Discovery of Icenticaftor (QBW251), a Cystic Fibrosis Transmembrane Conductance Regulator Potentiator with Clinical Efficacy in Cystic Fibrosis and Chronic Obstructive Pulmonary Disease.

Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) ion channel are established as the primary causative factor in the devastating lung disease cystic fibrosis (CF). More recently, cigarette smoke exposure has been shown to be associated with dysfunctional airway epithelial ion transport, suggesting a role for CFTR in the pathogenesis of chronic obstructive pulmonary disease (COPD). Here, the identification and characterization of a high throughput screening hit 6 as a potentiator of mutant human F508del and wild-type CFTR channels is reported. The design, synthesis, and biological evaluation of compounds 7-33 to establish structure-activity relationships of the scaffold are described, leading to the identification of clinical development compound icenticaftor (QBW251) 33, which has subsequently progressed to deliver two positive clinical proofs of concept in patients with CF and COPD and is now being further developed as a novel therapeutic approach for COPD patients.

Breaking the habit: a qualitative exploration of barriers and facilitators to smoking cessation in people with enduring mental health problems.

BACKGROUND: Smoking in people with mental health problems (MHPs) is an important public health concern as rates are two to three times higher than in the general population. While a strong evidence base exists to encourage and support smoking cessation in the wider population, there is limited evidence to guide the tailoring of interventions for people with MHPs, including minimal understanding of their needs. This paper presents findings from theoretically-driven formative research which explored the barriers and facilitators to smoking cessation in people with MHPs. The aim, guided by the MRC Framework for the development and evaluation of complex interventions, was to gather evidence to inform the design and content of smoking cessation interventions for this client group. METHODS: Following a review of the empirical and theoretical literature, and taking a critical realist perspective, a qualitative approach was used to gather data from key stakeholders, including people with enduring MHPs (n = 27) and professionals who have regular contact with this client group (n = 54). RESULTS: There was a strong social norm for smoking in participants with MHPs and most were heavily addicted to nicotine. They acknowledged that their physical health would improve if they stopped smoking and their disposable income would increase; however, more important was the expectation that, if they attempted to stop smoking, their anxiety levels would increase, they would lose an important coping resource, they would have given up something they found pleasurable and, most importantly, their mental health would deteriorate. Barriers to smoking cessation therefore outweighed potential facilitators and, as a consequence, impacted negatively on levels of motivation and self-efficacy. The potential for professionals to encourage cessation attempts was apparent; however, they often failed to raise the issue of smoking/cessation as they believed it would damage their relationship with clients. The professionals' own smoking status also appeared to influence their health promoting role. CONCLUSIONS: Many opportunities to encourage and support smoking cessation in people with MHPs are currently missed. The increased understanding provided by our study findings and literature review have been used to shape recommendations for the content of tailored smoking cessation interventions for this client group.

Discovery of a novel chemotype of potent human ENaC blockers using a bioisostere approach. Part 2: α-Branched quaternary amines.

We report the synthesis and biological evaluation of a series of novel α-branched pyrazinoyl quaternary amines for their ability to block ion transport via the epithelial sodium channel (ENaC) in human bronchial epithelial cells (HBECs). Compound 12 g has an IC(50) of 30 nM and is highly efficacious in the Guinea-pig tracheal potential difference (TPD) model of ENaC blockade with an ED(50) of 1 µg kg(-1) at 1h. In addition the SAR results demonstrate for the first time the chiral nature of the binding site of human ENaC. As such, pyrazinoyl quaternary amines represent a promising new class of ENaC blockers for the treatment of cystic fibrosis that are structurally distinct from the pyrazinoyl guanidine chemotype found in prototypical ENaC blockers such as amiloride.

Discovery of a novel chemotype of potent human ENaC blockers using a bioisostere approach. Part 1: quaternary amines.

We report the identification of a novel series of human epithelial sodium channel (ENaC) blockers that are structurally distinct from the pyrazinoyl guanidine chemotype found in prototypical ENaC blockers such as amiloride. Following a rational design hypothesis a series of quaternary amines were prepared and evaluated for their ability to block ion transport via ENaC in human bronchial epithelial cells (HBECs). Compound 11 has an IC(50) of 200nM and is efficacious in the Guinea-pig tracheal potential difference (TPD) model of ENaC blockade with an ED(50) of 44µgkg(-1) at 1h. As such, pyrazinoyl quaternary amines represent the first examples of a promising new class of human ENaC blockers.

A mixed-methods evaluation of the effectiveness of tailored smoking cessation training for healthcare practitioners who work with older people.

BACKGROUND: Older people who smoke derive significant health benefits from stopping smoking in later life. Healthcare practitioners have an important role to play in raising the issue of smoking cessation with this client group; however, they often fail to do so. AIM: To assess the effectiveness of smoking cessation training for healthcare practitioners who have regular contact with older adults. METHODS: Mixed-methods were used to explore satisfaction with the training, the participants' learning and any resultant changes in behaviour. The effectiveness of the training was assessed using a two-group parallel design randomised controlled trial, followed by semistructured qualitative interviews. Participants (n = 57) were recruited from a cohort of community nurses and allied health professionals (e.g., occupational therapists) working in Scotland. The intervention was 1-day brief intervention smoking cessation training. Validated measures of knowledge, attitudes and practice, were used to assess learning and behaviour at baseline, 1 week and 3 months post training. Data were analysed using two-factor repeated measure analysis of variance, where the factors were "group" and "time." Qualitative data were gathered from members of the intervention group during semistructured interviews (n = 8) and were analysed thematically. RESULTS/FINDINGS: Levels of satisfaction with the training were high. There was a statistically significant improvement in the knowledge and attitudes of the intervention group following the training, with a noticeable, but nonsignificant, improvement in practice. The qualitative findings demonstrate how the training impacted positively on practice. CONCLUSIONS: Smoking cessation interventions in later life are important, as older smokers generally have long-term conditions caused or complicated by smoking. The delivery of brief smoking cessation interventions is known to be highly cost-effective; however, research demonstrates that practitioners often fail to raise the issue of smoking cessation with older adults. This study has demonstrated the effectiveness of a 1-day training course for practitioners. Further research is recommended.

An exploration of lifestyle beliefs and lifestyle behaviour following stroke: findings from a focus group study of patients and family members.

BACKGROUND: Stroke is a major cause of disability and family disruption and carries a high risk of recurrence. Lifestyle factors that increase the risk of recurrence include smoking, unhealthy diet, excessive alcohol consumption and physical inactivity. Guidelines recommend that secondary prevention interventions, which include the active provision of lifestyle information, should be initiated in hospital, and continued by community-based healthcare professionals (HCPs) following discharge. However, stroke patients report receiving little/no lifestyle information.There is a limited evidence-base to guide the development and delivery of effective secondary prevention lifestyle interventions in the stroke field. This study, which was underpinned by the Theory of Planned Behaviour, sought to explore the beliefs and perceptions of patients and family members regarding the provision of lifestyle information following stroke. We also explored the influence of beliefs and attitudes on behaviour. We believe that an understanding of these issues is required to inform the content and delivery of effective secondary prevention lifestyle interventions. METHODS: We used purposive sampling to recruit participants through voluntary sector organizations (29 patients, including 7 with aphasia; 20 family members). Using focus group methods, data were collected in four regions of Scotland (8 group discussions) and were analysed thematically. RESULTS: Although many participants initially reported receiving no lifestyle information, further exploration revealed that most had received written information. However, it was often provided when people were not receptive, there was no verbal reinforcement, and family members were rarely involved, even when the patient had aphasia. Participants believed that information and advice regarding healthy lifestyle behaviour was often confusing and contradictory and that this influenced their behavioural intentions. Family members and peers exerted both positive and negative influences on behavioural patterns. The influence of HCPs was rarely mentioned. Participants' sense of control over lifestyle issues was influenced by the effects of stroke (e.g. depression, reduced mobility) and access to appropriate resources. CONCLUSIONS: For secondary prevention interventions to be effective, HCPs must understand psychological processes and influences, and use appropriate behaviour change theories to inform their content and delivery. Primary care professionals have a key role to play in the delivery of lifestyle interventions.

Staff attitudes towards working with drug users: development of the Drug Problems Perceptions Questionnaire.

AIM: To evaluate the psychometric properties of an adaptation of the Alcohol and Alcohol Problems Perceptions Questionnaire to measure the attitudes of staff to working with drug users (the DDPPQ). DESIGN: Postal survey: a questionnaire was mailed to participants on two occasions. SETTING: A large urban National Health Service (NHS) mental health service. PARTICIPANTS: A stratified random sample of medical staff, clinical psychologists, occupational therapists and nurses (n = 672) who work within generic mental health, adolescent psychiatry, forensic psychiatry and alcohol and drug services. Response rate at Time 1 was 56% and 68% at Time 2. MEASUREMENTS: A structured demographic questionnaire; individual item and total scores for the DDPPQ administered on two occasions 4 weeks apart; data relating to the content validity of the instrument. FINDINGS: A principal component analysis confirmed the DDPPQ's construct validity and participants confirmed its content validity. Following analysis of the instrument's test-retest reliability and its principal component structure it was reduced to a 20-item scale. Its five subscales related to role adequacy, role support, job satisfaction, role-specific self-esteem and role legitimacy. CONCLUSION: The refined DDPPQ was shown to be a valid and reliable tool which can be used to measure attitudes of people in relation to working with drug users.

Smoking after the age of 65 years: a qualitative exploration of older current and former smokers' views on smoking, stopping smoking, and smoking cessation resources and services.

The aim of this study was to explore older current/former smokers' views on smoking, stopping smoking, and smoking cessation resources and services. Despite the fact that older smokers have been identified as a priority group, there is currently a dearth of age-related smoking cessation research to guide practice. The study adopted a qualitative approach and used the health belief model as a conceptual framework. Twenty current and former smokers aged>or=65 years were recruited through general practices and a forum for older adults in the West of Scotland. Data were collected using a semistructured interview schedule. The audio-taped interviews were transcribed and then analysed using content analysis procedures. Current smokers reported many positive associations with smoking, which often prevented a smoking cessation attempt. The majority were aware that smoking had damaged their health; however, some were not convinced of the association. A common view was that 'the damage was done', and therefore, there was little point in attempting to stop smoking. When suggesting a cessation attempt, while some health professionals provided good levels of support, others were reported as providing very little. Some of the participants reported that they had never been advised to stop smoking. Knowledge of local smoking cessation services was generally poor. Finally, concern was voiced regarding the perceived health risks of using nicotine replacement therapy. The main reasons why the former smokers had stopped smoking were health-related. Many had received little help and support from health professionals when attempting to stop smoking. Most of the former smokers believed that stopping smoking in later life had been beneficial to their health. In conclusion, members of the primary care team have a key role to play in encouraging older people to stop smoking. In order to function effectively, it is essential that they take account of older smokers' health beliefs and that issues, such as knowledge of smoking cessation resources, are addressed.

Nurses' opportunistic interventions with patients in relation to smoking.

AIM: This paper reports a study exploring nurses' provision of opportunistic health education on smoking for hospital patients. BACKGROUND: Smoking cessation guidelines recommend assessment of patients' smoking habits and provision of smoking cessation advice when possible, and highlight the importance of the role of nurses in health promotion and health education. In the past, nurses have been criticized for lack of knowledge, skills and confidence in relation to health education and the perception that it is additional to, rather than integrated with, nursing care. METHODS: A qualitative case study design was selected to explore the health education practice of 12 nurses working in acute wards in three general hospitals in Scotland. Data were collected in 2000 through non-participant observation, semi-structured interviews and the use of a radio-microphone to record nurse-patient interactions. The data analysis was guided by four key elements of health education practice: 'the teachable moment', 'readiness to learn', 'the provision of health information' and 'oral communication'. FINDINGS: Smoking was part of the nurses' agenda, as most recognized opportunities to introduce health education on smoking during nursing care, suggesting a tentative move towards the integration of health education with nursing care. Evidence from patients' interactions indicated ample opportunity for nurses to provide smoking-related health information. However, the content of nurses' interactions on smoking was variable, with some limited by poor communication skills and inadequate knowledge of smoking and smoking cessation. The context of the interactions was also important in understanding some of the restrictions on conversational progress. CONCLUSIONS: Nurses require the knowledge and skills to perform a health education role, and the inclusion of smoking cessation guidelines in nursing curricula would contribute to this. Where patients are in hospitals for short periods of time, opportunistic health education on smoking needs to be introduced as the basis for more specialist intervention.

Survey of student nurses and midwives: smoking and alcohol use.

This article presents findings from a survey of 186 first year nursing and midwifery students that relate to their smoking and alcohol consumption. Of the students sampled, 28% were cigarette smokers. This is higher than the smoking rate of 25% for the adult population in the UK. The majority of the students who smoked said that they would like to stop smoking. Most of the students (86.5%) reported having drunk alcohol on at least one occasion during the previous week, with 26.5% having had a drink on three or four days. The amount consumed over the week ranged from no drinks to 90, with the mean being 13.72.Worryingly, 74% had exceeded the daily benchmarks for low-risk drinking on at least one occasion during the week for which consumption was reported, and 55% were drinking at binge levels. The findings raise concerns for the future health of many of our students and for their roles as health promoters.

Older people who smoke: why nurses should help them to stop.

Smoking is the greatest preventable cause of ill health and premature death in the UK. Although the prevalence of smoking is lower among adults over 65 years than in younger age groups, the actual number of older smokers is increasing steadily as the proportion of older adults in the population rises. If nurses are to function effectively in their role as health promoters it is important that they base their practice on appropriate research-based evidence. In this article we discuss the current evidence on the health consequences of smoking in later life and the benefits of cessation. We provide information on approaches that discuss some of the barriers to behavioural change. Our aim is to provide nurses with information that will help them to help older smokers make informed choices.

Developing research methods in qualitative research: using a radio microphone in a pilot study.

The diploma of higher education in nursing aims to produce a first level registered nurse with the necessary knowledge and skills to work safely as a competent practitioner. Implicit in this aim is the requirement for the nurse to be an effective commmunicator of diverse and sometimes complex information requiring application of knowledge and skill. The diploma incorporates health as a major theme in the curriculum.