Towards human ex vivo organ perfusion models to elucidate drug pharmacokinetics in health and disease

Abstract

To predict the absorption, distribution, metabolism and excretion (ADME) profile of candidate drugs a variety of preclinical models can be applied. The ADME and toxicological behavior of newly developed drugs are often investigated prior to assessment in humans, which is associated with long time-lines and high costs. Therefore, good predictions of ADME profiles earlier in the drug development process are very valuable. Good prediction of intestinal absorption and renal and biliary excretion remain especially difficult, as there is an interplay of active transport and metabolism involved. To study these processes, including enterohepatic circulation, ex vivo tissue models are highly relevant and can be regarded as the bridge between in vitro and in vivo models. In this review the current in vitro, in vivo and in more detail ex vivo models for studying pharmacokinetics in health and disease are discussed. Additionally, we propose novel models, i.e., perfused whole-organs, which we envision will generate valuable pharmacokinetic information in the future due to improved translation to the in vivo situation. These machine-perfused organ models will be particularly interesting in combination with biomarkers for assessing the functionality of transporter and CYP450 proteins.     

Risk and protective factors for wellbeing in older veterans in New Zealand

Objectives: To compare indicators relating to aging and health among veterans and non-veterans, and identify factors associated with subjective wellbeing (SWB) of older New Zealand veterans.

Methods: Self-reported data were obtained from participants in a longitudinal cohort study of New Zealand older adults. Responses from 352 veterans and 1500 non-veterans (age range of 55–86 and gender matched) were selected as a comparison group on indicators related to health and aging. The association of these indicators with veterans’ SWB were assessed using hierarchical regression.

Results: Apart from being older, smoking more, and having more chronic conditions, veterans did not differ from non-veterans on indicators of health and wellbeing. Mental health, physical health, purpose in life, housing satisfaction, and capabilities (choice and freedom) accounted for a significant amount of variance in veterans’ SWB.

Conclusion: Our results suggest that older veterans do not differ greatly on indices of health and aging from their non-veteran peers. Results support previous findings that lower mental and physical health is associated with lower SWB for veterans. Building upon prior findings, the current results demonstrate that interventions focusing on enhancing a sense of purpose in life, supporting one's capability to achieve, and strengthening social and physical environment through social connectedness, may serve as protective factors for SWB in veterans.     

Abstracting pain management documentation from the electronic medical record: comparison of three hospitals

BackgroundPain management science results are derived from research conducted using medical record.ApproachThis article describes methodological issues arising from abstracting pain management documentation (PMD) from the electronic medical record in three hospitals. After approval, PMD data were collected from the patient's history and physical, discharge summary, operative care notes, computerized nursing flow sheets, progress notes, and medication records.ResultsEach acute care facility required a different approach to abstract data. Inconsistent documentation in pain management assessments, interventions, and reassessments were identified across hospitals.DiscussionInconsistencies pose measurement threats and hinder benchmarking efforts. Work to standardize PMD across propriety computer systems is warranted.     

Efficacy of a Church-Based,Culturally Tailored Program to Promote Completion of Advance Directives Among Asian Americans

Having an Advance Directive (AD) can help to guide medical decision-making. Asian Americans (AA) are less likely than White Americans to complete an AD. This pilot study investigated the feasibility and efficacy of a church-based intervention to increase knowledge and behavior change related to AD among Chinese and Vietnamese Americans. This study utilized a single group pre- and post-intervention design with 174 participants from 4 churches. Domain assessed: demographics; AD-related knowledge, beliefs, attitudes, and intentions; AD completion; and conversations with a healthcare proxy. Data were analyzed using Chi square and multiple logistic regression techniques. We observed significant increases in participants’ AD-related knowledge, intentions, and a gain in supportive beliefs and attitudes about AD, resulting in 71.8 % AD completion, and 25.0 % having had a proxy conversation. Providing culturally-tailored intervention and step-by-step guidance can help to achieve significant changes in AD related knowledge and behavior in AA church goers.     

Evaluating the use of plerixafor in stem cell mobilisation – an economic analysis of the PHANTASTIC trial

Plerixafor is an effective haematopoietic stem cell mobilising agent in candidates for autologous transplantation, including patients with myeloma and lymphoma. Here we compare 98 plerixafor recipients in the PHANTASTIC trial with 151 historic controls mobilised by conventional chemotherapy (each with granulocyte colony‐stimulating factor, G‐CSF). Seventy (71.4%) plerixafor‐mobilised patients achieved the composite primary endpoint of ≥4 × 10⁶ CD34+ cells kg^?1 in ≤2 aphereses and no clinically significant neutropenia, compared to 48 (31.8%) historic controls (P < 0.001), and this significant advantage was maintained in scenario analyses testing components of this composite endpoint. A patient‐level cost analysis was undertaken for 249 patients, which included the cost of remobilising patients where initial mobilisation had failed. Combined mean treatment cost for plerixafor mobilised patients was £12,679 compared with £11,694 for historical controls. However, plerixafor produces an average saving of £3,828 per lymphoma patient but average cost increase by £5,245 per myeloma patient. The present data demonstrate cost‐effectiveness for plerixafor as a first line mobilisation agent, certainly for lymphoma patients, where substantial resource savings and achievement of the primary endpoint are likely. J. Clin. Apheresis 31:434–442, 2016. © 2015 Wiley Periodicals, Inc.     

Molecular composition of the alveolar lining fluid in the aging lung

As we age, there is an increased risk for the development of pulmonary diseases, including infections, but few studies have considered changes in lung surfactant and components of the innate immune system as contributing factors to the increased susceptibility of the elderly to succumb to infections. We and others have demonstrated that human alveolar lining fluid (ALF) components, such as surfactant protein (SP)-A, SP-D, complement protein C3, and alveolar hydrolases, play a significant innate immune role in controlling microbial infections. However, there is a lack of information regarding the effect of increasing age on the level and function of ALF components in the lung. Here we addressed this gap in knowledge by determining the levels of ALF components in the aging lung that are important in controlling infection. Our findings demonstrate that pro-inflammatory cytokines, surfactant proteins and lipids, and complement components are significantly altered in the aged lung in both mice and humans. Further, we show that the aging lung is a relatively oxidized environment. Our study provides new information on how the pulmonary environment in old age can potentially modify mucosal immune responses, thereby impacting pulmonary infections and other pulmonary diseases in the elderly population.     

A Strategic and Shared Agenda to Advance Mental Health in Schools through Family and System Partnerships

The paper reviews data on the gap between young people who need and young people who receive mental health care. The fact that need far outstrips available resources underscores the importance of moving forward a shared agenda that builds a coalition of shared values and goals among families, schools, mental health agencies and other community programs and stakeholders. The importance of a coordinated public health approach, emphasizing broad systems enhancement, early intervention, and more intensive programs and services, is emphasized, and recommendations for strategic action at local, state and national levels are presented.