Medicine and Health Sciences Commons^™

7,8-Dihydroxyflavone, A Selective Tyrosine Kinase Receptor B Agonist And Bdnf Mimic, Promotes Angiogenesis., Jeremy Williams

Undergraduate Honors Theses

7,8-dihydroxyflavone (7,8-DHF), which is a member of the flavonoid family, is a selective tyrosine kinase receptor B (TrkB) agonist that has neurotrophic effects in various neurological diseases such as ischemic stroke and Parkinson’s disease [3]. In this study, we assessed the angiogeneic effect of 7,8-DHF in endothelial cells derived from resistance vessel of the brain. Angiogenesis by 7,8-DHF is an important factor that helps prevent and treat various ischemic diseases. In this study, we found that rat RV cells used in the experiment possess the TrkB receptor. Our data also demonstrates that 7,8-DHF is able to stimulate cell proliferation in …

Reliability And Credibility Of Progress Test Criteria, Developed By Alumni, Faculty, And Mixed Alumni-Faculty Judge Panels, H. Glenn Anderson Pharmd, Arthur A. Nelson Phd

Pharmacy Practice & Administration

Objective. To compare the reliability and credibility of Angoff-based, absolute criteria derived by faculty, alumni, and a combination of alumni and faculty judge panels.

Methods. Independently, faculty, alumni, and mixed faculty-alumni judge panels developed pass/fail criteria for an 86-item test. Generalizability and decision studies were performed. Root mean square errors (RMSE) and 95% confidence intervals were calculated for reliability and credibility assessment. School graduate performance upon the North American Licensure Examination (NAPLEX) was the comparator for credibility assessment.

Results. RMSEs were 1.06%, 1.42%, and 2.32% for the alumni, faculty, and mixed judge panels respectively. The school's NAPLEX pass rate was …

Development Of Dual-Pathway Inhibitors Of Raf/Mek/Erk And Pi3k/Akt Signaling Pathways., Sasha Fraser

Theses and Dissertations

In the present study, we designed a new chemical template that contains an oxindole moiety as potential dual-pathway inhibitors of the Raf/MEK/ERK and PI3K/Akt signaling pathways. The design hypothesis is to evaluate whether the oxindole ring system will approximately orient functional groups in a similar manner to the thiazolidinedione moiety, and thus maintain biological activity as dual-pathway inhibitors of the Raf/MEK/ERK and PI3K/Akt signaling pathways. Furthermore, the oxindole ring will provide the flexibility to allow the introduction of various substituents on the oxindole moiety, thereby facilitating comprehensive SAR studies to further explore the biological activity.

Medication-Related Problems In Older Adults: A Focus On Underuse Of Warfarin And Warfarin-Antibiotic Interactions, Parinaz K. Ghaswalla

Theses and Dissertations

The work presented in this dissertation focuses on two important medication-related problems in older adults, that is, untreated indication and drug-drug interactions, specifically with respect to a high-risk medication such as warfarin. Warfarin is a challenge to use in clinical practice due to its narrow therapeutic index, variability in dose-response and its interactions with numerous foods and drugs. This dissertation presents the research from two projects. In the first project the prevalence and predictors of warfarin use in nursing home (NH) residents with atrial fibrillation (AF), and use of secondary stroke prevention strategies was determined, in order to understand the …

Development Of A Novel Approach To Assess Qualitative And Quantitative Dynamics Associated With The Subcutaneous Or Intramuscular Administration Of Pharmaceuticals And Associated Parenteral Delivery Systems, Eric Edwards

Theses and Dissertations

There has been a significant increase in the number of injectable pharmaceutical products over the last decade that have been incorporated into unique delivery systems such as pen injectors, auto-injectors, or pre-filled syringes. The advancement of these delivery systems and the paradigm shift towards administration of injectables in the out-of-hospital or home setting have introduced variables that can affect the bioavailability of injectable drugs and potential pharmacologic outcomes. An approach that allows for the qualitative and quantitative dispersion assessment of an injectable at the moment of tissue deposition coupled with an assessment of systemic exposure parameters could provide substantial information …

Effect Of Duration And Amplitude Of Direct Current When Lidocaine Is Delivered By Iontophoresis, Susan A. Saliba, Courtney L. Teeter-Heyl, Patrick O. Mckeon, Christopher D. Ingeroll, Ethan N. Saliba

Physical Therapy Faculty Publications

Dosage for the galvanic stimulation for iontophoresis varies. Clinicians manipulate the duration or the amplitude of the current, but it is not known which is more effective. We compared the anesthetic effect of lidocaine HCL (2%) by manipulating the current parameters on 21 healthy volunteers (age: 21.2 ± 4.2, height 170.7 ± 10.2 cm, mass 82.1 ± 19.2 kg). Three conditions were administered in a random order using a Phoresor II^® with 2 mL, 2% lidocaine HCL in an iontophoresis electrode. (1) HASD (40 mA_*min): High amplitude (4 mA), short duration (10 min); (2) LALD (40 mA.min): …

Fluctuations And Instantons In Complex Landscapes: From Ligand Unbinding To Proton Transfer, Justin Elenewski

Theses and Dissertations

Biophysical entities are complex systems systems with strong environmental coupling, dominated by fluctuations on a hierarchy of timescales. These properties confound simulation of ligand binding and catalysis, inflating the scale of the problem to one tractable only with a considerable outlay of resources. In an attempt to ameliorate this restriction, several techniques are developed to accelerate biomolecular simulations while collaterally lending physical insight. The first segment of this dissertation is concerned with directed simulations of ligand binding in a model system. Using the serum retinol binding protein as a prototype, the potential of mean force associated with ligand binding is …

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 …

Dietary Supplement Education In A Senior Population, Kimberly G. Elder, Sarah A. Nisly

Scholarship and Professional Work – COPHS

Background. Dietary supplements are widely used among United States senior citizens for various indications. Potential dangers with supplement use include the lack of regulation by the Food and Drug Administration (FDA) and the possibility for drug-supplement interactions. Senior focused education may in- crease the safe use of dietary supplements by older adults.

Objective. The primary objective of this study was to determine the effectiveness of a pharmacist driven educational seminar in a local senior population.

Methods. Participants aged 55 years and older in one of three senior programs were eligible for inclusion. Initially, a needs-assessment interview was con- ducted …

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 …

Novel Amino Acid Transporter-Targeted Radiotracers For Breast Cancer Imaging, Fanlin Kong

Dissertations & Theses (Open Access)

Breast cancer is the most common malignancy among women in the world. Its 5-year survival rate ranges from 23.4% in patients with stage IV to 98% in stage I disease, highlighting the importance of early detection and diagnosis. ¹⁸F-2-Fluoro-2-deoxy-glucose (¹⁸F-FDG), using positron emission tomography (PET), is the most common functional imaging tool for breast cancer diagnosis currently. Unfortunately, ¹⁸F-FDG-PET has several limitations such as poorly differentiating tumor tissues from inflammatory and normal brain tissues. Therefore, ¹⁸F-labeled amino acid-based radiotracers have been reported as an alternative, which is based on the fact that tumor cells uptake …

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 …

Relationship Between Vancomycin Trough Concentrations And Nephrotoxicity: A Prospective Multicenter Trial, John A. Bosso, Jean Nappi, Celeste Rudisill, Marlea Wellein, P Brandon Bookstaver, Jenna Swindler, Patrick D. Mauldin

Faculty Publications

Several single-center studies have suggested that higher doses of vancomycin, aimed at producing trough concentrations of >15 mg/liter, are associated with increased risk of nephrotoxicity. We prospectively assessed the relative incidence of nephrotoxicity in relation to trough concentration in patients with documented methicillin-resistant Staphylococcus aureus (MRSA) infections at seven hospitals throughout South Carolina. Adult patients receiving vancomycin for at least 72 h with at least one vancomycin trough concentration determined under steady-state conditions were prospectively studied. The relationship between vancomycin trough concentrations of >15 mg/ml and the occurrence of nephrotoxicity was assessed using univariate and multivariate analyses, controlling for age, …

Liposomal, Ring-Opened Camptothecins With Prolonged, Site-Specific Delivery Of Active Drug To Solid Tumors, Bradley D. Anderson, Vijay Joguparthi, Tiang-Xiang Xiang

Pharmaceutical Sciences Faculty Patents

A method for preparing a stable dispersion of a camptothecin, camptothecin prodrug, or analog thereof for administration to a patient in need thereof includes preparing a solution of the camptothecin, wherein the solution has a pH which places substantially an entirety of that camptothecin in a carboxylate form. The camptothecin may be a neutral camptothecin. The solution is next loaded into a liposome including at least one lipid, which may be a phospholipid. An intraliposomal pH is maintained which preserves substantially an entirety of the camptothecin in the carboxylate form. The liposomal dispersion is administered to an individual in need …

Removing Aluminum From Solution Using Chelating Compounds And Immobilized Tethered Chelators, Robert A. Yokel, Wesley R. Harris, Christopher D. Spilling, Chang-Guo Zhan

Pharmaceutical Sciences Faculty Patents

Methods are described for removing aluminum from a solution using novel di- and tripodal compounds as chelators.

Nanoparticulate Formulations Of Mithramycin Analogs For Enhanced Cytotoxicity, Daniel Scott, Jürgen Rohr, Younsoo Bae

Pharmaceutical Sciences Faculty Publications

Mithramycin (MTM), a natural product of soil bacteria from the Streptomyces genus, displays potent anticancer activity but has been limited clinically by severe side effects and toxicities. Engineering of the MTM biosynthetic pathway has produced the 3-side-chain-modified analogs MTM SK (SK) and MTM SDK (SDK), which have exhibited increased anticancer activity and improved therapeutic index. However, these analogs still suffer from low bioavailability, short plasma retention time, and low tumor accumulation. In an effort to aid with these shortcomings, two nanoparticulate formulations, poly(ethylene glycol)-poly(aspartate hydrazide) self-assembled and cross-linked micelles, were investigated with regard to the ability to load and pH …

Designing Allosteric Inhibitors Of Thrombin, Preetpal Sidhu

Theses and Dissertations

Thrombin is a key enzyme of the coagulation cascade exhibiting important roles in both pro-coagulation and anti-coagulation processes. Most clinically used anticoagulant drugs, including polymeric heparin, warfarin, hirudin, argatroban and the recently approved dabigatran, aim to reduce thrombin activity. There are several binding domains on thrombin including the active site, anion-binding exosites I and II, and the sodium binding site. We hypothesized that thrombin may be better regulated through an allosteric process mediated by small molecules binding to either exosite I or II. An appropriately designed allosteric regulator that reduces the procoagulant signal in a finely tuned manner may maintain …

Reactive Oxygen Species Modulation Of Na/K-Atpase Regulates Fibrosis And Renal Proximal Tubular Sodium Handling, Jiang Liu, David J. Kennedy, Yanling Yan, Joseph I. Shapiro Md

Pharmaceutical Science and Research

The Na/K-ATPase is the primary force regulating renal sodium handling and plays a key role in both ion homeostasis and blood pressure regulation. Recently, cardiotonic steroids (CTS)-mediated Na/K-ATPase signaling has been shown to regulate fibrosis, renal proximal tubule (RPT) sodium reabsorption, and experimental Dahl salt-sensitive hypertension in response to a high-salt diet. Reactive oxygen species (ROS) are an important modulator of nephron ion transport. As there is limited knowledge regarding the role of ROS-mediated fibrosis and RPT sodium reabsorption through the Na/K-ATPase, the focus of this review is to examine the possible role of ROS in the regulation of Na/K-ATPase …

Acetaminophen: Beyond Pain And Fever-Relieving, Eric R. Blough, Miaozong Wu

MIIR Faculty Research

Acetaminophen, also known as APAP or paracetamol, is one of the most widely used analgesics (pain reliever) and antipyretics (fever reducer). According to the U.S. Food and Drug Administration, currently there are 235 approved prescription and over-the-counter drug products containing acetaminophen as an active ingredient. When used as directed, acetaminophen is very safe and effective; however when taken in excess or ingested with alcohol hepatotoxicity and irreversible liver damage can arise. In addition to well known use pain relief and fever reduction, recent laboratory and pre-clinical studies have demonstrated that acetaminophen may also have beneficial effects on blood glucose levels, …

Functional Characterization And Analgesic Effects Of Mixed Cannabinoid Receptor/T-Type Channel Ligands, Haitao You, Vinicius M. Gadotti, Ravil R. Petrov, Gerald W. Zamponi, Philippe Diaz

Biomedical and Pharmaceutical Sciences Faculty Publications

Background: Both T-type calcium channels and cannabinoid receptors modulate signalling in the primary afferent pain pathway. Here, we investigate the analgesics activities of a series of novel cannabinoid receptor ligands with T-type calcium channel blocking activity. Results: Novel compounds were characterized in radioligand binding assays and in vitro functional assays at human and rat CB1 and CB2 receptors. The inhibitory effects of these compounds on transient expressed human T-type calcium channels were examined in tsA-201 cells using standard whole-cell voltage clamp techniques, and their analgesic effects in response to various administration routes (intrathecally, intraplantarly, intraperitoneally) assessed in the formalin model. …

Interferons As Therapeutic Agents In Infectious Diseases, Mckenzie C. Ferguson, Scott Bergman, Cathy Santanello

Pharmacy Faculty Research, Scholarship, and Creative Activity

This article explains the rationale for development of interferons as therapeutic agents, and describes commercial products available today. It also provides a summary of studies that have been performed with interferons for use as exogenous biological response modifiers in viral infections. Overall, the best data exist for treatment of viral hepatitis B and C, for which interferons are a cornerstone of therapy. Although infections with human papillomavirus and common cold viruses sometimes respond favorably to interferons, their outcomes are far from ideal. Finally, the role of interferons as vaccine adjuvants is still being explored but could be promising.

Sirt2 Maintains Genome Integrity And Suppresses Tumorigenesis Through Regulating Apc/C Activity, Hyun-Seok Kim, Athanassios Vassilopoulos, Rui-Hong Wang, Tyler Lahusen, Zhen Xiao, Xiaoling Xu, Cuiling Li, Timothy D. Veenstra, Bing Li, Hongtao Yu, Junfang Ji, Xin Wei Wang, Seong-Hoon Park, Yong I Cha, David Gius, Chu-Xia Deng

Pharmaceutical Sciences Faculty Publications

Members of sirtuin family regulate multiple critical biological processes, yet their role in carcinogenesis remains controversial. To investigate the physiological functions of SIRT2 in development and tumorigenesis, we disrupted Sirt2 in mice. We demonstrated that SIRT2 regulates the anaphase-promoting complex/cyclosome activity through deacetylation of its coactivators, APC(CDH1) and CDC20. SIRT2 deficiency caused increased levels of mitotic regulators, including Aurora-A and -B that direct centrosome amplification, aneuploidy, and mitotic cell death. Sirt2-deficient mice develop gender-specific tumorigenesis, with females primarily developing mammary tumors, and males developing more hepatocellular carcinoma (HCC). Human breast cancers and HCC samples exhibited reduced SIRT2 levels compared with …

Combinatorial-Designed Multifunctional Polymeric Nanosystems For Tumor-Targeted Therapeutic Delivery., Arun K. Iyer

Arun Iyer

By definition, multifunctional nanosystems include several features within a single construct so that these devices can target tumors or other disease tissue, facilitate in vivo imaging, and deliver a therapeutic agent. Investigations of these nanosystems are rapidly progressing and provide new opportunities in the management of cancer. Tumor-targeted nanosystems are currently designed based primarily on the intrinsic physico-chemical properties of off-the-shelf polymers. Following fabrication, the surfaces of these nanoscale structures are functionalized for passive or active targeted delivery to the tumors. In this Account, we describe a novel approach for the construction of multifunctional polymeric nanosystems based on combinatorial design …

Antiurolithic Activity Of Origanum Vulgare Is Mediated Through Multiple Pathways, Aslam Khan, Samra Bashir, Saeed R. Khan, Anwar H. Gilani

Department of Biological & Biomedical Sciences

Background: Origanum vulgare Linn has traditionally been used in the treatment of urolithiasis. Therefore, we investigated the crude extract of Origanum vulgare for possible antiurolithic effect, to rationalize its medicinal use. Methods: The crude aqueous-methanolic extract of Origanum vulgare (Ov.Cr) was studied using the in vitro and in vivo methods. In the in vitro experiments, supersaturated solution of calcium and oxalate, kidney epithelial cell lines (MDCK) and urinary bladder of rabbits were used, whereas, in the in vivo studies, rat model of urolithiasis was used for the study of preventive and curative effect. Results: In the in vitro experiments, Ov.Cr …

Novel Membrane-Associated Androgen Receptor Splice Variant Potentiates Proliferative And Survival Responses In Prostate Cancer Cells, Xi Yang, Zhiyong Guo, Feng Sun, Wei Li, Alan Alfano, Hermela Shimelis, Mingyuan Chen, Angela M H Brodie, Hegang Chen, Zhen Xiao, Timothy D. Veenstra, Yun Qiu

Pharmaceutical Sciences Faculty Publications

Progression from the androgen-sensitive to androgen-insensitive (or castration-resistant) stage is the major obstacle for sustained effectiveness of hormonal therapy for prostate cancer. The androgen receptor (AR) and its splice variants play important roles in regulating the transcription program essential for castration resistance. Here, we report the identification of a novel AR splice variant, designated as AR8, which is up-regulated in castration-resistant prostate cancer cells. AR8 is structurally different from other known AR splice variants because it lacks a DNA binding domain and therefore, unlikely functions as a transcription factor on its own. Immunofluorescence staining revealed that AR8 was primarily localized …

Neuroprotective Effects Of Bilobalide Are Accompanied By A Reduction Of Ischemia-Induced Glutamate Release In Vivo, Dorothee Lang, Cornelia Kiewert, Alexander Mdzinarishvili, Tina Maria Schwarzkopf, Rachita K. Sumbria, Joachim Hartmann, Jochen Klein

Pharmacy Faculty Articles and Research

Neuroprotective properties of bilobalide, a specific constituent of Ginkgo extracts, were tested in a mouse model of stroke. After 24 h of middle cerebral artery occlusion (MCAO), bilobalide reduced infarct areas in the core region (striatum) by 40–50% when given at 10 mg/kg 1 h prior to MCAO. Neuroprotection was also observed at lower doses, or when the drug was given 1 h past stroke induction. Sensorimotor function in mice was improved by bilobalide as shown by corner and chimney tests. When brain metabolism in situ was monitored by microdialysis, MCAO caused a rapid disappearance of extracellular glucose in the …

Methods And Pharmaceutical Compositions For Decorporation Of Radioactive Compounds, Michael Jay, Russell J. Mumper

Pharmaceutical Sciences Faculty Patents

A composition for removing a radioactive element or compound such as systemic transuranic compounds, from mammals comprises a pharmaceutical carrier and a decorporation agent comprising ester and amide derivatives of DTPA. A method of treating a mammal to remove systemic compounds utilizing the DTPA derivatives is also disclosed.

Therapeutic Efficacy And Safety Of Paclitaxel/Lonidamine Loaded Egfr-Targeted Nanoparticles For The Treatment Of Multi-Drug Resistant Cancer, Lara S. Jabr-Milane, Zhenfeng Duan, Mansoor M. Amiji

Mansoor M. Amiji

The treatment of multi-drug resistant (MDR) cancer is a clinical challenge. Many MDR cells over-express epidermal growth factor receptor (EGFR). We exploit this expression through the development of EGFR-targeted, polymer blend nanocarriers for the treatment of MDR cancer using paclitaxel (a common chemotherapeutic agent) and lonidamine (an experimental drug; mitochondrial hexokinase 2 inhibitor). An orthotopic model of MDR human breast cancer was developed in nude mice and used to evaluate the safety and efficacy of nanoparticle treatment. The efficacy parameters included tumor volume measurements from day 0 through 28 days post-treatment, terminal tumor weight measurements, tumor density and morphology assessment …