Pharmacy and Pharmaceutical Sciences Commons^™

Modeling Of Mpges-1 Three-Dimensional Structures: Applications In Drug Design And Discovery, Chang-Guo Zhan, Xiaoqin Huang, Adel Hamza

Pharmaceutical Sciences Faculty Patents

This invention relates to representations of prostaglandin synthase three-dimensional structures. Such representations are suitable for designing agents that modulate the activity of the enzyme by binding to the substrate binding domain.

New Approach To Develop Ultra-High Inhibitory Drug Using The Power Function Of The Stoichiometry Of The Targeted Nanomachine Or Biocomplex, Dan Shu, Fengmei Pi, Chi Wang, Peng Zhang, Peixuan Guo

Pharmaceutical Sciences Faculty Publications

AIMS: To find methods for potent drug development by targeting to biocomplex with high copy number.

METHODS: Phi29 DNA packaging motor components with different stoichiometries were used as model to assay virion assembly with Yang Hui's Triangle [Formula: see text], where Z = stoichiometry, M = drugged subunits per biocomplex, p and q are the fraction of drugged and undrugged subunits in the population.

RESULTS: Inhibition efficiency follows a power function. When number of drugged subunits to block the function of the complex K = 1, the uninhibited biocomplex equals q(z), demonstrating the multiplicative effect of stoichiometry on inhibition with …

Influence Of Linker Length And Composition On Enzymatic Activity And Ribosomal Binding Of Neomycin Dimers, Derrick Watkins, Sunil Kumar, Keith D. Green, Dev P. Arya, Sylvie Garneau-Tsodikova

Pharmaceutical Sciences Faculty Publications

The human and bacterial A site rRNA binding as well as the aminoglycoside-modifying enzyme (AME) activity against a series of neomycin B (NEO) dimers is presented. The data indicate that by simple modifications of linker length and composition, substantial differences in rRNA selectivity and AME activity can be obtained. We tested five different AMEs with dimeric NEO dimers that were tethered via triazole, urea, and thiourea linkages. We show that triazole-linked dimers were the worst substrates for most AMEs, with those containing the longer linkers showing the largest decrease in activity. Thiourea-linked dimers that showed a decrease in activity by …

Inhibition Of Aminoglycoside Acetyltransferase Resistance Enzymes By Metal Salts, Yijia Li, Keith D. Green, Brooke R. Johnson, Sylvie Garneau-Tsodikova

Pharmaceutical Sciences Faculty Publications

Aminoglycosides (AGs) are clinically relevant antibiotics used to treat infections caused by both Gram-negative and Gram-positive bacteria, as well as Mycobacteria. As with all current antibacterial agents, resistance to AGs is an increasing problem. The most common mechanism of resistance to AGs is the presence of AG-modifying enzymes (AMEs) in bacterial cells, with AG acetyltransferases (AACs) being the most prevalent. Recently, it was discovered that Zn²⁺ metal ions displayed an inhibitory effect on the resistance enzyme AAC(6')-Ib in Acinetobacter baumannii and Escherichia coli. In this study, we explore a wide array of metal salts (Mg²⁺, …

Flucytosine Pharmacokinetics In A Critically Ill Patient Receiving Continuous Renal Replacement Therapy, Megan E. Kunka, Elizabeth A. Cady, Heejung C. Woo, Melissa L. Thompson Bastin

Pharmacy Practice and Science Faculty Publications

Purpose. A case report evaluating flucytosine dosing in a critically ill patient receiving continuous renal replacement therapy. Summary. This case report outlines an 81-year-old male who was receiving continuous venovenous hemofiltration (CVVH) for acute renal failure and was being treated with flucytosine for the treatment of disseminated Cryptococcus neoformans infection. Due to patient specific factors, flucytosine was empirically dose adjusted approximately 50% lower than intermittent hemodialysis (iHD) recommendations and approximately 33% lower than CRRT recommendations. Peak and trough levels were obtained, which were supratherapeutic, and pharmacokinetic parameters were calculated. The patient experienced thrombocytopenia, likely due to elevated flucytosine …

Rna Nanoparticle As A Vector For Targeted Sirna Delivery Into Glioblastoma Mouse Model, Tae Jin Lee, Farzin Haque, Dan Shu, Ji Young Yoo, Hui Li, Robert A. Yokel, Craig Horbinski, Tae Hyong Kim, Sung-Hak Kim, Chang-Hyuk Kwon, Ichiro Nakano, Balveen Kaur, Peixuan Guo, Carlo M. Croce

Pharmaceutical Sciences Faculty Publications

Systemic siRNA administration to target and treat glioblastoma, one of the most deadly cancers, requires robust and efficient delivery platform without immunogenicity. Here we report newly emerged multivalent naked RNA nanoparticle (RNP) based on pRNA 3-way-junction (3WJ) from bacteriophage phi29 to target glioblastoma cells with folate (FA) ligand and deliver siRNA for gene silencing. Systemically injected FA-pRNA-3WJ RNPs successfully targeted and delivered siRNA into brain tumor cells in mice, and efficiently reduced luciferase reporter gene expression (4-fold lower than control). The FA-pRNA-3WJ RNP also can target human patient-derived glioblastoma stem cells, thought to be responsible for tumor initiation and deadly …

Use Of Parthenolide Derivatives As Antileukemic And Cytotoxic Agents, Peter A. Crooks, Craig T. Jordan, Xiaochen Wei

Pharmaceutical Sciences Faculty Patents

To read this abstract, please download this patent.

The Biosynthesis Of Capuramycin-Type Antibiotics: Identification Of The A-102395 Biosynthetic Gene Cluster, Mechanism Of Self-Resistence, And Formation Of Uridine-5'-Carboxamide, Wenlong Cai, Anwesha Goswami, Zhaoyong Yang, Xiaodong Liu, Keith D. Green, Sandra Barnard-Britson, Satoshi Baba, Masanori Funabashi, Koichi Nonaka, Manjula Sunkara, Andrew J. Morris, Anatol P. Spork, Christian Ducho, Sylvie Garneau-Tsodikova, Jon S. Thorson, Steven Van Lanen

Pharmaceutical Sciences Faculty Publications

A-500359s, A-503083s, and A-102395 are capuramycin-type nucleoside antibiotics that were discovered using a screen to identify inhibitors of bacterial translocase I, an essential enzyme in peptidoglycan cell wall biosynthesis. Like the parent capuramycin, A-500359s and A-503083s consist of three structural components: a uridine-5'-carboxamide (CarU), a rare unsaturated hexuronic acid, and an aminocaprolactam, the last of which is substituted by an unusual arylamine-containing polyamide in A-102395. The biosynthetic gene clusters for A-500359s and A-503083s have been reported, and two genes encoding a putative non-heme Fe(II)-dependent α-ketoglutarate:UMP dioxygenase and an l-Thr:uridine-5'-aldehyde transaldolase were uncovered, suggesting that C-C bond formation during assembly of …

Alternating Magnetic Field-Induced Hyperthermia Increases Iron Oxide Nanoparticle Cell Association/Uptake And Flux In Blood-Brain Barrier Models, Mo Dan, Younsoo Bae, Thomas A. Pittman, Robert A. Yokel

Pharmaceutical Sciences Faculty Publications

PURPOSE: Superparamagnetic iron oxide nanoparticles (IONPs) are being investigated for brain cancer therapy because alternating magnetic field (AMF) activates them to produce hyperthermia. For central nervous system applications, brain entry of diagnostic and therapeutic agents is usually essential. We hypothesized that AMF-induced hyperthermia significantly increases IONP blood-brain barrier (BBB) association/uptake and flux.

METHODS: Cross-linked nanoassemblies loaded with IONPs (CNA-IONPs) and conventional citrate-coated IONPs (citrate-IONPs) were synthesized and characterized in house. CNA-IONP and citrate-IONP BBB cell association/uptake and flux were studied using two BBB Transwell^® models (bEnd.3 and MDCKII cells) after conventional and AMF-induced hyperthermia exposure.

RESULTS: …

Microcystins As Agents For Treatment Of Cancer, Noel R. Monks, Shuqian Liu, Jeffrey A. Moscow

Pharmaceutical Sciences Faculty Patents

This invention relates to the use of microcystins as agents for treatment of cancer. Also provided are methods of screening for microcystins with improved cytotoxicity.

Prescription Drug Monitoring Program Utilization In Kentucky Community Pharmacies, Sarah E. Wixson, Karen Blumenschein, Amie J. Goodin, Jeffery Talbert, Patricia R. Freeman

Pharmacy Practice and Science Faculty Publications

OBJECTIVE: Identify characteristics of Kentucky community pharmacists and community pharmacists' practice environment associated with utilization of the Kentucky All Schedule Prescription Electronic Reporting Program (KASPER).

METHODS: Surveys were mailed to all 1,018 Kentucky pharmacists with a KASPER account and an additional 1,000 licensed pharmacists without an account. Bivariate analyses examined the association between KASPER utilization and practice type (independent or chain) and practice location (rural or urban). A multivariate Poisson regression model with robust error variance estimated risk ratios (RR) of KASPER utilization by characteristics of pharmacists' practice environment.

RESULTS: Responses were received from 563 pharmacists (response …

Drug Synergy Drives Conserved Pathways To Increase Fission Yeast Lifespan, Xinhe Huang, Markos Leggas, Robert C. Dickson

Pharmaceutical Sciences Faculty Publications

Aging occurs over time with gradual and progressive loss of physiological function. Strategies to reduce the rate of functional loss and mitigate the subsequent onset of deadly age-related diseases are being sought. We demonstrated previously that a combination of rapamycin and myriocin reduces age-related functional loss in the Baker's yeast Saccharomyces cerevisiae and produces a synergistic increase in lifespan. Here we show that the same drug combination also produces a synergistic increase in the lifespan of the fission yeast Schizosaccharomyces pombe and does so by controlling signal transduction pathways conserved across a wide evolutionary time span ranging from yeasts to …

Pharmacologically Distinct Nicotinic Acetylcholine Receptors Drive Efferent-Mediated Excitation In Calyx-Bearing Vestibular Afferents, J. Chris Holt, Kevin Kewin, Paivi M. Jordan, Peter Cameron, Marcin Klapczynski, J. Michael Mcintosh, Peter A. Crooks, Linda P. Dwoskin, Anna Lysakowski

Pharmaceutical Sciences Faculty Publications

Electrical stimulation of vestibular efferent neurons rapidly excites the resting discharge of calyx/dimorphic (CD) afferents. In turtle, this excitation arises when acetylcholine (ACh), released from efferent terminals, directly depolarizes calyceal endings by activating nicotinic ACh receptors (nAChRs). Although molecular biological data from the peripheral vestibular system implicate most of the known nAChR subunits, specific information about those contributing to efferent-mediated excitation of CD afferents is lacking. We sought to identify the nAChR subunits that underlie the rapid excitation of CD afferents and whether they differ from α9α10 nAChRs on type II hair cells that drive efferent-mediated inhibition in adjacent bouton …

High Activity Mutants Of Butyrylcholinesterase For Cocaine Hydrolysis, Chang-Guo Zhan, Fang Zheng, Wenchao Yang, Lin Xue, Shurong Hou

Pharmaceutical Sciences Faculty Patents

Butyrylcholinesterase (BChE) polypeptide variants of the presently-disclosed subject matter have enhanced catalytic efficiency for (−)-cocaine, as compared to wild-type BChE. Pharmaceutical compositions of the presently-disclosed subject matter include a BChE polypeptide variant having an enhanced catalytic efficiency for (−)-cocaine. A method of the presently-disclosed subject matter for treating a cocaine-induced condition includes administering to an individual an effective amount of a BChE polypeptide variant, as disclosed herein, to lower blood cocaine concentration.

A Coming Disruption In Pharmacy?, Frank Romanelli, Timothy S. Tracy

Pharmacy Practice and Science Faculty Publications

No abstract provided.

Factors Affecting The Pharmacokinetics And Pharmacodynamics Of Pegylated Liposomal Irinotecan (Ihl-305) In Patients With Advanced Solid Tumors, Huali Wu, Jeffrey R. Infante, Vicki L. Keedy, Suzanne F. Jones, Emily Chan, Johanna C. Bendell, Wooin Lee, Whitney P. Kirschbrown, Beth A. Zamboni, Satoshi Ikeda, Hiroshi Kodaira, Mace L. Rothenberg, Howard A. Burris, William C. Zamboni

Pharmaceutical Sciences Faculty Publications

IHL-305 is a PEGylated liposomal formulation of irinotecan (CPT-11). The objective of this study was to evaluate the factors associated with interpatient variability in the pharmacokinetics and pharmacodynamics of IHL-305 in patients with advanced solid tumors. IHL-305 was administered intravenously once every 4 weeks as part of a Phase I study. Pharmacokinetic studies of the liposomal sum total CPT-11, released CPT-11, SN-38, SN-38G, 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]-carbonyloxycamptothecin, and 7-ethyl-10-[4-amino-1-piperidino]-carbonyloxycamptothecin in plasma were performed. Noncompartmental and compartmental pharmacokinetic analyses were conducted using pharmacokinetic data for sum total CPT-11. The pharmacokinetic variability of IHL-305 is associated with linear and nonlinear clearance. Patients whose age …

Fret Detection Of Lymphocyte Function-Associated Antigen-1 Conformational Extension, Alexandre Chigaev, Yelena Smagley, Mark K. Haynes, Oleg Ursu, Cristian G. Bologa, Liliana Halip, Tudor Oprea, Anna Waller, Mark B. Carter, Yinan Zhang, Wei Wang, Tione Buranda, Larry A. Sklar

Pharmaceutical Sciences Faculty Publications

Lymphocyte function-associated antigen 1 (LFA-1, CD11a/CD18, αLβ2-integrin) and its ligands are essential for adhesion between T-cells and antigen-presenting cells, formation of the immunological synapse, and other immune cell interactions. LFA-1 function is regulated through conformational changes that include the modulation of ligand binding affinity and molecular extension. However, the relationship between molecular conformation and function is unclear. Here fluorescence resonance energy transfer (FRET) with new LFA-1-specific fluorescent probes showed that triggering of the pathway used for T-cell activation induced rapid unquenching of the FRET signal consistent with extension of the molecule. Analysis of the FRET quenching at rest revealed an …

Target-Directed Biosynthetic Evolution: Redirecting Plant Evolution To Genomically Optimize A Plant’S Pharmacological Profile, Dustin Paul Brown

Theses and Dissertations--Neuroscience

The dissertation describes a novel method for plant drug discovery based on mutation and selection of plant cells. Despite the industry focus on chemical synthesis, plants remain a source of potent and complex bioactive metabolites. Many of these have evolved as defensive compounds targeted on key proteins in the CNS of herbivorous insects, for example the insect dopamine transporter (DAT). Because of homology with the human DAT protein some of these metabolites have high abuse potential, but others may be valuable in treating drug dependence. This dissertation redirects the evolution of a native Lobelia species toward metabolites with greater activity …

Roles Of Abcg5 Abcg8 Cholesterol Transporter In Lipid Homeostasis, Yuhuan Wang

Theses and Dissertations--Pharmacy

The ABCG5 ABCG8 (G5G8) sterol transporter promotes cholesterol secretion into bile and opposes dietary sterol absorption in the small intestine. An emerging body of literature suggests that G5G8 links sterol flux to various risk factors for metabolic syndrome (MetS) and nonalcoholic fatty liver disease (NAFLD). Therapeutic approaches that accelerate G5G8 activity may augment reverse cholesterol transport (RCT) and provide beneficial effects in the prevention and treatment of cardiovascular and liver disease.

Mice lacking leptin (ob/ob) or its receptor (db/db) are obese, insulin resistant in part due to the reduced levels of hepatic G5G8 and biliary cholesterol. …

Medication Misadventures: The Case Of Benzodiazepines, Sarah E. Wixson

Theses and Dissertations--Pharmacy

For patients afflicted with symptoms of anxiety and insomnia, benzodiazepines are generally a safe and effective short-term pharmacological treatment option. Although considered safer than other sedative-hypnotic medications, substantial concern exists regarding the addictive nature and abuse potential of benzodiazepines along with potentially inappropriate prescribing and utilization in clinically vulnerable populations. These medication misadventures can have a significant impact on public health. Examples of medication misadventures as they pertain to benzodiazepines include the prescribing and use in clinically vulnerable populations for whom they are contraindicated or their efficacy has not been evaluated, the development of tolerance or addiction, abuse of the …

Kinetics And Mechanisms Of Crystal Growth Inhibition Of Indomethacin By Model Precipitation Inhibitors, Dhaval D. Patel

Theses and Dissertations--Pharmacy

Supersaturating Drug Delivery Systems (SDDS) could enhance oral bioavailability of poorly water soluble drugs (PWSD). Precipitation inhibitors (PIs) in SDDS could maintain supersaturation by inhibiting nucleation, crystal growth, or both. The mechanisms by which these effects are realized are generally unknown. The goal of this dissertation was to explore the mechanisms underpinning the effects of model PIs including hydroxypropyl β-cyclodextrins (HP-β-CD), hydroxypropyl methylcellulose (HPMC), and polyvinylpyrrolidone (PVP) on the crystal growth of indomethacin, a model PWSD. At high degrees of supersaturation (S), the crystal growth kinetics of indomethacin was bulk diffusion-controlled, which was attributed to a high energy form deposited …

Design, Synthesis, And Pharmacological Evaluation Of Three Series Of Lobelane Analogs As Inhibitors Of The Vesicular Monoamine Transporter (Vmat2), John P. Culver

Theses and Dissertations--Pharmacy

Methamphetamine (METH) abuse is a serious problem in the United States and worldwide. The reward experienced by METH users is due to the increase in extracellular dopamine (DA) concentrations caused by an interaction between METH and the DA transporter (DAT) as well as the Vesicular Monoamine Transporter-2 (VMAT2). The reward felt by users of METH leads to further use of the drug and subsequent abuse. The current project examined the ability of three novel series of lobelane analogs to interact with a binding site on the Vesicular Monoamine Transporter-2 (VMAT2) in an attempt to inhibit the effects of METH. Lobelane …

Chemoenzymatic Studies To Enhance The Chemical Space Of Natural Products, Jhong-Min Chen

Theses and Dissertations--Pharmacy

Natural products provide some of the most potent anticancer agents and offer a template for new drug design or improvement with the advantage of an enormous chemical space. The overall goal of this thesis research is to enhance the chemical space of two natural products in order to generate novel drugs with better in vivo bioactivities than the original natural products.

Polycarcin V (PV) is a gilvocarcin-type antitumor agent with similar structure and comparable bioactivity with the principle compound of this group, gilvocarcin V (GV). Modest modifications of the polyketide-derived tetracyclic core of GV had been accomplished, but the most …

A Molecular-Level View Of The Physical Stability Of Amorphous Solid Dispersions, Xiaoda Yuan

Theses and Dissertations--Pharmacy

Many pharmaceutical compounds being developed in recent years are poorly soluble in water. This has led to insufficient oral bioavailability of many compounds in vitro. The amorphous formulation is one of the promising techniques to increase the oral bioavailability of these poorly water-soluble compounds. However, an amorphous drug substance is inherently unstable because it is a high energy form. In order to increase the physical stability, the amorphous drug is often formulated with a suitable polymer to form an amorphous solid dispersion. Previous research has suggested that the formation of an intimately mixed drug-polymer mixture contributes to the stabilization …

Molecular And Functional Investigation Of Cancer-Type And Liver-Type Variants Of Organic Anion Transporting Polypeptide 1b3, Nilay Thakkar

Theses and Dissertations--Pharmacy

OATP1B3 belongs to the OATP (organic anion transporting polypeptides) superfamily, responsible for mediating the transport of various endogenous and xenobiotic substrates. OATP1B3 was initially reported to be expressed exclusively in the hepatocytes where it mediates the uptake of numerous endogenous substrates (e.g. bile acids, steroid hormone conjugates) and several clinically relevant drugs including anticancer drugs. Later, a number of studies reported that OATP1B3 is also frequently expressed in multiple types of cancers and may be associated with differing clinical outcomes. However, a detailed investigation on the expression, localization and functions of OATP1B3 expressed in cancer has been lacking. In this …

Antibiotics Targeting Tuberculosis: Biosynthesis Of A-102395 And Discovery Of Novel Actinomycins, Wenlong Cai

Theses and Dissertations--Pharmacy

The increase in antibiotic resistance of many bacterial strains including multidrug-resistant tuberculosis (MDR-TB) due to over- and misuse of antibiotics is a serious medical and economical problem. Therefore discovery and development of new antibiotics are urgently needed. Two projects were undertaken to address the need for new anti-tuberculosis antibiotics.

1. Discovery of new chemical entities. A-102395, a new nucleoside inhibitor of bacterial MraY (translocase I, EC 2.7.8.13) that is essential for bacterial survival, was isolated from the culture broth of Amycolatopsis sp. SANK 60206 in 2007. Although A-102395 is a potent inhibitor of translocase I with IC50 of 11 nM, …

Elucidating The Mechanism Of Lipl: A Non-Heme Fe(Ii), Α -Ketoglutarate: Uridine-5’-Monophosphate Dioxygenase, Anwesha Goswami

Theses and Dissertations--Pharmacy

Several nucleoside natural product antibiotics from Streptomyces sp. and actinomycetes have recently been shown to target bacterial peptidoglycan cell wall biosynthesis by inhibiting the bacterial translocase I (MraY). The biosynthetic gene clusters for A-90289, liposidomycins and caprazamycins revealed a protein with sequence similarity to proteins annotated as α-KG:taurine dioxygenases (TauD). This enzyme (LipL) is a mononuclear, non-heme, Fe(II) dependent α-keto glutarate (α-KG) :uridine monophosphate (UMP) dioxygenase responsible for the net dephosphorylation and two electron oxidation of UMP to uridine-5’-aldehyde. The postulated reaction coordinates involving the activation of the C-5’ center in UMP and the corresponding formation of uridine-5’-aldehyde are modeled …

Melampomagnolide B Derivatives As Antileukemic And Cytotoxic Agents, Peter A. Crooks, Craig T. Jordan, Shanshan Pei, Shama Nasim

Pharmaceutical Sciences Faculty Patents

Melampomagnolide B is disclosed as a new antileukemic sesquiterpene. A biotin-conjugated derivative of melampomagnolide B was prepared to elucidate its mechanism of action. Prodrugs of Melampomagnolide B are disclosed.

Pharmacy Law Brief: Alternative Dispute Resolution, Joseph L. Fink Iii

Pharmacy Practice and Science Faculty Publications

No abstract provided.

Ph-Sensitive Mucoadhesive Film-Forming Gels And Wax-Film Composites Suitable For Topical And Mucosal Delivery Of Molecules, Russell J. Mumper, Michael Jay

Pharmaceutical Sciences Faculty Patents

The present invention relates to pH-sensitive mucoadhesive film-forming gels and wax-film composites suitable for topical and mucosal delivery of molecules of interest, namely active pharmaceuticals. The gels comprise a pharmaceutically acceptable pH-sensitive polymer that responds to a lowering of pH by precipitating into films when in contact with the skin or mucosal surface. The films also comprise an adhesive polymer that allows the film to remain in contact with the tissue for an extended period of time. The wax-film composites comprise a bi-layer film having both the said pH-sensitive mucoadhesive layer to promote strong adherence to the skin and mucosal …