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 …

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 …

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 …

Transdermal And Transbuccal Delivery Of Lidocaine And Nicotine : Combined Effects Of Iontophoresis And Chemical Enhancers, Ran Wei

Theses

This study focused on the effects of iontophoresis and chemical enhancers on drug release. The transport of Lidocaine HCl (LHCl) and Nicotine Hydrogen Tartrate (NHT) through the skin and mucosa was evaluated for potential clinical applications. These two potential delivery routes have the advantage of avoiding first-pass effect. Samples were pretreated with enhancer solutions for one hour before the experiments. Passive or 0.3 mA iontophoresis-assisted drug diffusion was conducted for 8 hours to monitor the cumulative amount of drug released. Graphical methods and mathematical optimization techniques were implemented to analyze the data. The effects of chemical enhancers on the delivery …

Dissolution Testing Of Prednisone And Salicylic Acid Calibrator Tablets At Different Tablet Locations, Anandhavalavan Arulmozhi

Theses

Dissolution testing is routinely carried out in the pharmaceutical industry to determine the rate of dissolution of solid dosage forms. This test is one of the several tests that pharmaceutical companies typically conduct on oral dosage formulations (e.g., tablets) to determine compliance. The USP Dissolution Testing Apparatus 2 is the most common of the apparatuses listed in the USP. However, it has been shown previously that the dissolution profile of a tablet undergoing dissolution in the USP Dissolution Apparatus 2 can be affected by the tablet location in the apparatus.

In this work, the dissolution rates of both non-disintegrating tablets …

Dissolution Of Disintegrating Solid Dosage Forms In A Modified Dissolution Testing Apparatus 2, Shrutiben Rameshbhai Parekh

Theses

Dissolution tests are routinely carried out in the pharmaceutical industry to determine the dissolution rate of solid dosage forms. Dissolution testing serves as a surrogate for drug bioavailability through in vitro–in vivo correlation (IVIVR), and it additionally helps in guiding the development of new formulations and in assessing lot-to-lot consistency, thus ensuring product quality. The United States Pharmacopoeia (USP) Dissolution Testing Apparatus 2 is the device most commonly used for this purpose. Despite its widespread use, dissolution testing using this apparatus remains susceptible to significant error and test failures. There is documented evidence that this apparatus is sensitive to several …

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 …