A qualitative evaluation of the national rollout of a diabetes prevention programme in England.

BACKGROUND: The National Health Service Diabetes Prevention Programme (NHS DPP) was commissioned by NHS England in 2016 and rolled out in three 'waves' across the whole of England. It aims to help people with raised blood glucose levels reduce their risk of developing type 2 diabetes through behaviour change techniques (e.g., weight loss, dietary changes and exercise). An independent, longitudinal, mixed methods evaluation of the NHS DPP was undertaken. We report the findings from the implementation work package: a qualitative interview study with designated local leads, responsible for the local commissioning and implementation of the programme. The aim of the study was to explore how local implementation processes were enacted and adapted over time. METHODS: We conducted a telephone interview study across two time-points. Twenty-four semi-structured interviews with local leads across 19 sampled case sites were undertaken between October 2019 and January 2020 and 13 interviews with local leads across 13 sampled case sites were conducted between July 2020 and August 2020. Interviews aimed to reflect on the experience of implementation and explore how things changed over time. RESULTS: We identified four overarching themes to show how implementation was locally enacted and adapted across the sampled case sites: 1. Adapting to provider change; 2. Identification and referral; 3. Enhancing uptake in underserved populations; and 4. Digital and remote service options. CONCLUSION: This paper reports how designated local leads, responsible for local implementation of the NHS DPP, adapted implementation efforts over the course of a changing national diabetes prevention programme, including how local leads adapted implementation during the COVID-19 pandemic. This paper highlights three main factors that influence implementation: the importance of facilitation, the ability (or not) to tailor interventions to local needs and the role of context in implementation.

Reflections of patient and public involvement from a commissioned research project evaluating a nationally implemented NHS programme focused on diabetes prevention.

Patient and Public Involvement and Engagement (PPIE) in research is recognised by the National Institute for Health and Care Research as crucial for high quality research with practical benefit for patients and carers. Patient and public contributors can provide both personal knowledge and lived experiences which complement the perspectives of the academic research team. Nevertheless, effective PPIE must be tailored to the nature of the research, such as the size and scope of the research, whether it is researcher-led or independently commissioned, and whether the research aims to design an intervention or evaluate it. For example, commissioned research evaluations have potential limits on how PPIE can feed into the design of the research and the intervention. Such constraints may require re-orientation of PPIE input to other functions, such as supporting wider engagement and dissemination. In this commentary, we use the 'Guidance for Reporting Involvement of Patients and the Public' (GRIPP2) short form to share our own experiences of facilitating PPIE for a large, commissioned research project evaluating the National Health Service Diabetes Prevention Programme; a behavioural intervention for adults in England who are at high risk of developing type 2 diabetes. The programme was already widely implemented in routine practice when the research project and PPIE group were established. This commentary provides us with a unique opportunity to reflect on experiences of being part of a PPIE group in the context of a longer-term evaluation of a national programme, where the scope for involvement in the intervention design was more constrained, compared to PPIE within researcher-led intervention programmes. We reflect on PPIE in the design, analysis and dissemination of the research, including lessons learned for future PPIE work in large-scale commissioned evaluations of national programmes. Important considerations for this type of PPIE work include: ensuring the role of public contributors is clarified from the outset, the complexities of facilitating PPIE over longer project timeframes, and providing adequate support to public contributors and facilitators (including training, resources and flexible timelines) to ensure an inclusive and considerate approach. These findings can inform future PPIE plans for stakeholders involved in commissioned research.

Implementation, uptake and use of a digital COVID-19 symptom tracker in English care homes in the coronavirus pandemic: a mixed-methods, multi-locality case study.

BACKGROUND: COVID-19 spread rapidly in UK care homes for older people in the early pandemic. National infection control recommendations included remote resident assessment. A region in North-West England introduced a digital COVID-19 symptom tracker for homes to identify early signs of resident deterioration to facilitate care responses. We examined the implementation, uptake and use of the tracker in care homes across four geographical case study localities in the first year of the pandemic. METHODS: This was a rapid, mixed-methods, multi-locality case study. Tracker uptake was calculated using the number of care homes taking up the tracker as a proportion of the total number of care homes in a locality. Mean tracker use was summarised at locality level and compared. Semi-structured interviews were conducted with professionals involved in tracker implementation and used to explore implementation factors across localities. Template Analysis with the Consolidated Framework for Implementation Research (CFIR) guided the interpretation of qualitative data. RESULTS: Uptake varied across the four case study localities ranging between 13.8 and 77.8%. Tracker use decreased in all localities over time at different rates, with average use ranging between 18 and 58%. The implementation context differed between localities and the process of implementation deviated over time from the initially planned strategy, for stakeholder engagement and care homes' training. Four interpretative themes reflected the most influential factors appearing to affect tracker uptake and use: (1) the process of implementation, (2) implementation readiness, (3) clarity of purpose/perceived value and (4) relative priority in the context of wider system pressures. CONCLUSIONS: Our study findings resonate with the digital solutions evidence base prior to the COVID-19 pandemic, suggesting three key factors that can inform future development and implementation of rapid digital responses in care home settings even in times of crisis: an incremental approach to implementation with testing of organisational readiness and attention to implementation climate, particularly the innovation's fit with local contexts (i.e. systems, infrastructure, work processes and practices); involvement of end-users in innovation design and development; and enabling users' easy access to sustained, high-quality, appropriate training and support to enable staff to adapt to digital solutions.

Scale-up of ABC care bundle for intracerebral haemorrhage across two hyperacute stroke units in one region in England: a mixed methods evaluation of a quality improvement project.

BACKGROUND: Intracerebral haemorrhage (ICH) accounts for 10%-15% of strokes in the UK, but is responsible for half of all annual global stroke deaths. The ABC bundle for ICH was developed and implemented at Salford Royal Hospital, and was associated with a 44% reduction in 30-day case fatality. Implementation of the bundle was scaled out to the other hyperacute stroke units (HASUs) in the region from April 2017. A mixed methods evaluation was conducted alongside to investigate factors influencing implementation of the bundle across new settings, in order to provide lessons for future spread. METHODS: A harmonised quality improvement registry at each HASU captured consecutive patients with spontaneous ICH from October 2016 to March 2018 to capture process and outcome measures for preimplementation (October 2016 to March 2017) and implementation (April 2017 to March 2018) time periods. Statistical analyses were performed to determine differences in process measures and outcomes before and during implementation. Multiple qualitative methods (interviews, non-participant observation and project document analysis) captured how the bundle was implemented across the HASUs. RESULTS: HASU1 significantly reduced median anticoagulant reversal door-to-needle time from 132 min (IQR: 117-342) preimplementation to 76 min (64-113.5) after implementation and intensive blood pressure lowering door to target time from 345 min (204-866) preimplementation to 84 min (60-117) after implementation. No statistically significant improvements in process targets were observed at HASU2. No significant change was seen in 30-day mortality at either HASU. Qualitative evaluation identified the importance of facilitation during implementation and identified how contextual changes over time impacted on implementation. This identified the need for continued implementation support. CONCLUSION: The findings show how the ABC bundle can be successfully implemented into new settings and how challenges can impede implementation. Findings have been used to develop an implementation strategy to support future roll out of the bundle outside the region.

The challenges of integrating signposting into general practice: qualitative stakeholder perspectives on care navigation and social prescribing in primary care.

BACKGROUND: A national policy focus in England to address general practice workforce issues has led to a commitment to employ significant numbers of non-general practitioner (GP) roles to redistribute workload. This paper focuses on two such roles: the care navigation (CN) and social prescribing link worker (SPLW) roles, which both aim to introduce 'active signposting' into primary care, to direct patients to the right professional/services at the right time and free up GP time. There is a lack of research exploring staff views of how these roles are being planned and operationalised into general practice and how signposting is being integrated into primary care. METHODS: The design uses in-depth qualitative methods to explore a wide range of stakeholder staff views. We generated a purposive sample of 34 respondents who took part in 17 semi-structured interviews and one focus group (service leads, role holders and host general practice staff). We analysed data using a Template Analysis approach. RESULTS: Three key themes highlight the challenges of operationalising signposting into general practice: 1) role perception - signposting was made challenging by the way both roles were perceived by others (e.g. among the public, patients and general practice staff) and highlighted inherent tensions in the expressed aims of the policy of active signposting; 2) role preparedness - a lack of training meant that some receptionist staff felt unprepared to take on the CN role as expected and raised patient safety issues; for SPLW staff, training affected the consistency of service offer across an area; 3) integration and co-ordination of roles - a lack of planning and co-ordination across components of the health and care system challenged the success of integrating signposting into general practice. CONCLUSIONS: This study provides new insights from staff stakeholder perspectives into the challenges of integrating signposting into general practice, and highlights key factors affecting the success of signposting in practice. Clarity of role purpose and remit (including resolving tensions inherent the dual aims of 'active signposting'), appropriate training and skill development for role holders and adequate communication and engagement between stakeholders/partnership working across services, are required to enable successful integration of signposting into general practice.

Participatory codesign of patient involvement in a Learning Health System: How can data-driven care be patient-driven care?

BACKGROUND: A Learning Health System (LHS) is a model of how routinely collected health data can be used to improve care, creating 'virtuous cycles' between data and improvement. This requires the active involvement of health service stakeholders, including patients themselves. However, to date, research has explored the acceptability of being 'data donors' rather than considering patients as active contributors. The study aimed to understand how patients should be actively involved in an LHS. DESIGN: Ten participatory codesign workshops were conducted with eight experienced public contributors using visual, collective and iterative methods. This led contributors to challenge and revise not only the idea of an LHS but also revise the study aims and outputs. RESULTS: The contributors proposed three exemplar roles for patients in patient-driven LHS, which aligned with the idea of three forms of transparency: informational, participatory and accountability. 'Epistemic injustice' was considered a useful concept to express the risks of an LHS that did not provide active roles to patients (testimonial injustice) and that neglected their experience through collecting data that did not reflect the complexity of their lives (hermeneutic injustice). DISCUSSION: Patient involvement in an LHS should be 'with and by' patients, not 'about or for'. This requires systems to actively work with and respond to patient feedback, as demonstrated within the study itself by the adaptive approach to responding to contributor questions, to work in partnership with patients to create a 'virtuous alliance' to achieve change. PATIENT OR PUBLIC CONTRIBUTION: Public contributors were active partners throughout, and co-authored the paper.

Pre-hospital stroke recognition in a UK centralised stroke system: a qualitative evaluation of current practice.

BACKGROUND: A significant number of patients conveyed via ambulance to hyper acute stroke units (HASU) with suspected stroke have other diagnoses. This may delay treatment for non-stroke patients and cause burden to stroke teams. The Greater Manchester (GM) Connected Health Cities (CHC) stroke project links historical North West Ambulance Service NHS Trust (NWAS) data with Salford Royal Hospital electronic data to study stroke pathway compliance and accuracy of paramedic diagnosis and aims to use these data to improve pre-hospital clinicians' accurate recognition of stroke through development of service improvement innovations. We report on supplementary qualitative work required to understand stroke recognition from the pre-hospital clinician's perspective. METHODS: Focus groups and semi-structured interviews were conducted with pre-hospital clinicians of various grades, working in the GM area of NWAS. Focus groups and interviews were audio recorded and transcribed verbatim. We used thematic analysis informed by normalisation process theory (NPT) to analyse the data. This theory helps us to understand how innovations are developed, implemented and sustained into healthcare practice. RESULTS: Sixteen pre-hospital clinicians took part in two focus groups, one dyad interview and five one-to-one interviews. Analysis identified that respondents were unaware of false positive stroke rates entering onto the stroke pathway. Pre-hospital clinicians receive limited feedback from jobs and this impedes their ability to learn from their experiences. Respondents reported difficulty in ruling out stroke in certain patient cohorts and difficulty in recognising differential diagnoses. They expressed a lack of confidence to rule out stroke in the pre-hospital setting. They also expressed greater concern for 'missed strokes'. CONCLUSION: The qualitative findings support the development of innovations to improve accurate recognition of stroke in the pre-hospital setting.An enhanced FAST tool, better relations with HASU clinicians, feedback and education on the stroke pathway and differential diagnoses were all considered useful to improve accurate stroke recognition.

The Contradictions of Telehealth User Experience in Chronic Obstructive Pulmonary Disease (COPD): A Qualitative Meta-Synthesis.

OBJECTIVE: As the global burden of chronic disease rises, policy makers are showing a strong interest in adopting telehealth technologies for use in long term condition management, including COPD. However, there remain barriers to its implementation and sustained use. To date, there has been limited qualitative investigation into how users (both patients/carers and staff) perceive and experience the technology. We aimed to systematically review and synthesise the findings from qualitative studies that investigated user perspectives and experiences of telehealth in COPD management, in order to identify factors which may impact on uptake. METHOD: Systematic review and meta-synthesis of published qualitative studies of user (patients, their carers and clinicians) experience of telehealth technologies for the management of Chronic Obstructive Pulmonary Disease. ASSIA, CINAHL, Embase, Medline, PsychInfo and Web of Knowledge databases were searched up to October 2014. Reference lists of included studies and reference lists of key papers were also searched. Quality appraisal was guided by an adapted version of the CASP qualitative appraisal tool. FINDINGS: 705 references (after duplicates removed) were identified and 10 papers, relating to 7 studies were included in the review. Most authors of included studies had identified both positive and negative experiences of telehealth use in the management of COPD. Through a line of argument synthesis we were able to derive new insights from the data to identify three overarching themes that have the ability to either impede or promote positive user experience of telehealth in COPD: the influence on moral dilemmas of help seeking-(enables dependency or self-care); transforming interactions (increases risk or reassurance) and reconfiguration of 'work' practices (causes burden or empowerment). CONCLUSION: Findings from this meta-synthesis have implications for the future design and implementation of telehealth services. Future research needs to include potential users at an earlier stage of telehealth/service development.

A study to assess the feasibility of undertaking a randomized controlled trial of adherence with eye drops in glaucoma patients.

BACKGROUND: Adherence with therapy could influence the progression of glaucoma and ultimately affect the onset of visual impairment in some individuals. This feasibility study evaluated the measures to be used for a future randomized controlled trial assessing the effects of group-based education on adherence with eye drops. METHODS: People diagnosed with glaucoma within the previous 12 months attending a regional ophthalmology clinic in the North West of England were recruited. A two-session education program delivered one week apart had been devised as part of a previous project. A combined adult learning and health needs approach to education was taken. Outcomes measured were knowledge of glaucoma, self-report of adherence, illness perception, beliefs about medicines, patient enablement, and general health (Short Form-12). Adherence was also measured objectively using a Medical Events Monitoring System device. RESULTS: Twenty-six participants consented to undertake the educational program and 19 produced analyzable data. Knowledge of glaucoma, illness perception, beliefs about medicine, and patient enablement all showed statistically significant improvements after education. Mean adherence with eye drops was maintained above 85% before and for 3 months after attendance at the educational program. Self-report exaggerated adherence by at least 10% when compared with the objective Medical Events Monitoring System data, and in fact the kappa agreement was zero. CONCLUSION: All questionnaires other than the Short Form-12 were considered to be valuable measures and use of a Medical Events Monitoring System device was considered to be an objective surrogate measure for adherence with eye drops. A multicenter, randomized, controlled equivalence trial of group versus individualized education using adherence as the primary outcome is the next step.

Adherence to ocular hypotensive therapy: patient health education needs and views on group education.

BACKGROUND: In this study the authors sought both to understand the health education needs of patients with glaucoma, with particular regard to adherence to glaucoma treatment, and to examine these patients' views of group education. METHODS: Using a health promotion approach to health education, 27 qualitative interviews with new and established patients receiving glaucoma treatment were conducted. Health promotion is defined as a way of strengthening people's capacities to control and optimize their own health. The interviews were transcribed and were then analyzed thematically RESULTS: NINE CATEGORIES OF HEALTH EDUCATION NEEDS WERE IDENTIFIED FROM THE TRANSCRIPTS: (1) to understand glaucoma; (2) to understand their diagnosis or understand the difficulties in giving a diagnosis; (3) to understand the implications of eye drops, their side effects, and how to renew the eye drops; (4) to feel confident to put in eye drops; (5) to put the condition into perspective - to know how to manage their risk; (6) to be able to ask questions of clinicians; (7) to be able to navigate the health care system; (8) to understand and be able to manage own adherence behavior; and (9) to know where to access other sources of information. The majority of patients had something positive to say about group education, and about half of the patients said they would attend group education if they were offered the opportunity. CONCLUSION: A health promotion approach identified a wide range of patient-centered health education needs regarding adherence to glaucoma treatment. Group education will be attractive to some patients. Clinicians could use the health education needs identified in this study to guide the development of either individual or group-based educational intervention to improve adherence to glaucoma treatment. However, clinicians need to be aware that when developing a group intervention, attention will need to be given to making the education relevant to the circumstances of each patient.

Developing longitudinal qualitative designs: lessons learned and recommendations for health services research.

BACKGROUND: Longitudinal qualitative methods are becoming increasingly used in the health service research, but the method and challenges particular to health care settings are not well described in the literature.We reflect on the strategies used in a longitudinal qualitative study to explore the experience of symptoms in cancer patients and their carers, following participants from diagnosis for twelve months; we highlight ethical, practical, theoretical and methodological issues that need to be considered and addressed from the outset of a longitudinal qualitative study. RESULTS: Key considerations in undertaking longitudinal qualitative projects in health research, include the use of theory, utilizing multiple methods of analysis and giving consideration to the practical and ethical issues at an early stage. These can include issues of time and timing; data collection processes; changing the topic guide over time; recruitment considerations; retention of staff; issues around confidentiality; effects of project on staff and patients, and analyzing data within and across time. CONCLUSIONS: As longitudinal qualitative methods are becoming increasingly used in health services research, the methodological and practical challenges particular to health care settings need more robust approaches and conceptual improvement. We provide recommendations for the use of such designs. We have a particular focus on cancer patients, so this paper will have particular relevance for researchers interested in chronic and life limiting conditions.

Symptom experience in patients with gynecological cancers: the development of symptom cIusters through patient narratives.

The vast majority of the increasing cancer literature on physical and psychological symptom clusters is quantitative, attempting either to model clusters through statistical techniques or to test priori clusters for their strength of relationship. Narrative symptom clusters can be particularly sensitive outcomes that can generate conceptually meaningful hypotheses for symptom cluster research. We conducted a study to explore the explanation of patients about the development and coexistence of symptoms and how patients at tempted to self-manage them. We collected 2-month qualitative longitudinal data over four assessment points consisting of 39 interview data sets from 10 participants with gynecological cancer. Participants' experiences highlighted the presence of physical and psychological symptom clusters, complicating the patients 'symptom experience that often lasted 1 year. While some complementary and self-management approaches were used to manage symptoms, few options and interventions were discussed. The cancer care team maybe able to develop strategies for a more thorough patient assessment of symptoms reported as the most bother so mean and patient-centered sensitive interventions that encompass the physiological, psychological, sociocultural, and behavioral components of the symptom experience essential for effectives symptom management.

Interventions for cough in cancer.

BACKGROUND: Cough is a common symptom in patients with malignancies, especially in patients with lung cancer. Cough is not well controlled in clinical practice and clinicians have few management options to treat it. OBJECTIVES: The primary objective of this review was to determine the effectiveness of interventions, both pharmacological and non-pharmacological, (other than chemotherapy and external beam radiotherapy) in the management of cough in malignant disease (especially in lung cancer). SEARCH STRATEGY: Databases searched included: The Cochrane Central Register of Controlled Trials (CENTRAL) and the Database of Abstracts of Reviews of Effectiveness (DARE) (The Cochrane Library issue 4, 2009); MEDLINE (1966 to May 2010); EMBASE (1980 to May 2010); CINAHL (1980 to May 2010); PSYCHINFO (1980 to May 2010); AMED (1985 to May 2010); SIGLE (1980 to May 2010); British Nursing Index (1985 to May 2010); CancerLit (1975 to May 2010). We searched for cough suppressants, antitussives and other drugs with antitussive activity as well as non-pharmacological interventions (see Appendices 1-4 for search terms). SELECTION CRITERIA: We selected randomised controlled trials (RCTs) and clinical trials (quasi-experimental trials, and trials where there is a comparison group but no mention of randomisation) in participants with primary or metastatic lung cancer or other cancers. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed titles and abstracts of all studies, and extracted data from all selected studies before reaching consensus. A third review author arbitrated with any disagreement. Meta-analysis was not attempted due to the heterogeneity of studies. MAIN RESULTS: Seventeen studies met inclusion criteria and examined either brachytherapy, laser or photodynamic therapy (eight studies) or a variety of pharmacological therapies (nine studies). Overall, there was absence of credible evidence and the majority of studies were of low methodological quality and high risk of bias. Brachytherapy seemed to improve cough in a variety of doses in selected participants, suggesting that possibly the lowest effective dose should be used to minimise side effects. Photodynamic therapy was examined in one study, and while improvements in cough were observed, its role over other therapies for cough is unclear. Some indication of effect was observed with morphine, codeine, dihydrocodeine, levodropropizine, sodium cromoglycate and butamirate citrate linctus (cough syrup), although all studies had significant risk of bias. AUTHORS' CONCLUSIONS: No practice recommendations could be drawn from this review. There is an urgent need to increase the number and quality of studies evaluating the effects of interventions in the management of cough in cancer.

Symptom experience in patients with primary brain tumours: a longitudinal exploratory study.

PURPOSE: This study was undertaken to further understand the symptom experience and the impact of symptoms in daily life in people treated for brain tumours. METHODS: A qualitative prospective longitudinal design was used with 9 people who were interviewed over 4 time points (soon after diagnosis, 3 months, 6 months and 12-months post-diagnosis), providing 21 interviews in total. RESULTS: Key issues for these participants were ongoing fatigue, memory loss and inability to drive. Fatalistic views about the outcomes of their disease were the norm. Participants made adjustments to their lives to accommodate their functional limitations. These included making home alterations, introducing regular exercise to their lives and using complementary therapies. Their expectations did not always match with the reality of the situation, which made several participants angry and dissatisfied with health care professionals. CONCLUSIONS: Issues of quality of life are paramount in this group of poor prognosis patients, therefore, health professionals should provide preparatory information to patients on what to expect from the illness and its treatments. Health professionals should also assist patients to manage debilitating symptoms such as fatigue and cognitive impairment.

Symptoms before, during, and 14 months after the beginning of treatment as perceived by patients with lymphoma.

PURPOSE/OBJECTIVES: To explore occurrence of symptoms and relationships between them as perceived by patients with lymphoma before, during, and 14 months after the beginning of treatment. RESEARCH APPROACH: Qualitative and longitudinal. SETTING: A major oncology center in the United Kingdom. PARTICIPANTS: 10 adult patients with lymphoma (3 women and 7 men) were recruited at treatment initiation. METHODOLOGIC APPROACH: Semistructured audiotaped interviews were conducted with participants in median 15 days, 4 months, and 14 months after diagnosis. Analysis of the verbatim transcripts was inspired by interpretive description, which is a grounded approach articulating patterns emerging in relation to clinical phenomena. MAIN RESEARCH VARIABLES: Symptoms. FINDINGS: Symptoms commonly reported by patients in this sample were lack of energy, lymphadenopathy, weight loss, itching, pain, sadness, night sweats, sleeping difficulties, and hair loss. Co-occurring prediagnosis symptoms seem to have led patients to seek medical attention; co-occurring symptoms during treatment seem to have a cumulatively distressing effect. Several of the symptoms were described as interrelated, with one symptom leading to one or more other symptoms. CONCLUSIONS: The data confirm a complex symptomatology in patients with lymphoma. In addition, the findings support that co-occurring symptoms may have a synergistic effect on patients' health outcomes and add new knowledge about relationships between symptoms from patients' perspectives. INTERPRETATION: Illustrating symptoms and interrelationships between symptoms using diagrams may be useful to support communication as well as in identifying targets for symptom management.

In vitro and in vivo pharmacokinetic-pharmacodynamic relationships for the trisubstituted aminopurine cyclin-dependent kinase inhibitors olomoucine, bohemine and CYC202.

PURPOSE: To investigate pharmacokinetic-pharmacodynamic relationships for the trisubstituted aminopurine cyclin-dependent kinase inhibitors olomoucine, bohemine, and CYC202 (R-roscovitine; seliciclib) in the HCT116 human colon carcinoma model. EXPERIMENTAL DESIGN: The in vitro activity of the agents was determined in a human tumor panel using the sulforhodamine B assay. The concentration and time dependence was established in HCT116 cells. Molecular biomarkers, including RB phosphorylation and cyclin expression, were assessed by Western blotting. Pharmacokinetic properties were characterized in mice following analysis by liquid chromatography-tandem mass spectrometry. Based on these studies, a dosing regimen was developed for CYC202 that allowed therapeutic exposures in the HCT116 tumor xenograft. RESULTS: The antitumor potency of the agents in vitro was in the order olomoucine (IC50, 56 micromol/L) < bohemine (IC50, 27 micromol/L) < CYC202 (IC50, 15 micromol/L), corresponding to their activities as cyclin-dependent kinase inhibitors. Antitumor activity increased with exposure time up to 16 hours. The agents caused inhibition of RB and RNA polymerase II phosphorylation and depletion of cyclins. They exhibited relatively rapid clearance following administration to mice. CYC202 displayed the slowest clearance from plasma and the highest tumor uptake, with oral bioavailability of 86%. Oral dosing of CYC202 gave active concentrations in the tumor, modulation of pharmacodynamic markers, and inhibition of tumor growth. CONCLUSIONS: CYC202 showed therapeutic activity on human cancer cell lines in vitro and on xenografts. Pharmacodynamic markers are altered in vitro and in vivo, consistent with the inhibition of cyclin-dependent kinases. Such markers may be potentially useful in the clinical development of CYC202 and other cyclin-dependent kinase inhibitors.

A rationale for the clinical development of the thymidylate synthase inhibitor ZD9331 in ovarian and other solid tumours.

ZD9331 is an antifolate drug that potently and specifically inhibits thymidylate synthase (TS). In contrast with TS inhibitors such as raltitrexed, it cannot be polyglutamated, leading to antitumour activity independent of folylpolyglutamyl synthetase (FPGS) activity. The growth inhibition IC50 values for ZD9331 and raltitrexed were determined for a panel of 18 human tumour cell lines, that included six colon and six ovarian. The colon lines largely displayed overlapping sensitivities to both drugs with only one of the six lines being drug resistant. In contrast, the ovarian cell lines displayed non-overlapping sensitivities with four being highly resistant to raltitrexed and only one was cross-resistant to ZD9331. Studies were undertaken to explain these results. The colon and ovarian cell lines were characterised for TS activity, and TS and FPGS mRNA expression. TS activity correlated with sensitivity to ZD9331 (r=0.50; p=0.097) and raltitrexed (r=0.74; p=0.0063). Provided the data from the highly drug-resistant cell lines (BE and 41 M) were omitted, TS mRNA expression levels also correlated with ZD9331 (r=0.77; p=0.013) and raltitrexed IC50 (r=0.84; p=0.0031). FPGS mRNA expression correlated with higher sensitivity to raltitrexed relative to ZD9331 (higher ZD9331/raltitrexed IC50 ratios) (r=0.62; p=0.048). Similarly, cell lines with IC50 ratios>median expressed a 1.8-fold higher median level of FPGS mRNA (p=0.0087) compared with those with ratios