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School of Pharmacy
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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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Navigating the Unprecedented: A Study on How Senior Administrators in Higher Education Learned and Made Decisions During the COVID-19 PandemicThe purpose of this qualitative multi-case research study was to explore how senior administrators at four higher education institutions learned and made decisions during the first two years of the COVID-19 pandemic. Bandura’s social cognitive theory guided this study as it addressed how people learn enactively and vicariously as well as the triadic reciprocal causation between environmental, personal, and behavioral factors. The study included 13 senior administrators and data were collected through semi-structured interviews. The data analysis followed Creswell and Guetterman’s six-step process for analyzing and interpreting qualitative data. Data analysis involved both inductive and deductive coding and categorizing codes into sub-themes and themes. Trustworthiness was ensured through researcher reflexivity, peer debriefing, member checking, and thick description. All participants engaged in some form of observational learning, predominantly from within their own institution or across the university system. Perceived self-efficacy had a significant influence on leadership learning and decision-making. Participants shared their values of teamwork and collaboration and consistent communication in service to keeping their communities safe and continuing their institutional educational missions. The results of this study demonstrated the importance of observational learning on how leaders learned during the COVID-19 crisis, as well as the importance of self-efficacy including coping efficacy and its influence on a leader’s confidence, flexibility, and resolution during times of significant and rapid change. Practical implications include recommendations for crisis management planning, teambuilding, and communications strategies to improve academic leadership self-efficacy.
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From Zinc Fingers to Fe-S Clusters to Iron Nanoparticle Drugs: Understanding the Impact of Metals on Biological Proteins and FormulationsIron and zinc co-factored metalloproteins perform a variety of functions including providing structural integrity, aiding in transport and storage, and engaging in enzymatic activity. One important group of metalloproteins are zinc finger (ZF) proteins. In this thesis, I investigate two RNA-binding ZFs to understand both structural and functional aspects and aim to highlight their importance in biology. The cleavage and polyadenylation specificity factor 30 (CPSF30) is a non-classical ZF containing five CCCH-type and one CCHC-type ZF domains that binds RNA targets. One of CPSF30’s CCCH ZF domains can bind a 2Fe-2S cluster; however, the role of this cluster is poorly understood. RNA binding assays on CPSF30 determined that the CCCH domains bind AU-rich RNA and the CCHC domain binds U-rich RNA. Metal-catalyzed oxidation – mass spectrometry (MCO-MS) identified the site of the 2Fe-2S cluster as the second CCCH domain. Additional EPR and Mössbauer spectroscopies demonstrated the 2Fe-2S cluster is redox active, however, the redox activity doesn’t affect RNA binding. I characterized individual CCCH-type maquettes of CPSF30 to determine if Fe-S cluster binding can occur in the other domains. Not only can each individual domain load an Fe-S cluster as confirmed by UV-Vis and XAS, but the clusters are redox active, as confirmed by EPR. Another non-classical ZF is the Ran-binding domain containing protein 2 (ZRANB2). ZRANB2 contains two CCCC-type ZF domains and functions to bind RNA, interact with other proteins, and participate in alternate splicing. I determined the effect of zinc binding on ZRANB2 conformation and analyzed protein dynamics with RNA utilizing UV-Vis, CD, fluorescence assays, and HDX-MS. ZRANB2 is found to be persulfidated in a variety of cell lines when measured by persulfide specific proteomics. I demonstrate that isolated ZRANB2 is persulfidated by H2S in a Zn and O2 dependent manner via an in situ dimedone switch tagging method. Superoxide was determined to be an intermediate of the persulfidation reaction and persulfidation abrogated RNA binding. I proposed that this modification is linked to regulation of the spliceosome. Lastly at the end of my thesis, through a variety of techniques, I analyze the physicochemical properties of FDA-approved iron nanoparticle drug, Monoferric.
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Pharmacometric Model-Based Real-World Data Driven Framework to Refine Unfractionated Heparin Dosing in Pediatric PopulationUnfractionated heparin (UFH) is a commonly used anticoagulant in the pediatric population and is considered the gold standard in extracorporeal membrane oxygenation (ECMO) settings to prevent circuit thrombosis. Optimal pediatric dosing is challenging due to the paucity of clinical outcomes and pharmacokinetic/pharmacodynamic (PKPD) studies in pediatric age groups. Clinicians rely on clinical experience, local hospital protocols or extrapolation from adults to decide UFH dose in the pediatric population. Reaching therapeutic targets within 24 hours has been associated with improved clinical outcomes for UFH therapy. However, less than 20% of pediatric patients achieve this goal. The readily available PKPD information and the availability of an adequate number of subjects representing all pediatric age groups with minimal selection bias make real-world data (RWD) a promising approach for answering pediatric dosing questions. This thesis aims to leverage RWD to develop a PKPD model-based framework for the entire pediatric age spectrum (neonates - <19 years) that could be used as a platform to inform objective clinical decision making (i.e., better dose selection/titration) in pediatric patients in general and in the ECMO pediatric sub-population. RWD were curated, processed, and qualified from the electronic health records (EHR) of Texas Children’s Hospital (n = 490), Utah Children’s Hospital (n = 159) and University of Maryland Medical Center (n = 29). The retrieved data of pediatric patients treated with UFH for ECMO/ non-ECMO indications contained complete information about UFH dosing, monitoring, and patient demographics. The multicenter EHR data were integrated to develop and externally validate Bayesian UFH PKPD model. The Bayesian model leveraged prior knowledge from the literature and adequately described UFH PK, measured through anti-factor Xa assay, and PKPD relationship, where the PD measurements were activated partial thromboplastin time (aPTT) and activated clotting time (ACT). Based on simulations, optimized starting infusions were proposed to achieve the therapeutic target in 45-70% of pediatric patients after initial dose. Additionally, simulations suggested refined UFH titration nomograms that can attain therapeutic targets in > 90% of patients while minimizing the target exceeding to < 1% 24 hours post UFH treatment. The Bayesian model showed potential for personalized UFH therapeutic management. The developed Bayesian PKPD model along with the dose titration schemes could eventually be incorporated into a clinical decision support tool to objectively guide clinicians with UFH dosing decisions in pediatric anticoagulation or intensive care clinics.
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Novel Methods to Assess the In Vivo and In Vitro Performance and Selection of Amorphous Solid Dispersions of Poorly-Water Soluble DrugsThe number of poorly water-soluble drugs in the pipeline has increased, and they are often not well absorbed by the gastrointestinal tract. Amorphous solid dispersion (ASD) is an emerging strategy to improve drug solubility and absorption. The overall aim is to expand methods used to evaluate the performance of ASD as a strategy to improve water solubility. Firstly, we aimed to develop an in vitro-in vivo correlation (IVIVC) model to predict human pharmacokinetics (PK) of itraconazole tablets with different release rates from dissolution experiments and determine formulation and process parameters that affect in vivo performance. Human PK was successfully predicted from in vitro dissolution experiments, and the IVIVC model created here met internal predictability criteria. Secondly, liquid state proton nuclear magnetic resonance (1HNMR) techniques were used to streamline polymer selection for ASDs in a non-destructive and resource-sparing fashion. For three drug-polymer pairs (i.e. etravirine with each HPMC, HPMCAS-M, and PVP-VA), 1HNMR findings were compared to supersaturation studies. Our hypothesis was that strong molecular interactions between polymer and drug observed in 1HNMR predicted precipitation kinetics in the supersaturation studies. Supersaturation studies agreed with 1HNMR predictions, as HPMC and HPMCAS-M maintained etravirine in solution for a longer time than PVP-VA. Thirdly, a robust, viable, and resource-sparing method to measure partition coefficient P (logP) was developed using reverse-phase high-performance liquid chromatography (RP-HPLC). Highly lipophilic drugs lack reliable, experimentally determined logP values in the literature. The RP-HPLC method reported here can be used for high throughput estimation of logP of commonly used drugs. A larger pool of reliable logP values of commonly used drugs shows promise to improve quality of medicinal chemistry and PK models. Lastly, our goal was to assess, for lipophilic drugs, the impact of logP on human volume distribution at steady state (VDss) predictions using the Oie-Tozer, Rodgers-Rowland, GastroPlus, Korzekwa-Nagar, and TCM-New methods. Sensitivity and prediction error analyses were conducted with a range of logP values and specific logP. TCM-New was shown to be the best method for VDss prediction of highly lipophilic drugs, suggesting blood plasma ratio (BPR) as a favorable surrogate for drug partitioning in the tissues.
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Purification of paFur and Exploration of the Heme Regulation Mechanism over the phuS GenePseudomonas aeruginosa is a common bacteria that can cause various infections in the human body and survives in the body during chronic infections via iron from heme. The Wilks Lab is interested in finding ways to disrupt the transportation of heme to P. aeruginosa in order to cure infections. The PhuS protein is part of the heme uptake systems that affect heme delivery into P. aeruginosa and is known to be regulated by heme and iron. This project specifically focuses on finding the heme dependent transciptional regulator of the phuS gene promoter.
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Novel Next-generation Non-catalytic p38alpha/MK2 Immunomodulators with Endothelial-barrier-stabilizing and Anti-inflammatory ActivityWe have previously identified a small three-ring molecule, UM101, targeted to the ED substrate-docking domain of p38alpha MAPK. UM101 modified p38alpha/MK2 signaling, stabilized endothelial barrier and reduced expression of proinflammatory genes. A next-generation analog with modifications on the first and third ring, Gen-1124, has improved anti-inflammatory and endothelial barrier-stabilizing activity, is lung protective in mouse models of influenza and ARDS, and is currently in a Phase II clinical trial in ARDS. To develop additional therapeutic candidates, we designed and synthesized UM101 analogs with modifications on the middle ring and tested the novel compounds for endothelial barrier- stabilizing and anti-inflammatory activity.
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Mitigating Evidence Gaps: A Survey Template to Inform Patient-Centered Value AssessmentBackground: Necessary and informative patient-experience data (PED) needed for value/health technology assessments (V/HTA) are rarely available as they are not routinely collected in clinical trials, the traditional data source for V/HTA. Patient organizations frequently collect PED; however, inconsistent approaches in the methods and type of data collected limit their usefulness for V/HTA. A universal framework, such as a standard, disease-agnostic survey template, could coalesce efforts for collecting patient-centric data for application to V/HTA for more efficiency, alignment, and better patient centricity. Objective: Using a mixed-methods approach and by identifying PED concepts common across conditions (i.e., cross-cutting PED concepts), co-develop a disease-agnostic survey template that can be used to inform a standardized approach to fill patient-centered evidence gaps in V/HTA. Methods: This mixed-methods study used a triangulation of data sources: (1) Voice-of-the-Patient reports, (2) peer-reviewed literature, (3) V/HTA reports, (4) publicly available surveys used by patient organizations to collect and submit data for V/HTA, (5) elicitation from patient experiences with conditions and associated treatments, and (6) patient-advisor and other expert input to identify cross-cutting PED concepts and draft a disease-agnostic survey template. Cognitive interviews with patients were conducted to test and refine survey items and response choices. Following, the draft survey was pilot tested to evaluate and finalize the disease-agnostic survey template by assessing usability from the patient perspective. Results: The resulting survey template is comprised of thirty-one items asking patients about the impact of disease and treatment on health and daily life such as but not limited to symptoms, treatment and treatment-related experiences, ability to work, wellness, finances, healthcare utilization, condition stability, treatment preferences, healthcare and provider experiences, access to healthcare services and treatment, experiences living with the condition, impact on daily life, support from others, impact on others, and additional patient insights. Conclusions: The resulting survey template supports standardized PED collection while offering flexibility to tailor to a condition or population. Continuous patient engagement throughout the development and testing process increases the survey template’s utility as it reflects what patients, who actually live with a condition, experience and think.
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Progression, Prognostic Factors, and Economic Costs of Loss of Independence in Parkinson DiseaseIntroduction: Parkinson disease (PD) is a neurodegenerative disorder causing disability and loss of independence (LOI), impacting patients and families. The longitudinal patterns of LOI in PD, prognostic factors predicting LOI in different types of activities of daily living (ADLs), and costs associated with functional dependency (FD) in PD remain unclear. Methods: We used 2003-2020 data from a prospective PD cohort at a tertiary neurologic center. Disability with LOI was assessed using the modified Older Americans Resource and Services Daily Function Questionnaire at baseline and follow-up. Patterns of LOI were summarized using EventFlow data visualization software. Cox proportional hazards models identified prognostic factors for LOI on different types of ADLs. Costs borne by patients with PD (PWP) and their families were analyzed using 2018-2019 Financial and Social Impact of Parkinson’s Disease Survey data. We estimated the incremental costs comparing families of PWP with and without FD using generalized linear models. Results: Among 270 early-stage PD patients, 133 (45%) developed LOI on one or more ADL, where 57 regained independence at least once. Housework was the most frequent first ADL requiring help (mean time 4.6 years post-first visit). Longitudinal patterns of loss included transient and persistent loss. Strongest associations were dyskinesia (adjusted hazard ratios [aHR], 1.82; 95% CI, 1.12-2.96) for LOI on any ADL; falls (aHR, 1.72; 95% CI, 1.16-2.55) for basic ADLs (BADLs); gait impairment (aHR, 2.04; 95% CI, 1.43-2.91) and dyskinesia (aHR, 2.09; 95% CI, 1.29-3.37) for instrumental ADLs (IADLs); and dyskinesia (aHR, 1.68; 95% CI, 1.05-2.68) for walking. Compared to families of PWP without FD (n=882), families of PWP with FD (n=476) faced higher direct non-medical costs (adjusted average marginal effect [aAME], $3,438; 95% CI, $1,719-$5,157) and indirect costs (aAME, $11,479; 95% CI, $1,545-$21,413). Conclusion: This study provides novel information about LOI patterns in PD and the fluctuations in patients' functioning in daily tasks. We identified factors (e.g., dyskinesia and gait impairment) with varying impacts on BADLs and IADLs. The study quantifies the financial strain on families of PWP with FD, underscoring the need for interventions to delay or prevent LOI in PD.
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Scholarship Reconsidered: Integrating EDI into Appointment, Promotion and Tenure GuidelinesThe objective was to develop inclusive promotion and tenure (P&T) criteria at the University of Maryland School of Pharmacy (UMSOP) that reflect the UMSOP’s mission and values, recognize the rich potential of diverse faculty and reward a breadth of scholarly excellence.
