Pharmacy and Pharmaceutical Sciences Commons^™

Development Of A Combined Feedforward-Feedback Quality Control System For Extended-Release Granules Using A Quality By Design Approach, Yuxiang Zhao

Electronic Theses and Dissertations

Objectives

For a fluid bed film coating process to consistently deliver quality products, its control system needs to be robust against the variability of input materials and environmental disturbances. Presently, limited studies have been reported to understand the effects and interactions of the material attributes, environmental variables, and process parameters on the product in vitro drug dissolution. A control system can be developed with a proper understanding of the coating process, by adjusting the process parameters in feedback and feedforward manners to compensate for the undesired effect caused by disturbances, and ensure consistent product quality.

Methods

The control system was …

The Role Of Mek1/2 And Mek5 In Melatonin-Mediated Actions On Osteoblasts And Osteoclasts Differentiation, Bone Formation, Bone Microarchitecture, And Bone Biomechanics, Fahima Akter Munmun

Electronic Theses and Dissertations

Melatonin, the main endogenous hormone to entrain the circadian system, is not limited to its role in regulating the sleep-wake cycle; rather, it affects a wide variety of systems involving antioxidant, anti-inflammation, blood pressure regulation, seasonal reproduction, ovarian physiology, and immune function. Driven by the diversity of its action, melatonin for a long time has also been studied in the field of bone and mineral research both clinically and pre-clinically. Exogenous administration of melatonin in clinical trials in perimenopausal women (MOPS; NCT01152580); or postmenopausal women with osteopenia (MelaOST; NCT01690000 and MOTS; NCT01870115) confirmed improvement of bone mineral density (BMD) (MelaOST; …

Towards A "Universal Chemical Biology Toolbox" For Tackling Human Diseases, Christopher Swank

Electronic Theses and Dissertations

A lack of new drug targets and drug mechanisms, coupled with drug-pipeline attrition, represent significant problems in oncology drug discovery. Towards addressing this challenge, “fully-functionalized small-molecule probes” (FFSMPs) have been established, which are compounds that can be immediately used as “bait” to capture their protein targets under the same assay conditions used for oncology-based phenotypic screening. Specifically, each FFSMP library member contains one or more structural-diversity elements to promote interactions of the probe with different protein targets in living cells, an electrophile or photoreactive functional group for covalent attachment of the probe to interacting proteins via affinity or photoaffinity labeling, …

Measuring Routine Childhood Vaccination Coverage In 204 Countries And Territories, 1980–2019: A Systematic Analysis For The Global Burden Of Disease Study 2020, Release 1, Natalie C. Galles, Patrick Y. Liu, Rachel I. Updike, Stephen S. Lim, Jonathan F. Mosser, Asma Tahir Awan, Gbd 2020, Release 1, Vaccine Coverage Collaborators

Environmental & Global Health Faculty Research

Background: Measuring routine childhood vaccination is crucial to inform global vaccine policies and programme implementation, and to track progress towards targets set by the Global Vaccine Action Plan (GVAP) and Immunization Agenda 2030. Robust estimates of routine vaccine coverage are needed to identify past successes and persistent vulnerabilities. Drawing from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2020, Release 1, we did a systematic analysis of global, regional, and national vaccine coverage trends using a statistical framework, by vaccine and over time. Methods: For this analysis we collated 55 326 country-specific, cohort-specific, year-specific, vaccine-specific, and dose-specific …

Measuring Routine Childhood Vaccination Coverage In 204 Countries And Territories, 1980–2019: A Systematic Analysis For The Global Burden Of Disease Study 2020, Release 1, Natalie C. Galles, Patrick Y. Liu, Rachel L. Updike, Nancy Fullman, Jason Nguyen, Sam Rolfe, Ismaeel Yunusa, Et Al.

Faculty Publications

Background

Methods

Oral Bisacodyl Is Effective And Safe For Short Term Treatment Of Chronic Constipation, Akanksha Vaishnav

Clinical Research in Practice: The Journal of Team Hippocrates

A clinical decision report using

Kamm MA, Mueller-Lissner S, Wald A, Richter E, Swallow R, Gessner U. Oral bisacodyl is effective and well-tolerated in patients with chronic constipation. Clin Gastroenterol Hepatol. 2011;9(7):577-583. https://doi.org/10.1016/j.cgh.2011.03.026

to evaluate potential long term treatment with oral Bisacodyl in a patient with a history of chronic constipation and recent non-surgical treatment of ischemic colitis.

Comparative Efficacy, Safety, Tolerability, And Effectiveness Of Antipsychotics In The Treatment Of Dementia-Related Psychosis (Drp): A Systematic Literature Review, Ismaeel Yunusa, N. Rashid, V. Abler, Krithika Rajagopalan

Faculty Publications

Objectives

To evaluate the comparative efficacy, safety, tolerability, and effectiveness of atypical antipsychotics (AAPs) for the treatment of dementia related psychosis (DRP) in older adults.

Methods

In this systematic literature review (SLR), we qualitatively synthesized evidence on the comparative efficacy (based on neuropsychiatric inventory), tolerability (weight gain), and safety (cerebrovascular adverse events [CVAE], cardiovascular events, mortality, somnolence, extrapyramidal symptoms [EPS]) of AAPs used to treat DRP. We also assessed effectiveness based on all-cause discontinuations and discontinuations due to lack of efficacy or adverse events (AE). Published articles from through March 2021 from PubMed, EMBASE, PsycINFO, and Cochrane databases evaluated. We …

Protein-Based Nanofibers And Thin Films For Drug Delivery Applications, Christopher R. Gough

Theses and Dissertations

Corn zein and silk are both widely available, easy to extract proteins making them valuable replacements for synthetics. Zein and silk are also promising biomaterials in several applications. This work explores the use of both proteins as drug delivery vehicles by loading 1-Dimensional micro-nanofibers and 2-Dimensional thin films with model drugs or the topical therapeutic sodium citrate. Using a formic acid solvent, powdered zein protein or silk fibers were dissolved into solution and then casted into 2D films or spun into 1D fibers through air-spraying. During dissolution, therapeutic products are added. SEM images showed that fibers maintain their small diameter …

Uplc-Ms/Ms Analysis Of The Michaelis-Menten Kinetics Of Cyp3a-Mediated Midazolam 1′- And 4-Hydroxylation In Rat Brain Microsomes, Devaraj Venkatapura Chandrashekar, Barent Dubois, Reza Mehvar

Pharmacy Faculty Articles and Research

Midazolam (MDZ) is a short-acting benzodiazepine with rapid onset of action, which is metabolized by CYP3A isoenzymes to two hydroxylated metabolites, 1′-hydroxymidazolam and 4-hydroxymidazolam. The drug is also commonly used as a marker of CYP3A activity in the liver microsomes. However, the kinetics of CYP3A-mediated hydroxylation of MDZ in the brain, which contains much lower CYP content than the liver, have not been reported. In this study, UPLC-MS/MS and metabolic incubation methods were developed and validated for simultaneous measurement of low concentrations of both hydroxylated metabolites of MDZ in brain microsomes. Different concentrations of MDZ (1–500 µM) were incubated with …

Lapatinib And Poziotinib Overcome Abcb1-Mediated Paclitaxel Resistance In Ovarian Cancer, J. Robert Mccorkle, Justin W. Gorski, Jinpeng Liu, Mckayla J. Riggs, Anthony B. Mcdowell Jr., Nan Lin, Chi Wang, Frederick R. Ueland, Jill M. Kolesar

Markey Cancer Center Faculty Publications

Conventional frontline treatment for ovarian cancer consists of successive chemotherapy cycles of paclitaxel and platinum. Despite the initial favorable responses for most patients, chemotherapy resistance frequently leads to recurrent or refractory disease. New treatment strategies that circumvent or prevent mechanisms of resistance are needed to improve ovarian cancer therapy. We established in vitro paclitaxel-resistant ovarian cancer cell line and organoid models. Gene expression differences in resistant and sensitive lines were analyzed by RNA sequencing. We manipulated candidate genes associated with paclitaxel resistance using siRNA or small molecule inhibitors, and then screened the cells for paclitaxel sensitivity using cell viability assays. …

Insights Into The Mechanisms Of Brain Endothelial Erythrophagocytosis, Jiahong Sun, Prema Vyas, Samar Mann, Annlia Paganini-Hill, Ane C. F. Nunes, Wei Ling Lau, David H. Cribbs, Mark J. Fisher, Rachita K. Sumbria

Pharmacy Faculty Articles and Research

The endothelial cells which form the inner cellular lining of the vasculature can act as non-professional phagocytes to ingest and remove emboli and aged/injured red blood cells (RBCs) from circulation. We previously demonstrated an erythrophagocytic phenotype of the brain endothelium for oxidatively stressed RBCs with subsequent migration of iron-rich RBCs and RBC degradation products across the brain endothelium in vivo and in vitro, in the absence of brain endothelium disruption. However, the mechanisms contributing to brain endothelial erythrophagocytosis are not well defined, and herein we elucidate the cellular mechanisms underlying brain endothelial erythrophagocytosis. Murine brain microvascular endothelial cells (bEnd.3 …

Cost-Effectiveness Analysis Of Tisagenlecleucel, Blinatumomab, And Clofarabine For Treatment Of B-Cell Precursor Acute Lymphoblastic Leukemia, Kamron Lotfi

Pharmaceutical Sciences (MS) Theses

Acute lymphoblastic leukemia (ALL) is a common type of adolescent and young adult leukemia in the United States (U.S.). Patients who are refractory or relapsed after receiving two or more lines of systemic therapy have the option of taking tisagenlecleucel. Due to the high cost of this treatment, a cost-effectiveness analysis was performed to assess the treatments for tisagenlecleucel, clofarabine combination, and blinatumomab. Objectives

The objective of this study is to evaluate the cost-effectiveness of tisagenlecleucel; clofarabine, etoposide, cyclophosphamide; and blinatumomab for the treatment of relapse- refractory ALL for adolescents and young adults from the U.S. health care payer perspective. …

The Degree Of Polymerization And Sulfation Patterns In Heparan Sulfate Are Critical Determinants Of Cytomegalovirus Entry Into Host Cells, Dipanwita Mitra, Mohammad H. Hasan, John T. Bates, Michael A. Bierdeman

Faculty and Student Publications

Several enveloped viruses, including herpesviruses attach to host cells by initially interacting with cell surface heparan sulfate (HS) proteoglycans followed by specific coreceptor engagement which culminates in virus-host membrane fusion and virus entry. Interfering with HS-herpesvirus interactions has long been known to result in significant reduction in virus infectivity indicating that HS play important roles in initiating virus entry. In this study, we provide a series of evidence to prove that specific sulfations as well as the degree of polymerization (dp) of HS govern human cytomegalovirus (CMV) binding and infection. First, purified CMV extracellular virions preferentially bind to sulfated longer …

(E)-2,6,10-Trimethyldodec-8-En-2-Ol: An Undescribed Sesquiterpenoid From Copaiba Oil, Mohammed F. Hawwal, Zulfiqar Ali, Mei Wang, Jianping Zhao

Faculty and Student Publications

The use of copaiba oil has been reported since the 16th century in Amazon traditional medicine, especially as an anti-inflammatory ingredient and for wound healing. The use of copaiba oil continues today, and it is sold in various parts of the world, including the United States. Copaiba oil contains mainly sesquiterpenes, bioactive compounds that are popular for their positive effect on human health. As part of our ongoing research endeavors to identify the chemical constituents of broadly consumed herbal supplements or their adulterants, copaiba oil was investigated. In this regard, copaiba oil was subjected to repeated silica gel column chromatography …

Red Algal Sulfated Galactan Binds And Protects Neural Cells From Hiv-1 Gp120 And Tat, Vitor H. Pomin, Fakhri Mahdi, Weihua Jin, Fuming Zhang

Faculty and Student Publications

The potential neuroprotective capacity of four different sulfated glycans: Botryocladia occidentalis-derived sulfated galactan (BoSG) (MW > 100 kDa), Lytechinus variegatus-derived sulfated fucan (LvSF) (MW~90 kDa), high-molecular weight dextran sulfate (DxS) (MW 100 kDa), and unfractionated heparin (UFH) (MW~15 kDa), was assessed in response to the HIV-1 proteins, R5-tropic glycoprotein 120 (gp120) and/or trans-activator of transcription (Tat), using primary murine neurons co-cultured with mixed glia. Compared to control-treated cells in which HIV-1 proteins alone or combined were neurotoxic, BoSG was, among the four tested sulfated glycans, the only one capable of showing significant concentration-dependent neuroprotection against Tat and/or gp120, alone or combined. …

Critical Interactions Between Opioid And Cannabinoid Receptors During Tolerance And Physical Dependence Development To Opioids In The Murine Gastrointestinal Tract: Proof Of Concept, Agata Szymaszkiewicz, Mikołaj Świerczyński, Marcin Talar, Prabhakar Reddy Polepally

Faculty and Student Publications

Introduction: Tolerance (TOL) and physical dependence (PD) constitute important limitations of opioid therapy. The aim of our study was to validate research tools to investigate TOL and PD and to characterize the interactions between opioid (OR) and cannabinoid (CB) receptors in these processes in the GI tract. Methods: TOL was assessed through the comparison of morphine ability to inhibit electrically evoked smooth muscles contractility in the mouse ileum that was previously incubated with/without morphine for 1 h. To evaluate the PD, the ileum was incubated with morphine for 10 min, then challenged with naloxone to induce withdrawal response (WR). The …

Design, Synthesis, And Evaluation Of A Novel Cytotoxic Peptide-Doxorubicin Conjugate Targeting Triple-Negative Breast Cancer, Elmira Ziaei

Pharmaceutical Sciences (PhD) Dissertations

The aim of this thesis was to design, synthesize, and characterize a novel peptide-doxorubicin conjugate, evaluate in vitro stability and cytotoxicity properties of the conjugate and study its mechanism for uptake into the triple-negative breast cancer (TNBC) cells. For the synthesis of the conjugate, first, doxorubicin (Dox) was conjugated to a highly efficient established cross-linker, MCC, to give an intermediate product, MCC-Dox. MCC-Dox was characterized using NMR spectroscopy, mass spectrometry, and RP-HPLC and purified for subsequent reaction. Second, the 11-mer peptide 18-4 (NH₂-CWxEAAYQrFL-CONH₂) with high proteolytic stability and specificity for breast cancer cells was reacted with …

Hybrid Cyclic-Linear Cell-Penetrating Peptides Containing Alternative Positive And Hydrophobic Residues As Molecular Transporters, Sorour Khayyatnejad Shoushtari

Pharmaceutical Sciences (MS) Theses

The cell membrane properties create a significant obstacle in intracellular delivery of cell-impermeable and negatively charged molecules. Amphiphilic cyclic peptides containing alternative arginine and tryptophan such as [WR]₅ have been shown to enhance the transport of cargo molecules across the cell membrane. Herein, we report the synthesis and biological evaluation of a novel series of hybrid cyclic-linear peptides containing alternative positive and hydrophobic amino acids on the ring and side-chain [(RW)₅]K(RW)_X (X=1-5) to compare their molecular transporter efficiency. The peptides were synthesized through Fmoc solid-phase peptide synthesis. Final compounds were purified by a reversed-phase HPLC (High …

Establishing The Role Of Dc-Sign And Glycoprotein H For Kshv Entry In B Lymphocytes, Nancy Palmerin

Pharmaceutical Sciences (MS) Theses

Kaposi sarcoma-associated herpesvirus, also known as KSHV or HHV-8, is an emerging pathogen and the causative agent of multiple cancers in immunocompromised patients. KSHV is known to cause four types of malignancies: endothelial-based Kaposi Sarcoma (KS), two rare B cell- based lymphomas; Primary effusion lymphoma, Multicentric Castleman’s disease and a recently characterized inflammatory disorder called KSHV-associated inflammatory cytokine syndrome(KICS). Unfortunately, all of the diseases associated with KSHV infection are fatal, and to this day there is no known cure. The purpose of this study is to understand the viral entry process of KSHV in tonsil-derived B lymphocytes. This study will …

Characterization Of The Growth Factor Receptor Network Oncogenes In Lung Cancer, Ashley Duche

Pharmaceutical Sciences (MS) Theses

Lung cancer remains the leading cause of cancer related deaths worldwide, reportedly contributing to 1.8 million of the 10.0 million mortalities documented in the year 2020. Although advancements have been made in therapeutics and diagnostic methods, formulation of effective treatments and development of drug resistance continues to be a challenge. These challenges arise from our lack of understanding of intricate signaling pathways, such as the Growth Factor Receptor Network (GFRN), which contributes to complex lung tumor heterogeneity allowing for drug resistance development. In this study, gene expression signatures of six GFRN oncogenes overexpressed in human mammary epithelial cells (HMECs) were …