Medicine and Health Sciences Commons^™

Manganese Flux Across The Blood-Brain Barrier, Robert A. Yokel

Pharmaceutical Sciences Faculty Publications

Manganese (Mn) is essential for brain growth and metabolism, but in excess can be a neurotoxicant. The chemical form (species) of Mn influences its kinetics and toxicity. Significant Mn species entering the brain are the Mn²⁺ ion and Mn citrate which, along with Mn transferrin, enter the brain by carrier-mediated processes. Although the divalent metal transporter (DMT-1) was suggested to be a candidate for brain Mn uptake, brain Mn influx was not different in Belgrade rats, which do not express functional DMT-1, compared to controls. Brain Mn influx was not sodium dependent or dependent on ATP hydrolysis, but was …

Compositions Comprising Human Immunodeficiency Virus Tat Adsorbed To The Surface Of Anionic Nanoparticles, Russell J. Mumper, Jerold Woodward, Zhengrong Cui, Avindra Nath

Pharmaceutical Sciences Faculty Patents

Non-denatured, recombinant human immunodeficiency virus (HIV) Tat that is free of bacterial RNA and endotoxin is employed in an anti-HIV vaccine. A process of producing the recombinant Tat protein includes steps for removing bacterial RNA from the recombinant Tat and for removing endotoxin from the recombinant Tat protein. A Tat-adsorbed nanoparticle formulation and method of making the same. A method of vaccinating against and/or treating HIV infection comprises administering to a subject in need of such vaccination or treatment an immune-response inducing effective amount of the recombinant Tat protein.

Effects Of Genetic Deficiency Of Cyclooxygenase-1 Or Cyclooxygenase-2 On Functional And Histological Outcomes Following Traumatic Brain Injury In Mice, Matthew L. Kelso, Stephen W. Scheff, James R. Pauly, Charles D. Loftin

Pharmaceutical Sciences Faculty Publications

BACKGROUND: Neuroinflammation contributes to the pathophysiology of acute CNS injury, including traumatic brain injury (TBI). Although prostaglandin lipid mediators of inflammation contribute to a variety of inflammatory responses, their importance in neuroinflammation is not clear. There are conflicting reports as to the efficacy of inhibiting the enzymes required for prostaglandin formation, cyclooxygenase (COX) -1 and COX-2, for improving outcomes following TBI. The purpose of the current study was to determine the role of the COX isoforms in contributing to pathological processes resulting from TBI by utilizing mice deficient in COX-1 or COX-2.

RESULTS: Following a mild controlled cortical impact injury, …

Muc1 Is A Downstream Target Of Stat3 And Regulates Lung Cancer Cell Survival And Invasion, Jingchun Gao, Matthew J. Mcconnell, Bin Yu, Jiannong Li, Justin M. Balko, Esther P. Black, Joseph O. Johnson, Mark C. Lloyd, Soner Altiok, Eric B. Haura

Pharmaceutical Sciences Faculty Publications

Signal transducer and activator of transcription 3 (STAT3) is aberrantly activated in human cancer including lung cancer and has been implicated in transformation, tumorigenicity, and metastasis. One putative downstream gene regulated by Stat3 is MUC1 which also has important roles in tumorigenesis. We determined if Stat3 regulates MUC1 in lung cancer cell lines and what function MUC1 plays in lung cancer cell biology. We examined MUC1 expression in non-small cell lung cancer (NSCLC) cell lines and found high levels of MUC1 protein expression associated with higher levels of tyrosine phosphorylated STAT3. STAT3 knockdown downregulated MUC1 expression whereas constitutive STAT3 expression …

Programmable Multi-Dose Intranasal Drug Delivery Device, Daniel Wermeling, Ryan Vallance, Aravind Balasubramanian, Bruce L. Walcott, John A. Main, James E. Lumpp

Pharmacy Practice and Science Faculty Patents

An apparatus and method for the self-administration of a plurality of doses of an intranasal liquid pharmaceutical composition, including opioid analgesics, that includes a drug delivery device containing a plurality of sealed vials, each vial containing a predetermined volume of the pharmaceutical composition, a pump assembly for conveying the liquid pharmaceutical composition from the interior of the vial and discharging it as a nasal spray in response to manual activation by the patient, and programmable means for sequentially advancing a vial to the ready position after passage of a prescribed time interval following the last activation of the delivery device.

Method And System For In Situ Spectroscopic Evaulation Of An Object, Robert A. Lodder

Pharmaceutical Sciences Faculty Patents

A method and system for spectroscopically determining surface and product characteristics is employed for rapid detection of product characteristics and/or the presence or absence of suspected analytes, and the concentration of the analyte. The method and system uses a signal wide band detector that does not require focusing optics in many environments. It can be used for cleaning validation of pharmaceutical products and process equipment.

Genes Encoding Several Poly (Adp-Ribose) Glycohydrolase (Parg) Enzymes, The Proteins And Fragments Thereof, And Antibodies Immunoreactive Therewith, Myron Jacobson, Elaine L. Jacobson, Jean-Christoph Amé, Winston Lin

Pharmaceutical Sciences Faculty Patents

The isolation and characterization of cDNAs encoding poly(ADP-ribose) glycohydrolase (PARG) enzymes and the amino acid sequences of PARGs from several species are described. PARG is involved in the cellular response to DNA damage and its proper function is associated with the body's response to neoplastic disorder inducing agents and oxidative stress. Expression vectors containing the cDNAs and cells transformed with the vectors are described. Probes and primers that hybridize with the cDNAs are described. Expression of the cDNA in E. coli results in an enzymatically active protein of about 111 kDa and an active fragment of about 59 kDa. Methods …

A Gene Expression Predictor Of Response To Egfr-Targeted Therapy Stratifies Progression-Free Survival To Cetuximab In Kras Wild-Type Metastatic Colorectal Cancer, Justin M. Balko, Esther P. Black

Pharmaceutical Sciences Faculty Publications

BACKGROUND: The anti-EGFR monoclonal antibody cetuximab is used in metastatic colorectal cancer (CRC), and predicting responsive patients garners great interest, due to the high cost of therapy. Mutations in the KRAS gene occur in ~40% of CRC and are a negative predictor of response to cetuximab. However, many KRAS-wildtype patients do not benefit from cetuximab. We previously published a gene expression predictor of sensitivity to erlotinib, an EGFR inhibitor. The purpose of this study was to determine if this predictor could identify KRAS-wildtype CRC patients who will benefit from cetuximab therapy.

METHODS: Microarray data from 80 metastatic CRC patients subsequently …

Carbon Nanotube Membranes For Use In The Transdermal Treatment Of Nicotine Addiction And Opioid Withdrawal Symptoms, Caroline L. Strasinger, Nicole N. Scheff, Ji Wu, Bruce J. Hinds, Audra L. Stinchcomb

Pharmaceutical Sciences Faculty Publications

Transdermal systems are attractive methods of drug administration specifically when treating patients for drug addiction. Current systems however are deficient in therapies that allow variable flux values of drug, such as nicotine for smoking cessation or complex dosing regimens using clonidine when treating opioid withdrawal symptoms. Through the use of functionalized carbon nanotube (CNT) membranes, drug delivery to the skin can be controlled by applying a small electrical bias to create a programmable drug delivery system. Clearly, a transdermal patch system that can be tailored to an individual's needs will increase patient compliance as well as provide much more efficient …

Identification Of A Potent Herbal Molecule For The Treatment Of Breast Cancer, Srinivas Koduru, Srinivasan Sowmyalakshmi, Raj Kumar, Rohini Gomathinayagam, Jürgen Rohr, Chendil Damodaran

Pharmaceutical Sciences Faculty Publications

BACKGROUND: Breast cancer (BCa)-related mortality still remains the second leading cause of cancer-related deaths worldwide. Patients with BCa have increasingly shown resistance and high toxicity to current chemotherapeutic drugs for which identification of novel targeted therapies are required.

METHODS: To determine the effect of PDBD on BCa cells, estrogen-receptor positive (ER+)-MCF-7 and estrogen-receptor negative (ER-)-MDA 231 cells were treated with PDBD and the cell viability, apoptotic, cell cycle, Western blot and Promoter assays were performed.

RESULTS: PDBD inhibits cell viability of ER+ and ER- BCa cells by inducing apoptosis without causing significant toxicity in normal breast epithelial cells. While dissecting …

Experimental And Molecular Dynamics Simulation Studies Of Partitioning And Transport Across Lipid Bilayer Membranes, Ravindra Wadhumal Tejwani

University of Kentucky Doctoral Dissertations

Most drugs undergo passive transport during absorption and distribution in the body. It is desirable to predict passive permeation of future drug candidates in order to increase the productivity of the drug discovery process. Unlike drug-receptor interactions, there is no receptor map for passive permeability because the process of transport across the lipid bilayer involves multiple mechanisms. This work intends to increase the understanding of permeation of drug-like molecules through lipid bilayers.

Drug molecules in solution typically form various species due to ionization, complexation, etc. Therefore, species specific properties must be obtained to bridge the experiment and simulations. Due to …

Studies On Drug Solubilization Mechanism In Simple Micelle Systems, Shaoxin Feng

University of Kentucky Doctoral Dissertations

Poor aqueous solubilities of drug candidates limit the biopharmaceutical usefulness in either oral or parenteral dosage forms. Lipid assemblies, such as micelles, may provide a means of enhancing solubility. Despite their usefulness, little is known about the means by which micelles accomplish this result. The goal of the current dissertation is to provide the molecular level understanding of the mechanism by which simple micelle systems solubilize drugs. Specifically, the location, orientation and amount of the drug molecules in micelle systems are the focuses of the work.

Three series of model drugs, steroids, benzodiazepines and parabens, in three surfactant systems with …

Use Of Topical Nsaids In Acute Musculoskeletal Sports Injury: A Brief Review, Amit M. Deokar, Shawn J. Smith, Hatim A. Omar

Pediatrics Faculty Publications

The objective of this chapter is to summarize the current standards of pain management in minor sports-related musculoskeletal injuries. This chapter also addresses the topical form of non-steroidal anti-inflammatory drug as an effective pain management option in an outpatient setting. Design: Quantitive systematic review of randomized controlled trials. Methods: The data was obtained through literature review of articles published in the last 10 years. In addition, FDA information on non-steroidal anti-inflammatory medications was also reviewed. The patient population studied in the articles included children and adults. Conclusion: Current standards of managing pain resulting from sports injuries involve a number of …

Concepts Of Contraception For Adolescents With Obesity: Pathways Of Judicial Moderation, Donald E. Greydanus, Hatim A. Omar, Artemis Tsitsika

Pediatrics Faculty Publications

All sexually active youth, whether obese or normal weight, should be offered counseling regarding contraception and appropriate contraceptive methods. However, obese youth who are sexually active may be less likely than their normal weight peers to use contraceptives correctly. Methods of contraception for obese adolescents are reviewed in this discussion. Combined oral contraceptives (COCs) and the contraceptive patch have higher failure rates in obese versus normal weight females, though failure rates are lower than noted with barrier contraceptives. The risk for venous thrombosis is higher in obese youth on COCs. Progestin-only pills and the levonorgestrel intrauterine system appear to be …

Obesity And Contraception, Donald E. Greydanus, Hatim A. Omar, Artemis Tsitsika

Pediatrics Faculty Publications

All sexually active youth, whether obese or normal weight, should be offered counseling regarding contraception and appropriate contraceptive methods. However, obese youth who are sexually active may be less likely than their normal weight peers to use contraceptives correctly. Methods of contraception for obese adolescents are reviewed in this discussion. Combined oral contraceptives (COCs) and the contraceptive patch have higher failure rates in obese versus normal weight females, though failure rates are lower than noted with barrier contraceptives. The risk for venous thrombosis is higher in obese youth on COCs. Progestin-only pills and the levonorgestrel intrauterine system appear to be …

Insights Into Expression, Cellular Localization, And Regulation Of Supernatant Protein Factor, A Putative Regulator Of Cholesterol Biosynthesis, Elzbieta Ilona Stolarczyk

University of Kentucky Doctoral Dissertations

SPF (Supernatant Protein Factor) is a cytosolic protein that stimulates at least two enzymes in the cholesterol biosynthetic pathway: squalene monooxygenase and HMGCoA reductase. The mechanism of action has not been established but may be related to lipid transfer between intracellular membranes.

There are three human genes for SPF: SEC14L2 (SPF1), SEC14L3 (SPF2) and SEC14L4 (SPF3). The present study differentiates these closely related genes by evaluating their tissue-specific and relative expression levels. SPF1 mRNA was found to be most abundant in liver, mammary gland and stomach. SPF2 showed negligible expression in all tissues tested; SPF3 expression pattern was similar to …

Lipid-Based Paclitaxel And Doxorubicin Nanoparticles To Overcome P-Gp-Mediated Drug Resistance In Solid Tumors, Xiaowei Dong

University of Kentucky Doctoral Dissertations

Multidrug resistance (MDR) is a major obstacle limiting chemotherapeutic efficacy. The purpose of these studies was to investigate the potential application of injectable paclitaxel (PX) and doxorubicin (Dox)-loaded nanoparticles (NPs) engineered from oil-in-water microemulsion precursors for overcoming P-glycoprotein (P-gp)- mediated drug resistance in solid tumors.

An in-vitro study was performed to test whether the oil (stearyl alcohol and cetyl alcohol) used to make lipid nanoparticles could be metabolized. The results showed that the concentrations of the fatty alcohols within nanoparticles, which were quantitatively determined over time by gas chromatography, decreased to only 10-20% of the initial concentration after 15-24 h …

The Pharmacogenomics Of Egfr-Dependent Nsclc: Predicting And Enhancing Response To Targeted Egfr Therapy, Justin M. Balko

University of Kentucky Doctoral Dissertations

The introduction of tyrosine kinase inhibitors (TKI) targeting the epidermal growth factor receptor (EGFR) inhibitors to the clinic has resulted in an improvement in the treatment of non small cell lung cancer (NSCLC). However, many patients treated with EGFR TKIs do not respond to therapy. The burden of failed treatment is largely placed on the healthcare field, limiting the effectiveness of EGFR TKIs. Furthermore, responses are hindered by the emergence of resistance. Thus, two questions must be addressed to achieve maximum benefit of EGFR inhibitors: How can patients who will benefit from EGFR TKIs be selected a priori? How …

Preparation And Characterization Of Blackberry Extracts And Their Anticancer And Anti-Inflammatory Properties, Jin Dai

University of Kentucky Doctoral Dissertations

Blackberries are rich in polyphenols including anthocyanins. Polyphenols are hypothesized to have biological activities that impact positively on human health. The purpose of these studies was to develop phenolic extracts from selected cultivars of blackberries currently grown in Kentucky as potential Botanical Drug Products for the treatment and prevention of cancer and inflammatory diseases.

An ultrasound-assisted ethanol extraction method was employed to obtain anthocyanin-containing extracts (ACEs) from puree or powder (lyophilized puree) of blackberries. ACEs were analyzed for total anthocyanin and phenolics content, polymeric color, and total antioxidant capacity (TAC). The influence of water content in the extraction system was …

Synthesis And Evaluation Of Prouteolysis Taurgeting Chimeras (Protacs): A Potential Chemical Genetic Approach To Breast Cancer Therapy, Kedra C. Cyrus

University of Kentucky Doctoral Dissertations

The use of small molecules to probe the function of proteins is referred to as chemical genetics. The Proteolysis Targeting Chimera (PROTAC) is a chemical genetic tool that contains the ligand for a target protein of interest and the recognition motif for an E3 ubiquitin ligase attached by a linker. The PROTAC is capable of binding to and recruiting specific target proteins to the intracellular degradation system, the ubiquitin proteasome system (UPS). While the approach has had success it has not been optimized to be used on a broader scale.

Optimization efforts focused on elucidating the ideal linker length between …

Computational Design Of 3-Phosphoinositide Dependent Kinase-1 Inhibitors As Potential Anti-Cancer Agents, Mohamed Diwan Mohideen Abdulhameed

University of Kentucky Doctoral Dissertations

Computational drug design methods have great potential in drug discovery particularly in lead identification and lead optimization. 3-Phosphoinositide dependent kinase-1 (PDK1) is a protein kinase and a well validated anti-cancer target. Inhibitors of PDK1 have the potential to be developed as anti-cancer drugs. In this work, we have applied various novel computational drug design strategies to design and identify new PDK1 inhibitors with potential anti-cancer activity. We have pursued novel structure-based drug design strategies and identified a new binding mode for celecoxib and its derivatives binding with PDK1. This new binding mode provides a valuable basis for rational design of …