Guidance for Pharmacy Curricula to Incorporate Health, Wellness, and Health Inequities Stemming From Climate Change: The Report of the 2022-2023 AACP Argus Commission.

The 2022-2023 American Association of College of Pharmacy Argus Commission was charged to provide guidance to schools, curriculum committees, and faculty on how to incorporate health, wellness, and health inequities stemming from climate change into pharmacy curricula. The Argus Commission does not advocate for major changes in the curriculum or standards but suggests a concerted effort across the Academy to enhance the awareness of graduating students of the potential impact of climate change on health both now and in the future. Various examples, along with recommendations and suggestions, are provided of how the impact of climate change on health is currently being integrated into curricula in member schools, as well as a list of resources faculty can use to enhance their awareness of issues related to climate change and health. The Commission was also charged to provide guidance to the American Association of College of Pharmacy regarding future fundraising and business development opportunities. Recommendations in that regard are also included in this report.

Adaptability, Agency, and Association to Influence Change: The Report of the 2020-21 AACP Argus Commission.

EXECUTIVE SUMMARY The 2020-21 AACP Argus Commission was charged to 1) review the 2019-2020 standing committee reports; 2) describe the impact of COVID-19 on healthcare delivery with an emphasis on health equity and social justice, 3) identify strategies to work with other health professions associations to advance interprofessional education and practice, and 4) offer recommendations for activities for the Center to Accelerate Pharmacy Practice Transformation and Academic Innovation (CAPT). Two work groups divided charges 2 and 3 and provided assessments of how health care and education might change due to all we have experienced over the 12-plus months of the pandemic. A review of plans for the first year of the CAPT activities and recommendations for additional activities are included in report. The Commission has proposed two new policy statements on digital health, five recommendations for AACP and five suggestions for colleges and schools of pharmacy. The Argus Commission affirms academic pharmacy's adaptability, agency, and association to influence changes in healthcare delivery and interprofessional education and practice.

Advancing Our Pharmacy Reformation - Accelerating Education and Practice Transformation: Report of the 2019-2020 Argus Commission.

The Argus Commission examined changes that should be considered by colleges and schools of pharmacy to meet the bold aim of better integrating pharmacists' and physicians' practices articulated by President Sorensen. The Commission assessed the readiness of pharmacy educators to contribute to the acceleration of practice transformation. The primary focus of the report is on how the doctor of pharmacy curriculum and post-graduate training might be modified and better aligned to ensure that graduates complete their education ready to engage in roles partnered with primary care clinicians. The aim is to achieve comprehensive medication management and other pharmacist patient care services as standards of care. The Argus Commission provides preliminary recommendations for new or more intensified priorities by the 2020-21 AACP Strategic Planning Committee as they update the AACP plan. This includes the recommendation that AACP should create the Center for Academic Innovation and Practice Transformation, a hub to coordinate many current and emerging activities relevant to accelerating change in pharmacy education and practice.

Reinventing How Pharmacy Educators Connect as a Community.

The onset of the novel coronavirus (COVID-19) pandemic has added a new layer of complexity to an already difficult period for academic pharmacy. The need to follow social-distancing guidelines has resulted in rapid adoption of technology-enabled communication strategies. While these technologies provide unprecedented ways in which we can connect as an academic community, we must consider their effectiveness in not only promoting exchange of information, but also creating inspiration within the community and supporting the level of interdependence required to tackle the difficult challenges that lie ahead. As the connecting body within the community of pharmacy education, it is incumbent on the American Association of Colleges of Pharmacy (AACP) to consider how we will adapt during this period of disruption. We must adopt new strategies that will allow our members to connect in new, meaningful ways, ways that stimulate ideas, new partnerships, and an overall sense of hope for our future.

Novel models for assessing blood-brain barrier drug permeation.

INTRODUCTION: The blood-brain barrier (BBB) is a selectively permeable micro-vascular unit which prevents many central nervous system (CNS)-targeted compounds from reaching the brain. A significant problem in CNS drug development is the ability to model BBB permeability in a timely, reproducible and cost-effective manner. Through the years, several models have been used such as artificial membranes, cell culture and animal models. AREAS COVERED: In this focused review, the authors cover novel models which have been developed or are in the process of being developed which can be used in modeling BBB. These models can either be used to determine BBB permeability or whether a compound may be disrupting the BBB. Many of these models lend themselves to high-throughput screening. The main model organisms covered here are the grasshopper (Locusta migratoria), fruit fly (Drosophila melanogaster) and zebrafish (Danio rerio). EXPERT OPINION: Many of the models covered here have only recently been utilized for BBB studies and still needs to be fully studied for its impact on reducing costs during drug development. The strength of these models lay in the fact that a whole organism experiment can be done in high throughput fashion as compared with classical vertebrate models such as micro-dialysis.

The blood-brain barrier choline transporter.

Drug delivery to the brain is made difficult by the blood-brain barrier (BBB) which is selectively permeable to organic drug compounds. Several membrane solute and nutrient transporters are expressed in the BBB vasculature, which may be utilized as mechanism of delivery of drugs to the brain. Of interest to us, are the organic cation transporters which could be used to transport cationic compounds into the CNS. In this mini-review, we will review the current understanding of the structural requirements for designing compounds which could effectively use organic cation transporters (OCT). For the first time, structural requirements for both OCT1 and OCT2 versus the BBB choline transporter (BBBCHT) are discussed and compared. The information gained here could increase the success rate in successful CNS drug delivery and therapeutics.

3-D-QSAR and docking studies on the neuronal choline transporter.

The high affinity neuronal choline transporter (CHT1) is responsible for the uptake of choline into the pre-synaptic terminal of cholinergic neurons. Considering our past experience with modeling the blood-brain barrier choline transporter (BBBCHT) as drug delivery vector to the CNS, we investigated the 3-D-quantitative structure-activity relationship of the neuronal choline transporter. Comparative molecular field analysis (CoMFA) and comparative similarity index analysis (CoMSIA) yielded cross-validated models with a q(2) of 0.5, and a non-cross validated r(2) of 0.8. The electrostatic results of the 3-D-QSAR models are corroborated with a docking study into the bacterial choline transporter. Using this electrostatic map, we propose a putative binding site in a homology model of the CHT1. Knowledge gained from this study is useful to better understand the CHT1 as well as can be used in medicinal chemistry programs targeting this transporter.

Bis-azaaromatic quaternary ammonium salts as ligands for the blood-brain barrier choline transporter.

A series of bis-azaaromatic quaternary ammonium compounds containing flexible polymethylenic linkers as well as conformationally restricted linkers were evaluated for their affinity for the blood-brain barrier choline transporter (BBB-ChT). The preliminary structure-activity relationships obtained from this study suggest that incorporating a linear, conformationally restricted linker into the molecule improves affinity for the BBB-ChT.

Predictive screening model for potential vector-mediated transport of cationic substrates at the blood-brain barrier choline transporter.

A set of semi-rigid cyclic and acyclic bis-quaternary ammonium analogs, which were part of a drug discovery program aimed at identifying antagonists at neuronal nicotinic acetylcholine receptors, were investigated to determine structural requirements for affinity at the blood-brain barrier choline transporter (BBB CHT). This transporter may have utility as a drug delivery vector for cationic molecules to access the central nervous system. In the current study, a virtual screening model was developed to aid in rational drug design/ADME of cationic nicotinic antagonists as BBB CHT ligands. Four 3D-QSAR comparative molecular field analysis (CoMFA) models were built which could predict the BBB CHT affinity for a test set with an r(2) <0.5 and cross-validated q(2) of 0.60, suggesting good predictive capability for these models. These models will allow the rapid in silico screening of binding affinity at the BBB CHT of both known nicotinic receptor antagonists and virtual compound libraries with the goal of informing the design of brain bioavailable quaternary ammonium analogs that are high affinity selective nicotinic receptor antagonists.

bis-Pyridinium cyclophanes: novel ligands with high affinity for the blood-brain barrier choline transporter.

A series of bis-pyridinium cyclophane analogs designed as conformationally restricted bis-quaternary ammonium compounds were evaluated for their affinity for the blood-brain barrier (BBB) choline transporter. All the cyclophanes investigated exhibited high affinity compared to choline. Of these compounds, N, N'-(1,10-decanediyl)3,3'-(1,9-decadiyn-1,10-diyl)-bis-pyridinium diiodide (5c) and N,N'-(1,9-nonanediyl)3,3'-(1,9-decadiyn-1,10-diyl)-bis-pyridinium dibromide (5b) exhibited highest affinity with K(i) values of 0.8 microM and 1.4 microM, respectively, and constitute some of the most potent BBB choline transporter ligands reported.

Carrier-mediated transport of the quaternary ammonium neuronal nicotinic receptor antagonist n,n'-dodecylbispicolinium dibromide at the blood-brain barrier.

The quaternary ammonium compound N,N'-dodecyl-bispicolinium dibromide (bPiDDB) potently and selectively inhibits nicotinic receptors (nAChRs) mediating nicotine-evoked [(3)H]dopamine release and decreases nicotine self-administration, suggesting that this polar, charged molecule penetrates the blood-brain barrier (BBB). This report focuses on 1) BBB penetration of bPiDDB; 2) the mechanism of permeation; and 3) comparison of bPiDDB to the cations choline and N-octylnicotinium iodide (NONI), both of which are polar, charged molecules that undergo facilitated BBB transport. The BBB permeation of [(3)H]choline, [(3)H]NONI, and [(14)C]bPiDDB was evaluated using in situ rat brain perfusion methods. Cerebrovascular permeability surface-area product (PS) values for [(3)H]choline, [(3)H]NONI, and [(14)C]bPiDDB were comparable (1.33 +/- 0.1, 1.64 +/- 0.15, and 1.3 +/- 0.3 ml/s/g, respectively). To ascertain whether penetration was saturable, unlabeled substrate was added to the perfusion fluid. Unlabeled choline (500 microM) reduced the PS of [(3)H]choline to 0.15 +/- 0.06 microl/s/g (p < 0.01). Likewise, unlabeled bPiDDB (500 microM) reduced the PS of [(14)C]bPiDDB to 0.046 +/- 0.005 microl/s/g (p < 0.01), whereas unlabeled NONI reduced the PS for [(3)H]NONI by approximately 50% to 0.73 +/- 0.31 microl/s/g. The PS of [(14)C]bPiDDB was reduced (p < 0.05) in the presence of 500 microM choline, indicating that the BBB choline transporter may be responsible for the transport of bPiDDB into brain. Saturable kinetic parameters for [(14)C]bPiDDB were similar to those for [(3)H]choline. The current results suggest that bPiDDB uses the BBB choline transporter for approximately 90% of its permeation into brain, and they demonstrate the carrier-mediated BBB penetration of a novel bisquaternary ammonium nAChR antagonist.

Voltage-gated calcium channels provide an alternate route for iron uptake in neuronal cell cultures.

Recent studies suggest that iron enters cardiomyocytes via the L-type voltage-gated calcium channel (VGCC). The neuronal VGCC may also provide iron entry. As with calcium, extraneous iron is associated with the pathology and progression of neurodegenerative diseases such as Parkinson's and Alzheimer's disease. VGCCs, ubiquitously expressed, may be an important route of excessive entry for both iron and calcium, contributing to cell toxicity or death. We evaluated the uptake of (45)Ca(2+) and (55)Fe(2+) into NGF-treated rat PC12, and murine N-2alpha cells. Iron not only competed with calcium for entry into these cells, but iron uptake (similar to calcium uptake) was inhibited by nimodipine, a specific L-type VGCC blocker, and enhanced by FPL 64176, an L-VGCC activator, in a dose-dependent manner. Taken together, these data suggest that voltage-gated calcium channels are an alternate route for iron entry into neuronal cells under conditions that promote cellular iron overload toxicity.

Brain iron toxicity: differential responses of astrocytes, neurons, and endothelial cells.

Iron accumulation or iron overload in brain is commonly associated with neurodegenerative disorders such as Parkinson's and Alzheimer's diseases, and also plays a role in cellular damage following hemorrhagic stroke and traumatic brain injury. Despite the brain's highly regulated system for iron utilization and metabolism, these disorders often present following disruptions within iron metabolic pathways. Such dysregulation allows saturation of proteins involved in iron transport and storage, and may cause an increase in free ferrous iron within brain leading to oxidative damage. Not only do astrocytes, neurons, and brain endothelial cells serve unique purposes within the brain, but their individual cell types are equipped with distinct protective mechanisms against iron-induced injury. This review evaluates iron metabolism within the brain under homeostatic and pathological conditions and focuses on the mechanism(s) of brain cellular iron toxicity and differential responses of astrocytes, neurons, and brain vascular endothelial cells to excessive free iron.