Cytochrome P450 (CYP) 3A4 induction is an important cause of drug–drug interactions, making early identification of drug candidates with CYP3A4 induction liability in drug development a prerequisite. ...Here, we present three‐dimensional (3D) spheroid cultures of primary human hepatocytes (PHHs) as a novel CYP3A4 induction screening model. Screening of 25 drugs (12 known CYP3A4 inducers in vivo and 13 negative controls) at physiologically relevant concentrations revealed a 100% sensitivity and 100% specificity of the system. Three of the in vivo CYP3A4 inducers displayed much higher CYP3A4 induction capacity in 3D spheroid cultures as compared with in two‐dimensional (2D) monolayer cultures. Among those, we identified AZD1208, a proviral integration site for Moloney murine leukemia virus (PIM) kinase inhibitor terminated in phase I of development due to unexpected CYP3A4 autoinduction, as a CYP3A4 inducer only active in 3D spheroids but not in 2D monolayer cultures. Gene knockdown experiments revealed that AZD1208 requires pregnane X receptor (PXR) to induce CYP3A4. Rifampicin requires solely PXR to induce CYP3A4 and CYP2B6, while phenobarbital‐mediated induction of these CYPs did not show absolute dependency on either PXR or constitutive androstane receptor (CAR), suggesting its ability to switch nuclear receptor activation. Mechanistic studies into AZD1208 uncovered an involvement of the mitogen‐activated protein kinase/extracellular signal‐regulated kinase (MAPK/ERK) pathway in CYP3A4 induction that is sensitive to the culture format used, as revealed by its inhibition of ERK1/2 Tyrosine 204 phosphorylation and sensitivity to epidermal growth factor (EGF) pressure. In line, we also identified lapatinib, a dual epidermal growth factor receptor/human epidermal growth factor receptor 2 (EGFR/HER2) inhibitor, as another CYP3A4 inducer only active in 3D spheroid culture. Our findings offer insights into the pathways involved in CYP3A4 induction and suggest PHH spheroids for preclinical CYP3A4 induction screening.
The agricultural expansion and intensification required to meet growing food and agri-based product demand present important challenges to future levels and management of biodiversity and ecosystem ...services. Influential actors such as corporations, governments, and multilateral organizations have made commitments to meeting future agricultural demand sustainably and preserving critical ecosystems. Current approaches to predicting the impacts of agricultural expansion involve calculation of total land conversion and assessment of the impacts on biodiversity or ecosystem services on a per-area basis, generally assuming a linear relationship between impact and land area. However, the impacts of continuing land development are often not linear and can vary considerably with spatial configuration. We demonstrate what could be gained by spatially explicit analysis of agricultural expansion at a large scale compared with the simple measure of total area converted, with a focus on the impacts on biodiversity and carbon storage. Using simple modeling approaches for two regions of Brazil, we find that for the same amount of land conversion, the declines in biodiversity and carbon storage can vary two- to fourfold depending on the spatial pattern of conversion. Impacts increase most rapidly in the earliest stages of agricultural expansion and are more pronounced in scenarios where conversion occurs in forest interiors compared with expansion into forests from their edges. This study reveals the importance of spatially explicit information in the assessment of land-use change impacts and for future land management and conservation.
International corporations in an increasingly globalized economy exert a major influence on the planet's land use and resources through their product design and material sourcing decisions. Many ...companies use life cycle assessment (LCA) to evaluate their sustainability, yet commonly-used LCA methodologies lack the spatial resolution and predictive ecological information to reveal key impacts on climate, water and biodiversity. We present advances for LCA that integrate spatially explicit modelling of land change and ecosystem services in a Land-Use Change Improved (LUCI)-LCA. Comparing increased demand for bioplastics derived from two alternative feedstock-location scenarios for maize and sugarcane, we find that the LUCI-LCA approach yields results opposite to those of standard LCA for greenhouse gas emissions and water consumption, and of different magnitudes for soil erosion and biodiversity. This approach highlights the importance of including information about where and how land-use change and related impacts will occur in supply chain and innovation decisions.
Background and Objective
Many drugs, including proton pump inhibitors and certain antidepressants, are metabolized by the polymorphic cytochrome P450 (CYP) 2C19 enzyme. A significant portion of ...extensive metabolizers do not reach appropriate drug levels, and our objective was to investigate any genetic background.
Methods
The 5′‐flanking region of the CYP2C19 gene from subjects with rapid omeprazole metabolism was sequenced, and CYP2C19 phenotype‐genotype associations were analyzed in Swedish (n=107) and Ethiopian (n=126) extensive metabolizers. The relationship of the metabolic ratio of omeprazole (omeprazole/5‐hydroxyomeprazole in plasma 3 hours after drug intake) with the area under the plasma concentration‐time curve was used for prediction studies. Electrophoretic mobility shift assays were conducted by use of human nuclear protein extracts. Hepatic reporter vector transfections were carried out in CD1 mice.
Results
We identified a novel allele (CYP2C19*17) carrying −806C>T and −3402C>T, with a frequency of 18% in both Swedes and Ethiopians and 4% in Chinese subjects. In Swedes the metabolic ratio of omeprazole was higher in subjects homozygous for CYP2C19*1 (median, 0.50 interquartile range, 0.37–0.73) than in those homozygous for CYP2C19*17 (median, 0.25 interquartile range, 0.15–0.33) (P = .010). In Ethiopians a similar difference in the S/R‐mephenytoin ratio was observed between individuals homozygous for CYP2C19*1 (median, 0.20 interquartile range, 0.12–0.37) and those homozygous for CYP2C19*17 (median, 0.05 interquartile range, 0.03–0.06) (P=.013). Electrophoretic mobility shift assays showed specific binding of human hepatic nuclear proteins to an element carrying −806T but not −806C. Reporter vector experiments showed an increased transcriptional activity of the CYP2C19*17 allele in vivo in mice. Predictions revealed that CYP2C19*17 homozygotes would attain 35% to 40% lower omeprazole area under the plasma concentration‐time curve values than subjects homozygous for CYP2C19*1 taking standard doses of omeprazole.
Conclusion
CYP2C19*17 is likely to cause therapeutic failures in drug treatment with, for example, proton pump inhibitors and antidepressants.
Clinical Pharmacology & Therapeutics (2006) 79, 103–113; doi: 10.1016/j.clpt.2005.10.002
The production of palm oil, soy, beef and timber are key drivers of global forest loss. For this reason, over 470 companies involved in the production, processing or distribution of these commodities ...have issued commitments to eliminate or reduce deforestation from their supply chains. However, the effectiveness of these commitments is uncertain since there is considerable variation in ambition and scope and there are no globally agreed definitions of what constitutes a forest. Many commitments identify high conservation value forests (HCVFs), high carbon stock forests (HCSFs) and forests on tropical peatland as priority areas for conservation. This allows for mapping of the global extent of forest areas classified as such, to achieve an assessment of the area that may be at reduced risk of development if companies comply with their zero deforestation commitments. Depending on the criteria used, the results indicate that between 34% and 74% of global forests qualify as either HCVF, HCSF or forests on tropical peatland. However, we found that the total extent of these forest areas varies widely depending on the choice of forest map. Within forests which were not designated as HCVF, HCSF or forests on tropical peatland, there is substantial overlap with areas that are highly suitable for agricultural development. Since these areas are unlikely to be protected by zero-deforestation commitments, they may be subject to increased pressure resulting from leakage of areas designated as HCVF, HCSF and tropical peatland forests. Considerable uncertainties around future outcomes remain, since only a proportion of the global market is currently covered by corporate commitments. Further work is needed to map the synergies between corporate commitments and government policies on land use. In addition, standardized criteria for delineating forests covered by the commitments are recommended.
BackgroundAchieving health equity is important to improve population health; however, health equity is not typically well defined, integrated, or measured within health service and delivery systems. ...To improve population health, it is necessary to understand barriers and facilitators to health equity integration within health service and delivery systems. This study aimed to explore health equity integration among health systems workers and identify key barriers and facilitators to implementing health equity strategies within the health service and delivery system in Nova Scotia, ahead of the release of a Health Equity Framework, focused on addressing inequities within publicly funded institutions.MethodsPurposive sampling was used to recruit individuals working on health equity initiatives including those in high-level leadership positions within the Nova Scotia health system. Individual interviews and a joint interview session were conducted. Topics of discussion included current integration of health equity through existing strategies and perceptions within participant roles. The Consolidated Framework for Implementation Research (CFIR) was used to guide coding and analysis, with interviews transcribed and deductively analyzed in NVivo. Qualitative description was employed to describe study findings as barriers and facilitators to health equity integration.ResultsEleven individual interviews and one joint interview (n = 5 participants) were conducted, a total of 16 participants. Half (n = 8) of the participants were High-level Leaders (i.e., manager or higher) within the health system. We found that existing strategies within the health system were inadequate to address inequities, and variation in the use of indicators of health equity was indicative of a lack of health equity integration. Applying the CFIR allowed us to identify barriers to and facilitators of health equity integration, with the power of legislation to implement a Health Equity Framework, alongside the value of partnerships and engagement both being seen as key facilitators to support health equity integration. Barriers to health equity integration included inadequate resources devoted to health equity work, a lack of diversity among senior system leaders and concerns that existing efforts to integrate health equity were siloed.ConclusionOur findings suggest that health equity integration needs to be prioritized within the health service and delivery system within Nova Scotia and identifies possible strategies for implementation. Appropriate measures, resources and partnerships need to be put in place to support health equity integration following the introduction of the Health Equity Framework, which was viewed as a key driver for action. Greater diversity within health system leadership was also identified as an important strategy to support integration. Our findings have implications for other jurisdictions seeking to advance health equity across health service and delivery systems.
The rapid development of techniques in the area of genome analysis has facilitated identification of new pharmacogenomic biomarkers that can provide predictive tools for improved drug response and ...fewer adverse drug reactions. Such biomarkers mainly originate from genes encoding drug-metabolizing enzymes, drug transporters, drug targets and human leukocyte antigens. Some of these are now integrated by the USA Food and Drug Administration and the European Medicines Agency into drug label inserts. In this review, we examine the utility and mechanistic background of pharmacogenomic biomarkers in several areas of medicine, including cancer, infection and cardiovascular disease. We also discuss the use of these biomarkers in drug development and address the impact on personalized drug prescription, including opportunities and bottlenecks.
Improving palliative and end-of-life care for people with dementia is a growing priority globally. This study aimed to integrate multiple perspectives on end-of-life care for people with dementia and ...carers, to identify clinically relevant areas for improvement.
The mixed-methods study involved surveys, interviews, and workshops with two participant groups: healthcare professionals and carers (individuals who provided care and support to a family member or friend). Healthcare professionals were invited to complete an online adapted version of the Australian Commission on Safety and Quality in Health Care, End-of-Life Care Toolkit: Clinician Survey Questions. Carers completed a hard copy or online adapted version of the Views of Informal Carers-Evaluation of Services (Short form) (VOICES-SF) questionnaire. Interview schedules were semi-structured, and workshops followed a co-design format. Findings were integrated narratively using a weaving approach.
Five areas in which we can improve care for people with dementia at the end of life, were identified: 1) Timely recognition of end of life; 2) Conversations about palliative care and end of life; 3) Information and support for people with dementia and carers; 4) Person-and-carer-centred care; 5) Accessing quality, coordinated care.
There are multiple areas where we can improve the quality of end-of-life care people with dementia receive. The findings demonstrate that the heterogeneous and challenging experiences of living with and caring for people with dementia necessitate a multidisciplinary, multifaceted approach to end-of-life care. The identified solutions, including care coordination, can guide local development of co-designed models of end-of-life care for people with dementia.
Advance Care Planning (ACP) by Registered Nurses (RNs) has been emerging. However, there is limited understanding about what RNs experience as they incorporate ACP into their practice. This study ...aimed to elicit the experiences of ACP RNs with the implementation of a normalised ACP (NACP) service in hospital and community care settings.
A qualitative descriptive study invited four ACP RNs who delivered a nurse-led NACP for a 6 months duration at two hospital and two community health care settings in New South Wales (NSW), Australia. The experiences of the ACP RNs were captured through a semi-structured interview and weekly debriefing meetings. The interview recordings were transcribed verbatim and the minutes of weekly debriefing meetings were utilized. Data were analysed by two independent researchers using thematic analysis with the Normalisation Process Theory (NPT) as a methodological framework.
The ACP RNs were females with a mean age of 43 years old. Their nursing experiences ranged 2 to 25 years but they had minimal experiences with ACP and had not attended any education about ACP previously. The following four themes were identified in the experiences of the ACP RNs; 1) Embracing NACP service; 2) Enablers and barriers related to patients and health professionals; 3) Enablers and barriers related to ACP RNs; and 4) What it means to be an ACP RN.
The introduction of a NACP service into existing clinical systems is complex. The study demonstrated the capacity of RNs to engage in ACP processes, and their willingness to deliver an NACP service with a raft of locally specific enablers and barriers.
The study was retrospectively registered with the Australian New Zealand Clinical Trials Registry (Trial ID: ACTRN12618001627246 ). The URL of the trial registry record.
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