Innovative ideas, strategies, and resources to attract students to the pharmacy profession: Report of the 2023-2024 AACP Student Affairs Committee.

Over the past 2 decades, the Academy has witnessed an increase in new colleges and schools of pharmacy and, simultaneously, a decrease in student applications, resulting in a decline in enrollment across most institutions. Although the number of students pursuing a Doctor of Pharmacy degree has been dropping, the Academy is responsible for bolstering recruitment to effectively prepare a robust pharmacy workforce to care for our ever-growing and complex patient populations. The 2023-2024 Student Affairs Committee (SAC) was convened to explore new ideas, develop innovative strategies, and gather supportive resources that can be utilized by colleges and schools of pharmacy to attract students to the pharmacy profession. The SAC was charged with developing a framework for a video mini-series that utilizes the art of storytelling to promote the pharmacy profession to prospective students. Secondarily, the SAC was charged with developing a plan to engage with students who apply but do not ultimately get accepted into nonpharmacy health professions programs and consider recommendations for targeting pharmacy technicians to pursue a PharmD degree. To accomplish this work, we created videos and proposed other innovative tools and flexible pathways to assist in recruiting students into the pharmacy profession. We also conducted a literature and website review, engaged in professional networking across the Academy, and proposed best practices to enhance student recruitment. In addition, we offered 8 recommendations to the American Association of Colleges of Pharmacy and 7 suggestions to colleges and schools of pharmacy to attract students to the pharmacy profession.

An Integrative Review of Micro-Credentials and Digital Badges for Pharmacy Educators.

Micro-credentials (MCs) and digital badges (DBs) have gained popularity in recent years as a means to supplement traditional degrees and certifications. MCs and DBs can play a significant role in supporting student-centered learning by offering personalized and flexible learning pathways, emphasizing real-world relevance and practical skills, and fostering a culture of continuous learning and growth. However, barriers currently exist within health professions education, including pharmacy education, that could limit the full adoption and implementation of MCs and DBs. Research on the use of MCs and DBs in Doctor of Pharmacy degree programs is sparse. In this integrative review, literature on the use of MCs and DBs in health professions education is reviewed, and perspectives on the benefits, issues, and potential future uses within Doctor of Pharmacy degree programs are presented.

Assessment of Cultural Competence in Pharmacy Students Prior to Advanced Pharmacy Practice Experiences.

Objective. To assess various aspects of cultural competence in second year Doctor of Pharmacy students' and investigate the relationship between cultural competence and students' demographics, work experience, and prior education.Methods. A 63-item survey modified from the Clinical Cultural Competency Questionnaire (CCCQ) and comprising four domains (knowledge, skills, encounters or situations, and attitudes towards cultural competency) was administered to second year pharmacy students before they started their advanced pharmacy practice experiences (APPEs). Additional questions regarding their ability to identify and recognize elements of cultural competence were asked. The effects of demographics, work experience, and education on cultural competence also were assessed.Results. Ninety-seven students (86.6%) participated in the study. The majority of participants were Asian, female, and in their late 20s. Most students agreed or strongly agreed that they could identify and recognize elements of cultural competence. However, participants indicated they were only a little or somewhat comfortable when asked questions about knowledge, skills, and comfort. Students indicated they had "quite a bit" of competence regarding attitudes towards other cultures. Previous cultural diversity training in undergraduate studies and pharmacy school were associated with higher scores on the modified CCCQ.Conclusion. The findings emphasize the importance of schools providing training in the didactic and experiential portion of the pharmacy curriculum to increase pharmacy students' knowledge, skills, comfort, and attitudes towards other cultures.

Discovery of a Highly Selective Sigma-2 Receptor Ligand, 1-(4-(6,7-Dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)butyl)-3-methyl-1H-benzo[d]imidazol-2(3H)-one (CM398), with Drug-Like Properties and Antinociceptive Effects In Vivo.

The sigma-2 receptor has been cloned and identified as Tmem97, which is a transmembrane protein involved in intracellular Ca2+ regulation and cholesterol homeostasis. Since its discovery, the sigma-2 receptor has been an extremely controversial target, and many efforts have been made to elucidate the functional role of this receptor during physiological and pathological conditions. Recently, this receptor has been proposed as a potential target to treat neuropathic pain due to the ability of sigma-2 receptor agonists to relieve mechanical hyperalgesia in mice model of chronic pain. In the present work, we developed a highly selective sigma-2 receptor ligand (sigma-1/sigma-2 selectivity ratio > 1000), 1-(4-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)butyl)-3-methyl-1H- benzo[d]imidazol-2(3H)-one (CM398), with an encouraging in vitro and in vivo pharmacological profile in rodents. In particular, radioligand binding studies demonstrated that CM398 had preferential affinity for sigma-2 receptor compared with sigma-1 receptor and at least four other neurotransmitter receptors sites, including the norepinephrine transporter. Following oral administration, CM398 showed rapid absorption and peak plasma concentration (Cmax) occurred within 10 min of dosing. Moreover, the compound showed adequate, absolute oral bioavailability of 29.0%. Finally, CM398 showed promising anti-inflammatory analgesic effects in the formalin model of inflammatory pain in mice. The results collected in this study provide more evidence that selective sigma-2 receptor ligands can be useful tools in the development of novel pain therapeutics and altogether, these data suggest that CM398 is a suitable lead candidate for further evaluation.

The psychopharmacology of pseudobulbar affect.

Pseudobulbar affect (PBA) is characterized by uncontrollable emotional episodes disconnected or disproportionate with mood, in association with an array of neurologic conditions. PBA is associated with disruption of descending control of brainstem motor circuitry and dysregulation of serotonergic and glutamatergic function. PBA has been historically under recognized, though advances resulting in more specific diagnostic criteria, validated rating scales, and an approved pharmacotherapy offer opportunities for improved treatment outcomes.

An Individual Development Plan for Pharmacy Students for Career Planning and Tracking Accreditation Standards.

Objective. To create and implement individual development plans (IDPs) to assist pharmacy students in career planning and tracking their achievement of ACPE Standards 2016, Standard 4, for Personal and Professional Development. Methods. First-year Doctor of Pharmacy students completed IDPs, which were subsequently reviewed to ensure they addressed components of the ACPE Standard 4 key elements: self-awareness, leadership, innovation and entrepreneurship, and professionalism. Faculty advisors were surveyed regarding the utility of IDPs. Descriptive statistics were used to evaluate the results. Results. Self-awareness (100%) and professionalism (100%) were the key elements most commonly documented by pharmacy students, followed by leadership (51%), and innovation and entrepreneurship (22%). Faculty advisors reported IDPs as beneficial for stimulating individualized career planning and tracking achievement of ACPE Standard 4. Conclusion. Most students enter pharmacy school recognizing the importance of self-awareness and professionalism, but require additional training to instill leadership and innovation/entrepreneurship skills. Individual development plans can be implemented in pharmacy education as a cornerstone of personal and professional development planning, as well as a means of tracking a school's progress toward meeting accreditation standards.

Gedunin Inhibits Oligomeric Aß1-42-Induced Microglia Activation Via Modulation of Nrf2-NF-κB Signaling.

Alzheimer's disease (AD) is a neurodegenerative disorder and the leading cause of dementia in aged populations worldwide. The deposition of toxic protein aggregates such as amyloid beta (Aß) is a hallmark of AD, and there is growing awareness that a key driver of AD pathogenesis is the neuroinflammatory cascade triggered and sustained by these proteins. Consequently, interventions that suppress prolonged neuroinflammation represent viable therapeutic approaches for AD. In this context, we tested the natural product gedunin which is an anti-inflammatory molecule, found in the seeds of the neem tree (Azadirachta indica), whose mechanism of action remains to be fully elucidated. Using a mouse microglia cell line (IMG), we show that gedunin suppresses neuroinflammation arising from Aß1-42 oligomer exposure. Our results demonstrate that gedunin suppresses Aß1-42-induced NF-κB activation and its targets, including nitric oxide (NO) and IL-1ß, known proinflammatory molecules. Further, we show that gedunin inhibits neuroinflammation by activating nuclear factor 2 erythroid-related factor 2 (Nrf2) and its downstream targets γ-glutamylcysteine synthetase, heme oxygenase 1, and NADPH quinone dehydrogenase 1, which are involved in quenching reactive oxygen and nitrogen species (NO) generated by NF-κB activation. Nrf2 activation appears essential for the anti-inflammatory effect because when silenced, the proinflammatory effects of Aß1-42 are enhanced and the protective effect of gedunin against NO production is reduced. Additionally, using human neuronal cells (SH-SY5Y), we show that gedunin prevents neurotoxicity secondary to Aß-induced microglial activation. In conclusion, our findings highlight a potential therapeutic role of gedunin in neurodegenerative diseases.

Benzimidazolone-based selective σ2 receptor ligands: Synthesis and pharmacological evaluation.

Sigma receptors (σRs) are considered to be a significant and valid target for developing new medications to address several diseases. Their potential involvement in numerous central nervous system disorders, neuropathic pain, addiction, and cancer has been extensively reported. In particular, the σ2R has been identified as potential target for the development of pharmaceutical agents intended to treat the negative effects associated with drugs of abuse. As a continuation of our previous efforts to develop new selective σ2R ligands, a series of benzimidazolone derivatives were designed, synthesized, and characterized. The newly synthesized ligands were evaluated through in vitro radioligand binding assays to determine their affinity and selectivity towards both σ1 and σ2 receptors. Several derivatives displayed high affinity for the σ2R (Ki = 0.66-68.5 nM) and varied from preferring to selective, compared to σ1R (σ1/σ2 = 5.8-1139). Among them, compound 1-{4-[4-(4-fluorophenyl)piperazin-1-yl]butyl}-3-propyl-1,3-dihydrobenzimidazol-2-one dihydrochloride (14) displayed the ability to produce a dose-dependent reduction in the convulsive effects of cocaine in a rodent model after injecting 10 mg/kg (i.p.). These preliminary results support the use of selective σ2R ligands in the development of useful pharmacological tools or potential pharmacotherapies for cocaine toxicity.

Synthesis and Structural Elucidation of a Pyranomorphinan Opioid and in Vitro Studies.

During optimization of the synthesis of the mixed µ opioid agonist/δ opioid antagonist 5-(hydroxymethyl)oxymorphone (UMB425) for scale-up, it was unexpectedly discovered that the 4,5-epoxy bridge underwent rearrangement on treatment with boron tribromide (BBr3) to yield a novel opioid with a little-studied pyranomorphinan skeleton. This finding opens the pyranomorphinans for further investigations of their pharmacological profiles and represents a novel drug class with the dual profile (µ vs δ) predicted to yield lower tolerance and dependence. The structure was assigned with the help of 1D, 2D NMR and the X-ray crystal structure.

Deuterated (d6)-dextromethorphan elicits antidepressant-like effects in mice.

The over-the-counter antitussive dextromethorphan (DM) may have rapid antidepressant actions based on its overlapping pharmacology with ketamine, which has shown fast antidepressant effects but whose widespread use remains limited by problematic side effects. We have previously shown that DM produces antidepressant-like effects in the forced swim test (FST) and tail suspension test (TST) that are mediated in part through α-amino-3-hydroxy-5-methyl-4-isoxazole propionic (AMPA) and sigma-1 receptors, two protein targets associated with a faster onset of antidepressant efficacy. To utilize DM clinically, however, a major challenge that must be addressed is its rapid first-pass metabolism. Two strategies to inhibit metabolism of DM and maintain stable therapeutic blood levels are 1) chemically modifying DM and 2) adding quinidine, an inhibitor of the primary metabolizer of DM, the cytochrome P450 (CYP) 2D6 enzyme. The purpose of this study was to determine if modified DM (deuterated (d6)-DM) elicits antidepressant-like effects and if AMPA and sigma-1 receptors are involved. Furthermore, d6-DM was tested in conjunction with quinidine to determine if further slowing the metabolism of d6-DM affects its antidepressant-like actions. In the FST and TST, d6-DM produced antidepressant-like effects. Upon further investigation in the FST, the most validated animal model for predicting antidepressant efficacy, d6-DM produced antidepressant-like effects both in the absence and presence of quinidine. However, pretreatment with neither an AMPA receptor antagonist (NBQX) nor sigma-1 receptor antagonists (BD1063, BD1047) significantly attenuated the antidepressant-like effects. The data suggest d6-DM has antidepressant-like effects, though it may be recruiting different molecular targets and/or acting through a different mix or ratio of metabolites from regular DM.

Relationship Between Grit with Academic Performance and Attainment of Postgraduate Training in Pharmacy Students.

Objective. To determine if Grit-S scores correlate with academic success in a doctor of pharmacy (PharmD) program, as well as the pursuit and attainment of pharmacy postgraduate (residency or fellowship) training. Methods. A 28-item survey was administered to third- and fourth-year (P3 and P4) pharmacy students. Variables queried included Grit-S score, demographics, pharmacy experience prior to the PharmD program, and factors that may affect academic performance during didactic coursework. Didactic coursework GPA was used as a surrogate for academic success. Information about pursuit and attainment of a postgraduate training position was also documented and used in the analyses. Results. There was no significant correlation between Grit-S scores and variables related to academic success. However, students were more likely to pursue postgraduate training with higher academic success and higher Grit-S. Lastly, students with higher Grit-S were also more likely to obtain a postgraduate training position. Conclusion. Grit-S scores correlated with the pursuit and successful attainment of postgraduate training, but not with academic success during the didactic years of a PharmD program.

Sigma-1 Receptors and Neurodegenerative Diseases: Towards a Hypothesis of Sigma-1 Receptors as Amplifiers of Neurodegeneration and Neuroprotection.

Sigma-1 receptors are molecular chaperones that may act as pathological mediators and targets for novel therapeutic applications in neurodegenerative diseases. Accumulating evidence indicates that sigma-1 ligands can either directly or indirectly modulate multiple neurodegenerative processes, including excitotoxicity, calcium dysregulation, mitochondrial and endoplasmic reticulum dysfunction, inflammation, and astrogliosis. In addition, sigma-1 ligands may act as disease-modifying agents in the treatment for central nervous system (CNS) diseases by promoting the activity of neurotrophic factors and neural plasticity. Here, we summarize their neuroprotective and neurorestorative effects in different animal models of acute brain injury and chronic neurodegenerative diseases, and highlight their potential role in mitigating disease. Notably, current data suggest that sigma-1 receptor dysfunction worsens disease progression, whereas enhancement amplifies pre-existing functional mechanisms of neuroprotection and/or restoration to slow disease progression. Collectively, the data support a model of the sigma-1 receptor as an amplifier of intracellular signaling, and suggest future clinical applications of sigma-1 ligands as part of multi-therapy approaches to treat neurodegenerative diseases.

Single low-dose lipopolysaccharide preconditioning: neuroprotective against axonal injury and modulates glial cells.

AIM: Over 7 million traumatic brain injuries (TBI) are reported each year in the United States. However, treatments and neuroprotection following TBI are limited because secondary injury cascades are poorly understood. Lipopolysaccharide (LPS) administration before controlled cortical impact can contribute to neuroprotection. However, the underlying mechanisms and whether LPS preconditioning confers neuroprotection against closed-head injuries remains unclear. METHODS: The authors hypothesized that preconditioning with a low dose of LPS (0.2 mg/kg) would regulate glial reactivity and protect against diffuse axonal injury induced by weight drop. LPS was administered 7 days prior to TBI. LPS administration reduced locomotion, which recovered completely by time of injury. RESULTS: LPS preconditioning significantly reduced the post-injury gliosis response near the corpus callosum, possibly by downregulating the oncostatin M receptor. These novel findings demonstrate a protective role of LPS preconditioning against diffuse axonal injury. LPS preconditioning successfully prevented neurodegeneration near the corpus callosum, as measured by fluorojade B. CONCLUSION: Further work is required to elucidate whether LPS preconditioning confers long-term protection against behavioral deficits and to elucidate the biochemical mechanisms responsible for LPS-induced neuroprotective effects.

Benzylideneoxymorphone: A new lead for development of bifunctional mu/delta opioid receptor ligands.

Opioid analgesic tolerance remains a considerable drawback to chronic pain management. The finding that concomitant administration of delta opioid receptor (DOR) antagonists attenuates the development of tolerance to mu opioid receptor (MOR) agonists has led to interest in producing bifunctional MOR agonist/DOR antagonist ligands. Herein, we present 7-benzylideneoxymorphone (6, UMB 246) displaying MOR partial agonist/DOR antagonist activity, representing a new lead for designing bifunctional MOR/DOR ligands.

Behavioral and biochemical effects of ketamine and dextromethorphan relative to its antidepressant-like effects in Swiss Webster mice.

Ketamine has been shown to produce rapid and robust antidepressant effects in depressed individuals; however, its abuse potential and adverse psychotomimetic effects limit its widespread use. Dextromethorphan (DM) may serve as a safer alternative on the basis of pharmacodynamic similarities to ketamine. In this proof-of-concept study, behavioral and biochemical analyses were carried out to evaluate the potential involvement of brain-derived neurotrophic factor (BDNF) in the antidepressant-like effects of DM in mice, with comparisons to ketamine and imipramine. Male Swiss, Webster mice were injected with DM, ketamine, or imipramine and their behaviors were evaluated in the forced-swim test and the open-field test. Western blots were used to measure BDNF and its precursor, pro-BDNF, protein expression in the hippocampus and the frontal cortex of these mice. Our results show that both DM and imipramine reduced immobility time in the forced-swim test without affecting locomotor activity, whereas ketamine reduced immobility time and increased locomotor activity. Ketamine also rapidly (within 40 min) increased pro-BDNF expression in an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor-dependent manner in the hippocampus, whereas DM and imipramine did not alter pro-BDNF or BDNF levels in either the hippocampus or the frontal cortex within this timeframe. These data show that DM shares some features with both ketamine and imipramine. Additional studies examining DM may aid in the development of more rapid, safe, and efficacious antidepressant treatments.

Pharmacology of dextromethorphan: Relevance to dextromethorphan/quinidine (Nuedexta®) clinical use.

Dextromethorphan (DM) has been used for more than 50years as an over-the-counter antitussive. Studies have revealed a complex pharmacology of DM with mechanisms beyond blockade of N-methyl-d-aspartate (NMDA) receptors and inhibition of glutamate excitotoxicity, likely contributing to its pharmacological activity and clinical potential. DM is rapidly metabolized to dextrorphan, which has hampered the exploration of DM therapy separate from its metabolites. Coadministration of DM with a low dose of quinidine inhibits DM metabolism, yields greater bioavailability and enables more specific testing of the therapeutic properties of DM apart from its metabolites. The development of the drug combination DM hydrobromide and quinidine sulfate (DM/Q), with subsequent approval by the US Food and Drug Administration for pseudobulbar affect, led to renewed interest in understanding DM pharmacology. This review summarizes the interactions of DM with brain receptors and transporters and also considers its metabolic and pharmacokinetic properties. To assess the potential clinical relevance of these interactions, we provide an analysis comparing DM activity from in vitro functional assays with the estimated free drug DM concentrations in the brain following oral DM/Q administration. The findings suggest that DM/Q likely inhibits serotonin and norepinephrine reuptake and also blocks NMDA receptors with rapid kinetics. Use of DM/Q may also antagonize nicotinic acetylcholine receptors, particularly those composed of α3ß4 subunits, and cause agonist activity at sigma-1 receptors.

Salubrinal reduces oxidative stress, neuroinflammation and impulsive-like behavior in a rodent model of traumatic brain injury.

Traumatic brain injury (TBI) is the leading cause of trauma related morbidity in the developed world. TBI has been shown to trigger secondary injury cascades including endoplasmic reticulum (ER) stress, oxidative stress, and neuroinflammation. The link between secondary injury cascades and behavioral outcome following TBI is poorly understood warranting further investigation. Using our validated rodent blast TBI model, we examined the interaction of secondary injury cascades following single injury and how these interactions may contribute to impulsive-like behavior after a clinically relevant repetitive TBI paradigm. We targeted these secondary pathways acutely following single injury with the cellular stress modulator, salubrinal (SAL). We examined the neuroprotective effects of SAL administration on significantly reducing ER stress: janus-N-terminal kinase (JNK) phosphorylation and C/EBP homology protein (CHOP), oxidative stress: superoxide and carbonyls, and neuroinflammation: nuclear factor kappa beta (NFκB) activity, inducible nitric oxide synthase (iNOS) protein expression, and pro-inflammatory cytokines at 24h post-TBI. We then used the more clinically relevant repeat injury paradigm and observed elevated NFκB and iNOS activity. These injury cascades were associated with impulsive-like behavior measured on the elevated plus maze. SAL administration attenuated secondary iNOS activity at 72h following repetitive TBI, and most importantly prevented impulsive-like behavior. Overall, these results suggest a link between secondary injury cascades and impulsive-like behavior that can be modulated by SAL administration.

Dextromethorphan: An update on its utility for neurological and neuropsychiatric disorders.

Dextromethorphan (DM) is a commonly used antitussive and is currently the only FDA-approved pharmaceutical treatment for pseudobulbar affect. Its safety profile and diverse pharmacologic actions in the central nervous system have stimulated new interest for repurposing it. Numerous preclinical investigations and many open-label or blinded clinical studies have demonstrated its beneficial effects across a variety of neurological and psychiatric disorders. However, the optimal dose and safety of chronic dosing are not fully known. This review summarizes the preclinical and clinical effects of DM and its putative mechanisms of action, focusing on depression, stroke, traumatic brain injury, seizure, pain, methotrexate neurotoxicity, Parkinson's disease and autism. Moreover, we offer suggestions for future research with DM to advance the treatment for these and other neurological and psychiatric disorders.

Traumatic brain injury and epilepsy: Underlying mechanisms leading to seizure.

Post-traumatic epilepsy continues to be a major concern for those experiencing traumatic brain injury. Post-traumatic epilepsy accounts for 10-20% of epilepsy cases in the general population. While seizure prophylaxis can prevent early onset seizures, no available treatments effectively prevent late-onset seizure. Little is known about the progression of neural injury over time and how this injury progression contributes to late onset seizure development. In this comprehensive review, we discuss the epidemiology and risk factors for post-traumatic epilepsy and the current pharmacologic agents used for treatment. We highlight limitations with the current approach and offer suggestions for remedying the knowledge gap. Critical to this pursuit is the design of pre-clinical models to investigate important mechanistic factors responsible for post-traumatic epilepsy development. We discuss what the current models have provided in terms of understanding acute injury and what is needed to advance understanding regarding late onset seizure. New model designs will be used to investigate novel pathways linking acute injury to chronic changes within the brain. Important components of this transition are likely mediated by toll-like receptors, neuroinflammation, and tauopathy. In the final section, we highlight current experimental therapies that may prove promising in preventing and treating post-traumatic epilepsy. By increasing understanding about post-traumatic epilepsy and injury expansion over time, it will be possible to design better treatments with specific molecular targets to prevent late-onset seizure occurrence following traumatic brain injury.

Off-label use of transmucosal ketamine as a rapid-acting antidepressant: a retrospective chart review.

OBJECTIVE: This study evaluated the effectiveness and safety of subanesthetic doses of ketamine using an off-label, transmucosal administration route in patients with treatment-resistant depression. METHODS: A retrospective chart review was conducted to identify patients who met the inclusion criteria for treatment-resistant major depressive disorder. Seventeen such patients who received subanesthetic doses of ketamine were included. Patient demographics, efficacy (drug refill, clinician notes), side effects, and concurrent medications were assessed. RESULTS: Benefit from low-dose transmucosal ketamine was noted in 76% of subjects (average age 48 years, 88% female), with a dose duration lasting 7-14 days. No notable side effects were noted. The most common classes of concurrent medications to which ketamine was added were serotonin-norepinephrine reuptake inhibitors (59%), stimulants (47%), folate replacement (47%), and benzodiazepines (47%). CONCLUSION: Our results provide preliminary evidence of the effectiveness and safety of low-dose transmucosal ketamine in treatment-resistant patients. A controlled, prospective pilot study is warranted to validate these findings.