Medicine and Health Sciences Commons^™

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.

Binding, Transcytosis And Biodistribution Of Anti-Pecam-1 Iron Oxide Nanoparticles For Brain-Targeted Delivery, Mo Dan, David B. Cochran, Robert A. Yokel, Thomas D. Dziubla

Pharmaceutical Sciences Faculty Publications

OBJECTIVE: Characterize the flux of platelet-endothelial cell adhesion molecule (PECAM-1) antibody-coated superparamagnetic iron oxide nanoparticles (IONPs) across the blood-brain barrier (BBB) and its biodistribution in vitro and in vivo.

METHODS: Anti-PECAM-1 IONPs and IgG IONPs were prepared and characterized in house. The binding affinity of these nanoparticles was investigated using human cortical microvascular endothelial cells (hCMEC/D3). Flux assays were performed using a hCMEC/D3 BBB model. To test their immunospecificity index and biodistribution, nanoparticles were given to Sprague Dawley rats by intra-carotid infusion. The capillary depletion method was used to elucidate their distribution between the BBB and brain parenchyma.

RESULTS: Anti-PECAM-1 …

Pharmacy Law Brief: Pharmacy Law Exam For Licensure, Joseph L. Fink Iii

Pharmacy Practice and Science Faculty Publications

No abstract provided.

Release Of A Wound-Healing Agent From Plga Microspheres In A Thermosensitive Gel, H. A. Machado, J. J. Abercrombie, T. You, Patrick P. Deluca, K. P. Leung

Pharmaceutical Sciences Faculty Publications

The purpose of this research was to develop a topical microsphere delivery system in a thermosensitive 20% poloxamer 407 gel (Pluronic F127) to control release of KSL-W, a cationic antimicrobial decapeptide, for a period of 4-7 days for potential application in combat related injuries. KSL-W loaded microsphere formulations were prepared by a solvent extraction-evaporation method (water-oil-water), with poly (D,L-lactic-co-glycolic acid) (PLGA) (50 : 50, low-weight, and hydrophilic end) as the polymeric system. After optimization of the process, three formulations (A, B, and C) were prepared with different organic to water ratio of the primary emulsion while maintaining other components and …

Bis-Pyridino Containing Compounds For The Use In The Treatment Of Cns Pathologies, Peter A. Crooks, Linda P. Dwoskin, Joshua Ayers, Vladimir Grinevich, Sangeetha Sumithran

Pharmaceutical Sciences Faculty Patents

N-n-Alkylation of nicotine converts nicotine from an agonist into an antagonist specifically for neuronal nicotinic acetylcholine receptor subtypes mediating nicotine-evoked dopamine release. Conformationally restricted analogs exhibit both high affinity and selectivity at this site, and are able to access the brain due to their ability to act as substrates for the blood-brain barrier choline transporter.

Clinical Inertia In Type 2 Diabetes: A Retrospective Analysis Of Pharmacist-Managed Diabetes Care Vs. Usual Medical Care, Felix K. Yam, Aimee G. Adams, Holly Divine, Douglas Steinke, Mikael D. Jones

Pharmacy Practice and Science Faculty Publications

Background: Evidence suggests that patients with type 2 diabetes (T2DM) suffer from a high rate of “clinical inertia” or “recognition of the problem but failure to act.”

Objective: The aim of this study is to quantify the rate of clinical inertia between two models of care: Pharmacist-Managed Diabetes Clinic (PMDC) vs. Usual Medical Care (UMC).

Methods: Patients in a university based medical clinic with type 2 diabetes (T2DM) were analyzed in this retrospective cohort study. Patients were exposed to either PMDC or UMC. The difference in days to intervention in response to suboptimal laboratory values and time …

Psmb9 Codon 60 Polymorphisms Have No Impact On The Activity Of The Immunoproteasome Catalytic Subunit B1i Expressed In Multiple Types Of Solid Cancer, Ji Eun Park, Lin Ao, Zachary Miller, Kyungbo Kim, Ying Wu, Eun Ryoung Jang, Eun Young Lee, Kyung Bo Kim, Wooin Lee

Pharmaceutical Sciences Faculty Publications

The proteasome is a key regulator of cellular protein homeostasis and is a clinically validated anticancer target. The immunoproteasome, a subtype of proteasome expressed mainly in hematopoietic cells, was initially recognized for its role in antigen presentation during the immune response. Recently, the immunoproteasome has been implicated in several disease conditions including cancer and autoimmune disorders, but many of the factors contributing to these pathological processes remain unknown. In particular, the codon 60 polymorphism of the PSMB9 gene encoding the β1i immunoproteasome catalytic subunit has been investigated in the context of a variety of diseases. Despite this, previous studies have …

Pharmacy Law Brief: National Practitioner Data Bank - What Is It?, Joseph L. Fink Iii

Pharmacy Practice and Science Faculty Publications

No abstract provided.

Computational And Experimental Insights Into The Mechanism Of Substrate Recognition And Feedback Inhibition Of Protoporphyrinogen Oxidase, Ge-Fei Hao, Ying Tan, Sheng-Gang Yang, Zhi-Fang Wang, Chang-Guo Zhan, Zhen Xi, Guang-Fu Yang

Pharmaceutical Sciences Faculty Publications

Protoporphyrinogen IX oxidase (PPO; EC 1.3.3.4) is an essential enzyme catalyzing the last common step in the pathway leading to heme and chlorophyll biosynthesis. Great interest in PPO inhibitors arises from both its significance to agriculture and medicine. However, the discovery of PPO inhibitors with ultrahigh potency and selectivity is hampered due to lack of structural and mechanistic understanding about the substrate recognition, which remains a longstanding question central in porphyrin biology. To understand the mechanism, a novel binding model of protogen (protoporphyrinogen IX, the substrate) was developed through extensive computational simulations. Subsequently, amino acid residues that are critical for …

Metal-Based Nanoparticle Interactions With The Nervous System: The Challenge Of Brain Entry And The Risk Of Retention In The Organism, Robert A. Yokel, Eric A. Grulke, Robert C. Macphail

Pharmaceutical Sciences Faculty Publications

This review of metal-based nanoparticles focuses on factors influencing their distribution into the nervous system, evidence they enter brain parenchyma, and nervous system responses. Gold is emphasized as a model metal-based nanoparticle and for risk assessment in the companion review. The anatomy and physiology of the nervous system, basics of colloid chemistry, and environmental factors that influence what cells see are reviewed to provide background on the biological, physical–chemical, and internal milieu factors that influence nervous system nanoparticle uptake. The results of literature searches reveal little nanoparticle research included the nervous system, which about equally involved in vitro and in …

Pharmacy Law Brief: Exclusion Of Practitioners From Federally Funded Health Programs, Joseph L. Fink Iii

Pharmacy Practice and Science Faculty Publications

No abstract provided.

Gene Transfer Of Mutant Mouse Cholinesterase Provides High Lifetime Expression And Reduced Cocaine Responses With No Evident Toxicity, Liyi Geng, Yang Gao, Xiabin Chen, Shurong Hou, Chang-Guo Zhan, Zoran Radic, Robin J. Parks, Stephen J. Russell, Linh Pham, Stephen Brimijoin

Pharmaceutical Sciences Faculty Publications

Gene transfer of a human cocaine hydrolase (hCocH) derived from butyrylcholinesterase (BChE) by 5 mutations (A199S/F227A/S287G/A328W/Y332G) has shown promise in animal studies for treatment of cocaine addiction. To predict the physiological fate and immunogenicity of this enzyme in humans, a comparable enzyme was created and tested in a conspecific host. Thus, similar mutations (A199S/S227A/S287G/A328W/Y332G) were introduced into mouse BChE to obtain a mouse CocH (mCocH). The cDNA was incorporated into viral vectors based on: a) serotype-5 helper-dependent adenovirus (hdAD) with ApoE promoter, and b) serotype-8 adeno-associated virus with CMV promoter (AAV-CMV) or multiple promoter and enhancer elements (AAV-VIP). Experiments on …

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

Pharmaceutical Sciences Faculty Patents

To view this abstract, please download this patent.

Block Copolymer Self-Assembled And Cross-Linked Nanoassemblies For Combination Delivery Of Iron Oxide And Doxorubicin, Daniel Scott, Yihwa Beabout, Robert J. Wydra, Mo Dan, Robert A. Yokel, J. Zach Hilt, Younsoo Bae

Pharmaceutical Sciences Faculty Publications

We describe the development of nanoscale polymer drug carriers for the combinational delivery of an anticancer drug (doxorubicin: DOX) along with super paramagnetic iron oxide nanoparticles (IONPs). The drug molecules were electrostatically loaded into both block copolymer self-assembled nanoassemblies (SNAs) and cross-linked nanoassemblies (CNAs). Both nanoassemblies entrapped DOX and IONPs either individually or in tandem, maintaining sub-100 nm diameter. The IONP-loaded nanoassemblies generated heat in the presence of an alternating magnetic field (AMF). Incorporation of the drug payload, DOX, showed no adverse effects on the heating profile. Drug release from the SNAs and CNAs was accelerated as temperature increased from …

Amyloid-Β Probes: Review Of Structure-Activity And Brain-Kinetics Relationships, Todd J. Eckroat, Abdelrahman S. Mayhoub, Sylvie Garneau-Tsodikova

Pharmaceutical Sciences Faculty Publications

The number of people suffering from Alzheimer's disease (AD) is expected to increase dramatically in the coming years, placing a huge burden on society. Current treatments for AD leave much to be desired, and numerous research efforts around the globe are focused on developing improved therapeutics. In addition, current diagnostic tools for AD rely largely on subjective cognitive assessment rather than on identification of pathophysiological changes associated with disease onset and progression. These facts have led to numerous efforts to develop chemical probes to detect pathophysiological hallmarks of AD, such as amyloid-β plaques, for diagnosis and monitoring of therapeutic efficacy. …

Synthesis And Biological Evaluation Of Novel Folic Acid Receptor-Targeted, Β-Cyclodextrin-Based Drug Complexes For Cancer Treatment, Juan-Juan Yin, Sonali Sharma, Stepan P. Shumyak, Zhi-Xin Wang, Zhi-Wei Zhou, Yangde Zhang, Peixuan Guo, Chen-Zhong Li, Jagat R. Kanwar, Tianxin Yang, Shyam S. Mohapatra, Wanqing Liu, Wei Duan, Jian-Cheng Wang, Qi Li, Xueji Zhang, Jun Tan, Lee Jia, Jun Liang, Ming Q. Wei, Xiaotian Li, Shu-Feng Zhou

Nanobiotechnology Center Faculty Publications

Drug targeting is an active area of research and nano-scaled drug delivery systems hold tremendous potential for the treatment of neoplasms. In this study, a novel cyclodextrin (CD)-based nanoparticle drug delivery system has been assembled and characterized for the therapy of folate receptor-positive [FR(+)] cancer. Water-soluble folic acid (FA)-conjugated CD carriers (FACDs) were successfully synthesized and their structures were confirmed by 1D/2D nuclear magnetic resonance (NMR), matrix-assisted laser desorption ionization time-of-flight mass spectrometer (MALDI-TOF-MS), high performance liquid chromatography (HPLC), Fourier transform infrared spectroscopy (FTIR), and circular dichroism. Drug complexes of adamatane (Ada) and cytotoxic doxorubicin (Dox) with FACD were readily …

Glycosylate Derivatives Of Mithramycin, Method Of Preparation And Uses Thereof, Jürgen Rohr, Irfan Baig, Jose Antonio Salas Fernandez, Alfredo Fernandez Brana, Maria Perez Solares

Pharmaceutical Sciences Faculty Patents

The present invention provides compounds characterized by the formula (I), where each of the substituent radicals is described in the specification. The invention also describes the use of said compounds in the treatment of various diseases, including: cancer or tumoral processes in general, Paget's disease, hypercalcaemia, hypercalciuria and neurological diseases (inter alia, Parkinson's, Alzheimer's, Huntington's).

Biodistribution And Biopersistence Of Ceria Engineered Nanomaterials: Size Dependence, Robert A. Yokel, Michael T. Tseng, Mo Dan, Jason M. Unrine, Uschi M. Graham, Peng Wu, Eric A. Grulke

Pharmaceutical Sciences Faculty Publications

The aims were to determine the biodistribution, translocation, and persistence of nanoceria in the brain and selected peripheral organs. Nanoceria is being studied as an anti-oxidant therapeutic. Five, 15, 30, or 55 nm ceria was iv infused into rats which were terminated 1, 20, or 720 h later. Cerium was determined in blood, brain, liver, and spleen. Liver and spleen contained a large percentage of the dose, from which there was no significant clearance over 720 h, associated with adverse changes. Very little nanoceria entered brain parenchyma. The results suggest brain delivery of nanoceria will be a challenge.

FROM THE …

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, …

Pharmacy Law Brief: Contemporary Legal Issues For Leadership In Non-Profits - Iv, Joseph L. Fink Iii

Pharmacy Practice and Science Faculty Publications

No abstract provided.

Physicochemical Characterization And Aerosol Dispersion Performance Of Organic Solution Advanced Spray-Dried Cyclosporine A Multifunctional Particles For Dry Powder Inhalation Aerosol Delivery, Xiao Wu, Weifen Zhang, Don Hayes Jr., Heidi M. Mansour

Pharmaceutical Sciences Faculty Publications

In this systematic and comprehensive study, inhalation powders of the polypeptide immunosuppressant drug - cyclosporine A - for lung delivery as dry powder inhalers (DPIs) were successfully designed, developed, and optimized. Several spray drying pump rates were rationally chosen. Comprehensive physicochemical characterization and imaging was carried out using scanning electron microscopy, hot-stage microscopy, differential scanning calorimetry, powder X-ray diffraction, Karl Fischer titration, laser size diffraction, and gravimetric vapor sorption. Aerosol dispersion performance was conducted using a next generation impactor with a Food and Drug Administration-approved DPI device. These DPIs displayed excellent aerosol dispersion performance with high values in emitted dose, …

Block Copolymer Cross-Linked Nanoassemblies Improve Particle Stability And Biocompatibility Of Superparamagnetic Iron Oxide Nanoparticles, Mo Dan, Daniel F. Scott, Peter A. Hardy, Robert J. Wydra, J. Zach Hilt, Robert A. Yokel, Younsoo Bae

Pharmaceutical Sciences Faculty Publications

PURPOSE: To develop cross-linked nanoassemblies (CNAs) as carriers for superparamagnetic iron oxide nanoparticles (IONPs).

METHODS: Ferric and ferrous ions were co-precipitated inside core-shell type nanoparticles prepared by cross-linking poly(ethylene glycol)-poly(aspartate) block copolymers to prepare CNAs entrapping Fe(3)O(4) IONPs (CNA-IONPs). Particle stability and biocompatibility of CNA-IONPs were characterized in comparison to citrate-coated Fe(3)O(4) IONPs (Citrate-IONPs).

RESULTS: CNA-IONPs, approximately 30 nm in diameter, showed no precipitation in water, PBS, or a cell culture medium after 3 or 30 h, at 22, 37, and 43°C, and 1, 2.5, and 5 mg/mL, whereas Citrate-IONPs agglomerated rapidly (> 400 nm) in all …

Activation Of Thromboxane A2 Receptor (Tp) Increases The Expression Of Monocyte Chemoattractant Protein -1 (Mcp-1)/Chemokine (C-C Motif) Ligand 2 (Ccl2) And Recruits Macrophages To Promote Invasion Of Lung Cancer Cells, Xiuling Li, Hsin-Hsiung Tai

Pharmaceutical Sciences Faculty Publications

Thromboxane synthase (TXAS) and thromboxane A₂ receptor (TP), two critical components for thromboxane A₂ (TXA₂) signaling, have been suggested to be involved in cancer invasion and metastasis. However, the mechanisms by which TXA₂ promotes these processes are still unclear. Here we show that TXA₂ mimetic, I-BOP, induced monocyte chemoattractant protein -1(MCP-1)/chemokine (C-C motif) ligand 2 (CCL2) expression at both mRNA and protein levels in human lung adenocarcinoma A549 cells stably over-expressing TP receptor α isoform (A549-TPα). The induction of MCP-1 was also found in other lung cancer cells H157 and H460 that express relatively …

Design, Physicochemical Characterization, And Optimization Of Organic Solution Advanced Spray-Dried Inhalable Dipalmitoylphosphatidylcholine (Dppc) And Dipalmitoylphosphatidylethanolamine Poly(Ethylene Glycol) (Dppe-Peg) Microparticles And Nanoparticles For Targeted Respiratory Nanomedicine Delivery As Dry Powder Inhalation Aerosols, Samantha Ann Meenach, Frederick G. Vogt, Kimberly W. Anderson, J. Zach Hilt, Ronald C. Mcgarry, Heidi M. Mansour

Pharmaceutical Sciences Faculty Publications

Novel advanced spray-dried and co-spray-dried inhalable lung surfactant-mimic phospholipid and poly(ethylene glycol) (PEG)ylated lipopolymers as microparticulate/nanoparticulate dry powders of biodegradable biocompatible lipopolymers were rationally formulated via an organic solution advanced spray-drying process in closed mode using various phospholipid formulations and rationally chosen spray-drying pump rates. Ratios of dipalmitoylphosphatidylcholine (DPPC) and dipalmitoylphosphatidylethanolamine PEG (DPPE-PEG) with varying PEG lengths were mixed in a dilute methanol solution. Scanning electron microscopy images showed the smooth, spherical particle morphology of the inhalable particles. The size of the particles was statistically analyzed using the scanning electron micrographs and SigmaScan® software and were determined to be 600 …

Pharmacy Law Brief: Contemporary Legal Issues For Leadership In Non-Profits - Iii, Joseph L. Fink Iii

Pharmacy Practice and Science Faculty Publications

No abstract provided.