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.

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.

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.

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.

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.

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.

Optimizing the use of open-source software applications in drug discovery.

Drug discovery is a time consuming and costly process. Recently, a trend towards the use of in silico computational chemistry and molecular modeling for computer-aided drug design has gained significant momentum. This review investigates the application of free and/or open-source software in the drug discovery process. Among the reviewed software programs are applications programmed in JAVA, Perl and Python, as well as resources including software libraries. These programs might be useful for cheminformatics approaches to drug discovery, including QSAR studies, energy minimization and docking studies in drug design endeavors. Furthermore, this review explores options for integrating available computer modeling open-source software applications in drug discovery programs.

Neuronal dysfunction in Down syndrome: contribution of neuronal models in cell culture.

Down syndrome (DS) in humans, or trisomy of autosome 21, represents the hyperdiploidy that most frequently survives gestation, reaching an incidence of 1 in 700 live births. The condition is associated with multisystemic anomalies, including those affecting the central nervous system (CNS), determining a characteristic mental retardation. At a neuronal level, our group and others have shown that the condition determines marked alterations of action potential and ionic current kinetics, which may underlie abnormal processing of information by the CNS. Since the use of human tissue presents both practical and ethical problems, animal models of the human condition have been sought. Murine trisomy 16 (Ts16) is a model of the human condition, due to the great homology between human autosome 21 and murine 16. Both conditions share the same alterations of electrical membrane properties. However, the murine Ts16 condition is unviable (animals die in utero), thus limiting the quantity of tissue procurable. To overcome this obstacle, we have established immortal cell lines from normal and Ts16 mice with a method developed by our group that allows the stable in vitro immortalization of mammalian tissue, yielding cell lines which retain the characteristics of the originating cells. Cell lines derived from cerebral cortex, hippocampus, spinal cord and dorsal root ganglion of Ts16 animals show alterations of intracellular Ca2+ signals in response to several neurotransmitters (glutamate, acetylcholine, and GABA). Gene overdose most likely underlies these alterations in cell function, and the identification of the relative contribution of DS associated genes on such specific neuronal dysfunction should be investigated. This could enlighten our understanding on the contribution of these genes in DS, and identify new therapeutic targets.

Molecular modeling of blood-brain barrier nutrient transporters: in silico basis for evaluation of potential drug delivery to the central nervous system.

For drugs that act in the brain, the blood-brain barrier (BBB) is a considerable physical barrier which influences the distribution of drugs to the brain. The BBB is essentially impermeable for hydrophilic and/or charged compounds. Nutrient membrane transporters have an important physiological role in the transport of essential substances across the BBB required for normal brain function. We and others have shown that these transporters may have utility as drug delivery vectors, thereby increasing brain distribution of these compounds via these systems. In this review, we evaluate molecular (in silico) models of BBB transport proteins. Few BBB membrane transporters have been crystallized, but their crystal structures have a possibility for use in homology modeling. Other techniques commonly used are 2D quantitative structure-activity relationships (QSAR), as well as 3D-QSAR techniques including comparative molecular field analysis (CoMFA) and comparative similarity index analysis (CoMSIA). Each of these models provides valuable information for ascertaining their potential basis for BBB transport and brain drug delivery.

Novel D-penicillamine carrying nanoparticles for metal chelation therapy in Alzheimer's and other CNS diseases.

Metal ions accumulate in the brain with aging and in several neurodegenerative diseases. Aside from the copper storage disease, Wilson's disease, recent attention has focused on the accumulation of zinc, copper and iron in the Alzheimer's disease (AD) brain and the accumulation of iron in Parkinson's disease. In particular, the parenchymal deposition of beta-amyloid (Abeta) and its interaction with metal ions has been postulated to play a role in the progression of AD. Thus, the strategy of lowering brain metal ions and targeting the interaction of Abeta peptide and metal ions through the administration of chelators has merit. Our recent finding that nanoparticle delivery systems can cross the blood-brain barrier has led us to investigate whether chelators delivered conjugated to nanoparticles could act to reverse metal ion induced protein precipitation. In the present studies, the Cu (I) chelator D-penicillamine was covalently conjugated to nanoparticles via a disulfide bond or a thioether bond. Nanoparticle-chelator conjugates were stable between pH 6-8 in aqueous suspension if stored at 4 degrees C, and did not aggregate when challenged with salts and serum. Release of D-penicillamine from the nanoparticles was achieved using reducing agents such as dithiothreitol (as a model for glutathione). Nanoparticles treated only under reducing conditions that released the conjugated D-penicillamine were able to effectively resolubilize copper-Abeta (1-42) aggregates. These results indicate that nanoparticles have potential to deliver D-penicillamine to the brain for the prevention of Abeta (1-42) accumulation, as well as to reduce metal ion accumulation in other CNS diseases.

Inhibition of choline uptake by N-cyclohexylcholine, a high affinity ligand for the choline transporter at the blood-brain barrier.

The blood-brain barrier (BBB) choline transporter (CHT) may have utility as a drug delivery vector for drugs that act in the central nervous system. Previous studies suggested the importance of hydrophobic moieties on the cationic nitrogen of choline for improved affinity for this transporter. In a pilot study, we therefore designed five novel N-cycloalkyl derivatives of choline, one of which showed promising inhibition properties. This choline analogue had a cyclohexyl (UMBB-5) moiety substituting one of the methyl groups attached to the cationic nitrogen in choline. In situ experimental data were obtained from in situ rat brain perfusion studies. The binding affinity for the BBB-choline transporter found for UMBB-5 was K(i)=1.9 microM. Comparative molecular field analysis (CoMFA) suggested that the cyclohexyl moiety orientates towards a steric favourable area. Taken together, the results of these in situ and in silico studies provide further evidence or restrictions that occur with binding to this brain drug delivery vector.

A dorsal root ganglia cell line derived from trisomy 16 fetal mice, a model for Down syndrome.

We have established two immortalized cell lines from dorsal root ganglia of normal (G4b) and trisomy 16 mice (GT1), a model for Down syndrome. By immunohistochemistry, both cell lines exhibit neuronal traits and lack glial markers. GTl cells exhibited greater [3H]choline uptake than G4b cells. K+ and nicotine-mediated acetylcholine release was greater in GT1 cells. Basal intracellular Ca2+ concentration ([Ca2+]i) was significantly lower in GTl cells. More GTl cells responded to neurotransmitters with a transient [Ca2+]i increase compared to G4b cells, but both cell types showed similar amplitudes of [Ca2+]i responses. The results show that both cell lines retain neuronal characteristics and respond to specific neurotransmitter stimuli. Altered GT1 cell responses could be related to neuronal pathophysiology in Down's syndrome.

Paclitaxel nanoparticles for the potential treatment of brain tumors.

Despite the advances in tumor therapy, patients with primary brain tumors and brain metastases have a very poor prognosis. Low responses to chemotherapy are mainly attributed to impermeability of the blood-brain barrier to cytotoxic agents. Paclitaxel has been shown to be active against gliomas and various brain metastases. However, its use in treatment of brain tumors is limited due to low blood-brain barrier permeability and serious side effects associated with administration of the paclitaxel solvent, Cremophor EL. Lack of paclitaxel brain uptake is thought to be associated with the p-glycoprotein (p-gp) efflux transporter. In this work, paclitaxel (PX) was entrapped in novel cetyl alcohol/polysorbate nanoparticles. Paclitaxel nanoparticles (PX NPs) were characterized by means of size, short-term stability, drug entrapment efficiency, and release profile. The PX NP cytotoxicity profile was monitored using two different cell lines, U-118 and HCT-15. Brain uptake of PX NPs was evaluated using an in situ rat brain perfusion model. The results suggest that entrapment of paclitaxel in nanoparticles significantly increases the drug brain uptake and its toxicity toward p-glycoprotein expressing tumor cells. It was hypothesized that PX NPs could mask paclitaxel characteristics and thus limit its binding to p-gp, which consequently would lead to higher brain and tumor cell uptake of the otherwise effluxed drug.

Brain uptake of thiamine-coated nanoparticles.

Recently, a novel nanoparticle (NP) comprised of emulsifying wax and Brij 78 was shown to have significant brain uptake using the in-situ rat brain perfusion technique. To further these studies and to specifically target brain, we have incorporated thiamine as a surface ligand on the nanoparticles. Solid nanoparticles were prepared from oil-in-water microemulsion precursors. Nanoparticles were radiolabeled and a thiamine ligand (thiamine linked to distearoylphosphatidylethanolamine via a polyethylene glycol spacer) was coated on the surface of the nanoparticles. Initial experiments focused on assessing uptake of [3H]nanoparticles with and without thiamine surface ligands. Biodistribution nanoparticle studies were also carried out in BALB/c mice. The results showed: (1) the effectiveness of using microemulsions as precursors to engineer nanoparticles, (2) kinetic modeling for brain uptake of nanoparticles with and without the thiamine surface ligands, and (3) initial data suggesting mechanisms for nanoparticle brain entry. Comparison of NP brain uptake demonstrated that the thiamine-coated nanoparticle associated with the blood-brain barrier (BBB) thiamine transporter and had an increased K(in) between 45 and 120 s (thiamine coated NP 9.8 +/- 1.1 x 10(-3) ml/s/g versus uncoated NPs; 7.0 +/- 0.3 x 10(-3) ml/s/g). It was concluded that the thiamine ligand facilitated binding and/or association with blood-brain barrier thiamine transporters, which may be a viable mechanism for nanoparticle mediated brain drug delivery.

Manganese distribution across the blood-brain barrier. I. Evidence for carrier-mediated influx of managanese citrate as well as manganese and manganese transferrin.

Manganese (Mn) is an essential element and a neurotoxicant. Regulation of Mn movement across the blood-brain barrier (BBB) contributes to whether the brain Mn concentration is functional or toxic. In plasma, Mn associates with water, small molecular weight ligands and proteins. Mn speciation may influence the kinetics of its movement through the BBB. In the present work, the brain influx rates of 54Mn2+, 54Mn citrate and 54Mn transferrin (54Mn Tf) were determined using the in situ brain perfusion technique. The influx rates were compared to their predicted diffusion rates, which were determined from their octanol/aqueous partitioning coefficients and molecular weights. The in situ brain perfusion fluid contained 54Mn2+, 54Mn citrate or 54Mn Tf and a vascular volume/extracellular space marker, 14C-sucrose, which did not appreciably cross the BBB during these short experiments (15-180 s). The influx transfer coefficient (Kin) was determined from four perfusion durations for each Mn species in nine brain regions and the lateral ventricular choroid plexus. The brain Kin was (5-13) x 10(-5), (3-51) x 10(-5), and (2-13) x 10(-5) ml/s/g for 54Mn2+, 54Mn citrate, and 54Mn Tf, respectively. Brain Kin values for any one of the three Mn species generally did not significantly differ among the nine brain regions and the choroid plexus. However, the brain Kin for Mn citrate was greater than Mn2+ and Mn Tf Kin values in a number of brain regions. When compared to calculated diffusion rates, brain Kin values suggest carrier-mediated brain influx of 54Mn2+, 54Mn citrate and 54Mn Tf. 55Mn citrate inhibited 54Mn citrate uptake, and 55Mn2+ inhibited 54Mn2+ uptake, supporting the conclusion of carrier-mediated brain Mn influx. The greater Kin values for Mn citrate than Mn2+ and its presence as a major non-protein-bound Mn species in blood plasma suggest Mn citrate may be a major Mn species entering the brain.

Nanoparticle surface charges alter blood-brain barrier integrity and permeability.

PURPOSE: The blood-brain barrier (BBB) presents both a physical and electrostatic barrier to limit brain permeation of therapeutics. Previous work has demonstrated that nanoparticles (NPs) overcome the physical barrier, but there is little known regarding the effect of NP surface charge on BBB function. Therefore, this work evaluated: (1) effect of neutral, anionic and cationic charged NPs on BBB integrity and (2) NP brain permeability. METHODS: Emulsifying wax NPs were prepared from warm oil-in-water microemulsion precursors using neutral, anionic or cationic surfactants to provide the corresponding NP surface charge. NPs were characterized by particle size and zeta potential. BBB integrity and NP brain permeability were evaluated by in situ rat brain perfusion. RESULTS: Neutral NPs and low concentrations of anionic NPs were found to have no effect on BBB integrity, whereas, high concentrations of anionic NPs and cationic NPs disrupted the BBB. The brain uptake rates of anionic NPs at lower concentrations were superior to neutral or cationic formulations at the same concentrations. CONCLUSIONS: (1) Neutral NPs and low concentration anionic NPs can be utilized as colloidal drug carriers to brain, (2) cationic NPs have an immediate toxic effect at the BBB and (3) NP surface charges must be considered for toxicity and brain distribution profiles.