Pharmacy and Pharmaceutical Sciences Commons^™

Discovery Of An Aldo-Keto Reductase 1c3 (Akr1c3) Degrader, Angelica V. Carmona, Shirisha Jonnalagadda, Alfie M. Case, Krishnaiah Maddeboina, Sravan K. Jonnalagadda, Louise F. Dow, Ling Duan, Trevor M. Penning, Paul C. Trippier

Journal Articles: Pharmaceutical Sciences

Aldo-keto reductase 1C3 (AKR1C3) is a protein upregulated in prostate cancer, hematological malignancies, and other cancers where it contributes to proliferation and chemotherapeutic resistance. Androgen receptor splice variant 7 (ARv7) is the most common mutation of the AR receptor that confers resistance to clinical androgen receptor signalling inhibitors in castration-resistant prostate cancer. AKR1C3 interacts with ARv7 promoting stabilization. Herein we report the discovery of the first-in-class AKR1C3 Proteolysis-Targeting Chimera (PROTAC) degrader. This first-generation degrader potently reduced AKR1C3 expression in 22Rv1 prostate cancer cells with a half-maximal degradation concentration (DC₅₀) of 52 nM. Gratifyingly, concomitant degradation of ARv7 was …

Management Of Factor Xa Inhibitor-Related Traumatic Non-Intracranial Bleeding Events With Andexanet Alfa Or Four-Factor Prothrombin Complex Concentrate In A Us Multicenter Observational Study, Paul P. Dobesh, Craig I. Coleman, Mark Danese, Eva Lesén, Raymond C. Chang, Onivefu Odelade, Gregory J. Fermann

Journal Articles: Pharmacy Practice

OBJECTIVES: This study describes clinical characteristics and management strategies for patients with factor Xa (FXa) inhibitor-related traumatic non-intracranial bleeds who were treated with andexanet alfa or four-factor prothrombin complex concentrate (4F-PCC).

METHODS: An observational cohort study (ClinicalTrials.gov Identifier: NCT05548777) was conducted using electronic health records from 354 US hospitals. Included patients were hospitalized with rivaroxaban- or apixaban-related bleeding, had received andexanet alfa or 4F-PCC treatment during their hospitalization, and were discharged between May 2018 and September 2022. This analysis was performed in the subgroup of patients with traumatic non-intracranial critical compartment/non-compressible bleeds or other traumatic bleeds.

RESULTS: The study population …

Andexanet Alfa Versus Pcc Products For Factor Xa Inhibitor Bleeding: A Systematic Review With Meta-Analysis, C. Michael White, Kimberly Snow Caroti, Youssef Bessada, Adrian V. Hernandez, William L. Baker, Paul P. Dobesh, Heleen Van Haalen, Kirsty Rhodes, Craig I. Coleman

Journal Articles: Pharmacy Practice

Previous meta-analyses assessed andexanet alfa (AA) or prothrombin complex concentrate (PCC) products for the treatment of Factor Xa inhibitor (FXaI)-associated major bleeding. However, they did not include recent studies or assess the impact of the risk of bias. We conducted a systematic review with meta-analysis on the effectiveness of AA versus PCC products for FXaI-associated major bleeding, inclusive of the studies' risk of bias. PubMed and Embase were searched for comparative studies assessing major bleeding in patients using FXaI who received AA or PCC. We used the Methodological Index for NOn-Randomized Studies (MINORS) checklist and one question from the Joanna …

Paper-Based Ratiometric Sensor Array For Pathogenic Bacterial Species Identification, Aayushi Laliwala

Theses & Dissertations

Bacterial infections are the leading cause of mortality worldwide due to the lack of accurate diagnosis of the pathogens causing infections. Currently, microbiological and molecular techniques are used to identify pathogenic bacteria. However, these techniques have limitations as they are time-consuming, cost-inefficient, and require trained personnel. Therefore, timely and precise identification of pathogenic bacteria is crucial for public safety. Our lab previously synthesized a fluorescent sensor array (3-hydroxyflavone derivatives) encapsulated in hyaluronic acid-based nanoparticles to identify bacterial species and recognize their Gram status. Though promising, this technique was relatively time-consuming and required high sample and volumes.

To overcome these limitations, …

Towards A Mode Of Action For The Anti-Schistosomal Aryl Hydantoins, Thomas Schulze

Theses & Dissertations

Schistosomiasis is a significant human disease caused by the helminth parasite Schistosoma mansoni. Praziquantel remains the only clinically used treatment, yet it is rapidly metabolized and only effective against the adult stage worm infection. Ro 13-3978 (AR02) is a potent antischistosomal compound with activity against multiple S. mansoni life stages; however, it manifests anti-androgenic activity. Additionally, the mechanism of action for worm clearance remains unknown. The structure of Ro 13-3979 was used to generate optimized derivatives, including AR102, that show increased potency towards worms, reduced off-target anti-androgen effects, and extended half-life thereby increasing the feasibility for a single-dose curative treatment. …

Geospatial Distribution Of Pharmacist Diabetes Management Within A Patient Centered Medical Home Model In Omaha, Nebraska, Anthony Donovan

Capstone Experience: Master of Public Health

Patients with uncontrolled diabetes, defined as a hemoglobin A1c value greater than 9%, are at an increased risk of diabetes progression. Primary care is often the first point of contact where patients with uncontrolled diabetes are identified and treated. Pharmacists are utilized in diabetes medication management of patients with uncontrolled diabetes as one component of primary care multidisciplinary models of care. This descriptive project describes the geospatial distribution of patients with uncontrolled diabetes from a single institution in the Omaha, Nebraska area who were exposed to pharmacists within a Patient Centered Medical Home (PCMH) model of care compared to those …

Design And Synthesis Of Small Molecule Drugs For Cns Disorders, Kirsten T. Tolentino

Theses & Dissertations

Dopamine (DA) is an important neurotransmitter for the regulation and long-term function of the central nervous system (CNS). DA binds to Dopamine Receptors (DR) to stimulate or inhibit adenyl cyclase production to further elicit a pharmacological response. DRs were cloned, and it was determined that there are two families separated by their function and five total subtypes distinguished by their amino acid structure. The Dopamine 4 receptor (D4R) is the second least studied subtype but has high expression in the frontal cortex, amygdala, hippocampus, hypothalamus, globus pallidus, substantia nigra pars reticula, and thalamus. Dopamine signaling and transmission, especially in the …

Overcoming Resistance Mechanisms To Cdk4/6 Inhibitor Treatment Using Cdk6-Selective Protac, Sarah Truong

Theses & Dissertations

Hormone receptor-positive (HR+) breast cancer (BC) constitutes approximately 75% of all breast cancer patients. These tumors rely on hormones, estrogen and progesterone, for their proliferation. The interaction between the hormones and their respective receptors enhances cyclin D expression, which results in the persistent activation of CDK4 and CDK6. The CDK4/6-cyclin D complex engages in a phosphorylation cascade that ultimately allows the cells to proceed past the G1/S checkpoint of the cell cycle. Inhibition of CDK4/6 has been shown to trigger cell cycle arrest, inhibit tumor growth, and induce apoptosis. Currently, there are three FDA-approved CDK4/6 inhibitors (CDK4/6i). A limitation of …

Design, Synthesis, And Evaluation Of Novel Peptidomimetics As Neurolysin Activators For The Treatment Of Ischemic Stroke., Md. Shafikur Rahman

Theses & Dissertations

Stroke is the world's second-leading cause of death and disability. Ischemic stroke (IS), a primary subtype of stroke, has ineffective and limited treatment options, resulting in a significant unmet medical need for novel therapies. Tissue plasminogen activator (tPA) is the sole FDA-approved medication now in use; however, it has a narrow therapeutic window (3 to 4.5 h). Unfortunately, few individuals have this opportunity to be diagnosed with stroke in time to begin therapy with tPA. Additionally, treatment with tPA can have major adverse effects, such as bleeding, which can exacerbate the consequences of a stroke on the brain. To overcome …

Targeted Therapies For Improving The Treatment Of Sonic Hedgehog And Myc Driven Medulloblastoma, Bharti Sethi

Theses & Dissertations

The aim of this thesis to develop a novel potent dual inhibitor to target BDR4/PI3K and MDM2/ XIAP pathways to treat medulloblastoma. A series of new analogs were synthesized, characterized, and evaluated in vitro and in vivo using xenograft and orthotopic mouse models.

In Chapter 1 an overview of Blood brain barrier such as their components, physiology, current drug delivery system and nanomedicines to treat medulloblastoma.

Chapter 2 includes synthesis of new molecule MDP5, targeting both BRD4 and PI3K pathways. We used X-ray crystal structures and molecular modeling approach to confirm the interactions between MDP5 with BD domains from both …

Creation Of Tatde Rlnps For The Excision Of Integrated Hiv-1 Proviral Dna, Mahmudul Hasan

Theses & Dissertations

The persistence of integrated human immunodeficiency virus type 1 (HIV-1) proviral DNA despite combination antiretroviral therapy (ART) is the principal challenge to eliminating HIV-1 infection. This is made ever more complex based on the high viral mutation rates, diversity and resistance profiles. Taken together, these factors present principal obstacles towards any means to eliminate the virus from its infective human host. To address these factors, we have developed and validated a TatDE rLNP RNA delivery system. The system utilizes Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR) guide RNAs (gRNAs) to target multiple exons of an integrated proviral HIV-1 (tat_{1-2 …}

Intramuscular Administration Of The Host-Derived Immunostimulant Cpdi-02 Increases Protection Of Outbred Mice And Piglets Against Dermal Mrsa Infection In A Curative Setting And Is Well Tolerated After Repeated Administration, Jason P. Stewart

Theses & Dissertations

Staphylococcus aureus is the most common cause of bacterial skin and soft tissue infections (SSTIs) and the leading cause of hospital-associated infections in the United States. The abundance of S. aureus infections is due, in part, to its virulence factors that suppress host immune system and the development of antibiotic resistance strains such as methicillin-resistant S. aureus (MRSA). In contrast to antibiotics, Host-Directed Therapeutics (HDTs), avoid the pitfalls of antibiotics by targeting the host for immune system rather than targeting the pathogen. This mechanism of action avoids selective evolutionary pressure, which leads to antibiotic resistance and helps the host immune …

Assembly Of Synaptic Protein-Dna Complexes: Critical Role Of Non-Specific Interactions, Sridhar Vemulapalli, Mohtadin Hashemi, Anatoly B. Kolomeisky, Yuri L. Lyubchenko

Journal Articles: Pharmaceutical Sciences

The synaptic protein-DNA complexes, formed by specialized proteins that bridge two or more distant sites on DNA, are critically involved in various genetic processes. However, the molecular mechanism by which the protein searches for these sites and how it brings them together is not well understood. Our previous studies directly visualized search pathways used by SfiI, and we identified two pathways, DNA threading and site-bound transfer pathways, specific to the site-search process for synaptic DNA-protein systems. To investigate the molecular mechanism behind these site-search pathways, we assembled complexes of SfiI with various DNA substrates corresponding to different transient states and …

Amyloid Cascade Hypothesis For Alzheimer’S Disease. Does It Work Under Physiological Conditions?, Yuri L. Lyubchenko

Journal Articles: Pharmaceutical Sciences

Plaques in the brain consisting of proteins are a hallmark of diseases like Alzheimer’s disease (AD) and Parkinson’s disease (PD). Such aggregates can be assembled spontaneously by specialized proteins such as amyloid beta (Ab) proteins in the case of AD. Numerous in vitro studies made a foundation for the Amyloid Cascade Hypothesis (ACH), according to which the misfolding of proteins leads to their self-assembly into toxic oligomers along with the formation of amyloid fibrils assembled as plaques in the brain. Notably physiological concentration of Ab proteins in the brain is in the low nanomolar concentration, so no spontaneous aggregation of …

Lower Mortality With Andexanet Alfa Vs 4-Factor Prothrombin Complex Concentrate For Factor Xa Inhibitor-Related Major Bleeding In A U.S. Hospital-Based Observational Study, Paul P. Dobesh, Gregory J. Fermann, Mary J. Christoph, Bruce Koch, Eva Lesén, Hungta Chen, Belinda Lovelace, Theresa Dettling, Mark Danese, Julie Ulloa, Sherry Danese, Craig I. Coleman

Journal Articles: Pharmacy Practice

BACKGROUND: Well-designed studies with sufficient sample size comparing andexanet alfa vs 4-factor prothrombin complex concentrate (4F-PCC) in routine clinical practice to evaluate clinical outcomes are limited.

OBJECTIVES: To compare in-hospital mortality in patients hospitalized with rivaroxaban- or apixaban-related major bleeding who were treated with andexanet alfa or 4F-PCC.

METHODS: An observational cohort study (ClinicalTrials.gov identifier: NCT05548777) was conducted using electronic health records between May 2018 and September 2022 from 354 U.S. hospitals. Inclusion criteria were age ≥18 years, inpatient admission with diagnosis code D68.32 (bleeding due to extrinsic anticoagulation), a record of use of the factor Xa inhibitors rivaroxaban or …

Polymeric Chloroquine In Metastatic Pancreatic Cancer Therapy, Rubayat Islam Khan

Theses & Dissertations

Hydroxychloroquine (HCQ) is an established drug that has been used for the treatment of multiple diseases, including malaria, rheumatoid arthritis, and lupus erythematosus. Several recently published studies have highlighted its beneficial use in various types of cancers, and a plethora of clinical trials are currently evaluating its use in cancer therapies, wherein some of the results look promising. The preclinical studies to date suggest HCQ can work effectively in conjunction with traditional cancer treatments, as it has been shown to sensitize tumor cells to a wide range of chemotherapeutic agents. Polymeric HCQ (PCQ), a macromolecular multivalent version of HCQ, has …

The Association Of Lower Medication Adherence And Increased Medical Spending, Ryan A. Fuchs

Capstone: Master of Health Administration

Medical prescribing is a common occurrence in daily clinical practice. According to the Centers for Disease Control and Prevention, in 2015-2016 45.8% of the U.S. population used prescription drugs in the past 30 days. (CDC, 2019) Although drug therapy can be effective in treating disease, full benefits are often not realized because many patients do not take their medications as prescribed. There is quite a bit of research out there about non-adherence to medication. Some studies focus on the financial impacts of non-adherence, but most of the studies examine the reasons for medication non-adherence. A gap exists in research about …

Targeted Therpeutics For Prostate Cancer, Behind The Scenes Of Psma & Cysteine Protease Trapping Mechanism, Alireza Basiri

Theses & Dissertations

In an attempt to increase the residence time of PSMA-targeted theranostics inside the prostate cancer cells and tumors, we designed and prepared a CPTA-PSMATA resembling PSMA-617 by adding a well-known cysteine protease inhibitor (E-64) to the conjugate. Lysosomal proteases, including cysteine, serine, and aspartic families of hydrolytic enzymes, are expressed in high concentrations in the lysosomes and are responsible for the catabolism of proteins inside the cell [165, 278]. We proposed that after successful internalization of the PSMA-targeted conjugates into the cells, they will be conveyed to the endolysosomes. In these endolysosomal compartments, the E-64 moiety will covalently bind to …

Evaluation Of Medication Optimization In The Setting Of Ecmo Therapy: Assessment Of Therapeutic Effectiveness, Greg Peitz

Theses & Dissertations

A series of studies within the setting of extracorporeal membrane oxygenation (ECMO) was undertaken to specifically answer questions related to medication optimization during this complex therapy. These studies included medication therapies involving optimal anticoagulation, analgesia delivery, fluid resuscitation, and infection related outcomes in the context of ECMO. Each investigation was retrospective in nature and included patients from a single institution. The results of these studies indicated the following: 1.) various anticoagulation goals do not impact severe, life-threatening bleeding events during ECMO therapy; 2.) sepsis is a common occurrence in the setting of ECMO; 3.) the choice of either a crystalloid …

The Development And In Vivo Immunologic Assessment Of Biodegradable Microparticles Incorporating Cpdi-02 And Mucosal Protein Vaccine, Jacob E. Parriott

Theses & Dissertations

Encapsulation in biodegradable microparticles (MPs) is a promising approach to increase the efficacy of intranasally administered protein vaccines. The generation of long-lived adaptive immune responses against encapsulated protein vaccines, however, requires the incorporation of a suitable mucosal adjuvant. CPDI-02—a complement peptide-derived immunostimulant that selectively activates dendritic cells and macrophages over neutrophils while minimizing the inflammatory side effects of parent C5a—has previously been incorporated into both systemic and mucosal vaccine formulations via direct conjugation to chemical moieties, peptides, proteins, inactivated pathogens, and the surface of biodegradable particles, to enhance Th1-biased cellular immune responses. The effect of CPDI-02 surface conjugation to MPs …

Applications Of Population Pharmacokinetic Modeling In People Living With Hiv, Michelle M. Pham

Theses & Dissertations

Population pharmacokinetic modeling has become an important tool for the individualization of medicine in HIV care and clinical pharmacology in general. This dissertation explores many applications of population pharmacokinetic modeling to help identify drug exposure, drug-drug interactions, and sources of variability in populations living with HIV. Comprehensive HIV care involves simultaneous treatment of the disease and any co-infection and/or co-conditions.

The first objective was to identify potential drug-drug interactions affecting combination antiretroviral therapy (ART) consisting of efavirenz, tenofovir disoproxil fumarate and emtricitabine, from concomitant use of chemotherapy agents. Three models were developed with sparse sampling to characterize efavirenz, emtricitabine, and …

Biologically-Inspired Nanoparticles For Oncology Applications, Aishwarya Bapat

Theses & Dissertations

Cancer is the leading cause of death in the United States and its high mortality rate can be attributed towards poor diagnosis methods and less effective therapeutic treatments. Many nanotechnology-based diagnostics and therapeutics are being developed to improve cancer patient outcomes. In this work, we have studied nanoparticles for diagnostic and therapeutic applications in cancer treatment.

In the first work, novel fluorescent NPs loaded with indocyanine green (ICG) were developed for bioimaging applications of pancreatic cancer. Targeted fluorescent nanoparticles (NPs) are being developed to image a range of cancer types with the goal to improve patient outcomes by utilizing in …

The Development Of Thermoresponsive Hydrogel-Based Drug Delivery Systems For The Treatment Of Musculoskeletal Diseases, Ningrong Chen

Theses & Dissertations

Water-soluble polymers are one of the most commonly used drug delivery vehicles for musculoskeletal diseases. During the past few decades, various biocompatible polymers have been employed in the development of thermoresponsive hydrogels as drug delivery systems for the treatment of local musculoskeletal pathologies. As part of our laboratory’s contribution to this field of study, I have successfully developed three thermoresponsive hydrogel-based formulations for the treatment of three different pathologies associated with the musculoskeletal system.

As my initial effort, I have developed a bone-targeting injectable hydrogel drug delivery system based on Pluronic 127 (Poloxamer 407), which is a Generally Recognized As …

Design, Synthesis, And Biological Investigation Of Pyridine Sulfones As Anti-Chlamydia Trachomatis Agents, Mohamed A. Seleem

Theses & Dissertations

Chlamydia trachomatis is the most prominent cause of sexually transmitted bacterial infections worldwide, with around 128 million reported cases annually. This pathogen can cause severe urogenital and ocular consequences, resulting in infertility and trachoma. In its unique developmental cycle, Chlamydia fluctuates between two distinct forms, elementary bodies (EBs) and reticulate bodies (RBs). We hypothesized that caseinolytic protease P (ClpP), a conserved protease among bacterial species, drives the Chlamydia developmental cycle. Earlier work by the Ouellette group demonstrated that Chlamydia relies on its ClpP2 paralogue (ctClpP2) to differentiate between its developmental forms. Dysregulation of ctClpP2 had a significant …

Polymeric Nanocarriers For Delivery Of Small Molecules Inhibiting Tubulin Polymerization For The Treatment Of Pancreatic Cancer And Lung Metastatic Melanoma, Rajan Sharma Bhattarai

Theses & Dissertations

The aim of this thesis is to develop delivery systems for the novel small molecules which inhibit tubulin polymerization. One of the small molecules was modified to lipid conjugate to increase the lipophilicity of the molecules which in turn drastically improved the drug loading in amphiphilic polymeric system. The second molecule was conjugated to the amphiphilic polymeric backbone with pH sensitive Schiff’s linker for the tumor site specific delivery in lung metastatic melanoma model.

Chapter 1 discusses the tumor microenvironment for the solid tumor especially focusing on Pancreatic Ductal Adenocarcinoma (PDAC). Further the drug delivery system currently researched for addressing …

Interrogating Race And Place-Based Inequities In Hiv And Covid-19, Rohan Khazanchi

MD Honors Theses

Over the last four years, I have developed a research focus examining the intersections of race, place, and health. My M.D. Honors Thesis reflects a snapshot of these efforts. In this collection of brief research reports, I leverage area-based measures to investigate structural inequities in three contexts: the HIV epidemic in our hyperlocal community, the early stages of the COVID-19 pandemic, and clinical trials for novel COVID-19 therapeutics. I apply novel social epidemiologic tools to measure and explore disparate outcomes. And, in reflecting upon my findings, I discuss concrete implications for clinicians, researchers, and policymakers alike.

Chapter 1: Neighborhood-Level Deprivation …

Modulation Of Immune Homeostasis In Neurodegenerative Diseases, Pravin Yeapuri

Theses & Dissertations

Modulating the immune system via. transformation of CD4+ T cell effector to regulatory (Teff to Treg) or promoting microglial clearance of abnormal disease proteins are attractive therapeutic strategies to restore immunological balance in neurodegenerative diseases like Parkinson’s disease (PD) and Alzheimer’s disease (AD). In the past decade, we defined a safe and effective pathway for Treg induction through the cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF). GM-CSF was developed in PD animal models and early phase I human studies demonstrating proof-of-concept efficacy for ameliorating disease signs and symptoms. Despite the recorded efficacy, the medicine’s short half-life, limited bioavailability, and injection site reactions …

Development Of Bioactive Polymers For Anticancer Sirna Therapy, Siyuan Tang

Theses & Dissertations

Pancreatic ductal adenocarcinoma is a deadly disease with limited treatment options due to late diagnosis and resistance to conventional chemotherapy. Moreover, with the decreased survival rate in the past several years, pancreatic cancer may become the second leading cause of cancer-related death by surpassing breast cancer in 2030. CXCR4/CXCL12 pathway is crucial in tumor-supporting microenvironment, tumor progression, angiogenesis, metastasis and chemotherapy resistance. Small interfering RNA (siRNA) is one of the interfering RNA (RNAi), which targets mRNA specifically then knockdowns the overexpressed oncogene. Thus, siRNA has been widely used as a therapeutic strategy for various diseases including PDAC. In the research …

Assessing Nutritional Health Knowledge In Sharing Clinic Patients With Diabetes, Minden Huntrods

Capstone Experience: Master of Public Health

Effective diabetes prevention and management relies on nutritional behaviors, thus a basic level of health knowledge is important for patients with diabetes and their caregivers in their quest to acquire acute glycemic control and minimize negative health outcomes (Ley et al., 2014). The purpose of this study was to assess the nutrition-related health knowledge of patients living with diabetes who are seen at the UNMC Sharing Clinic by use of a verbal questionnaire. This nutritional health knowledge assessment was a quantitative, prospective, survey-based study utilizing descriptive statistics. Approximately 86% of patients were proficient in food group and nutritious foods knowledge …

Interrogating Race And Place-Based Inequities In Hiv And Covid-19, Rohan Khazanchi

EMET Projects

Over the last four years, I have developed a research focus examining the intersections of race, place, and health. My M.D. Honors Thesis reflects a snapshot of these efforts. In this collection of brief research reports, I leverage area-based measures to investigate structural inequities in three contexts: the HIV epidemic in our hyperlocal community, the early stages of the COVID-19 pandemic, and clinical trials for novel COVID-19 therapeutics. I apply novel social epidemiologic tools to measure and explore disparate outcomes. And, in reflecting upon my findings, I discuss concrete implications for clinicians, researchers, and policymakers alike.

Chapter 1: Neighborhood-Level Deprivation …