The University of Maryland School of Pharmacy, founded in 1841, is a thriving center for life sciences research and community service. Through its education, research, and service programs, the School of Pharmacy strives to improve the health and well-being of society by aiding in the discovery, development, and use of medicines.

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  • Time-based Analysis on Stability of Small Molecules using Nuclear Magnetic Resonance

    Bavadekar, Tanya Ashit; Xue, Fengtian, Ph.D. (2024-02-16)
    NMR is a widely used non-invasive and non-destructive analytical method to study the stability of small molecules in different chemical environments. It qualitatively identifies compounds and quantitatively monitors composition and degradation through the evaluation of impurities.1,2 v Potential impurities originate from starting materials, intermediate products, or by- products, and degradation of the original compound and residual solvents, which are detected by changes in peak structure that arise in the spectra.3 v A 400 MHz Varian spectrometer 1H NMR characterizes the behavior of small molecules by analyzing the changes in chemical shift, integration, and splitting of peaks in spectra over time to detect and identify small molecule contaminants.2,3,4,5 v This ongoing study analyzes small molecule samples of selective ALDH-2 inhibitors for non-alcoholic fatty liver disease and Gallium-Salophen complexes as Hem-O inhibitors against Pseudomonas aeruginosa by subjecting them to different media measured at various time points for stability
  • Hydroxypropyl-β-cyclodextrin (HPBCD) in Insoluble Drug-Loaded Nanoparticles Dissolution Studying: A New Approach to Overcoming Sink Limitations

    Wang, Yihan; Wang, Fang; Ibrahim, Ahmed; Yu, Dongyue; Pearson, Ryan; Vert-Wong, Katya; Jeremic, Jelena; Maqsood, Iram; Li, Xun; Shang, Jun; et al. (2024-04-24)
  • Generating Uptake Probabilities from Discrete-Choice Experiment-Derived Preferences for Application in Patient-Centered Value Assessment

    Poudel, Nabin; Ricci, Salome; dosReis, Susan; Amill-Rosario, Alejandro; Slejko, Julia F. (2024-05-07)
  • Missingness Patterns in a Survey of Barriers to Care Among Individuals Diagnosed with Cancer: An Exploratory Analysis

    Onukwugha, Eberechukwu; Hsu, Chia-Yun; Ali, Urooba; Le, Lana; Johnson, Abree; Wimbush, Jessica; Slejko, Julia F. (2024-05-06)
  • Capsule 2024

    University of Maryland, Baltimore. School of Pharmacy, 2024
  • The role of a cysteine residue within an ERK1/2 substrate docking site on signaling and proliferation of melanoma cells containing BRAF mutations

    Grogan, Lena; McClean, Nathaniel; Shapiro, Paul, Ph.D. (2024-04-12)
    The extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathway is crucial for cell proliferation. Specific types of cancers, including malignant melanoma, contain activating mutations in the BRAF kinase, which is an upstream regulator of ERK1/2, leading to uncontrolled proliferation. One docking site in ERK1/2 that has been targeted controls the activation of oncogenic transcription factors. Compounds identified to target this substrate docking site were found to covalently interact with a specific cysteine.1,2 To evaluate the role of this cysteine in ERK1/2 signaling, CRISPR CAS9 was used to generate isogenic cell lines with cysteine mutations in both ERK1 and ERK2. The proposed studies investigate the effects the ERK1/2 cysteine mutations have on A375 melanoma cells regarding cell signaling and proliferation
  • Genomic Landscape of Murine Metabolic-dysfunction Associated Steatohepatitis (MASH): Unveiling Key Molecular Signatures through Meta-Analysis and Fisher's Combined Probability Test of RNA-seq Data

    Andrade, Victor; Shu, Yan, Ph.D. (2024-04-12)
    Introduction: Metabolic dysfunction-associated steatohepatitis (MASH) presents as a complex and multifactorial liver disorder characterized by inflammation, hepatocyte injury, and fibrosis, representing an urgent unmet medical need. Understanding the underlying genomic architecture of MASH is crucial for elucidating its pathogenesis and identifying therapeutic targets. In this study, we conducted a comprehensive meta-analysis of transcriptomics data derived from diverse murine experimental models to dissect the molecular mechanisms governing MASH progression. Objective: This study seeks to integrate RNA-seq datasets to comprehensively characterize the molecular landscape associated with MASH. Specifically, we aim to delineate dysregulated genes and pathways associated with pathogenesis with the overarching goal of advancing the understanding of the disease and finding potential therapeutic targets. Methods: A systematic approach was employed to curate publicly available RNA-seq datasets from GEO, ensuring stringent quality control and adherence to rigorous analytical protocols. Per-study Differential Expression Analyses using DESeq2 were conducted using an established pipeline. Subsequently, Fisher’s Combined Probability Test was applied to integrate statistical evidence across datasets, facilitating the identification of molecular signatures associated with MASH. Results: Our meta-analysis included data from 100 samples across 10 distinct murine MASH cohorts. We identified 11 genes whose expressions exhibited significant correlations with crucial pathological mechanisms including cytokine activation, lysozyme acidification, glycemic control, and insulin resistance. Importantly, these genetic signatures were intricately linked to the clinical manifestation of the disease. Conclusion: The meta-analysis revealed a comprehensive understanding of the genetic landscape underlying MASH, shedding light on key molecular pathways driving disease progression. The identification of 11 genes associated with pivotal pathological processes underscores their potential as therapeutic targets, offering promising avenues for the development of targeted interventions.
  • Addressing Bioethical Concerns in Community-Engaged Research

    Senghor, Abdou; Medeiros, Michelle; Baquet, Claudia Rose; Lance, Frank; Mullins, C. Daniel (2024-04-07)
  • The Economic Burden of Chronic Obstructive Pulmonary Disease and Comparative Effectiveness of Maintenance Inhaler Medications in the United States

    Shah, Chintal; Zafari, Zafar (2023)
    Introduction: Chronic Obstructive Pulmonary Disease (COPD) is a highly prevalent condition in the United States (US). Among individuals with moderate to very severe COPD, inhalation therapy is the mainstay of disease management, with the goal to reduce COPD exacerbations. Maintenance medications, especially combinations of long-acting beta2 agonist (LABA)/long-acting muscarinic antagonist (LAMA) or LABA/inhaled corticosteroids (ICS), are commonly used. This dissertation aimed to examine the (i) economic burden of COPD, (ii) comparative effectiveness of LABA/LAMA and LABA/ICS fixed dose combination (FDC) single inhaler therapy across various subgroups, and (iii) comparative effectiveness of LABA/LAMA combinations with different ingredients and inhaler types, vilanterol/umeclidinium (VI/UMEC) and olodaterol/tiotropium (OLO/TIO). Methods: Medical Expenditure Panel Survey data was used to estimate the economic burden of COPD (Aim 1). COPD-specific (adjusted) costs were determined for various service categories using a regression-based weighted two-part model among patients aged 45 years and older. Medicare Chronic Conditions Warehouse data was used for the comparative effectiveness studies (Aim 2, Aim 3). A new user active comparator retrospective cohort study design was utilized, and the outcome of interest was time to first COPD exacerbation. To ensure comparability between groups, they were matched based on their high-dimensional propensity scores. Results: The total COPD-specific direct medical cost was 2018 US $4,322 (Standard Error (SE): US $577) per patient per year with prescription drugs contributing US $1,887 (SE: US $216). The resultant overall annual total COPD-specific cost was US $24.0 billion, with prescription drugs contributing US $10.5 billion. For the interclass comparative effectiveness analysis, the hazard ratio (HR) of time to COPD exacerbation was 0.846 (95% Confidence interval (CI): 0.776-0.923) for LABA/ICS compared to LABA/LAMA initiators. Among LABA/LAMA FDCs, the HR of time to first COPD exacerbation was 0.948 (95% CI: 0.813-1.105) for individuals initiating OLO/TIO versus VI/UMEC. Conclusion: This dissertation found that COPD poses a significant economic burden on the US healthcare system, with prescription drugs being a major contributor. Optimizing therapy can help reduce this burden. While a statistically significant interclass difference was observed between LABA/LAMA and LABA/ICS initiators, no statistically significant intraclass difference was observed between initiators of LABA/LAMA FDCs: VI/UMEC and OLO/TIO.
  • Non-Inferiority Study to Compare Instructional Videos for Breath-Actuated Inhaler Technique

    Rosario, Anyelis N.; Morgan, Jill A.; Kruger Howard, Amy (2024-03-22)
  • SILCS-WATER: Accounting for the Role of Water in Protein-Ligand Binding

    Kumar, Anmol; Goel, Himanshu; Yu, Wenbo; Zhao, Mingtian; MacKerell, Alexander D., Jr. (2024-02-12)
  • Effect of Medication Information Delivery Format on Cognitive Load and Knowledge Retention of Informal Caregivers

    McPherson, Mary Lynn M.; Cestone, Christina; Kulo, Violet; Gordes, Karen L.; Jun, Hyun-Jin; Stanfield, A; Lau, DT (2024-01-23)
  • Impact of Proactive Adherence Interventions on HIV RNA using Prescription Claims

    Pandit, Neha Sheth; Johnson, Abree; Lee, Tsung-Ying, M.S.; Onukwugha, Eberechukwu; Cassidy-Stewart, Hope (2024-03-03)

    Sharif, Suliman; Kumar, Anmol; MacKerell, Alexander D., Jr. (2024-02-11)
  • Poison Prevention Press 2024

    University of Maryland, Baltimore. School of Pharmacy. Maryland Poison Center, 2024
  • Immunomodulatory Nanoparticles as a Multimodal Approach to Attenuate Immune Dysregulation in Severe Inflammation and Sepsis

    Truong, Nhu; Pearson, Ryan M. (2023)
    Sepsis, a life-threatening condition triggered by an uncontrolled immune response to infection, currently lacks an FDA-approved therapeutic intervention to enhance patient survival. Severe inflammatory conditions can disrupt the balance of histone acetyltransferase (HAT)/histone deacetylase (HDAC) activity, leading to global cellular hypoacetylation. Histone deacetylase inhibitors (HDACi) restore acetylation profiles and reverse transcriptional silencing. Suberoylanilide hydroxamic acid (SAHA), a pan-HDACi, was modified by para-hydroxymethylation (termed SAHA-OH), which resulted in a favourable reduction in SAHA-associated toxicity under inflammatory lipopolysaccharide (LPS) challenge. SAHA-OH was incorporated into immunomodulatory nanoparticles (iNPs), previously developed by our lab, to form iNP-SAHA using a prodrug approach through the covalent modification with poly(lactic-co-glycolic acid) (PLGA). iNP-SAHA treatment significantly reduced proinflammatory cytokines in vitro and in vivo, improved the viability of LPS-stimulated primary macrophages, and enhanced survival of mice in an LPS-induced endotoxemia model. iNP-SAHA treatment did not significantly improved mice survival compared to the iNP treatment alone; however, the synergistic anti-inflammatory properties of iNP-SAHA are potentially promising for future exploration in alternative models of inflammatory disease. We evaluated the efficacy and cellular mechanism of iNP activity using a clinically relevant cecal ligation and puncture (CLP) murine model of polymicrobial sepsis. iNPs, when administered as an adjuvant to antibiotics, significantly improved survival compared to antibiotics alone. Interestingly, iNP treatment marginally affected local and systemic cytokine profiles, despite mitigating organ dysregulation. Minimal effects on immune cell proportions at local sites were observed, but iNP treatment normalized monocyte levels in peripheral blood and alveolar macrophages in lung tissues. Further studies enumerated that iNPs modulated cellular adhesion and migration surface marker expression as well as apoptotic levels on immune cells. These findings highlight the potential of iNPs as an adjunctive therapy for sepsis, particularly when combined with antibiotics, suggesting promising prospects for future clinical translation. Lastly, a high-throughput microfluidic approach for iNP formulation to enable facile scale-up was developed. We optimized the microfluidic method and the impact of polymer and surfactant concentrations, surfactant chemistry, flow rate ratio (FRR), and anti-inflammatory activity. This work demonstrated a controlled and reproducible microfluidic method for iNP formulation, showcasing their inherent anti-inflammatory properties and offering a promising avenue for inflammation management.
  • Conversion of Small-Molecule Inhibitors into Heterobifunctional Compounds in the Discovery of Novel Chemotherapeutics

    Chan, Alexandria; Fletcher, Steven (2023)
    Heterobifunctional polypharmacologic agents are compounds that have individual pharmacophores for at least two separate biological targets. Our work spans two distinct sets of heterobifunctional molecules: 1. Polypharmacologic agents that inhibit two proteins known to contribute to the disease state, and 2. Protein degraders: Proteolysis targeting chimeras (PROTACs) and molecular glues. Both types of protein degraders function through recruiting an E3 ligase to the protein of interest, resulting in a hijacking of the ubiquitin-proteasome system, and the subsequent destruction of the target protein. The use of type 1 compounds is rapidly growing as such polypharmacologic agents are postulated to exhibit distinct advantages over the monovalent, parent drug compounds from which they are constructed, including the ability to increase therapeutic effect, lower effective dosage, and circumvent treatment resistance. Type 2 compounds – the protein degraders – can eliminate a target of interest, requiring the cell to resynthesize the protein to regain its cellular function. These compounds may have a catalytic mechanism of action wherein the compounds are recycled after mediating the degradation of the target protein, thereby requiring non-stoichiometric amounts of drug while also directly countering resistance that manifests through target protein upregulation. Moreover, such degraders retain activity with resistant proteins where traditional, non-covalent small-molecule drugs fail. Due to these advantages, there is increasing enthusiasm that targeted protein degraders may herald a new class of anti-cancer therapeutics. Herein, our efforts towards the discovery of heterobifunctional pharmaceuticals for the treatment of drug-resistant hematological malignancies are described.
  • Utilizing Pharmacometrics to Facilitate Generic Drug Development of Orally Inhaled Products and Optimize Pharmacotherapy of Antifibrinolytics

    Li, Shuhui; Gobburu, Jogarao (2023)
    This thesis has two parts. The first part is related to the pharmacokinetic (PK) batch-to-batch variability of orally inhaled products, which may pose challenges for generic product development. I applied the techniques of pharmacometrics to propose and evaluate alternative PK bioequivalence (BE) study designs using Advair Diskus as an example product, aiming to facilitate generic development. First, population PK models for Advair Diskus were developed and qualified to simulate PK BE study. Next, the effect of batch-to-batch variability on the establishment of BE was evaluated using the developed models. Batch-to-batch variability substantially elevates the probability of reaching a false conclusion in a PK BE study for equivalent and inequivalent comparisons. Therefore, ignoring batch-to-batch variability when presenting will increase the risk of either patients being treated with an inequivalent formulation or pharmaceutical companies not obtaining approval for an equivalent formulation. This calls for alternative PK BE approaches to account for the batch-to-batch variability. I proposed and evaluated a two-phase study framework that uses a pilot study to select reference and test batches for the pivotal BE study. A parallel design with ≥ 12 patients per sequence or a crossover design with ≥ 6 patients per sequence is recommended for the pilot study design. The proposed criteria for selecting batches based on the pilot study results include (1) 0.9 ≤ T/R ≤ 1.11 and (2) higher conditional power. The two-phase study design offers the flexibility to select batches in a PK study to minimize the impact of batch-to-batch variability on the generics development. The two-phase framework might be applied to other products with similar characteristics and high batch-to-batch variability in the reference products. The second part of this thesis used pharmacometrics to optimize the pharmacotherapy of an anti-fibrinolytic, tranexamic acid (TXA), in special patient populations. The PK and pharmacodynamics (PD) of TXA in special populations are understudied; therefore, the PK/PD-driven optimal doses for them are unknown. First, I characterized the PK and PD of TXA in pregnancy and found that pregnant women have up to 30% higher clearance and volume of distribution than the general non-pregnant population. A dose of 650 mg maintains both PK and PD targets for > 1 hour in most patients, which is recommended as the postpartum prophylactic dose for future confirmatory clinical studies. In addition, I evaluated a current dosing regimen for cardiac surgery patients who use cardiopulmonary bypass (CPB) during their surgeries from a PK perspective. This dosing regimen consists of a long infusion of TXA at 100 mg/hr for 5 hours before CPB initiation, a 1 g bolus of TXA at CPB initiation, and another 1 g bolus at the end of CPB. While kidney function affects the clearance of TXA, and the CPB procedure increases the volume of distribution of TXA, the current dosing regimen was confirmed to provide sufficient TXA exposure (15 mg/L) from CPB initiation till 3 hours post-CPB, achieving the therapeutic goal. Both studies contribute to understanding how TXA dosing can be optimized in special patient populations.

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