrin inhibitors:
a new angle on some
age-old problems
T
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
17
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
O
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
18
Professor Robert Hider: http://bit.ly/1uuXcHJ
https://kclpure.kcl.ac.uk/portal/sukhi.bansal.html
Running head
Living better with
Parkinson’s disease
I
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
19
3.
Drug formulation
and development
3. Drug formulation and development
Targeted drug delivery through
the use of nanomedicines
D
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
21
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
22
https://kclpure.kcl.ac.uk/portal/sarah.thomas.html
3. Drug formulation and development
Challenges in developing novel
inhaled medicines
D
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
23
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
D
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
24
https://kclpure.kcl.ac.uk/portal/stuart.jones.html
3. Drug formulation and development
Image guided drug delivery:
targeted treatments for cancer
D
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
25
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
26
https://kclpure.kcl.ac.uk/portal/lea_ann.dailey.html
3. Drug formulation and development
Dial-up medicine gets personal
P
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
27
4.
Natural
medicines
4. Natural medicines
At one with nature under the sun
L
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
29 27
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
30
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
F
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
31
5.
From bench
to bedside
5. From bench to bedside
Is simplifying drug
regimes always better?
I
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
33
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
P
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
34
https://kclpure.kcl.ac.uk/portal/john.weinman.html
5. From bench to bedside
Children are not just
half-sized adults
D
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
35
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
36
https://kclpure.kcl.ac.uk/portal/david.taylor.html
6.
Science
in action
6. Science in action
Helping teenagers
take science into space
I
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
39
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
40
https://kclpure.kcl.ac.uk/portal/kim.wolff.html
6. Science in action
The complexities of assessing
drug-driving
F
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
41
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
W
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
42
40
https://kclpure.kcl.ac.uk/portal/david.a.cowan.html
Institute of Pharmaceutical Science
Faculty of Life Sciences & Medicine
5th Floor
Franklin-Wilkins Building
King’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 Science’s Divisional Manager
This publication is also available online at: www.kcl.ac.uk/ips
Written by Dr Eleanor Roberts