Pharmacy and Pharmaceutical Sciences research at Manchester provides an integrated, multidisciplinary environment for pharmacists, natural scientists (biologists, chemists, physicists), technologists, economists, social scientists and psychologists to undertake leading-edge interdisciplinary medicines and related research translating into the clinic, industry and healthcare. High quality academic output (top-rated RAE 5A by external peer review) combined with a successful track record of innovation (2 ventures realised and over 20 patents filed in the last year), continue to provide an environment for consistent, long term growth of our research base. Individualised medicines research (relating to variable drug responses) is our major research theme, and together with anti-cancer and anti-microbial drugs, integrates our main 3 areas of expertise: drug design and action, drug delivery and pharmacokinetics, drug usage in primary care and pharmacy practice research. There is a great deal of joint research carried out across our research programmes which are outlined below with links for general enquiries and to individual staff for prospective graduate students, researchers, collaborators or customers to contact us and find out more about our research, or our facilities, services and intellectual property.
DRUG DELIVERY & PHARMACOKINETICS GROUP
DRUG DESIGN & ACTION
Physiological abnormalities, drug design and synthesis and and drug resistance in cancer and infectious disease
The abnormal physiology of diseases (eg cancer) leads to major spatial and temporal gradients in tissue (eg oxygen and nutrients in solid tumours), which vary between and within (eg tumour type/grade) individuals and impact on treatment outcomes. The level of and response to hypoxia (low oxygen tension) is providing unique therapeutic and targeting strategies including: bioreductive drugs specifically-activated by particular reductases, hypoxia-mediated gene therapy, cell growth factor inhibitors, manipulation of nitric oxide synthesis and the influence of oestrogen levels. Transcription factor studies are particularly focused on the hypoxia inducible factor (HIF), which functions via the aromatic hydrocarbon nuclear translocator (ARNT); knocking-out HIF increases tumour response to radiotherapy providing a new therapeutic target (I.J. Stratford). ARNT also heterodimerises with the aromatic hydrocarbon receptor (AhR) and binds xenobiotic response elements (XREs), controlling drug metabolising (CYP) enzymes. Recombinant and molecular genetic methods are used extensively to construct drug metabolism models and to support structural studies probing drug resistance and DNA repair (J. Andrews).
DNA repair systems are important in the clinical development of tumour resistance The basis of inherent drug resistance is being investigated using testicular cancers as models (C.M. Chresta). Studies on the molecular mechanisms of DNA repair include: oxoguanine repair by the human FPG protein, the human HAT system and the E. coli Mut proteins.
The molecular basis of antibiotic resistance and drug design and action is being probed using high field NMR, molecular modelling and distance geometry which also rational development of novel DNA-, RNA- and protein-directed ligands. Structural studies of DNA-ligand interaction is developing novel DNA cleavers, target-assembled DNA probes, split-oligo antisense systems, and new ligands for tRNA. The work on DNA structure interfaces intimately with School activities on transcription factors, DNA repair, and design of novel molecular diagnostic systems (see below). Rational drug design has led to our synthesis of new compounds targeting tryanothione reductase, which are active in trypanosome/leishmania-infected macrophages, and has also produced the first example of rational drug design overcoming the clinical resistance mutations against pyrimethamine in malaria (K.T. Douglas). Analogues of myo-inositol phosphates are being synthesised for potential treatment of cystic fibrosis and for mechanistic studies with inositol monophosphatase, an enzyme of importance in manic depression. The design and synthesis of bioactive molecules and their prodrugs is important for the inhibiton of growth factors, for example TGF- b and thymidine phosphorylase, for potential use in wound healing and the treatment of solid tumours (S. Freeman). Isotopic substitution is being developed as a novel method to modulate the properties of therapeutic proteins. Whilst the large size of the bacterial ribosome still precludes the application of rational drug design to this important drug target, we have developed a semi-rational method based on NMR studies of conformation and physical organic chemistry. In collaboration with industry we are seeking to rehabilitate an old macrolide and develop a new macrolide with activity against Gram-negative bacteria (J. Barber). Plant cell cultures are being developed as a means of producing drugs, other useful secondary metabolites and excipients (G.B Lockwood).
Microorganisms in the biofilm state demonstrate marked physiological differences, including increased resistance to antimicrobials, compared to their planktonic state. Enabled by novel methods to study biofilms, antimicrobial systems are being designed and evaluated to combat microbial biofilms (in infected medical implants, industrial and food preparation plants, and water supplies), which, for example, has led to a novel catalytic method of control. Allied to this are studies on biospecific exoploymers, slime prevention, the impact of disinfection and cleansing programs on removal of biofilms, and the development of a poloxamer hydrogel model system to reproducibly determine the resistance properties of biofilms, now proposed as a European standard (P. Gilbert). Studies of the regulation of biofilm physiology by quorum sensing mechanisms have shown that bacterial extracellular products (eg homoserine lactones) influence the detachment and dispersal of bacteria from biofilms (D.G. Allison).
DRUG DELIVERY & PHARMACOKINETICS
Pharmacokinetics, drug metabolism and pharmacogenomics
For many drugs, much of the variability of response is ascribable to pharmacokinetics, as opposed to pharmacodynamics. To address this issue, as well as improve drug design and selection in early drug discovery, a major programme is underway to predict the pharamacokinetic behaviour, incorporating variability, in humans. Specifically, in vitro human biological information, together with structural and phtsicohemcial properties of compounds, is being integrated through a variety of scaling steps, within the framework of whole-body physiological modelling, to predict events in vivo, with validation of all steps using animal models.
A promising start has been made in demonstrating the ability to predict hepatic metabolic clearance in vivo from enzyme kinetic data, derived from in vitro systems comprising either hepatocytes or microsomes, now moving to heterologously-expressed human enzyme systems. A whole-organ liver model based on dispersion principles is being developed and refined to predict the influence of changes in protein binding, membrane permeability, and vascular perfusion on hepatic clearance. Through sensitivity analysis and formal lumping procedures, tractable whole body mathematical models, are being built, which have the ability to be both expanded or contracted in complexity, as needed (J.B. Houston).
These models are being used: to understand the pharmacokinetic behaviour of oligonucleotides; to study drug-drug interactions (including the use of human metabolic enzymes expressed in various cell lines); to identify the strengths and limitations of various in vitro metabolic systems for quantitative predictive relationships; to provide a rational basis for developing quantitative structure-pharmacokinetic relationshps; and to predict pharmacokinetic behaviour in humans from in vitro data for even relatively complex molecules, such as cyclosporin. Strong collaboration has developed with the Department of Gastrointestinal Sciences, initially aimed at delineating the physicochemical and physiological determinants of intestinal paracellular absorption of drugs. Collaboration has now been extended to two areas thought to limit the oral absorption of a diverse range of compounds. The basic structural requirements and functional role of a variety of human intestinal efflux transporters and the interrelationships between transport and metabolism is now being examined using molecular biology and other tools (M. Rowland).
Prediction of pharmacokinetics is one of the broad themes now being addressed by the Centre for Applied Pharmacokinetic Research, which engages in generic research of direct interest to the pharmaceutical industry and is funded through a consortium. CAPKR is also strongly engaged in research into the use of simulation modelling, incorporating mechanistically-based pharmacokinetic/pharmacodynamic relationships and their variability, to improve the design of clinical trials during the late phase of drug development. This work is complimented by research into the use of Bayesian and other statistical techniques to estimate from sparse data, as frequently arises in clinical settings, both inter-occasional and inter-subject variability in pharmacokinetic parameters within the population and into models that take into account variability in patient compliance patterns (L.J. Aarons).
Genetic factors are often of more consequence than the traditional measures, such as weight, age, and gender, in explaining patient variability in drug response; in particular they are key in elucidating inter-individual drug metabolising capabilities. Recognising this and the rapidly advances in molecular biology, genomics as well as microchip and related high throughput technologies, a major new chair initiative in pharmacogenomics has been funded (?1100K, ~?200K per annum for 6 years, Medeval) to spearhead research into the molecular basis for genetic variability in response. Establishing the relationships between genomic make-up and expression, and metabolomic functionality of the proteome, will ultimately produce diagnostics that will improve substantially the ability to predict a priori an individual's optimal drug requirements. A prime area for application is the cytochrome P450 enzyme family, and the establishment of quantitative prediction strategies for the complexities of its phenotypic response based on genotypic characteristics. The pharmacogenetics of this enzyme, responsible for the metabolism of almost the entire armoury of therapeutic agents, although is well documented at a qualitative level needs to progress quantitatively by linking its numerous functionalities (determinable though the use of mass spectrometry and high throughput technologies), characterising the expression levels of specific isoforms (requiring the development of novel detection approaches in cultured cellular systems), and identifying its genomic characteristics through the application of bioinformatics (Medeval Chair).
Drawing on bioimaging methods such as fluorescent recovery after photobleaching (FRAP, and other developments see FCS, TRF, DWI, below), the delivery, extravasation, tissue penetration and action of macromolecular systems, particularly gene therapy constructs in tumour, other tissues and model systems, are being studied. Quantitative imaging and measurement of diffusion in live tumour models is revealing for the first time the major physical and biological characteristics determining the delivery of genes and other macromolecular delivery systems, which is a prelude to overcoming existing limitations and realising the potential of these important systems. (D.A. Berk).
Drug delivery, diagnostics and imaging research
Polymeric and self-assembling drug delivery systems are being developed to modify or respond to the variability of biological pathways for the controlled and regional delivery of drugs, including therapeutic peptides, proteins and DNA. Biodegradable block copolymers and thermally-reversible gels are being developed as non-surgical sub-cutaneous implants for sustained release of drugs. Novel amphiphilic assemblies are being developed to avoid the low and/or variable bioavailability of first pass (hepatic and intestinal) metabolism of orally administered drugs (and peptides, proteins), by the promotion of delivery via the lymphatic system, and to deliver larger particles through mucosal barriers, as demonstrated by imaging their biodistribution (D. Attwood). The group is in a unique position to design and tailor GRAS polymers to solve formulation and delivery problems, which has led to extensive collaboration with industry, including for biopharmaceuticals, and for achieving biodegradability, hydrophilicity and solubilisation, mechanical integrity, taste masking etc. (J.H. Collett). Regional delivery in the GI tract has concentrated on developing and testing in vivo floating systems for the stomach, and delayed and responsive release systems for the colon (J.T. Fell). NMR, ESEM and erosion studies have provided detailed insight into the mechanism of erosion of polyanhydrides. Liquid crystal and polymeric systems are being developed for the pulsatile and responsive release of drugs (A.J. D'Emanuele). Novel fractal supermolecules (dendrimers) are under investigation for solubilising drugs with low aqueous solubility. The development of Pharmweb as a global source of pharmaceutical and pharmacy information has led to study of the use of IT in the pharmaceutical care of patients.
Novel fluor probes and detection systems are being developed to provide the high sensitivity and specificity necessary to move from in vitro assays to biological (cellular and in vivo) systems and to understand and develop biological pathways to target drugs. Emerging from high field NMR and molecular modelling studies of probe interactions with DNA (see above), a new family of highly specific probes are being developed that only produce specific signal on binding to target molecules. Novel bioresponsive lipopeptide assemblies are being developed that uniquely switch-on when immunotargeted to cells, when responding to cellular activities (eg pH, redox, exported proteins such as toxins and proteases) or when binding drugs (eg using P glycoprotein, AhR mimics). Novel peptides are also being developed to mimic the immuno-modulation behaviours of pathogens, particularly immunocamouflage and inflammation. Bioresponsive liposomes and lipopeptides are being evaluated to target tumours, drug resistant and intracellular pathogens, for the trafficking of DNA for gene therapy, and to detect low numbers of pathogens. Detection of individual molecular assemblies is being developed to provide ultrasensitive biodetection and the high spatial resolution required to advance microscopic imaging and micro-array high throughput screening. High speed (to GHz) digital photon correlation is being developed to analyse the train of photons emitted from individual fluor probes to provide for the first time continuous, time resolved fluorescence (TRF) and fluorescent correlation spectroscopy (FCS) analysis in biological materials. Photon correlation is also being developed to resolve optical information from turbid materials (eg drug formulations) and uniquely deep within tissue using diffusing wave imaging (DWI). Related methods are also being developed in informatics to correlate sparse data (D.J. Clarke).
DRUG USAGE & PHARMACY PRACTICE
Medicines usage in primary care and health services research
Since its inception in 1995, the group has been a partner in the DH-funded National Primary Care R&D Centre (NPCRDC), with two researchers holding joint appointments between NPCRDC and DUPP. A 4-year external review of NPCRDC, at the end of 1998, observed: "links with pharmacy have been successful. .........an important programme of research on the role of community pharmacists has been undertaken. .........the jointly funded appointments have been very productive, resulting in some excellent research." The Department of Health also funded a Pharmacy Practice Research Resource Centre (RRC) within the Group from 1991-6, which has led to an emphasis on method and structure development in practice research, and getting research into practice. The RRC has since engaged in a practice-research agenda-setting exercise for RPSGB, development of practice research in Sweden, and the establishment of an experimental community pharmacy panel. For the last five years the group has been a member of a seven-nation European Evaluation Network for Drug Expenditure and Policy (ENDEP). This is health policy analysis group with a particular interest in the pricing, costs and charging in the pharmaceutical sector.
The major research interests of DUPP are:
Prescribing - collaboration in the area of appropriateness of long term prescribing between NPCRDC and DUPP have been particularly productive. Building on expertise on influences on prescribing, an NHS HSR Training Fellowship has been secured to research variations in GP prescribing. As a partner in ENDEP, we are examining the impact of prescription charges on consumer and prescriber decision-making, having already completed work on the impact of deregulation of products on their NHS prescribing.
Health Care Consumers and Community Pharmacy - this has been a major area of activity of the group's own work programme and contribution to NPCRDC's programme on "population health, need and demand for care". Studies include health care consumer use of pharmacies, variation and appropriateness of advice giving in community pharmacy, and the communication of risk on de-regulated medicines.
Management of Minor Ailments - a study is underway to evaluate the feasibility of transferring the management of minor ailments from general medical practice to community pharmacies. Complementing this study the group has established, for an experimental period, a research panel of community pharmacies along the M62 corridor to study the management of minor ailments through community pharmacies. A detailed study is being made of information sources, particularly mass media used by young people (16-24 year olds) in the self management of minor ailments.
Pharmaceutical Care - the group was commissioned to evaluate a model of pharmaceutical care involving community pharmacists in the management of coronary heart disease, which demonstrated an improvement in lifestyle parameters in stable angina patients. The need for post operative pharmaceutical care is now being explored in short stay surgical patients, and liver transplant patients.
Health Economics - this is a relatively new aspect of the group's work but major funding has already been awarded for a pharmacy-led project to study the relative cost effectiveness of anaesthetic agents and techniques used in day surgery in adults and children. An MRC HSR Training Award to determine the cost effectiveness of managing in the entry of new drugs into the NHS, has been placed with the group.
? 2001 School of Pharmacy and Pharmaceutical Sciences, University of Manchester