Pharmacy and Pharmaceutical Sciences Commons^™

Novel Paclitaxel Nanoparticles For Enhanced Therapeutic Effects In Breast Cancer, Pallabita Chowdhury

Theses and Dissertations (ETD)

Drug delivery to triple negative breast cancer (TNBC) remains a formidable challenge. Given the lack of expressions of estrogen (ER), progesterone (PR) and human epidermal growth factor receptor (HER2), there is no specific prognostic marker for targeting this aggressive cancer. In spite of rapid advancement in breast cancer with agents such as Trastuzumab in HER2 positive, chemotherapy with cytotoxic agents remains the mainstay treatment for TNBC. Although these cytotoxic agents are potent in managing the tumor progression, yet they pose adverse effects on healthy tissues. Paclitaxel (PTX) has been used as a gold standard chemotherapeutic agent for breast, ovarian, pancreatic …

Muc13 Modulated Nanomechanical And Biophysical Responses In Pancreatic Cancer Cells, Andrew E. Massey

Theses and Dissertations (ETD)

Pancreatic adenocarcinoma is one of the deadliest forms of cancer. Even with recent advances in diagnostic tools, chemotherapeutic regimens, and biomarkers for earlier detection, it still has dismal survival rates. Part of the reason for this is the inherent difficulty in detecting and treating this disease. Recent findings suggest that the altered expression of mucins, including MUC13, may be useful molecular signatures for early disease diagnosis, chemotherapy response and predicting patient survival. MUC13, a recently identified transmembrane glycoprotein, is normally associated with forming a protective barrier on epithelial tissues. However, its overexpression/aberrant subcellular localization has been associated with cancer, disease …

A Novel Elvitegravir Nanoformulation For Drug Delivery Across The Blood-Brain Barrier To Suppress Hiv-1 In Macrophages And Microglia, Yuqing Gong

Theses and Dissertations (ETD)

Over the last two decades, the use of antiretroviral therapy (ART) has remarkably decreased the morbidity associated with HIV-1 infection. However, the prevalence of HIV-1-associated neurocognitive disorders (HAND) is still increasing. The appearance and persistence of HAND are partially due to the entry of HIV-1-infected monocytes into the brain. Within the central nervous system (CNS), HIV-1-infected macrophages and microglia serve as the major viral reservoirs and provide active viral replication even when systemic viral suppression has been achieved by ART. Efficient viral suppression of CNS macrophages and microglia is important for an effective HIV-1 treatment in the brain. The primary …

Tobacco/Hiv-1-Induced Myeloid Cell-Derived Extracellular Vesicles In Hiv-1 Pathogenesis, Sanjana Haque

Theses and Dissertations (ETD)

Introduction. Smoking, which is highly prevalent in people living with HIV/AIDS, has been shown to exacerbate HIV-1 replication, in part via cytochrome P450 (CYP)-induced oxidative stress. CYP enzymes metabolize cigarette smoke condensate (CSC), causing oxidative stress and cytotoxicity. Our previous studies have demonstrated that CSC and specific CSC constituents, benzo(a)pyrene and nicotine, potentially induce CYPs, resulting in higher oxidative stress and subsequent exacerbation of HIV-1 replication in monocytes and macrophages. However, the exact mechanism behind tobacco-induced, oxidative stress-mediated enhancement of HIV-1 replication is still poorly understood. Extracellular vesicles (EVs) have recently gained attention for their unique nature as intercellular messengers …

The Discovery And Development Of Thienopyrimidines As Inhibitors Of Helicobacter Pylori, Alex Kagabo Mugengana

Theses and Dissertations (ETD)

The rate of successful treatment for Helicobacter pylori infections, with the clarithromycin triple therapy, is only 75%. The triple therapy, which consists of a proton pump inhibitor and two broad-spectrum antibiotics such as clarithromycin and amoxicillin, is becoming less effective due to the rise of strains with resistance against these antibiotics. In the search for narrow spectrum drugs for the treatment of H. pylori infections, a high-throughput screen was performed to identify selective compounds against H. pylori. This screen revealed two selective and structurally related thienopyrimidines. Structure-activity relationship of the thienopyrimidines against H. pylori was examined through the synthesis of …

An Update On Pharmaceutical Strategies For Oral Delivery Of Therapeutic Peptides And Proteins, Nirnoy Dan

Theses and Dissertations (ETD)

Peptides and proteins are imperative for the human body and play crucial roles in governing various bio-chemical processes. Recent advances in molecular biology and biochemistry helped in understanding the role of these endogenous macromolecules in different pathological and disease conditions. Currently, small molecule drugs (< 900dalton) in comparison to the therapeutic peptides and proteins-based drugs (TPP) dominate pharmaceutical market. However, the game is changing with the recent advances of biotechnological tools like recombinant DNA technology, solid phase protein synthesis etc., which enabled large-scale production of therapeutic peptides and proteins. The Success of Human Insulin, the first FDA approved commercial recombinant protein based therapeutic in 1982, revolutionized the field of TPPs. The number of FDA approved TPPs reached about to ~239 in 2017 compared to where it was only ~130 in 2008. Rapid progress in this sector can be attributed to several advantages of proteins and peptides over small molecule drugs both financially and clinically. From a clinical perspective, proteins and peptides are inherently more specific to the target site than the small molecules drugs, which lead to less interferences with normal biological system of the patient and caused minimal off-target side effects. A handful of proteins which are used for different clinical complications are less immunogenic because they are produced in the body naturally. Furthermore, proteins and peptides also take part in several complex and complicated biological processes, which is difficult to be to be mimicked by the small molecule drugs. From a financial standpoint, median total pre-market development times were shorter for biologics (10.6 years) than the small molecules drugs (12.6 years) estimated using Merck Index. In 2009, US Congress passed the Biologics Price Competition and Innovation Act (BPCIA) which gave new biologics 12 years of guaranteed exclusivity. The most commonly utilized routes for administering TPPs are I.V, I.P or I.M injections, which largely suffer from patient compliances. There are ~350 TPPs under clinical development and among them only 2 are given orally which is Interferon-α and Human growth hormone. Currently, most efforts in both industry and academia are centered around enhancing bioavailability of orally administered TPPs which typically are less than 1%. Oral administration is the non-invasive, most preferred route of drug administration for the patients. Furthermore, oral dosage forms are cheaper to manufacture as well as to administer, because they do not need to be produced under sterile conditions or administered in clinics. However, unfavorable physicochemical characteristics of TPPs like high molecular weight, hydrophilicity, poor stability in the physiological conditions, short biological half-life, low permeability through the epithelial barrier in the small intestine put up a massive barrier in the development of orally available dosage forms of TPPs. In this review, we will discuss the challenges associated with oral delivery of TPPs and the ongoing efforts to solve them.

Investigation Of Narrow Spectrum Targets In Antibacterial Drug Discovery, Jesse Jones

Theses and Dissertations (ETD)

Background: Significant concerns are associated with the use of broad-spectrum antibacterial agents, including collateral eradication of beneficial bacteria from the human microbiome, the onset of antibacterial-associated infections, and continued emergence of antibacterial drug resistance. As such, a critical need for novel and selective antibacterial targets exists. The investigation of two such targets, each pertaining to the highly concerning infections caused by streptococcal species and Clostridioides difficile, are presented herein. Bacterial topoisomerase I represents a potentially promising narrow-spectrum target as studies have arisen demonstrating its essentiality in bacterial species lacking the only other type IA topoisomerase (topoisomerase III). Additionally, recent studies …

Identification Of Novel Cyp2e1 Inhibitor To Investigate Cellular And Exosomal Cyp2e1-Mediated Toxicity, Mohammad Arifur Rahman

Theses and Dissertations (ETD)

Cytochrome P450 2E1 (CYP2E1)-mediated hepatic and extra-hepatic toxicity is of significant clinical importance. Diallyl sulfide (DAS) has been shown to prevent xenobiotics such as alcohol- (ALC/ETH), acetaminophen- (APAP) induced toxicity and disease (e.g. HIV-1) pathogenesis. DAS imparts its beneficial effect by inhibiting CYP2E1-mediated metabolism of xenobiotics, especially at high concentration. However, DAS also causes toxicity at relatively high dosages and with long exposure times. The objective of the first project was to find potent DAS analogs which can replace DAS as a research tool or as potential adjuvant therapy in CYP2E1-mediated pathologies.

Injectable Systems For Long-Lasting Insulin Therapy, Kumar Kulldeep Niloy

Theses and Dissertations (ETD)

Diabetes mellitus is one of the major global health problems and the prevalence rate is ever increasing reaching to 48% increase by the year of 2040 causing significant economic burdens. Insulin therapy has been the mainstay of diabetes treatment since its discovery in 1922. However, insulin is an unstable peptide with a half-life of only 4-6 min which poses significant challenge in prolonging duration of action of insulin. Nevertheless, the advances in recombinant DNA technology and protein engineering have enabled the development of several long-acting insulin analogue products which show duration of action up to 42 h. However, these insulin …

Genetic Exploration Of Hereditary Immune Diseases, Cheng Tian

Theses and Dissertations (ETD)

An autoimmune disease is a condition arising from an abnormal immune response to a normal body part. There are at least 80 types of autoimmune diseases, rheumatoid arthritis and systemic sclerosis are two of them. My study focuses on these two diseases. Our hypothesis is that mutated genes lead to autoimmune diseases that cause the immune system to attack the human body. The mutated genes cause the gene expression levels to change which fail to properly regulate the body's functions, resulting in immune system diseases. I used existing mouse models to improve the understanding of these two diseases.

The first …

Development Of Multiple Microemulsion Eye Drops For Sustained Release Of New Glaucoma Drug, Doaa Nabih Ahmed Maria

Theses and Dissertations (ETD)

Persistent or repeated elevation of intraocular pressure (IOP) is a primary risk factor of visual field loss in glaucoma, therefore IOP reduction is the first-line therapeutic option in the disease management. Unfortunately, the current therapies are associated with a lot of deficiencies including several daily dosing, reduced efficacy and systemic side effects all of which resulted in poor patient compliance. Previously we have identified Calcium voltage-gated channel auxiliary subunit Alpha2delta 1 gene (Cacna2d1) as a novel modulator of IOP and confirmed that pregabalin targeted CACNA2D1 in eye tissues (ciliary body and trabecular meshwork) to lower IOP in a …

Understanding The Impact Of Bcrp And Pgp Efflux Transporters On The Disposition Of Their Endogenous, Xenobiotic And Dietary Substrates, Samit Ganguly

Theses and Dissertations (ETD)

Breast Cancer Resistant Protein (BCRP) and P-glycoprotein (PGP) are membrane-bound efflux transporters that transport multiple chemical classes of compounds and act as barriers to tissue permeability, thereby regulating tissue exposure of their substrates. The role of these transporters in therapeutic resistance of their xenobiotic substrates due to their expression and efflux function at target organs/tissues, especially in brain and intestine, is well established, which has fueled investigation toward identification of their inhibitors. Multiple clinically used drugs and dietary chemicals have been reported to inhibit these transporters and potentially increase the exposure of concomitantly administered BCRP and/or PGP substrates, which might …

Novel Determinants That Influence Azole Susceptibility In Candida Glabrata And Candida Albicans, Sarah Garland Whaley

Theses and Dissertations (ETD)

Despite the scientific and medical communities’ best efforts, the incidence of fungal infections in susceptible populations continues to rise. The most common cause of these opportunistic fungal infections is Candida. In fact, Candida is the fourth most common pathogen associated with nosocomial blood stream infections. Reported mortality rates for patients with candidemia vary, but have not decreased in the past fifteen years and are reported to be as high as 50%. Candida glabrata, second only to Candida albicans among Candida infections, expresses high rates of resistance to treatment with arguably the best class of currently available antifungals - …

Rheological Studies Of Injectable Thermoresponsive Biodegradable Hydrogels And Porcine Ocular Tissues, Chandana Reddy Damera

Theses and Dissertations (ETD)

This research has evaluated the rheological properties of two types of materials which include (i) semi-synthetic polymer-based injectable hydrogels [P(NIPAAm-co-DEX-Lactate HEMA) and P(NIPAAm-co-HA-AEMA)], and (ii) biological tissues (porcine ocular tissues).

A series of thermoresponsive and biodegradable in situ hydrogel based on N-isopropyacrylamide (NIPAAm) monomer and hydrolytically degradable oligolactate Dextran-lactate-HEMA or Hyaluronic acid (HA)-AEMA macromer were investigated as encapsulation matrices (scaffolds) for DPSCs/ADSCs and assess their applicability in dental/retinal tissue engineering. The rheological properties of the hydrogels were strongly dependent on the reaction conditions and composition of the hydrogels. Both the hydrogels exhibited linear viscoelasticity, and the values of storage moludus …

Somatic Mutation Detection In Leukemia-Derived Circulating Dna: Utility In Monitoring Clonal Dynamics And Disease Response In Pediatric Acute Lymphoblastic Leukemia, Sarah Hisham Abdelaziz Youssef

Theses and Dissertations (ETD)

Despite the improved outcome associated with current treatment strategies ofpediatric acute lymphoblastic leukemia (ALL), relapse still represents a major challenge. Pediatric ALL demonstrates branched evolution in response to selective pressure exerted by therapy; relapse founder clones emerge from pre-leukemic clones or minor subclones present at diagnosis. It is hence crucial to develop biomarkers capable of tracking subclones throughout therapy. Current practices for monitoring disease response in leukemia rely on the analysis of BM biopsy sample at specific time points throughout therapy. Not only the invasiveness of the BM biopsy hinders the sequential sampling, but also, the currently implied techniques are …

Characterization Of The Hepatotoxicity Of Rifampicin And Isoniazid, Christopher T. Brewer

Theses and Dissertations (ETD)

In a mouse model, rifampicin and isoniazid combination treatment results in cholestatic liver injury that is associated with an increase of protoporphyrin ix (PPIX), the penultimate heme precursor. Excess PPIX is believed to bind to bile acids, precipitate in bile canaliculi, and form bile plugs leading to cholestasis fol owed by liver injury. Both ferrochelatase (FECH/Fech) and aminolevulinic acid synthase 1 (ALAS1/Alas1) are crucial enzymes in regulating heme biosynthesis. Isoniazid has recently been reported to up-regulate Alas1 but down-regulate Fech protein levels in mice; however the mechanism of isoniazid mediated heme synthesis …

Discovery Of Novel Tubulin Inhibitors And Selective Survivin Inhibitors For Advanced Melanoma And Total Synthesis Of Bioactive 20s-Hydroxyvitamin D3, Qinghui Wang

Theses and Dissertations (ETD)

According to the statistics from American Cancer Society, the 5-year survival rate for patients with advanced melanoma is as low as 5%. Treatment of advanced melanoma, therefore, represents an unmet medical need. In this dissertation, I will show the effort to develop new generations of bioavailable tubulin inhibitors targeting the colchicine binding site and selective small-molecule survivin inhibitors for treating advanced melanoma. Extensive structure-activity relationship (SAR) studies of lead molecules ABI-231 and UC-112 have been performed.

Chapter 1 will introduce the current situation of advanced or metastatic melanoma, its clinical drug treatments, as well as problems in current drug treatments. …

Design, Synthesis, And Evaluation Of Novel Positron Emission Tomography Radiotracers, Christopher Philip Surdock

Theses and Dissertations (ETD)

Neuroblastoma (NB) is the most common extracranial tumor in patients under 1 year of age and it constitutes about 8-10% of all childhood cancer. It originates from neural crest cells that normally differentiate to form the sympathetic ganglia, adrenal medulla and other paraspinal sites where sympathetic nervous system tissue is present. Even with an extensive treatment regimen that typically includes surgery, chemotherapy, total body irradiation and autologous stem cell transplantation, the 5-year event-free survival is <50% for high risk patients, and there are numerous long-term side effects associated with treatment. This body of work investigated two projects for improving patient outcomes through the development of positron emission tomography (PET) radiotracers that could be used for therapy planning. The goal of the first project was to design, synthesize, and evaluate PET radiotracers that could measure the enzymatic activation of Irinotecan (CPT-11), a potent chemotherapeutic used in the treatment of colon cancer and several pediatric solid tumors. CPT-11 itself is a prodrug which is converted in vivo to SN-38, via metabolism by carboxylesterase (CE) enzymes. St. Jude Children’s Research Hospital researchers have designed a two-pronged protocol of tumor-targeted CPT-11 chemotherapy combining the complementary approaches of a) specific modulation of human CE in normal tissues to improve drug delivery, and b) tumor-targeted activation of prodrug using neural progenitor cells (NPC) transfected with a mutant human CE cDNA. The tumor-selective trafficking of NPC allows over-expression of CE within the tumor. This prodrug/activating enzyme therapeutic approach has shown extremely encouraging preclinical results in the treatment of NB (90% 1-year survival in mice). However, successful translation of this novel therapeutic approach into general clinical practice requires a better understanding of progenitor cell trafficking, duration and intensity of enzymatic activity and the ultimate biological fate of the therapeutic construct. Toward this end, PET radiotracers were developed based on extensive structure-activity relationship (SAR) studies of CE binding. The goal of the second project was to design, synthesize, and evaluate PET radiotracers that could identify the presence of the tropomyosin receptor kinase B (TrkB). TrkB is not normally found in sympathetic nervous tissue, which is the tissue NB develops from, and thus is a potential target for imaging and therapy. The presence of TrkB and its neurotrophin, brain derived neurotrophic factor (BDNF), have been reported to protect neuroblastoma tumor cells from chemotherapy-induced apoptosis via a phosphatidylinositol 3’-kinase pathway. Radiotracers were synthesized and evaluated for their ability to identify TrkB both in vitro and in vivo. PET radiosynthetic procedures were optimized to synthesize novel radiotracers for imaging targets that could help clinicians monitor therapy or identify markers that would aid in therapy planning for NB patients. The method development could be applied to future compounds that show improved chemical characteristics for synthesis and selectivity.

Translational Pharmacokinetic-Pharmacodynamic Modeling And Simulation In The Development Of Spectinamides, A Novel Class Of Anti-Tuberculosis Agents, Chetan Rathi

Theses and Dissertations (ETD)

New chemotherapeutic agents are urgently needed to control the spread of multidrug-resistant (MDR) and extensively drug-resistant (XDR) forms of tuberculosis, which still remains an important public health challenge globally. Recently, spectinamides have emerged as a novel class of anti-tuberculosis agents that overcomethe native drug efflux. Spectinamides bind to the 30S bacterial ribosomal subunit which interferes with ribosomal translocation, and ultimately results in inhibition of protein synthesis. They have potent in vitro activity against drug resistant Mycobacterium tuberculosis (Mtb), and also demonstrated sustained efficacy in (Mtb)-infected mouse models. Pharmacokinetic (PK)/ pharmacodynamic (PD) analyses play a critical role in identifying …

Cannabinoid Receptor 2 (Cb2) Ligands Downregulate Pro-Inflammatory Markers In Stimulated Primary Human Periodontal Ligament Fibroblasts (Hpdlfs), Ammaar Hasan Abidi

Theses and Dissertations (ETD)

There are approximately 743 million individuals suffering from chronic periodontitis (PD) making it the sixth most prevalent condition worldwide. The affected adult population in the U.S. are nearly 64.7 million and the healthcare costs exceeds $14 billion. Recently, host response to pathogenic infection has been seen critical to the progression of PD and exhibit increase in various inflammatory markers. Marijuana is well known for its recreational usage and is a risk factor for periodontal disease, which is seen as a concern in society for its negative health consequences. However, many medical conditions can benefit from the pharmacological effects of cannabinoids. …

Age-Associated Expression Patterns Of Oatp 1b1 And Oatp 1b3 And Their Effect On The Disposition Of Fexofenadine, Margaret Mary Thomson

Theses and Dissertations (ETD)

As part of the drug disposition process (absorption, distribution, metabolism, excretion), an often overlooked aspect is transport. In order for drugs to be metabolized and excreted from the body they go through the liver or other drug removal organs. For drugs that are polar or are large they must rely upon transport mechanisms to transport them across the biomembranes of the drug removal organs. OATP1B1 and OATP1B3 are transporters on the sinusoidal membrane of the liver which work in concert with the drug metabolizing enzymes as part of the drug removal process. It is known that the development of each …

Synthesis Of 20s-Hydroxyvitamin D3 Analogs And Their 1Α-Hydroxyl Derivatives As Potent Anti-Inflammatory Agents, Zongtao Lin

Theses and Dissertations (ETD)

Rheumatoid arthritis (RA) is one of the autoimmune diseases, and is affecting 2.5 million Americans in total. Among the treatment options of RA, 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3] is the only steroidal drug used clinically for anti-inflammatory and immune diseases. However, long-term use of 1,25(OH)2D3 (625 µg/day) in human would result in hypercalcemia (toxicity), and 1,25(OH)2D3 has substantial hypercalcemic effects (toxicity) in mice at a dose as low as only 2 µg/kg. Fortunately, during the investigation of novel metabolic pathway of vitamin D3 by cytochrome P450 enzymes, we found 20S-hydroxyvitamin D3 [20S(OH)D3] as a good lead compound. 20S(OH)D3 suppressed disease symptoms at …

Biophysical And Biochemical Screening Approaches For Antimicrobial Drug Discovery Targeting S. Aureus Clpp, Aman Preet Singh

Theses and Dissertations (ETD)

The discovery of antibacterial drugs has been among most significant achievements of mankind in saving millions of lives across the planet from infectious diseases. With rise in resistance to almost all existing chemotypes, the design of next generation novel antibiotics has become much more challenging and difficult. The early 21st century witnessed the advancement of multiple novel chemotypes during golden age of antibiotics however the pace of antibiotic drug discovery has slowed down tremendously, contributing to life threatening antimicrobial discovery void since 1980’s. Therefore the need to develop novel antibiotics with unique mechanism of action to leverage against multi drug …

The Development Of Methods To Account For Physiologic Dynamic Changes And Their Effects On The Pharmacokinetics Of Therapeutic Monoclonal Antibodies And Other Therapeutics, Josiah Thomas Ryman

Theses and Dissertations (ETD)

Physiologic changes in the body can drastically affect the clearance of a medication, and therefore increase the variability in exposure to the medication. Physiologic changes that can have a profound effect on the exposure of a medication can stem from changes CYP enzymes, transport proteins, binding protein expression, organ function, immune reactivity, and health status to name a few; with the focus of this dissertation on the dynamic changes in the ontogeny of MRP2 (an apical liver transport protein) and the dynamic changes caused by an immune response to a therapeutic monoclonal antibody (mAb). Several approaches can be used to …

Biodegradable Polymeric Biomaterials In Different Forms For Long-Acting Contraception And Drug Delivery To The Eye And Brain, Dileep Reddy Janagam

Theses and Dissertations (ETD)

Efficacy of many of the new and existing therapeutics is often hampered by the lack of an effective and compliant method of delivery. Typically, drugs have poor water solubility, short half-lives, and low permeability across the biological membranes. The result is low bioavailability of the drugs at the target site and can cause toxicity and side effects at high doses. Often the conventional dosage forms fail to overcome these limitations. In the recent decades, biodegradable polymeric drug delivery systems have emerged as promising candidates to solve the challenges of poor solubility, low permeability and sustained release owing to the advantages …

Discovery Of Natural Product-Based Antimycobacterial Agents Effective Against Non-Replicating Bacilli, Shajila Siricilla

Theses and Dissertations (ETD)

New antimycobacterial molecules that kill non-replicating Mycobacterium tuberculosis (Mtb) were identified by screening libraries of synthetic natural products. De novo screening of a 400-membered library of aurachin RE analogs resulted in discovery of UT-317 ((R)-20). UT-317 is a selective vitamin K2 biosynthesis (MenA) inhibitor that killed replicating and non-replicating Mtb at 2.31 μg/mL (MIC) and 0.85 μg/mL, respectively. A 50-membered library of capuramycin analogs was evaluated in their enzymatic inhibitory activities against translocase I (MraY/MurX) and prenyl-phosphate-GlcNAc-1-phosphate transferase (WecA). UT-01320 (45) is identified as a selective WecA inhibitor that kills both replicating and non-replicating Mtb at 1.50 μg/mL (MIC) and …

Regulation Of Cancer Metastasis By Protein Kinase D1: A Global Regulatory Cascade, Aditya Ganju

Theses and Dissertations (ETD)

Protein Kinase D1 (PKD1) is a serine threonine kinase which is downregulated in Prostate, Breast and Colon Cancer. It functions as a tumor suppressor in different cancer cells. Downregulation of PKD1 is known to be associated with aggressiveness of the cancer. PKD1 is known to regulate many key oncogenic signaling pathways such as E-cadherin, β-catenin and Androgen Receptor signaling pathways. Aberrant expression of these oncogenic pathways leads to transformation of cells from normal to malignant phenotype, thereby leading to increased proliferation, growth and metastasis to distant organs of these cancer cells. Literature evidence also points to the fact that E-cadherin …

Repeated Zolpidem Treatment Effects On Sedative Tolerance, Withdrawal, Mrna Levels, And Protein Expression, Brittany T. Wright

Theses and Dissertations (ETD)

Zolpidem and benzodiazepines (BZs) potentiate the inhibitory action of gamma-Aminobutyric acid (GABA) by allosterically binding to GABAA receptors (GABAAR). Prolonged use of GABAAR positive allosteric modulators (PAM) can lead to behavioral tolerance, the diminished response to the same drug dose with repeated use, and withdrawal, a group of symptoms that occur due to abrupt end of drug treatment. Zolpidem is a short-acting, non-BZ GABAAR PAM whose potential for tolerance and withdrawal is unclear. Zolpidem demonstrates sedative efficacy similar to BZs and has become a main treatment of insomnia in lieu of BZs. Zolpidem replaced BZs due to lower incidences of …

Antibiotic Drug Discovery With An Eye Towards Overcoming Drug Resistance, Daniel Towner Hoagland

Theses and Dissertations (ETD)

As a species, humans have become ever reliant on the use of antibiotics to facilitate our everyday lives. The widespread emergence of resistance to currently used antibiotics is commonly attributed to an over use in our society. Such resistance, coupled with a lack of innovation and production of novel antibiotic drugs, threatens to return humanity to an era similar to one before the discovery of the first antibiotics. The need to find new agents to be used in this fight is paramount, as well as learning from our recent failures to produce such compounds. This document will highlight my efforts …

Discoveries Of Targets And Novel Agents For The Treatment Of Ischemic Retinopathy And Neovascular Disease, Jordan Javad Toutounchian

Theses and Dissertations (ETD)

Diabetic retinopathy (DR) and age-related macular degeneration (AMD) are among the most common causes of blindness in adults. Vision loss can occur during the advanced stages of DR and AMD as a consequence of unregulated and dysfunctional growth of new blood vessels, or neovascularization (NV) in the retina or choroid. NV can also be triggered by numerous other ocular insults and diseases including radiation retinopathy (RR) and retinal vein occlusion. These latter cases are generally less common but, like DR and AMD, they are characterized by an initial injury, chronic inflammation, and ischemia which perpetuates episodes of retinal neovascularization (RNV). …