Medicine and Health Sciences Commons^™

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 …

Bevacizumab Effect On Topotecan Pharmacokinetics In A Murine Orthotopic Rhabdomyosarcoma Xenograft Model, Zaifang Huang

Theses and Dissertations (ETD)

Increasing evidence suggests that inhibition of vascular endothelial growth factor (VEGF) can transiently normalize tumor vasculature, thereby improving delivery of systemic chemotherapy. Bevacizumab (BEV), an anti-VEGF antibody, has been shown to transiently normalize tumor vasculature by increasing tumor vessel maturity, decreasing tumor vessel permeability, and increasing tumor oxygenation in an Rh30 orthotopic rhabdomyosarcoma xenograft model. However, the effects of BEV on the pharmacokinetics of TPT and the antitumor activity of TPT have not been evaluated. This study aimed to investigate the effect of BEV on TPT systemic and tumoral pharmacokinetics and to determine how these changes affect the efficacy of …

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 …

Synthesis And Computational Studies On Hiv-1 Integrase Inhibitors, Horrick Sharma

Theses and Dissertations (ETD)

HIV-1 integrase (IN) is essential for viral replication and offers a promising target for the development of anti-retroviral drugs. Two decades of extensive research has lead to the recent approval of raltegravir as the first IN inhibitor. Advancement of drug candidate elvitegravir, which is currently in Phase III clinical trial, has furthermore accelerated efforts against this potential target for combating HIV. However, the emergence of resistance against raltegravir and elvitegravir demands exploration of novel chemical scaffolds that could circumvent resistance against currently used HIV-1 IN inhibitors. With the goal of discovering new agents targeting HIV, a novel structural class of …

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 …

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 …

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, …

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 …

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 …

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 …