Medicine and Health Sciences Commons^™

Discovery Of A Diaminopyrimidine Flt3 Inhibitor Active Against Acute Myeloid Leukemia, Jamie A. Jarusiewicz, Jae Yoon Jeon, Michele C. Connelly, Yizhe Chen, Lei Yang, Sharyn D. Baker, R. Kiplin Guy

Pharmaceutical Sciences Faculty Publications

Profiling of the kinase-binding capabilities of an aminopyrimidine analogue detected in a cellular screen of the St. Jude small-molecule collection led to the identification of a novel series of FMS-like tyrosine kinase 3 (FLT3) inhibitors. Structure–activity relationship studies led to the development of compounds exhibiting good potency against MV4-11 and MOLM13 acute myelogenous leukemia cells driven by FLT3, regardless of their FLT3 mutation status. In vitro pharmacological profiling demonstrated that compound 5e shows characteristics suitable for further preclinical development.

Toxic And Essential Trace Element Content Of Commonly Administered Pediatric Oral Medications, Robert A. Yokel, Sarah E. Seger, Jason M. Unrine

Pharmaceutical Sciences Faculty Publications

OBJECTIVES: The aim of this study was to test the hypothesis that commonly administered pediatric oral medications are a significant source of toxic elements. The concentrations of 16 elements were determined in 14 frequently used pediatric oral medications.

METHODS: Samples were prepared for analysis by dilution or nitric acid microwave-assisted digestion and analyzed by inductively coupled plasma mass spectrometry. The intake of each element from administration for 1 week of the medication's maximum recommended daily dose to 6-month-olds was calculated and compared to an exposure guideline for that element. Exposure guidelines used for adverse effects were minimal risk levels, oral …

Biokinetics Of Nanomaterials: The Role Of Biopersistence, Peter Laux, Christian Riebeling, Andy M. Booth, Joseph D. Brain, Josephine Brunner, Cristina Cerrillo, Otto Creutzenberg, Irina Estrela-Lopis, Thomas Gebel, Gunnar Johanson, Harald Jungnickel, Heiko Kock, Jutta Tentschert, Ahmed Tlili, Andreas Schäffer, Adriënne J. A. M. Sips, Robert A. Yokel, Andreas Luch

Pharmaceutical Sciences Faculty Publications

Nanotechnology risk management strategies and environmental regulations continue to rely on hazard and exposure assessment protocols developed for bulk materials, including larger size particles, while commercial application of nanomaterials (NMs) increases. In order to support and corroborate risk assessment of NMs for workers, consumers, and the environment it is crucial to establish the impact of biopersistence of NMs at realistic doses. In the future, such data will allow a more refined categorization of NMs. Despite many experiments on NM characterization and numerous in vitro and in vivo studies, several questions remain unanswered including the influence of biopersistence on the toxicity …

The Effect Of Sazetidine-A And Other Nicotinic Ligands On Nicotine Controlled Goal-Tracking In Female And Male Rats, S. Charntikov, A. M. Falco, K. Fink, Linda P. Dwoskin, R. A. Bevins

Pharmaceutical Sciences Faculty Publications

Nicotine is the primary addictive component of tobacco products and its complex stimulus effects are readily discriminated by humans and non-human animals. Previous preclinical research investigating directly the nature of the nicotine stimulus has been limited to male rodents. The current study began to address this significant gap in the literature by training female and male rats to discriminate 0.4 mg/kg nicotine from saline in the discriminated goal-tracking task. In this task, access to sucrose was intermittently available on nicotine session. On saline session, intermixed with nicotine sessions on separate days, sucrose was not available. Both sexes acquired the discrimination …

Aluminum And Phthalates In Calcium Gluconate: Contribution From Glass And Plastic Packaging, Robert A. Yokel, Jason M. Unrine

Pharmaceutical Sciences Faculty Publications

Introduction: Aluminum contamination of parenteral nutrition solutions has been documented for three decades. It can result in elevated blood, bone, and whole body aluminum levels associated with neurotoxicity, reduced bone mass and mineral content, and perhaps hepatotoxicity. The primary aluminum source among parenteral nutrition components is glass-packaged calcium gluconate, in which aluminum concentration the past three decades has averaged~ 4000 [mu]g/L, compared to < 200 [mu]g/L in plastic container-packaged calcium gluconate. A concern about plastic packaging is leaching of plasticizers, including phthalates, which have the potential to cause endocrine (male reproductive system) disruption and neurotoxicity.

Methods: Aluminum was quantified in samples collected periodically over more than two years from three calcium gluconate sources used to prepare parenteral nutrition solutions; two packaged in glass (from France and the US) and one in plastic …

Developmental Toxicity Of Nicotine: A Transdisciplinary Synthesis And Implications For Emerging Tobacco Products, Lucinda J. Enland, Kjersti Aagaard, Michele Bloch, Kevin Conway, Kelly Cosgrove, Rachel Grana, Thomas J. Gould, Dorothy Hatsukami, Frances Jensen, Denise Kandel, Bruce Lanphear, Frances Leslie, James R. Pauly, Jenae Neiderhiser, Mark Rubinstein, Theodore A. Slotkin, Eliot Spindel, Laura Stroud, Lauren Wakschlag

Pharmaceutical Sciences Faculty Publications

While the health risks associated with adult cigarette smoking have been well described, effects of nicotine exposure during periods of developmental vulnerability are often overlooked. Using MEDLINE and PubMed literature searches, books, reports and expert opinion, a transdisciplinary group of scientists reviewed human and animal research on the health effects of exposure to nicotine during pregnancy and adolescence. A synthesis of this research supports that nicotine contributes critically to adverse effects of gestational tobacco exposure, including reduced pulmonary function, auditory processing defects, impaired infant cardiorespiratory function, and may contribute to cognitive and behavioral deficits in later life. Nicotine exposure during …

An Arginine Finger Regulates The Sequential Action Of Asymmetrical Hexameric Atpase In The Double-Stranded Dna Translocation Motor, Zhengyi Zhao, Gian Marco De-Donatis, Chad T. Schwartz, Huaming Fang, Jingyuan Li, Peixuan Guo

Pharmaceutical Sciences Faculty Publications

Biological motors are ubiquitous in living systems. Currently, how the motor components coordinate the unidirectional motion is elusive in most cases. Here, we report that the sequential action of the ATPase ring in the DNA packaging motor of bacteriophage ϕ29 is regulated by an arginine finger that extends from one ATPase subunit to the adjacent unit to promote noncovalent dimer formation. Mutation of the arginine finger resulted in the interruption of ATPase oligomerization, ATP binding/hydrolysis, and DNA translocation. Dimer formation reappeared when arginine mutants were mixed with other ATPase subunits that can offer the arginine to promote their interaction. Ultracentrifugation …

Red-Shifted Aequorin Variants Incorporating Non-Canonical Amino Acids: Applications In In Vivo Imaging, Kristen M. Grinstead, Laura Rowe, Mark Ensor, Smita Joel, Pirouz Daftarian, Emre Dikici, Jean-Marc Zingg, Sylvia Daunert

Pharmaceutical Sciences Faculty Publications

The increased importance of in vivo diagnostics has posed new demands for imaging technologies. In that regard, there is a need for imaging molecules capable of expanding the applications of current state-of-the-art imaging in vivo diagnostics. To that end, there is a desire for new reporter molecules capable of providing strong signals, are non-toxic, and can be tailored to diagnose or monitor the progression of a number of diseases. Aequorin is a non-toxic photoprotein that can be used as a sensitive marker for bioluminescence in vivo imaging. The sensitivity of aequorin is due to the fact that bioluminescence is a …

Data Publication With The Structural Biology Data Grid Supports Live Analysis, Peter A. Meyer, Stephanie Socias, Jason Key, Elizabeth Ransey, Emily C. Tjon, Alejandro Buschiazzo, Ming Lei, Chris Botka, James Withrow, David Neau, Kanagalaghatta Rajashankar, Karen S. Anderson, Richard H. Baxter, Stephen C. Blacklow, Titus J. Boggon, Alexandre M. J. J. Bonvin, Dominika Borek, Tom J. Brett, Amedeo Caflisch, Chung-I Chang, Walter J. Chazin, Kevin D. Corbett, Michael S. Cosgrove, Sean Crosson, Sirano Dhe-Paganon, Enrico Di Cera, Catherine L. Drennan, Michael J. Eck, Brandt F. Eichman, Qing R. Fan, Oleg V. Tsodikov

Pharmaceutical Sciences Faculty Publications

Access to experimental X-ray diffraction image data is fundamental for validation and reproduction of macromolecular models and indispensable for development of structural biology processing methods. Here, we established a diffraction data publication and dissemination system, Structural Biology Data Grid (SBDG; data.sbgrid.org), to preserve primary experimental data sets that support scientific publications. Data sets are accessible to researchers through a community driven data grid, which facilitates global data access. Our analysis of a pilot collection of crystallographic data sets demonstrates that the information archived by SBDG is sufficient to reprocess data to statistics that meet or exceed the quality of the …

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 …

Distribution, Elimination, And Biopersistence To 90 Days Of A Systemically Introduced 30 Nm Ceria-Engineered Nanomaterial In Rats, Robert A. Yokel, Tu C. Au, Robert Macphail, Sarita S. Hardas, D. Allan Butterfield, Rukhsana Sultana, Michael Goodman, Michael T. Tseng, Mo Dan, Hamed Haghnazar, Jason M. Unrine, Uschi M. Graham, Peng Wu, Eric A. Grulke

Pharmaceutical Sciences Faculty Publications

Nanoceria is used as a catalyst in diesel fuel, as an abrasive in printed circuit manufacture, and is being pursued as an antioxidant therapeutic. Our objective is to extend previous findings showing that there were no reductions of cerium in organs of the mononuclear phagocyte (reticuloendothelial) system up to 30 days after a single nanoscale ceria administration. An ~5% aqueous dispersion of citrate-stabilized 30 nm ceria, synthesized and characterized in-house, or vehicle, was iv infused into rats terminated 1, 7, 30, or 90 days later. Cageside observations were obtained daily, body weight weekly. Daily urinary and fecal cerium outputs were …

Plant Phenolics: Extraction, Analysis And Their Antioxidant And Anticancer Properties, Jin Dai, Russell J. Mumper

Pharmaceutical Sciences Faculty Publications

Phenolics are broadly distributed in the plant kingdom and are the most abundant secondary metabolites of plants. Plant polyphenols have drawn increasing attention due to their potent antioxidant properties and their marked effects in the prevention of various oxidative stress associated diseases such as cancer. In the last few years, the identification and development of phenolic compounds or extracts from different plants has become a major area of health- and medical-related research. This review provides an updated and comprehensive overview on phenolic extraction, purification, analysis and quantification as well as their antioxidant properties. Furthermore, the anticancer effects of phenolics in-vitro …

Role Of The Genomics Revolution In Pharmaceutics, Daniel A. Brazeau, Gayle A. Brazeau

Pharmaceutical Sciences Faculty Publications

Highlights the examples of Thiopurine S-methyltransferase (TPMT) and Warfarin as a means of describing some of the problems that are common to many pharmacogenetic cases. The pharmacogenetic literature contains many examples of confusing, or even contradictory, studies that arise due to unknown environmental factors that result in poor outcomes; drugs whose metabolism/transport are affected by multiple genes in multiple pathways; and clinically important genes that have many rare allelic variants with similar phenotypes variation in the frequencies of allelic variants among ethnic groups that mask the role of any one variant. These issues are common to most gene/drug dynamics and …

The Influence Of Citrate, Maltolate And Fluoride On The Gastrointestinal Absorption Of Aluminum At A Drinking Water-Relevant Concentration: A 26Al And 14C Study, Yuzhao Zhou, Wesley R. Harris, Robert A. Yokel

Pharmaceutical Sciences Faculty Publications

The objectives were to test the null hypotheses that (1) citrate, maltolate, and fluoride do not significantly influence oral Al bioavailability, C_max or T_max at an Al dose relevant to drinking water exposure; and (2) Al citrate and maltolate are absorbed intact from the gastrointestinal tract. Male Fisher rats were given 1 ml of solution intra-gastrically containing 1 nCi ²⁶Al (65 nmol total Al) as the Al³⁺ ion, or as complexes with ¹⁴C-citrate, ¹⁴C-maltolate or fluoride, during concurrent ²⁷Al iv infusion. Blood was repeatedly collected for serum ²⁶Al, total Al and ^{14 …}

The Speciation Of Metals In Mammals Influences Their Toxicokinetics And Toxicodynamics And Therefore Human Health Risk Assessment, Robert A. Yokel, Stephen M. Lasley, David C. Dorman

Pharmaceutical Sciences Faculty Publications

Chemical form (i.e., species) can influence metal toxicokinetics and toxicodynamics and should be considered to improve human health risk assessment. Factors that influence metal speciation (and examples) include: (1) carrier-mediated processes for specific metal species (arsenic, chromium, lead and manganese), (2) valence state (arsenic, chromium, manganese and mercury), (3) particle size (lead and manganese), (4) the nature of metal binding ligands (aluminum, arsenic, chromium, lead, and manganese), (5) whether the metal is an organic versus inorganic species (arsenic, lead, and mercury), and (6) biotransformation of metal species (aluminum, arsenic, chromium, lead, manganese and mercury). The influence of speciation on metal …

Manganese Distribution Across The Blood-Brain Barrier. Iv. Evidence For Brain Influx Through Store-Operated Calcium Channels, Janelle S. Crossgrove, Robert A. Yokel

Pharmaceutical Sciences Faculty Publications

Manganese (Mn) is a required co-factor for many ubiquitous enzymes; however, chronic Mn overexposure can cause manganism, a parkinsonian-like syndrome. Previous studies showed Mn influx into brain is carrier-mediated, though the putative carrier(s) were not established. Studies conducted with cultured bovine brain microvascular endothelial cells (bBMECs), which comprise the blood–brain barrier, revealed ⁵⁴Mn (II) uptake positively correlated with pH, was temperature-dependent, and was sodium- and energy-independent. Brain ⁵⁴Mn uptake correlated inversely with calcium (Ca) concentration, but ⁴⁵Ca uptake was unaltered by high Mn concentration. Lanthanum (La), a non-selective inhibitor of several Ca channel types, as well as …

Manganese Distribution Across The Blood-Brain Barrier. I. Evidence For Carrier-Mediated Influx Of Managanese Citrate As Well As Manganese And Manganese Transferrin, Janelle S. Crossgrove, David D. Allen, Bonny L. Bukaveckas, Susan S. Rhineheimer, Robert A. Yokel

Pharmaceutical Sciences Faculty Publications

Manganese (Mn) is an essential element and a neurotoxicant. Regulation of Mn movement across the blood–brain barrier (BBB) contributes to whether the brain Mn concentration is functional or toxic. In plasma, Mn associates with water, small molecular weight ligands and proteins. Mn speciation may influence the kinetics of its movement through the BBB. In the present work, the brain influx rates of ⁵⁴Mn²⁺, ⁵⁴Mn citrate and ⁵⁴Mn transferrin (⁵⁴Mn Tf) were determined using the in situ brain perfusion technique. The influx rates were compared to their predicted diffusion rates, which were determined from …

The Toxicology Of Aluminum In The Brain: A Review, Robert A. Yokel

Pharmaceutical Sciences Faculty Publications

Aluminum is environmentally ubiquitous, providing human exposure. Usual human exposure is primarily dietary. The potential for significant Al absorption from the nasal cavity and direct distribution into the brain should be further investigated. Decreased renal function increases human risk of Al-induced accumulation and toxicity. Brain Al entry from blood may involve transferrin-receptor mediated endocytosis and a more rapid process transporting small molecular weight Al species. There appears to be Al efflux from the brain, probably as Al citrate. There is prolonged retention of a fraction of Al that enters the brain, suggesting the potential for accumulation with repeated exposure. Al …

Novel Function Of Phosphoinositide 3-Kinase In T Cell Ca2+ Signaling, Ao-Lin Hsu, Tsui-Ting Ching, Goutam Sen, Da-Sheng Wan, Subbarao Bondada, Kalwant S. Authi, Ching-Shih Chen

Pharmaceutical Sciences Faculty Publications

This study presents evidence that phosphoinositide (PI) 3-kinase is involved in T cell Ca²⁺ signaling via a phosphatidylinositol 3,4,5-trisphosphate PI(3,4,5)P₃-sensitive Ca²⁺entry pathway. First, exogenous PI(3,4,5)P₃ at concentrations close to its physiological levels induces Ca²⁺ influx in T cells, whereas PI(3,4)P₂, PI(4,5)P₂, and PI(3)P have no effect on [Ca²⁺]_i. This Ca²⁺ entry mechanism is cell type-specific as B cells and a number of cell lines examined do not respond to PI(3,4,5)P₃ stimulation. Second, inhibition of PI 3-kinase by wortmannin and by overexpression of the …