Digital Commons Network^™

N-Myristoylglutamic Acid Derivative Of 3′-Fluoro-3′- Deoxythymidine As An Organogel, Bhupender S. Chhikara, Rakesh Tiwari, Keykavous Parang

Pharmacy Faculty Articles and Research

Designing microbicidal gels of anti-HIV drugs for local application to prevent HIV infection is a subject of major interest. 3′-Fluoro-3′-deoxythymidine (FLT), a nucleoside reverse transcriptase inhibitor (NRTI), was conjugated with a N-myristoylglutamate scaffold. The conjugate showed gelation at 1% (w/w) in different organic solvents, such as toluene, dichloromethane, and chloroform. The gels were opaque and stable at room temperature. The results indicate that myristoyl glutamate derivative of FLT can form an organogel. The gel could have potential application as a topical anti-HIV microbicidal agent.

Phytochemical Studies On The Medicinal Plant Sutherlandia Frutescens, Xiang Fu

Electronic Theses and Dissertations

Sutherlandia frutescens (L.) R. Br (Fabaceae) is a multipurpose medicinal plant with diverse biological activities, and has been widely used for the treatment of cancer, AIDS, diabetes, and infectious diseases in southern Africa. The primary goal of this study was to investigate the chemical constituents of S. frutescens and develop an analytical method to analyze this plant and the dietary supplements derived from this plant. The dissertation is composed of six chapters. Chapter 1 introduces the general background of S. frutescens, including traditional uses and chemical and biological studies on the plant. Chapter 2 describes the phytochemical studies that have …

Functional Studies Of Novel Bioactives From Complex Host-Microbiomes As Drug Leads For Cancer, Infectious Disease, Depression And Pain, John Jason Bowling

Electronic Theses and Dissertations

The drug discovery process has become increasingly complex in comparison to early efforts particularly those involving diseases or conditions that affect large numbers of the human population. It is difficult to point directly to one factor leading evolution of the process but the definition of a mechanism of pharmacological action for a drug lead has noticeably become a higher priority. This evolution has helped diminish the stigma of natural products and compound supply issues. The issue of compound supply has also been addressed to some extent with the emergence of recombinant technologies and new synthetic methodology. With approximately 60 years …

Localization And Functional Characterization Of Oatp4c1 Transporter In In Vitro Cell Systems And Human/Rat Tissues, Kuei-Ling Kuo

Theses and Dissertations--Pharmacy

The organic anion transporting polypeptide 4c1 (Oatp4c1) was previously identified as a novel uptake transporter predominantly expressed at the basolateral membrane in the rat kidney proximal tubules. Its functional role was suggested to be a vectorial transport partner of an apically-expressed efflux transporter for the efficient translocation of physiological substrates into urine, some of which were suggested to be uremic toxins. In vitro studies in polarized cell lines showed that upon transfection rat Oatp4c1 localizes at the apical membrane. The objectives of this project were to further validate the subcellular localization of Oatp4c1/OATP4C1 in rat and human tissues as well …

Antimalarials From Plant Pathogenic Fungi, Mallika Kumarihamy

Electronic Theses and Dissertations

The purpose of this study was to discover antimalarial compounds from necrotropic plant pathogenic fungi. Various phytotoxins released by necrotropic plant pathogenic fungi may inhibit the plant-like metabolic pathways in the apicoplast, a chloroplast-like organelle, essential for the survival of apicomplexan parasites, such as Plasmodium which cause malaria in humans. This dissertation describes the isolation, characterization, and biological evaluation of secondary metabolites of eight fungal strains. In addition to the antiplasmodial assay, all the extracts were subjected to phytotoxic, antimicrobial, and cytotoxic bioassays. Isolation of metabolites was performed by chromatographic methods and identification was carried out by spectroscopic and spectrometric …

Discovery, Isolation, And Identification Of Antimalarials From Fungal Endophytes, Andrekeus Lee

Electronic Theses and Dissertations

We examined fungal endophytes for their ability to inhibit bacterial, fungal and protozoal pathogens. Once antimalarial activity was discovered and confirmed, we sought to isolate and identify the active constituent(s) of our extracts. Bioassay-guided fractionation techniques were used to isolate our active compound, the structure of which was elucidated using 1H- and 13C-NMR. 2D-NMR and LC-MS analyses helped confirm that our endophytes were indeed producing artemisinin. Growth versus production studies were conducted to optimize our growth and extraction conditions while several other variables, like temperature and culture medium, were evaluated in an effort to improve our yields. Artemisinin production under …

Mechanism Of Action Of A Novel Antifungal Compound, Amber Ward

Honors Theses

Opportunistic fungal infections have become problematic in recent years. There has been an emergence of new fungal pathogens, development of antifungal resistance, and increasing prevalence. In addition, toxicity, resistance, and lack of efficacy as a single agent limit the effectiveness of current antifungal drugs. Therefore, new drugs targeting new pathways are greatly needed. An analog derived from the marine natural product phloeodictine, analog PHL5-34A, was identified as having strong in vitro antifungal activity. In this study, its mechanism of action (MOA) was investigated in the model yeast, Saccharomyces cerevisiae. This study made use of a collection of 166 yeast mutants …

An Expanded Age Range For Meningococcal Meningitis: Molecular Diagnostic Evidence From Population-Based Surveillance In Asia, Soon Kim, Dong Kim, Bai Dong, Jung Kim, Dang Anh, Paul E. Kilgore

Wayne State University Associated BioMed Central Scholarship

Abstract

Background

To understand epidemiologic patterns of meningococcal disease in Asia, we performed a retrospective molecular analysis of cerebrospinal fluid (CSF) specimens collected in prospective surveillance among children aged < 5 years of age in China, South Korea, and Vietnam.

Methods

A total of 295 isolates and 2,302 CSFs were tested by a meningococcal species- and serogroup-specific polymerase chain reaction (PCR) assay targeting the Neisseria meningitidis (Nm) ctrA gene. Multi-locus sequence typing (MLST) was performed in Nm gene amplification analysis and incidence rates for meningococcal meningitis were estimated.

Results

Among 295 isolates tested, 10 specimens from Vietnam were confirmed as serogroup B and all were Sequence Type (ST) 1576 by MLST. …

Predictors Of Carbapenem Resistant Gram-Negative Bacteria In A Consortium Of Academic Medical Center Hospitals, Mera Ababneh

Theses and Dissertations

Background: Gram-negative resistance is a growing problem worldwide. It is generally believed that rates of resistant bacteria within a hospital are a function of antibiotic use, resistant organisms brought into the hospital, infection control efforts, and underlying severity of patient illness. The relative contribution of each to a particular resistance phenotype is unclear. P. aeruginosa is responsible for many hospital acquired infections and it may become resistant to carbapenems. In addition, newer threats to the future utility of the carbapenems are carbapenemase-producing K. pneumoniae Purpose: To determine if there is an association between the volume and composition of antibiotic use, …

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, …

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.

Research News: 2011, University Of Mississippi. School Of Pharmacy

Research News: Grants and Publications (2000-2014)

Grants, publications, technology transfer, special announcements

A System Dynamics Model Of Pharmaceutical Opioids: Medical Use, Diversion, And Nonmedical Use, Teresa Schmidt, Wayne Wakeland, J. David Haddox

Complex Systems Faculty Publications and Presentations

A dramatic rise in the nonmedical of pharmaceutical opioids has presented the United States with a substantial public health problem. Nonmedical use of prescription pain relievers has become increasingly prevalent in the US over the last two decades, and diversion of medicines obtained by prescription is assumed to be a major source of supply for nonmedical opioid use. Policymakers striving to protect population health by ameliorating the adverse outcomes of nonmedical use of opioid analgesics could benefit from a systems-level model which reflects the complexity of the system and incorporates the full range of available data. To address this need, …

Influenza And Bacterial Coinfections In The 20th Century, Xuan-Yi Wang, Paul E. Kilgore, Kyung Ah Lim, Song-Mei Wang, Jeongseok Lee, Wei Deng, Mei-Qi Mo, Batmunkh Nyambat, Jing-Chen Ma, Michael O. Favorov, John D. Clemens

Department of Pharmacy Practice

To help understand the potential impact of bacterial coinfection during pandemic influenza periods, we undertook a far-reaching review of the existing literature to gain insights into the interaction of influenza and bacterial pathogens. Reports published between 1950 and 2006 were identified from scientific citation databases using standardized search terms. Study outcomes related to coinfection were subjected to a pooled analysis. Coinfection with influenza and bacterial pathogens occurred more frequently in pandemic compared with seasonal influenza periods. The most common bacterial coinfections with influenza virus were due to S. pneumoniae, H. influenzae, Staphylococcus spp., and Streptococcus spp. …

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 …

Inhibition Of Bacterial Growth And Biofilm Production By Metabolites From Hypericum Spp, S.A. Sarkisian, G.E. Henry, K.L. Laplant, D.C. Rowley

Discovery@URI

Biofilm embedded bacterial pathogens such as Staphylococcus spp., Escherichia coli, Pseudomonas aeruginosa, and Acinetobacter baumannii are difficult to eradicate and are major sources of bacterial infections. New drugs are needed to combat these pathogens. Hypericum is a plant genus that contains species known to have antimicrobial properties. However, the specific metabolites responsible for the antimicrobial properties are not entirely known, nor have most compounds been tested as inhibitors of biofilm development. The investigation presented here tested seven secondary metabolites isolated from the species Hypericum densiflorum, Hypericum ellipticum, Hypericum prolificum and Hypericum punctatum as inhibitors of bacterial growth and biofilm production. …

Potential Role Of Tigecycline In The Treatment Of Community-Acquired Bacterial Pneumonia, M. L. Townsend, M. W. Pound, R. H. Drew

Pharmacy Practice

Tigecycline is a member of the glycylcycline class of antimicrobials, which is structurally similar to the tetracycline class. It demonstrates potent in vitro activity against causative pathogens that are most frequently isolated in patients with community-acquired bacterial pneumonia (CABP), including (but not limited to) Streptococcus pneumoniae (both penicillin-sensitive and -resistant strains), Haemophilus influenzae and Moraxella catarrhalis (including β-lactamase-producing strains), Klebsiella pneumoniae, and ‘atypical organisms’ (namely Chlamydophila pneumoniae, Mycoplasma pneumoniae, and Legionella pneumophila). Comparative randomized clinical trials to date performed in hospitalized patients receiving tigecycline 100 mg intravenous (IV) × 1 and then 50 mg IV twice daily thereafter have demonstrated …

Influence Of Continuous Venovenous Hemofiltration And Continuous Venovenous Hemodiafiltration On The Disposition Of Doripenem, Iolanda Cirillo, Nicole Vaccaro, Dainius Balis, Rebecca Redman, Gary R. Matzke

Pharmacotherapy and Outcomes Science Publications

The pharmacokinetics, safety, and tolerability of a single 1-hour, 500-mg intravenous infusion of doripenem were assessed in dialysis-dependent subjects with stage 5 chronic kidney disease undergoing continuous renal replacement therapy (CRRT) via 12-hour continuous venovenous hemofiltration (CVVH) (n = 6) or continuous venovenous hemodiafiltration (CVVHDF) (n = 5). Healthy volunteers were also assessed (n = 12). Concentrations of doripenem and the primary metabolite doripenem-M-1 were measured in plasma and ultrafiltrate or ultrafiltrate/dialysate by a validated liquid chromatography-tandem mass spectrometry method. In dialysis-dependent subjects, levels of systemic exposure to doripenem and doripenem-M-1 were approximately 3- and 5-fold greater, respectively, than those …

Efficacy Of Limited Cefuroxime Prophylaxis In Pediatric Patients After Cardiovascular Surgery, Chad A. Knoderer, Elaine G. Cox, Michelle D. Berg, Andrea H. Webster, Mark W. Turrentine

Scholarship and Professional Work – COPHS

Purpose The efficacy of limited cefuroxime prophylaxis in pediatric patients after cardiovascular surgery was evaluated.

Methods All patients age 18 years or younger who underwent cardiovascular surgery and received postoperative care from the cardiovascular surgery team between February and July 2006 (preintervention group) and between August 2006 and January 2007 (postintervention group) were eligible for study inclusion. Patients were excluded if they did not receive cefuroxime as postoperative prophylaxis, had a preexisting infection, underwent cardiac transplantation or extracorporeal membrane oxygenation, or underwent delayed sternal closure. The preintervention group received prolonged cefuroxime prophylaxis, and the postintervention group received 24 hours of …

Systematic Review Of Chimpanzee Use In Monoclonal Antibody Research And Drug Development: 1981-2010, Raija Bettauer

Experimentation Collection

This survey examines the extent to which live chimpanzees have been used in monoclonal antibody (mAb) research and the drug approval process. The survey covers 193 scientific articles published during the years 1981-2010, as well as preclinical studies leading to the approval of mAb drugs by the Food and Drug Administration of the United States. The frequency of the articles has decreased by more than two-thirds from their highs in the late 1980’s, and the aggregate number of chimpanzees used in these studies has decreased by more than 90%.

The experimental protocols ranged from single or multiple blood draws to …

Assessment Of Web-Based Training (Wbt) Modules On Learning Facilitation For Advanced Pharmacy Practice Experiences (Appe) In Pediatrics, Jennifer L. Morris, Chad A. Knoderer

Scholarship and Professional Work – COPHS

OBJECTIVES: To assess the effectiveness of web-based training (WBT) modules to enhance and facilitate student pharmacists’ learning and their ability to provide pharmaceutical care to children during a pediatric advanced pharmacy practice experience (APPE).

METHODS: Pediatric-specific WBT modules were developed for completion by APPE students during a 4- week rotation. Pediatric modules covered developmental pharmacology; antimicrobial use and monitoring; fluids, electrolytes, and dehydration; and drug information. Students were responsible for completing all modules within the first week of the APPE. Preassessments and postassessments consisted of 8 to 10 multiple-choice questions, with scores ranging from 0 to 100 points. Data were …

Hyperphosphatemia In Pediatric Oncology Patients Receiving Liposomal Amphotericin B, Chad A. Knoderer, Holly M. Knoderer

Scholarship and Professional Work – COPHS

OBJECTIVE: After transitioning our front-line amphotericin product to the liposomal formulation, we observed an increased incidence of hyperphosphatemia. We aimed to determine the incidence of hyperphosphatemia in children with oncologic disorders receiving an amphotericin B product and to establish whether the incidence varies depending on amphotericin formulation.

METHODS: This retrospective review of the medical record was conducted at a tertiary, free standing children’s hospital. Pharmacy data revealed 159 patients receiving an amphotericin product between November 2006 and December 2008. Doses of amphotericin, serum phosphorous, calcium and creatinine concentrations were recorded at daily time points during the 10 days following both …

Evaluation Of Vancomycin Dosing And Corresponding Drug Concentrations In Pediatric Patients, Lauren Maurer Pharmd, Jenny Boucher Pharmd, Bcps, Ejd

Department of Pharmacy

No abstract provided.

Postgraduate Year One (Pgy1) Department Of Pharmacy Residency Program, Jessica Price Pharmd, Bcps

Department of Pharmacy

No abstract provided.

Natural Products Chemistry Of Leads Acting On Mrsa, Hcv, Malaria, And Depression Disorders, Mohamed Ali Mohamed Ali Ibrahim

Electronic Theses and Dissertations

Nature has proven to be an endless source of abundant diversity of chemical entities with varying biological activities. The World Health Organization (WHO) estimates that 80% of the world's population depends on traditional medicine for treating their everyday health problems. According to Gordon Cragg, former director of the natural products branch of the NCI, ″Nature has produced wonderfully complex molecules that no synthetic chemist could ever dream up.″ Moreover, he emphasized that over 60% of cancer therapeutics have been derived from nature whether directly through isolation or indirectly through semi-synthesis. Various examples have been reported such as extracts from Catharanthus …

Current Therapies For Chronic Hepatitis C, Mckenzie C. Ferguson

Pharmacy Faculty Research, Scholarship, and Creative Activity

Hepatitis C virus affects more than 180 million people worldwide and as many as 4 million people in the United States. Given that most patients are asymptomatic until late in the disease progression, diagnostic screening and evaluation should be performed in patients who display high-risk behaviors associated with acquisition of hepatitis C. Chronic hepatitis C is associated with cirrhosis, hepatic failure, and death; therefore, treatment is aimed at reducing these complications, as well as improving quality of life and minimizing adverse effects. The American Association for the Study of Liver Diseases Practice Guidelines on the Diagnosis, Management, and Treatment of …

Target Validation Of Uk-101 And Functional Studies Of Β1i, Marie V. Wehenkel

Theses and Dissertations--Pharmacy

β1i is a major catalytic subunit of the immunoproteasome, an alternative form of the constitutive proteasome, and its upregulation has been demonstrated in a variety of disease states including cancer. Our lab has developed a small molecule inhibitor of β1i, dubbed UK-101. While UK-101 causes apoptosis in cancer cell lines, it was not clear whether this apoptotic effect was directly mediated by its irreversible inhibition of β1i. Since off-target effects are major roadblocks for the development of new and effective pharmaceuticals, target validation studies in this system would assist in the further progression of β1i inhibitors towards preclinical trials. Our …

Synthesis, Screening And Cocrystallization Of Adenosine Based Inhibitors With Methyltransferases, Ermc' And Ksga, Matthew Baker

Theses and Dissertations

Antibiotic resistance threatens to throw mankind back into an era when infectious disease was the predominant cause of death. In an effort to mitigate this danger, we targeted ErmC’ and KsgA. Both methylate N6-adenosine of ribosomal RNA, though each serve different roles in their bacterial host. ErmC’ dimethylates A2058 on 23S rRNA, conferring resistance to MLSB antibiotics (macrolides, lincosamides, streptogramin B). KsgA aids in ribosome assembly, binding inactive 30S until dimethylating A1518/A1519 of 16S rRNA. Like most methyltransferases, ErmC’ and KsgA use cofactor S-adenosylmethionine (SAM) as their methyl source, which binds adjacent to their specific adenosine substrate. ErmC’ inhibitors could …

Novel Approaches To The Control Of Infectious Diseases, Damaris Agathe Meujo Foping

Electronic Theses and Dissertations

As part of our ongoing efforts to find new drug leads against infectious diseases, several terrestrial and marine macro- and microorganisms were investigated. Several bioactive molecules, presented below, were isolated from these natural products. The mass-screening of dozens of marine Actinomycetes was completed and several Streptomyces with interesting biological activity profiles identified. A few examples are the Streptomyces code H747 and the Streptomyces code H668, a bacterium from which a new (5) and two known polyethers, the antimalarial agent K41-A (6) and its C-29 analog (7) were isolated. Five new six-membered ring cyclic peroxides: plakinastreloic acid A (8), methyl plakinastreloate …

Cumulative Clinical Experience From Over A Decade Of Use Of Levofloxacin In Community Acquired Pneumonia; Critical Appraisal And Role In Therapy, Ayman M. Noreddin, Walid F. Elkhatib, Kenji M. Cunnion, George G. Zhanel

Pharmacy Faculty Articles and Research

Levofloxacin is the synthetic L-isomer of the racemic fluoroquinolone, ofloxacin. It interferes with critical processes in the bacterial cell such as DNA replication, transcription, repair, and recombination by inhibiting bacterial topoisomerases. Levofloxacin has broad spectrum activity against several causative bacterial pathogens of community-acquired pneumonia (CAP). Oral levofloxacin is rapidly absorbed and is bioequivalent to the intravenous formulation such that patients can be conveniently transitioned between these formulations when moving from the inpatient to the outpatient setting. Furthermore, levofloxacin demonstrates excellent safety, and has good tissue penetration maintaining adequate concentrations at the site of infection. The efficacy and tolerability of …