Pharmacological characterisation of GSK3335103, an oral αvß6 integrin small molecule RGD-mimetic inhibitor for the treatment of fibrotic disease.

Fibrosis is the formation of scar tissue due to injury or long-term inflammation and is a leading cause of morbidity and mortality. Activation of the pro-fibrotic cytokine transforming growth factor-ß (TGFß) via the alpha-V beta-6 (αvß6) integrin has been identified as playing a key role in the development of fibrosis. Therefore, a drug discovery programme to identify an orally bioavailable small molecule αvß6 arginyl-glycinyl-aspartic acid (RGD)-mimetic was initiated. As part of a medicinal chemistry programme GSK3335103 was identified and profiled in a range of pre-clinical in vitro and in vivo systems. GSK3335103 was shown to bind to the αvß6 with high affinity and demonstrated fast binding kinetics. In primary human lung epithelial cells, GSK3335103-induced concentration- and time-dependent internalisation of αvß6 with a rapid return of integrin to the cell surface observed after washout. Following sustained engagement of the αvß6 integrin in vitro, lysosomal degradation was induced by GSK3335103. GSK3335103 was shown to engage with the αvß6 integrin and inhibit the activation of TGFß in both ex vivo IPF tissue and in a murine model of bleomycin-induced lung fibrosis, as measured by αvß6 engagement, TGFß signalling and collagen deposition, with a prolonged duration of action observed in vivo. In summary, GSK3335103 is a potent αvß6 inhibitor that attenuates TGFß signalling in vitro and in vivo with a well-defined pharmacokinetic/pharmacodynamic relationship. This translates to a significant reduction of collagen deposition in vivo and therefore GSK3335103 represents a potential novel oral therapy for fibrotic disorders.

Diversity, Equity, and Inclusion in Nursing: The Pathway to Excellence Framework Alignment.

The promotion of diversity, equity, and inclusion (DEI) in nursing is a topic of renewed importance, given the civil unrest following the death of George Floyd and identified disparities in health and health outcomes during the COVID-19 pandemic. Despite its progress, the nursing profession continues to struggle with recruiting and retaining a workforce that represents the cultural diversity of the patient population. The authors completed a review of the literature on DEI in nursing and found a scarcity of studies, and that a limitation exists due to the strength of the evidence examined. This article aims to provide a review of the literature on DEI in nursing, outcomes and strategies associated with organizational DEI efforts, and knowledge on how the American Nurses Credentialing Center Pathway to Excellence® Designation Program framework supports DEI initiatives. The authors further provided recommendations for nurse leaders and a checklist of proposed questions for assessing commitment, culture, and structural empowerment initiatives toward a more diverse, equitable, and inclusive organization.

Antimicrobial stewardship and infection prevention interventions targeting healthcare-associated Clostridioides difficile and carbapenem-resistant Klebsiella pneumoniae infections: a scoping review.

OBJECTIVES: This study assessed antimicrobial stewardship (AMS) and infection prevention (IP) interventions targeting healthcare-associated Clostridioides difficile and carbapenem-resistant Klebsiella pneumoniae (CRKP) infections, their key outcomes and the application of behaviour change principles in these interventions. DESIGN: This scoping review was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-analysis Extension for Scoping Reviews (PRISMA-ScR) guidelines while focusing on acute healthcare settings in both low-to-middle income and high-income countries. DATA SOURCES: The databases searched were MEDLINE, PubMed, Web of Science and CINAHL between 22 April 2020 and 30 September 2020. ELIGIBILITY: The review included peer-reviewed articles published in English language between 2010 and 2019. Studies that focussed on IP and/or AMS interventions primarily targeting C. difficile or CRKP were included. Studies that assessed effectiveness of diagnostic devices or treatment options were excluded from this review. DATA EXTRACTION AND SYNTHESIS: An abstraction sheet calibrated for this study was used to extract data on the main study characteristics including the population, intervention and outcomes of interest (antimicrobial use, compliance with IP interventions and risk for C. difficile and CRKP). A narrative synthesis of the results is provided. RESULTS: The review included 34 studies. Analysis indicates that interventions targeting C. difficile and CRKP include Education, Surveillance/Screening, Consultations, Audits, Policies and Protocols, Environmental measures, Bundles, Isolation as well as Notifications or alerts (represented using the ESCAPE-BIN acronym). The identified outcomes include antimicrobial use, resistance rates, risk reduction, adherence to contact precautions, hospital stay and time savings. AMS and IP interventions tend to be more adhoc with limited application of behaviour change principles. CONCLUSION: This scoping review identified the AMS and IP interventions targeting C. difficile and CRKP in healthcare settings and described their key outcomes. The application of behaviour change principles in AMS and IP interventions appears to be limited.

Translational pharmacology of an inhaled small molecule αvß6 integrin inhibitor for idiopathic pulmonary fibrosis.

The αvß6 integrin plays a key role in the activation of transforming growth factor-ß (TGFß), a pro-fibrotic mediator that is pivotal to the development of idiopathic pulmonary fibrosis (IPF). We identified a selective small molecule αvß6 RGD-mimetic, GSK3008348, and profiled it in a range of disease relevant pre-clinical systems. To understand the relationship between target engagement and inhibition of fibrosis, we measured pharmacodynamic and disease-related end points. Here, we report, GSK3008348 binds to αvß6 with high affinity in human IPF lung and reduces downstream pro-fibrotic TGFß signaling to normal levels. In human lung epithelial cells, GSK3008348 induces rapid internalization and lysosomal degradation of the αvß6 integrin. In the murine bleomycin-induced lung fibrosis model, GSK3008348 engages αvß6, induces prolonged inhibition of TGFß signaling and reduces lung collagen deposition and serum C3M, a marker of IPF disease progression. These studies highlight the potential of inhaled GSK3008348 as an anti-fibrotic therapy.

Perceptions of the impact of disability and impairment on health, quality of life and capability.

OBJECTIVE: The impact of impairment and disability on quality of life can be considerable, however advances in assistive technology can help to optimise physical and psychosocial functioning. Little is known about how impairment and subsequent adaptation influences health state perceptions, particularly amongst the general public. The aim of this pilot project was to examine student perceptions of what it would be like to live with a physical or sensory impairment, and how adaptation influences health and quality of life. RESULTS: In total 151 undergraduate Psychology students were invited to participate in a questionnaire-based survey. Ethical approval was granted by an academic ethics committee. The survey included a range of validated outcome measures relating to illness perceptions and quality of life, including the B-IPQ, EQ-5D-3L and ICECAP-O. Surveys were divided into two parts: firstly, participants were asked to self-report their own health; and secondly participants were asked to estimate the health impacts of a range of hypothetical states of impairment. Severe adapted impairments were perceived to have less impact on health status than moderate un-adapted impairments. Hearing impairment was perceived to have the least impact on health status, whilst mobility impairment was perceived to have the largest impact on health status.

What influences persistence with medicines? A multinational discrete choice experiment of 2549 patients.

AIM: The aim was to examine patients' stated preferences to persist with medicines and to explore the influence of psychosocial and sociocognitive factors. METHODS: Community-dwelling, hypertensive patients recruited from nine European countries were invited to complete a discrete choice experiment (DCE) with attributes for treatment benefits, mild yet common adverse drug reactions (ADRs), rare but potentially life-threatening ADRs and dosing frequency. Patients responded to the binary choice of which medicine would they be most likely to continue taking. Data were analyzed using a random effects logit model. RESULTS: Two thousand five hundred and forty-nine patients from Austria (n = 321), Belgium (n = 175), England (n = 315), Germany (n = 266), Greece (n = 288), Hungary (n = 322), the Netherlands (n = 231), Poland (n = 312) and Wales (n = 319) completed the DCE. All attributes significantly influenced patients' stated preference to persist with medications (P < 0.05). Patients were willing to accept decreases in treatment benefits of 50.6 percentage points (95% CI 46.1, 57.9) for a very rare (as opposed to rare) risk of severe ADR, 28.3 percentage points (95% CI 25.2, 33.1) for a once daily instead of twice daily dosing and 0.74 percentage points (95% CI 0.67, 0.85) for a 1% point reduction in mild ADRs. Models accounting for psychosocial and sociocognitive characteristics were significantly different from the base case. CONCLUSION: Patients' intention to persist with treatment was associated with their willingness to trade potential benefits, harms and dosing frequency. Psychosocial and sociocognitive factors influenced the extent of trading. The utility model may have value in assessing patients' likelihood of persisting with medicines and to tailor treatment to maximize persistence.

Adherence of patients to long-term medication: a cross-sectional study of antihypertensive regimens in Austria.

OBJECTIVE: The objective of this study was to evaluate adherence and causes for non-adherence to antihypertensive therapy in Austrian patients. A special focus was placed on social parameters and behavioural theories. METHODS: Patients were invited via advertisements in community pharmacies in Austria to complete an online survey. Inclusion criteria were an age of 18 years or older, a diagnosis of arterial hypertension and a current prescription of antihypertensive medication. Adherence was measured by the four-item Morisky scale. Non-adherence was defined by at least one point in the Morisky scale. Several demographic, social and behavioural parameters were analysed as potential co-variables associated with adherence. RESULTS: A total of 323 patients completed the online survey, of which 109 (33.7%) met the criteria for non-adherence. In a multivariable model, self-efficacy and age were associated with adherence, whereas intention and barriers were linked to non-adherence; 56 patients (17.3%) were classified as intentionally non-adherent. CONCLUSION: This study demonstrates that non-adherence affects an important proportion of patients in the treatment of arterial hypertension. Young age was a particularly important risk factor for non-adherence, and this patient population is, therefore, in need of special attention. Modifiable risk factors were identified that could help improving the treatment of arterial hypertension and potentially other chronic conditions.

Predictors of self-reported adherence to antihypertensive medicines: a multinational, cross-sectional survey.

BACKGROUND: Nonadherence to antihypertensive medicines limits their effectiveness, increases the risk of adverse health outcome, and is associated with significant health care costs. The multiple causes of nonadherence differ both within and between patients and are influenced by patients' care settings. OBJECTIVES: The objective of this article was to identify determinants of patient nonadherence to antihypertensive medicines, drawing from psychosocial and economic models of behavior. METHODS: Outpatients with hypertension from Austria, Belgium, England, Germany, Greece, Hungary, The Netherlands, Poland, and Wales were recruited to a cross-sectional online survey. Nonadherence to medicines was assessed using the Morisky Medication Adherence Scale (primary outcome) and the Medication Adherence Rating Scale. Associations with adherence and nonadherence were tested for demographic, clinical, and psychosocial factors. RESULTS: A total of 2595 patients completed the questionnaire. The percentage of patients classed as nonadherent ranged from 24% in The Netherlands to 70% in Hungary. Low age, low self-efficacy, and respondents' perceptions of their illness and cost-related barriers were associated with nonadherence measured on the Morisky Medication Adherence Scale across several countries. In multilevel, multivariate analysis, low self-efficacy (odds ratio = 0.73; 95% confidence interval 0.70-0.77) and a high number of perceived barriers to taking medicines (odds ratio = 1.70; 95% confidence interval 1.38-2.09) were the main significant determinants of nonadherence. Country differences explained 11% of the variance in nonadherence. CONCLUSIONS: Among the variables measured, patients' adherence to antihypertensive medicines is influenced primarily by their self-efficacy, illness beliefs, and perceived barriers. These should be targets for interventions for improving adherence, as should an appreciation of differences among the countries in which they are being delivered.

Predicting adherence to medications using health psychology theories: a systematic review of 20 years of empirical research.

OBJECTIVES: This review sought to identify the empirical evidence for the application of models from sociocognitive theory, self-regulation theory, and social support theory at predicting patient adherence to medications. METHODS: A systematic review of the published literature (1990-2010) using MEDLINE, EMBASE, Cochrane Library, CINAHL, and PsychINFO identified studies examining the application of health psychology theory to adherence to medication in adult patients. Two independent reviewers extracted data on medication, indication, study population, adherence measure, theory, model, survey instruments, and results. Heterogeneity in theoretical model specification and empirical investigation precluded a meta-analysis of data. RESULTS: Of 1756 unique records, 67 articles were included (sociocognitive = 35, self-regulation = 21, social support = 11). Adherence was most commonly measured by self-report (50 of 67). Synthesis of studies highlighted the significance (P ≤ 0.05) of self-efficacy (17 of 19), perceived barriers (11 of 17), perceived susceptibility (3 of 6), necessity beliefs (8 of 9), and medication concerns (7 of 8). CONCLUSIONS: The results of this review provide a foundation for the development of theory-led adherence-enhancing interventions that could promote sustainable behavior change in clinical practice.

In vitro pharmacological characterization of vilanterol, a novel long-acting ß2-adrenoceptor agonist with 24-hour duration of action.

Vilanterol trifenatate (vilanterol) is a novel, long-acting ß(2)-adrenoceptor (ß(2)-AR) agonist with 24 h activity. In this study, we describe the preclinical pharmacological profile of vilanterol using radioligand binding and cAMP studies in recombinant assays as well as human and guinea pig tissue systems to characterize ß(2)-AR binding and functional properties. Vilanterol displayed a subnanomolar affinity for the ß(2)-AR that was comparable with that of salmeterol but higher than olodaterol, formoterol, and indacaterol. In cAMP functional activity studies, vilanterol demonstrated similar selectivity as salmeterol for ß(2)- over ß(1)-AR and ß(3)-AR, but a significantly improved selectivity profile than formoterol and indacaterol. Vilanterol also showed a level of intrinsic efficacy that was comparable to indacaterol but significantly greater than that of salmeterol. In cellular cAMP production and tissue-based studies measuring persistence and reassertion, vilanterol had a persistence of action comparable with indacaterol and longer than formoterol. In addition, vilanterol demonstrated reassertion activity in both cell and tissue systems that was comparable with salmeterol and indacaterol but longer than formoterol. In human airways, vilanterol was shown to have a faster onset and longer duration of action than salmeterol, exhibiting a significant level of bronchodilation 22 h after treatment. From these investigations, the data for vilanterol are consistent, showing that it is a novel, potent, and selective ß(2)-AR receptor agonist with a long duration of action. This pharmacological profile combined with clinical data is consistent with once a day dosing of vilanterol in the treatment of both asthma and chronic obstructive pulmonary disease (COPD).

A new taxonomy for describing and defining adherence to medications.

Interest in patient adherence has increased in recent years, with a growing literature that shows the pervasiveness of poor adherence to appropriately prescribed medications. However, four decades of adherence research has not resulted in uniformity in the terminology used to describe deviations from prescribed therapies. The aim of this review was to propose a new taxonomy, in which adherence to medications is conceptualized, based on behavioural and pharmacological science, and which will support quantifiable parameters. A systematic literature review was performed using MEDLINE, EMBASE, CINAHL, the Cochrane Library and PsycINFO from database inception to 1 April 2009. The objective was to identify the different conceptual approaches to adherence research. Definitions were analyzed according to time and methodological perspectives. A taxonomic approach was subsequently derived, evaluated and discussed with international experts. More than 10 different terms describing medication-taking behaviour were identified through the literature review, often with differing meanings. The conceptual foundation for a new, transparent taxonomy relies on three elements, which make a clear distinction between processes that describe actions through established routines ('Adherence to medications', 'Management of adherence') and the discipline that studies those processes ('Adherence-related sciences'). 'Adherence to medications' is the process by which patients take their medication as prescribed, further divided into three quantifiable phases: 'Initiation', 'Implementation' and 'Discontinuation'. In response to the proliferation of ambiguous or unquantifiable terms in the literature on medication adherence, this research has resulted in a new conceptual foundation for a transparent taxonomy. The terms and definitions are focused on promoting consistency and quantification in terminology and methods to aid in the conduct, analysis and interpretation of scientific studies of medication adherence.

CRACM/Orai ion channel expression and function in human lung mast cells.

BACKGROUND: Influx of extracellular Ca(2+) into human lung mast cells (HLMCs) is essential for the FcεRI-dependent release of preformed granule-derived mediators and newly synthesized autacoids and cytokines. However, the identity of the ion channels underlying this Ca(2+) influx is unknown. The recently discovered members of the CRACM/Orai ion channel family that carries the Ca(2+) release-activated Ca(2+) current are candidates. OBJECTIVES: To investigate the expression and function of CRACM channels in HLMCs. METHODS: CRACM mRNA, protein, and functional expression were examined in purified HLMCs and isolated human bronchus. RESULTS: CRACM1, -2, and -3 mRNA transcripts and CRACM1 and -2 proteins were detectable in HLMCs. A CRACM-like current was detected following FcεRI-dependent HLMC activation and also in HLMCs dialyzed with 30 µM inositol triphosphate. The Ca(2+)-selective current obtained under both conditions was blocked by 10 µM La(3+) and Gd(3+), known blockers of CRACM channels, and 2 distinct and specific CRACM-channel blockers-GSK-7975A and Synta-66. Both blockers reduced FcεRI-dependent Ca(2+) influx, and 3 µM GSK-7975A and Synta-66 reduced the release of histamine, leukotriene C(4), and cytokines (IL-5/-8/-13 and TNFα) by up to 50%. Synta-66 also inhibited allergen-dependent bronchial smooth muscle contraction in ex vivo tissue. CONCLUSIONS: The presence of CRACM channels, a CRACM-like current, and functional inhibition of HLMC Ca(2+) influx, mediator release, and allergen-induced bronchial smooth muscle contraction by CRACM-channel blockers supports a role for CRACM channels in FcεRI-dependent HLMC secretion. CRACM channels are therefore a potential therapeutic target in the treatment of asthma and related allergic diseases.

The discovery of long-acting saligenin ß2 adrenergic receptor agonists incorporating hydantoin or uracil rings.

A series of novel, potent and selective human ß(2) adrenoceptor agonists incorporating a hydantoin or a uracil ring on the right-hand side phenyl ring of (R)-salmeterol is presented. Hydantoin 12a had long duration of action in vitro on guinea pig trachea, and 12h in guinea pigs in vivo at its EC(90) 25 µM. It had lower oral absorption than salmeterol in rats, and lower bioavailability than salmeterol in vivo in both rats and dogs (2% and 5%, respectively). An improved method for measuring the absorbed fraction of analogues dosed to rats, which considers the glucuronidated fraction is presented. Compound 12a was metabolised in human liver microsomes and hepatocytes to the active hydantoic acid 12m.

Synthesis and structure-activity relationships of long-acting beta2 adrenergic receptor agonists incorporating metabolic inactivation: an antedrug approach.

A series of saligenin beta(2) adrenoceptor agonist antedrugs having high clearance were prepared by reacting a protected saligenin oxazolidinone with protected hydroxyethoxyalkoxyalkyl bromides, followed by removal of the hydroxy-protecting group, alkylation, and final deprotection. The compounds were screened for beta(2), beta(1), and beta(3) agonist activity in CHO cells. The onset and duration of action in vitro of selected compounds were assessed on isolated superfused guinea pig trachea. Compound 13f had high potency, selectivity, fast onset, and long duration of action in vitro and was found to have long duration in vivo, low oral bioavailability in the rat, and to be rapidly metabolized. Crystalline salts of 13f (vilanterol) were identified that had suitable properties for inhaled administration. A proposed binding mode for 13f to the beta(2)-receptor is presented.

Synthesis and structure-activity relationships of long-acting beta2 adrenergic receptor agonists incorporating arylsulfonamide groups.

A series of saligenin alkoxyalkylphenylsulfonamide beta(2) adrenoceptor agonists were prepared by reacting a protected saligenin oxazolidinone with alkynyloxyalkyl bromides, followed by Sonogashira reaction, hydrogenation, and deprotection. The meta-substituted primary sulfonamide was more potent than the para- and the ortho-analogues. Primary sulfonamides were more potent than the secondary and tertiary analogues. The onset and duration of action in vitro of selected compounds was assessed on isolated superfused guinea pig trachea. Sulfonamide 29b had the best profile of potency, selectivity, onset, and duration of action on both guinea pig trachea and human bronchus. Furthermore, 29b was found to have low oral bioavailability in rat and dog and also to have long duration of action in an in vivo model of bronchodilation. Crystalline salts of 29b were identified that had suitable properties for inhaled administration. A proposed binding mode for 29b to the beta(2)-receptor is presented.

GW627368X ((N-{2-[4-(4,9-diethoxy-1-oxo-1,3-dihydro-2H-benzo[f]isoindol-2-yl)phenyl]acetyl} benzene sulphonamide): a novel, potent and selective prostanoid EP4 receptor antagonist.

1. N-{2-[4-(4,9-diethoxy-1-oxo-1,3-dihydro-2H-benzo[f]isoindol-2-yl)phenyl]acetyl}benzene sulphonamide (GW627368X) is a novel, potent and selective competitive antagonist of prostanoid EP4 receptors with additional human TP receptor affinity. 2. At recombinant human prostanoid EP4 receptors expressed in HEK293 cells, GW627368X produced parallel rightward shifts of PGE2 concentration-effect (E/[A]) curves resulting in an affinity (pKb) estimate of 7.9 +/- 0.4 and a Schild slpoe not significantly different from unity. The affinity was independent of the agonist used. 4. In rings of phenylephrine precontracted piglet saphenous vein, GW627368X (30-300 nM) produced parallel rightward displacement of PGE2 E/[A] curves (pKb = 9.2 +/- 0.2; slope = 1). 4. GW627368X appears to bind to human prostanoid TP receptors but not the TP receptors of other species. In human washed platelets, GW627368X (10 microM) produced 100% inhibition of U-46619 (EC100)-induced aggregation (approximate pA2 approximately 7.0). However, in rings of rabbit and piglet saphenous vein and of guinea-pig aorta GW627368X (10 microM) did not displace U-46619 E/[A] curves indicating an affinity of < 5.0 for rabbit and guinea-pig prostanoid TP receptors. 5. In functional assays GW627368X is devoid of both agonism and antagonist affinity for prostanoid CRTH2, EP2, EP3, IP and FP receptors. At prostanoid EP1 receptors, GW627368X was an antagonist with a pA2 of 6.0, and at prostanoid IP receptors the compound increased the maximum effect of iloprost by 55%. At rabbit prostanoid EP2 receptors the pA2 of GW627368X was < 5.0. 6. In competition radioligand bioassays, GW627368X had affinity for human prostanoid EP4 and TP receptors (pKi = 7.0 +/- 0.2 (n = 10) and 6.8 (n = 2), respectively). Affinity for all other human prostanoid receptors was < 5.3. 7. GW627368X will be a valuable tool to explore the role of the prostanoid EP4 receptor in many physiological and pathological settings.