Pharmacy and Pharmaceutical Sciences Commons^™

Design And Synthesis Of Fused Pyrimidines As Single Agents With Combination Chemotherapy Potential, As Tubulin Polymerization And One-Carbon Metabolism Inhibitors For Cancer, Tasdique Quadery

Electronic Theses and Dissertations

This dissertation describes the design, synthesis, and biological evaluation of bicyclic fused pyrimidines as single agents with combination chemotherapy potential with both antiangiogenic and cytotoxic effects. The dissertation also discusses one-carbon metabolism inhibitors and tumor targeting proteolysis targeting chimeras (PROTACs).

In cancer chemotherapy, the two major limitations are the dose-limiting toxicities of clinically used agents and the development of resistance to the treatment. Combination chemotherapy with antiangiogenic agents and microtubule targeting agents has shown an advantage against both these drawbacks. Single agents with both antiangiogenic activity and cytotoxicity would afford a therapy that circumvents pharmacokinetic problems of multiple agents, avoid …

Decreasing Unintentional Pregnancies For Tennesseans, Paula M. Todd

Electronic Theses and Dissertations

In 2018, 49% of all pregnancies in the United States were unintended, with women with a lower- income status being five times more likely to experience an unplanned pregnancy. Tennessee has a high rate of unintended pregnancies, particularly among the uninsured, low-income, and rural teen populations; some 22% of these unintended pregnancies end in abortion. Oral or transdermal contraceptives that are affordable and accessible for women of childbearing age can reduce unintentional pregnancies. The addressed gap in clinical practice was that contraceptives are not currently available over the counter in Tennessee pharmacies without a prescription, which necessitates a costly medical …

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 …

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, …

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; …

Histone Deacetylases In Alcohol Associated Liver Disease., Srineil Bodduluri

Electronic Theses and Dissertations

Alcohol abuse is endemic worldwide and there is no FDA approved treatment for Alcohol-Associated Liver Disease (ALD). Many scholars have posited that targeting Histone Deacetylases (HDAC) may be therapeutic in ALD intervention. In this study, the changes in hepatic gene expression and immune phenotyping of mice undergoing chronic plus binge alcohol exposure was examined. The characterization of relative mRNA levels for all 18 HDAC were performed. Results showed decreased expression of the genes HDAC 1,7,9,10,11 and Sirtuin enzymes (SIRT) 3,4,5,7. Other pathways related to lipid metabolism as well as systemic inflammation and hepatic injury also exhibited significant changes. These altered …

Clinical Pharmacy Services And Medication Utilization In Hospice Care, Aishwarya Kulkarni

Electronic Theses and Dissertations

Background: As discussed within the guidelines from the American Society of Health-System Pharmacists (ASHP), pharmacists are an integral part of the hospice multidisciplinary team involved in optimizing the treatments. Methadone, a long-active opioid, is particularly useful in this population but may be clinically underutilized. Additionally, the cost share of medication utilization in hospice and palliative care is shifting towards hospice providers. The assessment of medication utilization and methadone use in this setting can help develop overall cost/clinical optimization strategies. Thus, there is a need to understand the use and expenditure of various medications and pharmacists' role in providing methadone …

The Role Of Src In Nsclc Cell And Lung Fibroblast Migration On 3d Cell-Derived Matrix., Austin M Krueger

Electronic Theses and Dissertations

Lung cancer is responsible for the most cancer deaths between males and females, with a 6% five-year survival rate. Cancer metastasis is one of the leading causes of lung cancer lethality. Our lab has developed a method to culture cells on cell-derived matrix (CDM) and study cell-ECM interactions. This study utilized multiple cell migration methods to investigate the migration of NSCLC cells and IMR90 lung fibroblasts, both together and independently, on 2D plastic and 3D CDM. Our results showed that inhibiting Src, a significant influencer of cell migration and member of integrin activation, blocked cancer cell migration on 2D and …

Pde4 Inhibition: A Novel Therapeutic Strategy In Liver Fibrosis., Mohamed Elnagdy

Electronic Theses and Dissertations

Background: Liver fibrosis is accumulation of extracellular matrix (ECM) proteins due to chronic liver injury. Chronic hepatic damage can occur due to multiple causes including, alcohol, non-alcoholic steatohepatitis and chronic viral hepatitis. Liver fibrosis is a critical problem worldwide due to the extremely high incidence of alcohol associated liver damage and chronic viral hepatitis. Moreover, there is no FDA approved therapy for liver fibrosis. Activation and transdifferentiation of quiecent hepatic stellate cells (HSCs) to myofibroblasts (MFBs) is the main event contributing to liver fibrosis. This process involves two phases, the initiation and the perpetuation phases. Hepatocyte injury and inflammatory response …

The Place And Role Of Pharmacy Benefit Management (Pbm) Companies In Us Healthcare System, George Mattis Ii

Electronic Theses and Dissertations

On average, prescription drugs cost US consumers more than any other developed country in the world. US drug makers claim that intermediaries in the prescription drug supply chain, companies called pharmacy benefit managers (PBM), are forcing them to increase their drug prices. PBMs counter that the discounts they receive from drug makers are channeled to insurers. This thesis will examine the role that PBMs play in the prescription drug supply chain and determine what effect they have on drug prices. This thesis will utilize a comparative static model, Structure, Conduct, Performance (SCP) framework to analyze the pharmaceutical manufacturing and the …

Nmr-Based Characterization Of A Glucan Isolated From Ganoderma Lucidum, Alysia Gonzales

Electronic Theses and Dissertations

Ganoderma lucidum is a polypore fungus commonly known as Lingzhi, Youngji or Reishi mushroom in East Asia. It is frequently marketed as an herbal supplement and often utilized as traditional Chinese medicine. Our research comprises the structural investigation of the principal polysaccharide from this fungus. After proper purification, the fungal glucan was subjected to multiple experiments of NMR spectroscopy, including 1D 1H and 13C, 2D; 1H-1H COSY, 1H-1H TOCSY, 1H-1H NOESY, 1H-13C HSQC, 1H-1H Phase Sensitive-TOCSY, and 1H-13C TOCSY-HSQC NMR spectra. Data has confirmed that this fungal polysaccharide contains residues of glucose (91.31%) as major, galactose (4.99%), and mannose (3.69%) …

Influence Of Rage Signaling On Cellular Communication In Diabetes-Mediated Vascular Calcification, Amber Michelle Kennon

Electronic Theses and Dissertations

Chronic hyperglycemia is one of the main characteristics of type 2 diabetes mellitus (T2DM). With the increased prevalence of T2DM, the risk of cardiovascular complications, including heart attack or stroke, is increased. Complications linked to the vasculature are increased vascular calcification (VC) or mineral deposition within the medial layer of conducting arteries. Under calcification conditions, vascular smooth muscle cells (VSMCs) undergo an osteogenic switch to an osteoblast-like cell and begin producing bone proteins. Chronic hyperglycemia can also result in increased extracellular matrix (ECM) synthesis, accumulation, and crosslinking. One of the cell types responsible for increased ECM synthesis are ‘activated’ fibroblasts …

Hot-Melt Extrusion Based Fused Deposition Modeling 3d Printing Of Atorvastatin Calcium Tablets: Impact Of Shape And Infill Density On Printability And Performance, Preethi Mandati

Electronic Theses and Dissertations

The main objective of the current research is to investigate the effect of shapes (heart and round shape tablets) and infill densities (50% and 100%) on drug release profiles of tablets prepared by hot melt extrusion (HME) coupled fused deposition modeling (FDM) technique. Two different commercial FDM 3D printers with different filament feeding mechanisms were evaluated for suitability of printing. Drug-loaded filaments of 1.5 mm and 2.5 mm diameters were extruded using Process 11 mm HME, using atorvastatin as a model drug and Kollicoat® IR, Kollidon® VA64, Kollidon®12PF, and Kolliphor® P407 as hydrophilic polymers. Filaments of Kollicoat® IR in combination …

Development Of Site - Specific Drug Delivery Systems Using Hot Melt Extrusion And Fused Deposition Modeling 3d Printing, Nagireddy Reddy Dumpa

Electronic Theses and Dissertations

Due to preferential site of drug absorption and the need for increased concentration of medication at the required tissues, dosage forms should be designed or formulated in such a way that medication is released at a specific site or after a specific time in the gastrointestinal tract (GIT). Knowledge of transit times of dosage forms in each part of GIT, by use of particular polymers or employing specific delivery systems such as floating systems, delivery of medication to specific sites in the GIT can be achieved. HME coupled FDM 3D printing has the capability to create customized dosage forms for …

Isolation Of Marker Compounds From Copaiba Essential Oil And Mimosa Pigra For Quality Evaluation Of Dietary Supplements, Mohammed Hawwal

Electronic Theses and Dissertations

Natural products have been used as a primary means of treating illness since ancient times, and they remain an important pool of U.S. FDA approved drugs. Approximately 33% of all current pharmaceutical medications discovered between 1981 and 2014 are either natural products or derived from natural products (Newman and Cragg 2016). The process of isolating specialized metabolites from medicinal plants has led to the development of particularly important medicines worldwide (Rakotomalala, Agard et al. 2013) such as Taxol® from Taxus brevifolia Nutt. (Taxaceae) and salicylic acid from the bark of Salix spp. This research is composed of five chapters; the …

Responses Of Myxobacteria To Plant-Related Chemosignals Suggests Their Roles In The Rhizobiome, Barbara Iyare Adaikpoh

Electronic Theses and Dissertations

In the rhizosphere, plants curate and maintain distinct rhizobiome, some of which serve as secondary defense mechanisms against pathogenic microorganisms. Additionally, in response to biotic stress, plants generate phytohormones which regulate signaling pathways to activate systemic resistance. These phytohormones contribute to the chemical space within the rhizosphere in addition to other low-molecular-weight metabolites used for cell-to-cell communication within species and across kingdoms. However, little is known about the influences of stress-related phytohormones on beneficial bacteria even though biocontrol strategies abundantly explore plant-beneficial microorganisms to manage pathogens in agricultural systems. Myxobacteria are competent predators of plant pathogens and have demonstrated responses …

An In-Depth Approach For Functional Oligosaccharide Analysis, Hao Liu

Electronic Theses and Dissertations

Heparin and heparan sulfate (Hp/HS) are linear complex glycosaminoglycans (GAGs), which are involved in diverse biological processes. Although Hp/HS GAGs influence numerous physiological and pathophysiological processes, their high degree of size polydispersity and sequence microheterogeneity make structure-function characterization challenging. In addition, it is hard to understand the structures that underlie any of the various functions with MS, because of the lability of the sulfate group during tandem mass spectrometry (MS/MS) analysis. The work presented here describes an in-depth approach for functional oligosaccharide characterization including chemical derivatization of Hp to inhibit COVID-19 infection, multi-dimensional liquid chromatography (LC) fractionation method, chemical derivatization …

Computational Modeling Of Non-Active Functional States Of The Cannabinoid Receptor 1 And Its Ligands, Ayooluwa Olufunmi Aderibigbe

Electronic Theses and Dissertations

The cannabinoid receptor 1 (CB1) is a class A G-protein coupled receptor that is implicated in a variety of physiological processes, such as energy homeostasis, appetite regulation, cognition and motor control, and mood regulation. CB1 is widely distributed throughout the body, but is mainly expressed in the brain. Molecules that reduce CB1 signaling exhibit anti-obesity properties due to their effect in reducing appetite and body weight gain. However, the consequence of reducing CB1 signaling in the CNS includes adverse neuropsychiatric effects such as depression and suicidal ideation. Two methods of scientific interest for developing CB1 antagonists as anti-obesity drugs are …

Towards A New Method Of Determining Protein Structure, Niloofar Abolhasani Khaje

Electronic Theses and Dissertations

Hydroxyl radical protein footprinting (HRPF) by fast photochemical oxidation of proteins (FPOP) is a mass spectrometry-based technique that measures the apparent protein oxidation rate by freely diffusing hydroxyl radicals at different regions in a protein, and correlates changes in this apparent rate with changes in the solvent accessibility of the protein target based on quantifying the amount of oxidation of different regions of a protein. While there have been many advancements in HRPF-FPOP, oxidation measurement still suffers from high variability between measurements. High variability reduces the power statistical power this technique even in the presence of radical dosimetry measurements and …

Development, Optimization, And In Vitro Characterization Of Different Anesthetic Wound Products, Alia Alshammari

Electronic Theses and Dissertations

ABSTRACTAcute and chronic wounds can be a significant source of pain. In the past, pain associated with chronic wounds has been perceived as an inevitable complication of wound care. Fortunately, recent approaches in wound care have developed strategies to prevent and reduce pain when carrying out wound care. Local anesthetics have been used to that end. Lidocaine is the most widely used topical anesthetic in wound care. However, literature on topical Lidocaine has focused almost exclusively on the clinical application on intact skin. This dissertation aims to advance our understanding of anesthetic wound product formulation and development. Anesthetic wound ointments …

Responses Of Predatory Myxobacteria To Prey Signaling Molecules & Features Of A Pseudomonas Prey Avoiding Predation, Shukria Akbar

Electronic Theses and Dissertations

Gram-negative unicellular myxobacteria, along with their multicellular lifestyle andbiologically active specialized metabolites, are known for the predatory interactions with Gram-negative/ Gram-positive bacteria and fungi. Although myxobacterial predation range have been exploited extensively, little is known about the prey associated molecules contributing to myxobacterial predator-prey dynamics. By employing transcriptomics and untargeted metabolomics approaches, we demonstrate two structurally distinct classes of signaling molecules from Gram-negative bacterial prey elicit significant omics responses from myxobacteria, Myxococcus xanthus and Cystobacter ferrugineus. An overlapping and general response to acylhomoserine lactones, whereas a distinctive response to a quinolone signaling molecule is observed from both myxobacteria. Similarly, by …

Rap1a Overlaps The Age/Rage Signaling Cascade In Type 2 Diabetes Mellitus, Stephanie Burr

Electronic Theses and Dissertations

Diabetic individuals have an increased risk for developing cardiovascular disease due to stiffening of the left ventricle, which is thought to occur, in part, by increased AGE/RAGE signaling. Advanced glycation end products (AGEs) accumulate within the body over time, and under hyperglycemic conditions, the formation and accumulation of AGEs is accelerated. AGEs exert their effect by binding to their receptor (RAGE) and can induce myofibroblast differentiation, oxidative stress, cell-extracellular matrix contraction, and cell migration. Previous findings from our lab have demonstrated that preventing the production of Rap1a, a Ras-like GTPase signaling protein, in cardiac fibroblasts will decrease type 2 diabetes …

Abuse Deterrent Formulation Using Hot Melt Extrusion Technology, Vishvesh Raje

Electronic Theses and Dissertations

The purpose of the current study was to formulate hot melt extruded (HME) abuse deterrent pellets of acetaminophen(APAP), a model drug with the aid of high molecular weight hydroxypropyl methylcellulose (HPMC 4M ) and gelling agents (starch, pectin and carbopol). The formulated HME pellets were assessed for their abuse-deterrence (AD) potential using Category- 1 laboratory in-vitro evaluation standards. The pellets were examined for the particle size reduction (PSR), extraction in small volume, syringeability, thermal manipulation and dissolution for evaluating the resilience of the AD properties. Though, most of the formulation showed complete particle size reduction after grinding, grounded pellets were …

Applications Of Hot-Melt Extrusion (Hme) Technology And Investigation Of A Screening Tool For Hme, Gauri Deepak Shadambikar

Electronic Theses and Dissertations

Hot-melt extrusion (HME), an adaptable technology, has established its position in manufacturing operations like amorphous solid dispersions, immediate and controlled oral formulations, implants and taste masked products. In recent years the industrial focus has shifted towards continuous manufacturing, thus HME is being explored for new applications. The aim of this research was to investigate the novel applications of HME by carrying out an in-depth study to understand the interaction between the process and product and to investigate a screening tool for its small-scale formulation and development.As HME consumes large amount of samples during the developmental phase, we investigated a screening …

Design And Synthesis Of Salvinorin-Based Compounds For The Opioid Receptors., Nicholas S. Akins

Electronic Theses and Dissertations

Opioid receptors (OR) are expressed throughout both the peripheral and central nervous system and play crucial roles in the modulation of antinociception, addiction, anxiety, and depression. Salvinorin A, the main isolate of the hallucinogenic plant Salvia divinorum, is one of the most potent naturally occurring kappa opioid receptor agonists. Salvinorin A possesses beneficial effects as a therapeutic in a variety of CNS disorders, but due to its strong hallucinating, anxiogenic effects, and short half-life(t1/2), it has never advanced to clinical trials. Instead, salvinorin A has been used as an important prototype for the development of related drug candidates. Our initial …

Metal-Organic Frameworks As Bacteria Mimicking Delivery Systems For Tuberculosis, Ailin Guo

Electronic Theses and Dissertations

Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis (M.tb), with an estimated 1.5 million deaths and 10 million infections each year. Although TB can be effectively treated with antibiotics, because of the complications and length of treatment, many people fail to complete the treatment which exacerbates the emergence of drug-resistant M. tb strains. The goal of this work is to develop biomimetic particles as host-directed therapy to target the infected macrophages. Two types of metal-organic frameworks (MOFs), MIL-100(Fe) and MIL-88A(Fe) were developed for bacteriamimicking particles. As a proof-of-concept, Mannose was selected as a ligand to target macrophages because …

Development Of Thiol Specific Fluorogenic Benzofurazan Derivatives For Live Cell Subcellular Organelle Thiol Imaging, Shenggang Wang

Electronic Theses and Dissertations

No abstract provided.

A Role For The Hydroxybenzoic Acid Metabolites Of Flavonoids And Aspirin In The Prevention Of Colorectal Cancer, Ranjini Sankaranarayanan

Electronic Theses and Dissertations

Flavonoids are a group of polyphenolic compounds, with established antioxidant properties, that are present ubiquitously in plants, fruits, and vegetables. Their universal presence in nature is evident by the fact that more than 4000 types of flavonoids have been identified till date. Additionally, they have also become part of the daily diet through consumption of fruits such as berries, grapes, pomegranate, and cherries, and vegetables such as onions, kale, and eggplant. High levels of flavonoids are also consumed through beverages such as tea and red wine. Numerous studies have demonstrated that a diet rich in flavonoids decreases the incidences of …

Development Of Ibuprofen Tablet With Polyethylene Oxide Using Fused Deposition Modeling (Fdm) 3d Printing Coupled With Hot-Melt Extrusion, Sooyeon Chung

Electronic Theses and Dissertations

Ibuprofen is known to plasticize several polymers used in the pharmaceutical field, and it is considered challenging to achieve an immediate release by fused deposition modeling (FDM). Therefore, this study aimed to print ibuprofen tablet with a focus on achieving immediate release. Polyethylene oxide (Polyox WSR N80) was used as a main matrix to form the ibuprofen filament due to its water-soluble property and manifesting suitable mechanical property even with the high drug loading (40% w/w). Several release modifiers such as Kollidon VA64, Kollidon 12PF, Kollicoat IR, Kollidon CL, and Mannitol were added separately to the formulation to enhance the …

Methylene Blue As Light And Reactive Oxygen Species Sensitive Ligand: Appicability In Hybrid Drug And Material Synthesis, Huy Dao

Electronic Theses and Dissertations

Methylene blue (MB) with a 10-N-carbamoyl linkage was discovered and developed as a multifunctional far-red (660 nm) photocleavable ligand capable of rendering a series of MB conjugated compounds with off-to-on fluorescence switch properties through the controlled release of MB. The released MB was successfully demonstrated to be an effective photosensitizer, imaging probe, and therapeutic agent. The complete release of MB was achieved with a cumulative light dose of 15 J/cm2. The photosensitivity was demonstrated to be dependent on the type of chemical bond at 10-N of the phenothiazine ring which links MB to a side group. Specifically, the urea bond-based …