Pharmacy and Pharmaceutical Sciences Commons^™

Methods To Impair Hematologic Cancer Progenitor Cells And Compounds Related Thereto, Craig T. Jordan

Pharmaceutical Sciences Faculty Patents

Primitive or progenitor hematologic cancer cells have been implicated in the early stages and development of leukemia and malignant lymphoproliferative disorders, including acute myelogenous leukemia (AML), chronic myelogenous leuke mia (CML) and chronic lymphoid leukemia (CLL). Interleu kin-3 receptor alpha chain (IL-3Ra or CD123) is strongly expressed on progenitor hematologic cancer cells, but is vir tually undetectable on normal bone marrow cells. The present invention provides methods of impairing progenitor hemato logic cancer (e.g., leukemia and lymphomic) cells by selec tively targeting cells expressing CD123. These methods are useful in the detection and treatment of leukemias and malig nant lymphoproliferative …

Effects Of Three Low-Doses Of D-Tagatose On Glycemic Control Over Six Months In Subjects With Mild Type 2 Diabetes Mellitus Under Control With Diet And Exercise, Mark Ensor, Jarrod Williams, Rebecca Smith, Amy Banfield, Robert A. Lodder

Pharmaceutical Sciences Faculty Publications

The primary objective of this study was to evaluate the safety and the effect of D-tagatose on the glycemic control of subjects with type 2 diabetes as determined by HbA_1c levels at the end of 6 months of therapy using the subject's own baseline HbA_1c level as a comparator. The determination of the minimal dose required to cause a statistically significant reduction in HbA_1c was of particular interest. Eight weeks after screening, the qualifying subjects were randomized to receive one of three doses of D-tagatose: 2.5 g TID, 5.0 g TID or 7.5 g TID. Blood levels …

The Yin: An Adverse Health Perspective Of Nanoceria: Uptake, Distribution, Accumulation, And Mechanisms Of Its Toxicity, Robert A. Yokel, Salik Hussain, Stavros Garantziotis, Philip Demokritou, Vincent Castranova, Flemming R. Cassee

Pharmaceutical Sciences Faculty Publications

This critical review evolved from a SNO Special Workshop on Nanoceria panel presentation addressing the toxicological risks of nanoceria: accumulation, target organs, and issues of clearance; how exposure dose/concentration, exposure route, and experimental preparation/model influence the different reported effects of nanoceria; and how can safer by design concepts be applied to nanoceria? It focuses on the most relevant routes of human nanoceria exposure and uptake, disposition, persistence, and resultant adverse effects. The pulmonary, oral, dermal, and topical ocular exposure routes are addressed as well as the intravenous route, as the latter provides a reference for the pharmacokinetic fate of nanoceria …

Systematic Review Of Potential Health Risks Posed By Pharmaceutical, Occupational And Consumer Exposures To Metallic And Nanoscale Aluminum, Aluminum Oxides, Aluminum Hydroxide And Its Soluble Salts, Calvin C. Willhite, Nataliya A. Karyakina, Robert A. Yokel, Nagarajkumar Yenugadhati, Thomas M. Wisniewski, Ian M. F. Arnold, Franco Momoli, Daniel Krewski

Pharmaceutical Sciences Faculty Publications

Aluminum (Al) is a ubiquitous substance encountered both naturally (as the third most abundant element) and intentionally (used in water, foods, pharmaceuticals, and vaccines); it is also present in ambient and occupational airborne particulates. Existing data underscore the importance of Al physical and chemical forms in relation to its uptake, accumulation, and systemic bioavailability. The present review represents a systematic examination of the peer-reviewed literature on the adverse health effects of Al materials published since a previous critical evaluation compiled by Krewski et al. (2007).

Challenges encountered in carrying out the present review reflected the experimental use of different physical …

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

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.

Mono Quaternary Ammonium Salts And Methods For Modulating Neuronal Nicotinic Acetylcholine Receptors, Peter A. Crooks, Linda P. Dwoskin, Guangrong Zheng, Sangeetha Sumithran, Zhenfa Zheng

Pharmaceutical Sciences Faculty Patents

Provided are monoquaternary ammonium compounds which are modulators of nicotinic acetylcholine receptors. Also provided are methods of using the compounds for modulating the function of a nicotinic acetylcholine receptor, and for the prevention and/or treatment of central nervous system disorders, substance use and/or abuse, and or gastrointestinal tract disorders.

Thymidylate Synthase Genotype-Directed Chemotherapy For Patients With Gastric And Gastroesophageal Junction Cancers, Laura W. Goff, Nilay Thakkar, Liping Du, Emily Chan, Benjamin R. Tan, Dana B. Cardin, Howard L. Mcleod, Jordan D. Berlin, Barbara Zehnbauer, Chloe Fournier, Joel Picus, Andrea Wang-Gillam, Wooin Lee, A. Craig Lockhart

Pharmaceutical Sciences Faculty Publications

BACKGROUND: Retrospective studies indicate associations between TSER (thymidylate synthase enhancer region) genotypes and clinical outcomes in patients receiving 5-FU based chemotherapy, but well-controlled prospective validation has been lacking.

METHODS: In this phase II study (NCT00515216 registered through ClinicalTrials.gov, http://clinicaltrials.gov/show/NCT00515216), patients with "good risk" TSER genotypes (at least one TSER*2 allele) were treated with FOLFOX chemotherapy to determine whether prospective patient selection can improve overall response rates (ORR) in patients with gastric and gastroesophageal junction (GEJ) cancers, compared with historical outcomes in unselected patients (estimated 43%).

RESULTS: The ORR in genotype-selected patients was 39.1% (9 partial responses out …

High-Activity Mutants Of Butyrylcholinesterase For Cocaine Hydrolysis And Method Of Generating The Same, Chang-Guo Zhan, Hoon Cho, Hsin-Hsiung Tai

Pharmaceutical Sciences Faculty Patents

A novel computational method and generation of mutant butyrylcholinesterase for cocaine hydrolysis is provided. The method includes molecular modeling a possible BChE mutant and conducting molecular dynamics simulations and hybrid quantum mechanical/molecular mechanical calculations thereby providing a screening method of possible BChE mutants by predicting which mutant will lead to a more stable transition state for a rate determining step. Site-directed mutagenesis, protein expression, and protein activity is conducted for mutants determined computationally as being good candidates for possible BChE mutants, i.e., ones predicted to have higher catalytic efficiency as compared with wild-type BChE. In addition, mutants A199S/A328W/Y332G, A199S/F227A/A328W/Y332G, A199S/S287G/A328W/Y332G, …

Applying Accelerator Mass Spectrometry For Low-Level Detection Of Complex Engineered Nanoparticles In Biological Media, Binghui Wang, George S. Jackson, Robert A. Yokel, Eric A. Grulke

Pharmaceutical Sciences Faculty Publications

Complex engineered nanoparticles (CENPs), which have different core and surface components, are being developed for medicinal, pharmaceutical and industrial applications. One of the key challenges for environmental health and safety assessments of CENPs is to identify and quantity their transformations in biological environments. This study reports the effects of in vivo exposure of citrate-coated nanoalumina with different rare isotope labels on each component. This CENP was dosed to the rat and accelerator mass spectrometry (AMS) was used to quantify ²⁶Al, ¹⁴C, and their ratio in the dosing material and tissue samples. For CENPs detected in the liver, the …

In Vivo Processing Of Ceria Nanoparticles Inside Liver: Impact On Free-Radical Scavenging Activity And Oxidative Stress, Uschi M. Graham, Michael T. Tseng, Jacek B. Jasinski, Robert A. Yokel, Jason M. Unrine, Burtron H. Davis, Alan K. Dozier, Sarita S. Hardas, Rukhsana Sultana, Eric A. Grulke, D. Allan Butterfield

Pharmaceutical Sciences Faculty Publications

The cytotoxicity of ceria ultimately lies in its electronic structure, which is defined by the crystal structure, composition, and size. Despite previous studies focused on ceria uptake, distribution, biopersistance, and cellular effects, little is known about its chemical and structural stability and solubility once sequestered inside the liver. Mechanisms will be presented that elucidate the in vivo transformation in the liver. In vivo processed ceria reveals a particle-size effect towards the formation of ultrafines, which represent a second generation of ceria. A measurable change in the valence reduction of the second-generation ceria can be linked to an increased free-radical scavenging …

Persistent Hepatic Structural Alterations Following Nanoceria Vascular Infusion In The Rat, Michael T. Tseng, Qiang Fu, Khoua Lor, G. Rafael Fernandez-Botran, Zhong-Bin Deng, Uschi M. Graham, D. Allan Butterfield, Eric A. Grulke, Robert A. Yokel

Chemistry Faculty Publications

Understanding the long-term effects and possible toxicity of nanoceria, a widely utilized commercial metal oxide, is of particular importance as it is poised for development as a therapeutic agent based on its autocatalytic redox behavior. We show here evidence of acute and subacute adverse hepatic responses, after a single infusion of an aqueous dispersion of 85 mg/kg, 30 nm nanoceria into Sprague Dawley rats. Light and electron microscopic evidence of avid uptake of nanoceria by Kupffer cells was detected as early as 1 hr after infusion. Biopersistent nanoceria stimulated cluster of differentiation 3⁺ lymphocyte proliferation that intermingled with nanoceria-containing …

Neuroinflammation And Neurodegeneration In Adult Rat Brain From Binge Ethanol Exposure: Abrogation By Docosahexaenoic Acid, Nuzhath Tajuddin, Kwan-Hoon Moon, Simon Alex Marshall, Kimberly Nixon, Edward J. Neafsey, Hee-Yong Kim, Michael A. Collins

Pharmaceutical Sciences Faculty Publications

Evidence that brain edema and aquaporin-4 (AQP4) water channels have roles in experimental binge ethanol-induced neurodegeneration has stimulated interest in swelling/edema-linked neuroinflammatory pathways leading to oxidative stress. We report here that neurotoxic binge ethanol exposure produces comparable significant effects in vivo and in vitro on adult rat brain levels of AQP4 as well as neuroinflammation-linked enzymes: key phospholipase A2 (PLA2) family members and poly (ADP-ribose) polymerase-1 (PARP-1). In adult male rats, repetitive ethanol intoxication (3 gavages/d for 4 d, ∼ 9 g/kg/d, achieving blood ethanol levels ∼ 375 mg/dl; "Majchrowicz" model) significantly increased AQP4, Ca+2-dependent PLA2 GIVA (cPLA2), phospho-cPLA2 GIVA …

A Filtration System That Greatly Reduces Aluminum In Calcium Gluconate Injection, Usp Used To Prepare Parenteral Nutrition Solutions, Robert A. Yokel, Wesley R. Harris, Christopher D. Spilling, Vasiliy P. Abramov, Jason M. Lone, Robert J. Kuhn

Pharmaceutical Sciences Faculty Publications

OBJECTIVE: The study objective was to reduce aluminum (Al) in Calcium Gluconate Injection, US Pharmacopeia (USP) used in the preparation of parenteral nutrition (PN) solutions.

METHODS: A flow-through filter containing an immobilized chelator that complexes Al from Calcium Gluconate Injection, USP as it flows through the filter was designed, refined by design modifications, and extensively tested. When a small-volume parenteral vial containing 100 mL of Calcium Gluconate Injection, USP is connected on the inlet side of the filter, and the outlet side is connected to an evacuated receiving vial, the filtered solution is drawn into the receiving vial. This constitutes …

Pharmacy Law Brief: The Federal False Claims Act, Joseph L. Fink Iii

Pharmacy Practice and Science Faculty Publications

No abstract provided.

Finding Of Widespread Viral And Bacterial Revolution Dsdna Translocation Motors Distinct From Rotation Motors By Channel Chirality And Size, Gian Marco De-Donatis, Zhengyi Zhao, Shaoying Wang, Lisa P. Huang, Chad T. Schwartz, Oleg V. Tsodikov, Hui Zhang, Farzin Haque, Peixuan Guo

Nanobiotechnology Center Faculty Publications

BACKGROUND: Double-stranded DNA translocation is ubiquitous in living systems. Cell mitosis, bacterial binary fission, DNA replication or repair, homologous recombination, Holliday junction resolution, viral genome packaging and cell entry all involve biomotor-driven dsDNA translocation. Previously, biomotors have been primarily classified into linear and rotational motors. We recently discovered a third class of dsDNA translocation motors in Phi29 utilizing revolution mechanism without rotation. Analogically, the Earth rotates around its own axis every 24 hours, but revolves around the Sun every 365 days.

RESULTS: Single-channel DNA translocation conductance assay combined with structure inspections of motor channels on bacteriophages P22, SPP1, HK97, T7, …

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.

Opioid-Ketamine And Norketamine Codrug Combinations For Pain Management, Joseph R. Holtman, Peter A. Crooks, Ujjwal Chakraborty

Pharmaceutical Sciences Faculty Patents

The present invention relates to the field of pain management, and more particularly to synergistic codrugs comprising an opioid and ketamine or norketamine which have been combined to form a single chemical codrug entity. When the codrug is administered it produces a synergistic analgesic response to pain.

Opioid-Nornicotine Codrugs Combinations For Pain Management, Joseph R. Holtman, Peter A. Crooks, Ujjwal Chakraborty

Pharmaceutical Sciences Faculty Patents

The present invention relates to the field of pain management, and more particularly to synergistic codrugs comprising an opioid and nornicotine which have been combined to form a single chemical codrug entity. When the codrug is administered it produces a synergistic analgesic response to pain.

A Random Sequential Mechanism Of Aminoglycoside Acetylation By Mycobacterium Tuberculosis Eis Protein, Oleg V. Tsodikov, Keith D. Green, Sylvie Garneau-Tsodikova

Pharmaceutical Sciences Faculty Publications

An important cause of bacterial resistance to aminoglycoside antibiotics is the enzymatic acetylation of their amino groups by acetyltransferases, which abolishes their binding to and inhibition of the bacterial ribosome. Enhanced intracellular survival (Eis) protein from Mycobacterium tuberculosis (Mt) is one of such acetyltransferases, whose upregulation was recently established as a cause of resistance to aminoglycosides in clinical cases of drug-resistant tuberculosis. The mechanism of aminoglycoside acetylation by MtEis is not completely understood. A systematic analysis of steady-state kinetics of acetylation of kanamycin A and neomycin B by Eis as a function of concentrations of these aminoglycosides …

Compositions And Methods For Selectively Targeting Cancer Cells Using A Thiaminase Compound, Jeffrey A. Moscow, Shuqian Liu, Younsoo Bae

Pharmaceutical Sciences Faculty Patents

Compositions and methods of treating cancer using a thiaminase compound are described. The presently-disclosed subject matter includes a method of treating cancer by administering a thiaminase compound and a thiamine-dependent enzyme inhibitor.

Pharmacy Law Brief: Medications And Lawful Executions, Joseph L. Fink Iii

Pharmacy Practice and Science Faculty Publications

No abstract provided.

Bis-Quaternary Ammonium Cyclophane Compounds That Interact With Neuronal Nicotinic Acetylcholine Receptors, Peter A. Crooks, Linda P. Dwoskin, Guangrong Zheng, Sangeetha Sumithran, Davis D. Allen, Zhenfa Zheng, Paul Lockman

Pharmaceutical Sciences Faculty Patents

Provided are bis-quaternary ammonium cyclophane compounds which are modulators of nicotinic acetylcholine receptors. Also provided are methods of using the compounds for modulating the function of a nicotinic acetylcholine receptor, and for the prevention and/or treatment of central nervous system disorders, substance use and/or abuse, and or gastrointestinal tract disorders.

Enhancing Transdermal Delivery Of Opioid Antagonists And Agonists Using Codrugs Linked To Bupropion Or Hydroxybupropion, Audra L. Stinchcomb, Peter A. Crooks, Mohamad O. Hamad, Paul K. Kiptoo

Pharmaceutical Sciences Faculty Patents

The present invention is directed to novel codrugs comprising bupropion or hydroxybupropion and an opioid antagonist or an opioid agonist joined together by chemical bonding. The codrugs provide a significant increase in the transdermal flux across human skin, as compared to the basic opioid antagonist or opioid agonist.

Ivivc From Long Acting Olanzapine Microspheres, Susan D'Souza, Jabar A. Faraj, Stefano Giovagnoli, Patrick P. Deluca

Pharmaceutical Sciences Faculty Publications

In this study, four PLGA microsphere formulations of Olanzapine were characterized on the basis of their in vitro behavior at 37°C, using a dialysis based method, with the goal of obtaining an IVIVC. In vivo profiles were determined by deconvolution (Nelson-Wagner method) and using fractional AUC. The in vitro and in vivo release profiles exhibited the same rank order of drug release. Further, in vivo profiles obtained with both approaches were nearly superimposable, suggesting that fractional AUC could be used as an alternative to the Nelson-Wagner method. A comparison of drug release profiles for the four formulations revealed that the …

Tetrakis-Quaternary Ammonium Salts And Methods For Modulating Neuronal Nicotinic Acteylcholine Receptors, Peter A. Crooks, Linda P. Dwoskin, Zhnefa Zhang, Marharyta Pivavarchyk

Pharmaceutical Sciences Faculty Patents

Provided are tetrakis-quaternary ammonium compounds which are modulators of nicotinic acetylcholine receptors. Also provided are methods of using the compounds for modulating the function of a nicotinic acetylcholine receptor, and for the prevention and/or treatment of central nervous system disorders, substance use and/or abuse, and or gastrointestinal tract disorders.

Pharmacy Law Brief: Implications Of Being A Specialist, Joseph L. Fink Iii

Pharmacy Practice and Science Faculty Publications

No abstract provided.

Beyond Peroxisome: Abcd2 Modifies Pparα Signaling And Identifies A Subclass Of Peroxisomes In Mouse Adipose Tissue, Xiaoxi Liu

Theses and Dissertations--Pharmacy

ABCD2 (D2) has been proposed as a peroxisomal long-chain acyl-CoA transporter that is essential for very long chain fatty acid metabolism. In the livers of mice, D2 is highly induced by fenofibrate, a PPARα ligand that has been widely used as a lipid lowering agent in the treatment of hypertriglyceridemia. To determine if D2 is a modifier of fibrate responses, wild-type and D2 deficient mice were treated with fenofibrate for 14 days. The absence of D2 altered expression of gene clusters associated with lipid metabolism, including PPARα signaling. Using 3T3-L1 adipocytes, which express high levels of D2, we confirmed that …

Quantification Of Factors Governing Drug Release Kinetics From Nanoparticles: A Combined Experimental And Mechanistic Modeling Approach, Kyle Daniel Fugit

Theses and Dissertations--Pharmacy

Advancements in nanoparticle drug delivery of anticancer agents require mathematical models capable of predicting in vivo formulation performance from in vitro characterization studies. Such models must identify and incorporate the physicochemical properties of the therapeutic agent and nanoparticle driving in vivo drug release. This work identifies these factors for two nanoparticle formulations of anticancer agents using an approach which develops mechanistic mathematical models in conjunction with experimental studies.

A non-sink ultrafiltration method was developed to monitor liposomal release kinetics of the anticancer agent topotecan. Mathematical modeling allowed simultaneous determination of drug permeability and interfacial binding to the bilayer from release …

Synthesis And Biological Evaluation Of Novel Resveratrol And Combretastatin A4 Derivatives As Potent Anti-Cancer Agents, Nikhil Reddy Madadi

Theses and Dissertations--Pharmacy

Resveratrol has been reported as a potential anticancer agent but cannot be used as an antitumor drug due to its chemical and metabolic instability. We have designed and synthesized 184 novel compounds related to resveratrol in an attempt to produce more potent and drug-like molecules. We have identified a tetrazole analog of resveratrol, ST-145(a) as a lead anticancer agent from the resveratrol analog series of compounds with a GI₅₀ value of less than 10nM against almost all the human cancer cell lines in the National Cancer Institute’s screening panel.

In a separate study, we tested the hypothesis that the …

Multi-Component Microparticulate/Nanoparticulate Dry Powder Inhalation Aerosols For Targeted Pulmonary Delivery, Xiaojian Li

Theses and Dissertations--Pharmacy

The aim of the work was to design, manufacture, and characterize targeted multi-component dry powder aerosols of (non-destructive) mucolytic agent (mannitol), antimicrobial drug (tobramycin or azithromycin), and lung surfactant mimic phospholipids (DPPC:DPPG=4:1 in molar ratio). The targeted dry powder for inhalation formulation for deep lung delivery with a built-in rationale of specifically interfering several disease factors of chronic infection diseases in deep lungs such as cystic fibrosis, pneumonia, chronic bronchitis, and etc. The dry powder aerosols consisting of selected chemical agents in one single formulation was generated by using spray drying from organic solution.

The physicochemical properties of multi-component dry …