Pharmacologic Activities of 3’-Hydroxypterostilbene: Cytotoxic, Anti- Oxidant, Anti-Adipogenic, Anti-Inflammatory, Histone Deacetylase and Sirtuin 1 Inhibitory Activity

Purpose: Delineate the selected pharmacodynamics of a naturally occurring stilbene 3’- Hydroxypterostilbene. Objective: Characterize for the first time the pharmacodynamics bioactivity in several in-vitro assays with relevant roles in heart disease, inflammation, cancer, and diabetes etiology and pathophysiology. Methods: 3’-Hydroxypterostilbene was studied in in-vitro assays to identify possible bioactivity. Results: 3’-Hydroxypterostilbene demonstrated anti-oxidant, anti-inflammatory, cytotoxic, antiadipogenic, histone deacetylase, and sirtuin-1 inhibitory activity. Conclusions: The importance of understanding individual stilbene pharmacologic activities were delineated. Small changes in chemical structure of stilbene compounds result in significant pharmacodynamic differences

Transforming Prescription Opioid Practices in Primary Care With Change Theory

The opioid epidemic continues to be an ongoing public health crisis. Many primary health care providers aptly serve as the gate keeper to opioid prescriptions. The opioid epidemic has challenged the primary care profession whilst many of these providers have opted out of opioid prescribing altogether. This unintended consequence affirms erosion to primary care that is vital to the ecosystem of opioid management. The purpose of this study was to understand strategies to deliver opioids safely and effectively. Results indicate primary care providers are uniquely positioned to make a positive opioid impact through focused change initiatives. Five common themes arose from the inductive analysis: (1) provide leadership support; (2) define standard of work; (3) conduct pre-visit reviews; (4) conduct post-visit reviews; and (5) measure progress. Then, each common theme was deductively analyzed through a view of Kotter’s change theory to support an effective proxy for implementing and sustaining chronic opioid therapy in a primary care context. These finding have potential to provide actionable implications for health care management professionals and primary care organizations such as hospitals and group practices

Enhanced numeracy skills following team-based learning in United States pharmacy students: a longitudinal cohort study

Purpose: The literature suggests that the ability to numerate cannot be fully understood without accounting for the social context in which mathematical activity is represented. Team-based learning (TBL) is an andragogical approach with theoretical links to sociocultural and community-of-practice learning. This study aimed to quantitatively explore the impact of TBL instruction on numeracy development in 2 cohorts of pharmacy students and identify the impact of TBL instruction on numeracy development from a social perspective for healthcare education. Methods: Two cohorts of students were administered the Health Science Reasoning Test-Numeracy (HSRT-N) before beginning pharmacy school. Two years after using TBL as the primary method of instruction, both comprehensive and domain data from the HSRT-N were analyzed. Results: In total, 163 pharmacy student scores met the inclusion criteria. The students’ numeracy skills measured by HSRT-N improved after 2 years of TBL instruction. Conclusion: Numeracy was the most significantly improved HSRT-N domain in pharmacy students following two years of TBL instruction. Although a closer examination of numeracy development in TBL is warranted, initial data suggest that TBL instruction may be an adequate proxy for advancing numeracy in a cohort of pharmacy students. TBL may encourage a social practice of mathematics to improve pharmacy students’ ability to numerate critically

Changes in insulin sensitivity over time and associated factors in HIV-infected adolescents

OBJECTIVE: To compare prevalence of insulin resistance between perinatally HIV-infected (PHIV+) and perinatally HIV-exposed, but uninfected adolescents (PHEU), determine incidence of and contributory factors to new and resolved cases of insulin resistance in PHIV+, and evaluate glucose metabolism. DESIGN: Cross-sectional design for comparison of prevalence among PHIV+ and PHEU. Longitudinal design for incidence and resolution of insulin resistance among PHIV+ at risk for these outcomes. METHODS: The source population was adolescents from pediatric HIV clinics in the United States and Puerto Rico participating in the Pediatric HIV/AIDS Cohort Study, an ongoing prospective cohort study designed to evaluate impact of HIV infection and its treatment on multiple domains in preadolescents and adolescents. Insulin resistance was assessed by homeostatic model assessment of insulin resistance. Those with incident insulin resistance underwent 2-h oral glucose tolerance test and HbA1c. Baseline demographic, metabolic, and HIV-specific variables were evaluated for association with incident or resolved insulin resistance. RESULTS: Unadjusted prevalence of insulin resistance in PHIV+ was 27.3 versus 34.1% in PHEU. After adjustment for Tanner stage, age, sex, and race/ethnicity, there was no significant difference between groups. Factors positively associated with developing insulin resistance included female sex, higher BMI z score, and higher waist circumference; those associated with resolving insulin resistance included male sex and lower BMI z score. CONCLUSION: Prevalence of insulin resistance in PHIV+ and PHEU was substantially higher than that reported in HIV-uninfected nonoverweight youth, but similar to that in HIV-uninfected obese youth. Factors associated with incident or resolved insulin resistance among PHIV+ were similar to those reported in HIV-negative obese youth. However, a contributory role of HIV infection and/or its treatment to the incident risk of insulin resistance cannot be excluded

Vorinostat with Sustained Exposure and High Solubility in Poly(ethylene glycol)-b-poly(DL-lactic acid) Micelle Nanocarriers: Characterization and Effects on Pharmacokinetics in Rat Serum and Urine

The histone deacetylase inhibitor suberoylanilide hydroxamic acid, known as vorinostat, is a promising anti-cancer drug with a unique mode of action; however, it is plagued by low water solubility, low permeability, and suboptimal pharmacokinetics. In this study, poly(ethylene glycol)-b-poly(DL-lactic acid) (PEG-b-PLA) micelles of vorinostat were developed. Vorinostat’s pharmacokinetics in rats were investigated after intravenous (i.v.) (10 mg/kg) and oral (50 mg/kg) micellar administrations and compared to a conventional PEG400 solution and methylcellulose suspension. The micelles increased the aqueous solubility of vorinostat from 0.2 mg/ml to 8.15 ± 0.60 mg/ml and 10.24 ± 0.92 mg/ml at drug to nanocarrier ratios of 1:10 and 1:15, respectively. Micelles had nanoscopic mean diameters of 75.67 ± 7.57 nm and 87.33 ± 8.62 nm for 1:10 and 1:15 micelles, respectively, with drug loading capacities of 9.93 ± 0.21% and 6.91 ± 1.19 %, and encapsulation efficiencies of 42.74 ± 1.67% and 73.29 ± 4.78%, respectively. The micelles provided sustained exposure and improved pharmacokinetics characterized by a significant increase in serum half-life, area under curve, and mean residence time. The micelles reduced vorinostat clearance particularly after i.v. dosing. Thus, PEG-b-PLA micelles significantly improved the oral and intravenous pharmacokinetics and bioavailability of vorinostat, which warrants further investigation

Transcriptional repressor ZEB2 promotes terminal differentiation of CD8⁺ effector and memory T cell populations during infection

ZEB2 is a multi-zinc-finger transcription factor known to play a significant role in early neurogenesis and in epithelial-mesenchymal transition-dependent tumor metastasis. Although the function of ZEB2 in T lymphocytes is unknown, activity of the closely related family member ZEB1 has been implicated in lymphocyte development. Here, we find that ZEB2 expression is up-regulated by activated T cells, specifically in the KLRG1(hi) effector CD8(+) T cell subset. Loss of ZEB2 expression results in a significant loss of antigen-specific CD8(+) T cells after primary and secondary infection with a severe impairment in the generation of the KLRG1(hi) effector memory cell population. We show that ZEB2, which can bind DNA at tandem, consensus E-box sites, regulates gene expression of several E-protein targets and may directly repress Il7r and Il2 in CD8(+) T cells responding to infection. Furthermore, we find that T-bet binds to highly conserved T-box sites in the Zeb2 gene and that T-bet and ZEB2 regulate similar gene expression programs in effector T cells, suggesting that T-bet acts upstream and through regulation of ZEB2. Collectively, we place ZEB2 in a larger transcriptional network that is responsible for the balance between terminal differentiation and formation of memory CD8(+) T cells

Analytical Method Development, Pharmacokinetics, and Pharmacodynamics of Selected Polyphenols

Novel analytical methods were developed and validated according to the International Conference on Harmonization guidelines using high-performance liquid chromatography (HPLC) with ultraviolet (UV) and/or electrospray ionization (ESI) – mass spectrometry (MS) for the separation, isolation, and detection of sakuranetin, β-glucogallin, gallic acid, oxyresveratrol, and 3’–hydroxypterostilbene in biological matrices. The selected polyphenols were quantified in samples from rice, apples, oranges, grapefruit juice, matico, and/or Indian gooseberry through the application of the developed analytical methods. As these polyphenols are distributed in a variety of botanicals and are widely consumed as plants and nutraceuticals, the pharmacokinetics and pharmacodynamics were studied.These methods were applied to fecal, serum, and urine samples obtained from a rat model to characterize the pharmacokinetics of the selected polyphenols and major metabolites after intravenous or oral administration. The pharmacokinetic parameters of each polyphenol were delineated for the first time. These studies uniformly demonstrated poor bioavailability, rapid metabolism to glucuroconjugates and elimination of the selected polyphenols via renal and non-renal pathways. The clinical pharmacokinetics and attempts to increase bioavailability remain to be evaluated.Effects of sakuranetin, β–glucogallin, gallic acid, oxyresveratrol, and 3’–hydroxypterostilbene in in–vitro and/or in–vivo models of adipogenesis, oxidative stress, inflammation and pain, histone deacetylase / sirtuin 1 modulation, and cell proliferation were examined. In these studies sakuranetin, gallic acid, oxyresveratrol, and 3’–hydroxypterostilbene demonstrated anti’adipogenic properties. All polyphenols studied maintained their ability to scavenge free radicals as anti’oxidants. All of the selected polyphenols were effective in reducing cyclooygenase’1 and’2 activities. Racemic sakuranetin and 3’–hydroxypterostilbene was able to inhibit the synthesis of prostaglandins. β’glucogaglucogallin, gallic acid, and 3’–hydroxypterostilbene also demonstrated anti-nociceptive activity. The study of polyphenols may lead to the alternative treatments for inflammation and pain. Although the selected polyphenols were not potent anti’proliferative agents in the cancer cell lines examined as determined using the Alamar blue method, their ability to inhibit histone deacetylase activity was evident. Given their ability to inhibit HDAC the utility of polyphenols as mood stabilizers or anti’epilectics should be studied

Team Based Learning

Ready for a change in your classroom? Team Based Learning (TBL) is an active learning strategy that motivates students to take charge of their learning experience while growing skills in accountability, critical thinking, problem solving, communication, and teamwork. In this workshop, you will learn more about how to: 1. Explain the key components of a successful TBL module and elements of productive teams 2. Summarize how to convert a current course/lecture into a TBL module

Pharmacokinetic Evaluation of a DSPE-PEG2000 Micellar Formulation of Ridaforolimus in Rat

The rapamycin analog, ridaforolimus, has demonstrated potent anti-proliferative effects in cancer treatment, and it currently is being evaluated in a range of clinical cancer studies. Ridaforolimus is an extremely lipophilic compound with limited aqueous solubility, which may benefit from formulation with polymeric micelles. Herein, we report the encapsulation of ridaforolimus in 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-methoxy-poly(ethylene glycol 2000) (DSPE-PEG2000) via a solvent extraction technique. Micelle loading greatly improved the solubility of ridaforolimus by approximately 40 times from 200 μg/mL to 8.9 mg/mL. The diameters of the drug-loaded micelles were 33 ± 15 nm indicating they are of appropriate size to accumulate within the tumor site via the enhanced permeability and retention (EPR) effect. The DSPE-PEG2000 micelle formulation was dosed intravenously to rats at 10 mg/kg and compared to a control of ridaforolimus in ethanol/PEG 400. The micelle significantly increased the half-life of ridaforolimus by 170% and decreased the clearance by 58%, which is consistent with improved retention of the drug in the plasma by the micelle formulation

Pharmacokinetic Evaluation of a DSPE-PEG2000 Micellar Formulation of Ridaforolimus in Rat

The rapamycin analog, ridaforolimus, has demonstrated potent anti-proliferative effects in cancer treatment, and it currently is being evaluated in a range of clinical cancer studies. Ridaforolimus is an extremely lipophilic compound with limited aqueous solubility, which may benefit from formulation with polymeric micelles. Herein, we report the encapsulation of ridaforolimus in 1,2-distearoyl- sn -glycero-3-phosphoethanolamine- N -methoxy-poly(ethylene glycol 2000) (DSPE-PEG 2000 ) via a solvent extraction technique. Micelle loading greatly improved the solubility of ridaforolimus by approximately 40 times from 200 μg/mL to 8.9 mg/mL. The diameters of the drug-loaded micelles were 33 ± 15 nm indicating they are of appropriate size to accumulate within the tumor site via the enhanced permeability and retention (EPR) effect. The DSPE-PEG 2000 micelle formulation was dosed intravenously to rats at 10 mg/kg and compared to a control of ridaforolimus in ethanol/PEG 400. The micelle significantly increased the half-life of ridaforolimus by 170% and decreased the clearance by 58%, which is consistent with improved retention of the drug in the plasma by the micelle formulation