Pharmacy and Pharmaceutical Sciences Commons^™

Compound 49b: A Novel Beta-Adrenergic Receptor Agonist In The Treatment Of Diabetic Retinopathy, Kimberly Williams-Guy

Theses and Dissertations (ETD)

Diabetic retinopathy is the leading cause of blindness in working Americans. While there are therapeutic regimens for the disease, more effective methods are needed. We have previously shown that a non-specific beta-adrenergic receptor agonist, isoproterenol, was effective in preventing functional and morphological changes associated with diabetic retinopathy in the rat. Isoproterenol also produced left ventricle remodeling suggesting it entered the systemic circulation. We therefore synthesized various novel beta-adrenergic receptor compounds and screened these compounds in vitro for their ability to reduce markers of inflammation and apoptosis. Of the various compounds tested, Compound 49b was able to reduce both inflammation and …

Development And Evaluation Of Nano‑Scale Systems For Targeted Delivery To Treat Liver Fibrosis, Ningning Yang

Theses and Dissertations (ETD)

Excessive deposition of ECM is the common characteristic of liver fibrosis. During hepatic fibrosis, various inflammatory cytokines are released and trigger the activation of quiescent HSCs. The activated HSCs play the major role in producing extra amount collagen. It becomes very crucial to focus on HSCs to find out therapeutics, such as inhibiting collagen synthesis, inhibiting activation to myofibroblasts, or controlling inflammation.

To control excessive collagen synthesis, one triplex forming oligonucleotides (TFO), was systemically administrated to prevent type I collagen mRNA transcription. To enhance circulation time and targeted delivery efficiency, TFO was conjugated to M6P‑HPMA and showed efficient targeted delivery …

Preclinical Pharmacology Of The Mdm2 Antagonist Nutlin-3a, Fan Zhang

Theses and Dissertations (ETD)

Nutlin-3a is an MDM2-p53 interaction antagonist that is under investigation in preclinical models for a variety of pediatric malignancies, including neuroblastoma, retinoblastoma, leukemia, and rhabdomyosarcoma. In the current research, we conducted preclinical pharmacology studies of nutlin-3a to evaluate the synergistic effect of the nutlin-3a and topotecan combination on neuroblastoma cell growth, to assess the effect of nutlin-3a on breast cancer resistance protein (BCRP), and to characterize the disposition of nutlin-3a in the mouse plasma and multiple tissues.

Activating the p53 pathway might offer a new therapy for neuroblastoma. In the first part of the study, we assessed the effect of …

Evaluating Consumer Preferences For Medicare Part D Using Conjoint Analysis, La'marcus Wingate

Theses and Dissertations (ETD)

The establishment of an outpatient prescription drug benefit in Medicare, Medicare Part D, was one of the more significant events in United States healthcare reform history. Many seniors have chosen to enroll in the plan as the program has an enrollment of over 27 million. One central premise of Medicare Part D was that the plan would be administered entirely through private insurance plans. Because many plans would be competing against one another for potential beneficiaries, it was expected that companies would offer seniors plans with high quality benefits at lower costs that would presumably be attractive to seniors. However, …

The Design And Synthesis Of Autotaxin Inhibitors And Analogs Of Lysophosphatidic Acid, Renuka Niranjan Gupte

Theses and Dissertations (ETD)

Lysophosphatidic acid (LPA) is a naturally occurring bioactive phospholipid. It has a wide array of biological effects like cell proliferation, survival, migration, apoptosis invasion, wound healing and angiogenesis. Autotaxin (ATX) was identified as an autocrine tumor cell motility factor from A2058 melanoma conditioned medium. ATX has lysophospholipase D enzyme activity and is responsible for the cleavage of lysophophatidylcholine (LPC) leading to the generation of LPA. Antagonists of Autotaxin would have a potential therapeutic application in cancer research. Chapter 1 is an introduction of LPA and autotaxin. It provides the background and significance of the research. Chapter 2 explores the synthesis …

Rna Interference For Improving The Outcome Of Islet Transplantation And Polymeric Micelle‑Based Nanomedicine For Cancer Therapy, Feng Li

Theses and Dissertations (ETD)

Ex vivo gene transfer has been used to improve the outcome of islet transplantation for treating type I diabetes. RNA interference is an effective approach for reducing gene expressions at the mRNA level. The application of RNA interference to improve the outcome of islet transplantation was reviewed in Chapter 2, where I summarized biological obstacles to islet transplantation, various types of RNAi techniques, combinatorial RNAi in islet transplantation, and different delivery strategies.

Upregulation of inducible nitric oxide synthase (iNOS) and subsequent product of radical nitric oxide (NO) impair islet β cell function. Therefore, we hypothesized that iNOS gene silencing could …

Pharmacokinetic And Pharmacodynamic Studies Of A Novel Spectinamide Series Of Antituberculosis Agents, V. N. R. Pavan Kumar Vaddady

Theses and Dissertations (ETD)

Spectinamides are novel amide derivatives of the antibiotic spectinomycin that have emerged as a new class of agents to treat tuberculosis. These agents showed potent in vitro activity against Mycobacterium tuberculosis (MTB) compared to spectinomycin and in a preliminary in vivo study in interferon gamma (IFN‑γ) knockout mice, spectinamide Lee1329 reduced the lung bacillary load of TB comparable to streptomycin. We hypothesized that the application of an iterative pharmacokinetics and pharmacodynamics (PK/PD) guided approach would facilitate the optimization of these lead compounds suitable for further development.

A series of in vitro experiments including parallel artificial membrane permeability assay (PAMPA), microsomal …

Analysis Of Out-Of-Pocket Expenditures Of Oral Oncologics For Tennessee Recipients Of Medicare Part D, Eve Carolyn Elias

Theses and Dissertations (ETD)

Background: There are few studies that examine patients' costs of oral oncology drugs from Medicare Part D plan providers. These drugs can impose a financial burden to beneficiaries, and, due to their cost, place beneficiaries in the coverage gap in a short period of time. In addition to examining costs, there is little published concerning the potential impact of drug utilization management techniques on access to these drugs in Medicare Part D plans. This study examined the roles of prior authorization, step-therapy, and placement of drugs in higher formulary tiers on patients' out-of-pocket costs, and access to therapy.

Methods …

A Novel Shear Thinning And Thixotropic Plga Micro Particulate Suspension System For Controlled Drug Delivery, Sonia Bedi

Theses and Dissertations (ETD)

Poly lactide‑co‑glycolide (PLGA) polymer has been the polymer of choice for many parenteral controlled drug release applications. This is mainly due to the inherent advantages of this polymer i.e. biodegradability, biocompatibility and non-toxic nature. The polymer, however, has a characteristic degradation pattern whereby the final erosion phase does not begin until the polymer reaches a certain molecular weight (MW) limit. After this, the accumulated acidic degradation byproducts initiate a bulk erosion phenomenon that leads to a disruption of the polymer matrix and release of the remaining drug in a short period of time. Furthermore, most of the delivery systems or …

Development And Evaluation Of Paclitaxel-Loaded Liposomal Formulations For Targeted Drug Delivery To Breast Cancer, Vinayagam Kannan

Theses and Dissertations (ETD)

The objective of this work was to develop and evaluate paclitaxel-loaded liposomal formulations for targeted drug delivery to breast cancer. The liposomal formulation was optimized to maximize drug loading and physical stability. Cholesterol and saturated lipid content showed a negative influence on paclitaxel loading. Short-term stability studies showed that optimum drug-lipid ratio is necessary for adequate physical stability. Biodistribution studies in mouse xenografts bearing MDA-MB-231 breast cancer using near infrared fluorescence imaging showed that the accumulation of tumor vasculature targeted long-circulating liposomes (LCL) in the tumor was significantly less than non-targeted LCL at 48 h. The accumulation of these liposomes …

Therapeutic Gene Delivery To Human Pancreatic Islets For Treatment Of Diabetes And The Effect Of Tfo On Liver Fibrosis Induced By Bile Duct Ligation, Ravikiran Panakanti

Theses and Dissertations (ETD)

Ex vivo gene transfer can improve the outcome of islet transplantation for treating Type I diabetes. Earlier we have shown co‑expression of human vascular endothelial growth factor (hVEGF) and human interleukin‑1 receptor antagonist (hI‑1Ra) after transfection of plasmid DNA encoding these two genes. Due to poor transfection efficiency of plasmid DNA and the better known islet transduction efficiency of adenoviral (Adv) vectors, in this study, we constructed Adv‑hVEGF‑hIL‑1Ra by cloning hVEGF and hIL‑1Ra coding sequences and polyA signal under separate cytomegalovirus (CMV) promoters in Adenoquick plasmid (Ad 13.1). There was dose and time dependent expression of these genes after transduction …

Development And Evaluation Of Therapeutics In The Setting Of Radiation Injury, Karin Emmons Thompson

Theses and Dissertations (ETD)

The possibility of an incident involving radiation exposure is at the forefront of public attention in the current global environment. With a greater number of entities possessing nuclear weapons and increased demand for nuclear power, the concern for uncontained exposure to radiation is increasing. In light of these developments, the need for treatments that may be easily stored and administered to large numbers of people who have been exposed to high doses of total body irradiation (TBI) is more urgent than ever before.

Our goal was to identify and develop novel, drug-like small molecules that would exhibit radiomitigating activity for …

Design Of Lipid And Polymeric Carriers For Nucleic Acid Delivery, Lin Zhu

Theses and Dissertations (ETD)

The objectives of the study were to investigate and develop lipid and polymeric carriers for nucleic acid delivery. These included: i) to develop novel cationic lipids for plasmid, oligonucleotide, and siRNA delivery; ii) to develop a novel polymeric delivery system, polyethylene glycol (PEG) based bio–conjugate, for oligonucleotide delivery; iii) to develop a novel bio–conjugate delivery system for siRNA delivery.

In Chapter 2, we discussed the barriers and strategies of nucleic acid delivery, as well as summarized the commonly used lipids, polymers, and the corresponding carriers in terms of their characteristics, applications, advantages and limitations.

Cationic lipids are most commonly used …

Synthesis Of Novel Cannabinoid Ligands And Their Use As Anti-Glioma And Anti-Inflammatory Agents, Steven Neal Gurley

Theses and Dissertations (ETD)

Following the discovery of the cannabinoid receptors, research in the field of cannabinoids has grown exponentially over the last two decades. Cannabinoids have been shown to have tremendous therapeutic potential in the treatment of several pathological conditions ranging from inflammation to asthma, multiple sclerosis, Parkinson’s disease, epilepsy, glaucoma, septic shock, hemorrhagic shock, and cancer. Our research has focused on two major conditions for which cannabinoids hold great promise for drug development, namely, cancer and inflammation.

Our focus in the field of cancer has been on the devastatingly lethal brain tumor glioblastoma multiforme. Due to the high expression of the CB2 …

Tdiscovery And Development Of Novel Therapeutic Agents For Advanced Melanoma, Zhao Wang

Theses and Dissertations (ETD)

Malignant melanoma is the most dangerous form of skin cancer and accounts for about 75% of skin cancer deaths. Once diagnosed at the metastatic stage, it has a very poor prognosis with a median survival rate of 6 months and a 5-year survival rate of less than 5%. In addition, melanoma has become an important public health hazard owing to its rising incidence, which has been well documented over the past 50 years. Currently there is no effective way to treat melanoma. It is highly resistant to existing chemotherapy, radiotherapy, and immunotherapy. Over the past 30 years, only two drugs …

Tamoxifen: Mechanisms Of Resistance, Cyrus Mccoy Adams

Theses and Dissertations (ETD)

The role of estrogen in breast cancer has been recognized for decades. The selective estrogen receptor modulator tamoxifen was the first targeted therapy for the treatment of breast cancer. It was also the first drug approved by the FDA for the reduction of breast cancer risk. While tamoxifen has extended the lives of countless patients with breast cancer, resistance to tamoxifen remains a significant clinical problem. Work over the last two decades has greatly enhanced our understanding of the molecular mechanisms by which breast cancer cells may become resistant to tamoxifen treatment. Here I review our current understanding of the …

The Design And Synthesis Of Novel Antimicrobial Agents For Use In The Battle Against Bacterial Resistance, Joshua Randal Brown

Theses and Dissertations (ETD)

There is an ever increasing need to develop new antimicrobial agents with novel mechanisms of action. These new agents will help to combat the steady rise of antibiotic-resistant bacteria which are becoming more and more difficult to treat due to the dwindling number of antibiotics available to treat such organisms. This body of work brings to light the many ways in which medicinal chemistry plays a vital role in the discovery of novel antimicrobial agents. Chapter 1 is an introduction into antimicrobial agents. It provides a brief history of the discovery of antimicrobial agents, and delves into reasons why new …

Transcriptional Regulation Of Azole Antifungal Resistance And Tolerance In Candida Glabrata, Kelly E. Caudle

Theses and Dissertations (ETD)

Azole antifungal resistance has emerged as a significant problem in the management of infections caused by fungi including Candida species. In recent years, Candida glabrata has become the second most common cause of mucosal and invasive fungal infections in humans second to Candida albicans. Not only are systemic C. glabrata infections characterized by high mortality rates, treatment failures to the azole class of antifungals, the most widely used antifungal for treatment of Candida infections, have been reported. Contributing to this problem, C. glabrata exhibits intrinsic reduced susceptibility to the azole antifungals, and the development of high-level azole resistance …

Population Pharmacokinetics Of Therapeutic Monoclonal Antibodies: Examples And Estimation Method Performance Differences, Nathanael Le Dirks

Theses and Dissertations (ETD)

Over the past two decades, there has been an increase in the research and development and therapeutic application of monoclonal antibodies (mAbs). An application of pharmacokinetic (PK) and pharmacodynamic concepts that has likely contributed to the success of the pre-clinical and clinical drug development of therapeutic mAbs is population PK, which attempts to quantify the typical disposition characteristics and sources of PK variability (such as between-subject, within-subject, and inter-occasion variability) within study populations. Population PK also attempts to identify and quantify the impact of covariates on systemic drug exposure and assess their potential implications for clinical dosing. The general theme …

Discovery Of Quinic Acid Derivatives As Oral Anti-Inflammatory Agents, Kui Zeng

Theses and Dissertations (ETD)

Quinic acid (QA) esters found in hot water extracts of Uncaria tomentosa (a.k.a. Cat’s claw) exert anti-inflammatory activity through mechanisms involving inhibition of the pro-inflammatory transcription factor nuclear factor kappa B (NF-κB). Herein, we described the synthesis and biological testing of novel QA derivatives. Inhibition of NF-κB was assessed using A549 (Type II alveolar epithelial-like) cells that stably express a secreted alkaline phosphatase (SEAP) reporter driven by an NF-κB response element. A549- NF-κB cells were stimulated with TNF-α (10 ng/mL) in the presence or absence of QA derivative for 18 hours followed by measurement of SEAP activity. Amide substitution at …

Application Of Different Bioanalytical Workflows For Proteomics Of Prostate Cancer, Li Chen

Theses and Dissertations (ETD)

In the current dissertation, we focused on the development and application of multiple mass spectrometry-based bioanalytical platforms for phosphoproteomic characterization in cell culture and clinical specimens of prostate cancer; and on the application of optimized methods to analysis of differential protein expression to reveal molecular mechanism of drug action in animal model of prostate cancer.

Characterization of the phosphoproteome in prostate cancer

Our study in phosphoprotein signatures on a large scale in prostate cancer focused on the LNCaP human prostate cancer cell line, and on human prostate cancer tissue.

For the LNCaP prostate cancer cell line, we applied a combination …

Preferences And Willingness To Pay For Osteoarthritis Treatments Among The Medicare Population, Meghan Alexis Hufstader

Theses and Dissertations (ETD)

The design of this study is a non-random cross sectional survey to determine Medicare beneficiaries’ preferences and willingness to pay for osteoarthritis (OA) treatments. The population of interest in this study is the Medicare eligible (over age 65) population in Memphis, TN, and surrounding cities. Data were collected at Senior Centers and one internal medicine practice. The sample size was 181.

Choice-based conjoint analysis technique was utilized. The preferences and willingness to pay were determined using choice-based conjoint analysis, advanced design module with a dual-response none option. Choice-based conjoint analysis uses computer guided surveys to elicit patient preference for a …

A Pharmacokinetics And Pharmacodynamics (Pk/Pd) Guided Approach To Lead Optimization Of Nitrofuranylamide Anti-Tuberculosis Agents, Nageshwar Rao Budha

Theses and Dissertations (ETD)

Currently used treatment strategies for tuberculosis (TB) involve administration of multiple drug combinations for a minimum of 6-9 months. However, these prolonged regimens do not always achieve sterilization, as evidenced by post-therapy relapse in a subgroup of treated individuals. In an effort to develop novel therapeutic agents for TB a new class of chemical agents, nitrofuranylamides, is being developed at the University of Tennessee Health Science Center. We hypothesized that the application of an iterative pharmacokinetics and pharmacodynamics (PK/PD) guided approach would facilitate the optimization of nitrofuranylamide lead compounds suitable for further development.

First, we examined the biopharmaceutic properties and …

Targeted Delivery Of Surface Modified Nanoparticles: Modulation Of Inflammation For Acute Lung Injury, Hari R. Desu

Theses and Dissertations (ETD)

The objective of the study is to demonstrate alleviation of pulmonary inflammation associated with acute lung injury (ALI) using novel surface modified nanoparticles. ALI is characterized by three main pathological events: I) pulmonary edema, II) excessive pro-inflammatory cytokines and chemokines production from alveolar epithelial and endothelial cells and III) leukocyte migration from blood circulation into alveoli. Currently, there is no FDA approved pharmacological treatment available except the supportive mechanical ventilation therapy. Numerous clinical trials involving pharmacological therapies aimed at different pathological targets turned unsuccessful. National Institute of Heart Lung and Blood Institute (NHLBI) cited underappreciation of drug delivery systems as …

The Use Of Spectroscopic Techniques In The Characterization Of Mycobacterial Metabolites, Engy Abdelhameed Mahrous

Theses and Dissertations (ETD)

The mycobacterial cell wall metabolites have always imposed great challenges to researchers due to their unusual complexity and structural diversity. A lot of research efforts have been directed towards the evaluation of these metabolites and the role they play in the pathogenesis and virulence of different serious human pathogens including Mycobacterium tuberculosis the causative agent of tuberculosis (TB). In the genomic era, it is crucial to develop new methodologies to analyze these components from a global perspective in a comprehensive and well-validated manner.

Towards this end, we developed a rapid NMR-based approach to produce metabolic profiles in the form of …

Structure-Activity Relationship And Mechanistic Studies On The Chemopreventive Activity Of Dipyridamole And Its Analogues, Ja’Wanda Shavon Grant

Theses and Dissertations (ETD)

There is an escalating demand in the area of cancer prevention and control for the development of novel agents and molecular targets that have potential to reduce the incidence of cancer. In this study, the JB6 mouse epidermal cell-culture based transformation model was used in efforts to identify novel chemopreventive agents and targets. The nucleoside transport inhibitor dipyridamole (DPM) showed potent chemopreventive activity against JB6 P⁺cells (tumor promotion sensitive). To probe the effects of DPM structural features on its antitumor promotion activity, the soft-agar colony forming efficiency assay was used to screen an in-house library of …

Synthesis And Evaluation Of Tetramic Acids As Antimicrobial Agents, Jason B. Wilson

Theses and Dissertations (ETD)

As bacterial infectious diseases are a major cause of morbity and mortality throughout the world, and many causative organisms are resistant to currently available antibiotics, the motivation for the development of new drugs is readily apparent. A number of natural products exhibiting antimicrobial activity possess a tetramic acid (2,4-pyrrolidinedione) functional group. As their antibacterial mechanism of action is different from that of many of the currently available antibiotics, these compounds have potential to serve as a basis for a pharmacophore in synthetic compounds. However, toxicity to eukaryotic cells is frequently a problem with currently known tetramic acids. The purpose of …

Structure- And Ligand-Based Design Of Novel Antimicrobial Agents, Kirk Edward Hevener

Theses and Dissertations (ETD)

The use of computer based techniques in the design of novel therapeutic agents is a rapidly emerging field. Although the drug-design techniques utilized by Computational Medicinal Chemists vary greatly, they can roughly be classified into structure-based and ligand-based approaches. Structure-based methods utilize a solved structure of the design target, protein or DNA, usually obtained by X-ray or NMR methods to design or improve compounds with activity against the target. Ligand-based methods use active compounds with known affinity for a target that may yet be unresolved. These methods include Pharmacophore-based searching for novel active compounds or Quantitative Structure-Activity Relationship (QSAR) studies. …

Controlled Release Of Insulin And Modified Insulin From A Novel Injectable Biodegradable Gel, Om Anand

Theses and Dissertations (ETD)

The objective of the study was to develop a controlled release dosage form of
insulin, which can provide basal concentrations of insulin in diabetic rats for 1 to 2 weeks after a single subcutaneous injection.
A biodegradable injectable drug delivery gel was prepared by dissolving a
biodegradable polymer, polylactic-co-glycolic acid (PLGA), in biocompatible
plasticizer(s), triethyl citrate (TEC) and/or acetyl triethyl citrate (ATEC). Insulin was
then loaded into the blank gel to form an insulin suspension in the polymer solution.
After the insulin-loaded gel was injected subcutaneously, the plasticizer(s) dissolved in the aqueous media and were gradually taken away from the …

Flavonoids And Related Compounds As Nucleoside Transporter Inhibitors, Surekha Ravaji Pimple

Theses and Dissertations (ETD)

Mammalian nucleoside transporters can be classified into two main categories, namely, equilibrative nucleoside transporters (ENTs) and concentrative nucleoside transporters (CNTs). ENTs are ubiquitous, and mediate sodium-independent bi-directional facilitated diffusion nucleoside transport processes. CNTs on the other hand, are secondary active unidirectional transporters that are sodium-dependent. Both the equilibrative and the concentrative nucleoside transporters have several family members which are ENT1 to ENT4 and CNT1 to CNT6. Over the past two decades, important advances in the understanding of nucleoside transporter functions have been made. Identification and molecular cloning of the ENT and CNT families from mammals and protozoan parasites have provided …