Pharmacy and Pharmaceutical Sciences Commons^™

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 …

Design, Synthesis, And Evaluation Of Small Molecules In The Discovery Of Novel Antimicrobial Agents, Kimberly D. Grimes

Theses and Dissertations (ETD)

The increasing prevalence of antibiotic-resistant bacteria, including Mycobacterium tuberculosis, Streptococcus pneumoniae, Staphylococcus aureus, and Enterococcus faecalis, pushes us to discover new antibacterial agents to maintain adequate patient coverage. This body of work highlights the use of medicinal chemistry methodologies that encompass cross-disciplinary fields of study. Chapter 1 gives an introduction to the antibacterial drug targets, resistance, and how scientists are working to overcome obstacles encountered with drug-resistant bacteria. It also details modern medicinal chemistry applications in antimicrobial drug discovery. Chapter 2 details the use of a structure-guided library approach to drug design, in which large virtual libraries against the target …

Why Pharmacists Choose To Seek Or Not Seek Board Certification In Pharmacy Practice: A Comparison Of Motivation And Motivating Factors, Mark Tankersley

Theses and Dissertations (ETD)

The stated mission of the Board of Pharmaceutical Specialties (BPS) with regard to specialization is, via board certification, to recognize specialty areas, define skill standards for those specialty areas, and evaluate the knowledge and skills of individual Pharmacy specialists. The perceived or real benefits to the pharmacist of pursuing board certification are unknown. These benefits can be evaluated by separating into values (valences) and instrumentalities, the latter of which is the perceived or known probability that a performance will lead to an outcome. The primary purpose of this study was to determine the differences in values and instrumentalities perceived by …

Synthesis Of Novel Sulfonamide-Based Calpain Inhibitors And Their Potential As Anti-Tumor Agents, Jin Xu

Theses and Dissertations (ETD)

Calpain is a class of intracellular cytoplasmic cysteine proteases.1 The enzyme participates in different intracellular signaling pathways that are mediated by Ca2+.2 The two major isoforms of calpain universally distributed in most mammalian tissues are calpain 1 (µ-calpain) and calpain 2 (m-calpain). The exact in vivo function of the enzyme is not clear, but calpain has been implicated in a variety of physiological and pathological conditions,3 such as cancer, stroke, cardiac ischaemia, muscular dystrophy, cataract and Alzheimer’s disease. Calpain inhibitors are therefore of interest as therapeutic agents and as biomedical tools.

Several potent calpain inhibitors isolated from natural sources as …

Development And Evaluation Of Brain Tumor Targeted Liposome Delivery System For Paclitaxel, Murali Krishna Divi

Theses and Dissertations (ETD)

Primary brain tumors are a relatively common cause of cancer-related deaths. High-grade gliomas are the most common type of primary brain cancer, and the affected patients have a median survival of less than 1 year. Almost all malignant gliomas are incurable with the present standards of healthcare. Currently accepted therapeutic adjuvants to surgery, such as radiotherapy and chemotherapy, provide only a minor improvement in the disease course and life expectancy for patients diagnosed with malignant gliomas. Often, chemotherapy has failed to make any significant impact on the prognosis of disease because of significant local and systemic toxicity, problems with transport …

Age-Associated Hepatic Drug Transporter Expression And Its Implications For Pediatric Pharmacotherapyflexibility Affect Dna Topoisomerase I Function, Lisa Tang

Theses and Dissertations (ETD)

Members of the ATP-binding cassette (ABC) family of drug transporter proteins translocate various endogenous and exogenous substrates across intra- and extracellular membranes. Two specific ABC transporters, the multidrug resistance 1/P-glycoprotein (MDR1/P-gp) and the multidrug resistance protein 2 (MRP2), serve as major hepatic transporters that mediate the biliary excretion of various organic anions and cations along with glutathione-, glucuronate-, or sulfate-conjugates of several drug substrates. However, very little is known about the expression of these transporters in the early infant and childhood ages of human development. We, therefore, characterized the ontogeny of these transporters by measuring their gene and protein expression. …

The Role Of Multi-Drug Resistance Associated Protein 4 And P-Glycoprotein In Resistance Of Neuroblastoma To Topotecan And Irinotecan, Patricia Kellie Turner

Theses and Dissertations (ETD)

High-risk neuroblastoma presents a significant therapeutic challenge because the 5-year survival rate remains less than 30% despite the use of surgery, multi-agent chemotherapy, radiation, and autologous bone marrow transplant. Novel therapeutic modalities are under development. The camptothecin analogs topotecan and irinotecan have been identified as successful cytotoxic agents. For topotecan, pharmacokinetically guided dosing to achieve a systemic exposure associated with preclinical anti-tumor activity in neuroblastoma xenograft models is feasible and has elicited favorable responses in children with high-risk neuroblastoma. However, some children with high-risk disease did not respond to the putatively effective topotecan systemic exposure. These children represent a subset …

Role Of Medial Prefrontal Cortical Group Ii Metabotropic Glutamate Receptor In The Development Of Cocaine Sensitization, Xiaohu Xie

Theses and Dissertations (ETD)

The current studies examined the role of medial prefrontal cortical (mPFC) group II metabotropic glutamate receptors (mGluR_2/3) in the development of cocaine sensitization. Initial studies demonstrated that intra-mPFC injection of the mGluR_2/3 receptor agonist, APDC, dose-dependently reduced acute behavioral response to cocaine (0.015-15 nmol/side with significant effects starting at 1.5nmol/side). The effects of APDC were prevented by intra-mPFC co-injections of an mGluR_2/3 antagonist, LY341495 (1.5 nmol/side). Repeated intra-mPFC APDC (1.5 nmol/side) injections also prevented the initiation of behavioral and neurochemical sensitization, which is defined as enhanced nucleus accumbens (NAc) dopamine response to cocaine. Once sensitization was …

Novel Carbopol-Wax Blends For Controlled Release Oral Dosage Forms, Natarajansoundarapandian Mariageraldrajan

Theses and Dissertations (ETD)

Carbopol is crosslinked acrylic acid. Carbopol can be used in developing formulations for transdermal, oral, rectal use. It is forms strong gel in low concentration. Therefore, it can be used in low concentration in developing controlled release formulations. This increases the cost effectiveness and number of formulation options. In spite of its effectiveness, carbopol is one of the most efficient however underutilized polymer in oral controlled drug delivery system development. This is attributed to the difficulty in processing the carbopol. Carbopol has poor flow characteristics and stickiness. Objective of our research is to eliminate processing difficulties of carbopol using hot …

Fatty Liver And Metabolism Of Xenobiotics In The Rat, Joyce D. Stone

Theses and Dissertations (ETD)

No abstract provided.