Pharmacy and Pharmaceutical Sciences Commons^™

Sexual Dimorphism In Aortic Function Of Uc Davis Type 2 Diabetes Mellitus Rat Model: Estrogen Specific Responses, Farjana Akther

University of the Pacific Theses and Dissertations

Little is known about the interaction between diabetes and sex in vasculature. This study was designed to investigate the effects of estrogen as well as type 2 diabetes (T2D) on aortic function in rats with respect to sex. To test the effects of T2D and sex, UC Davis Type 2 Diabetes Mellitus (UCD-T2DM) rat model was used. To study the effects of estrogen, ovariectomized Sprague- Dawley female rats and UCD-T2DM rats at pre-diabetic stage were used and the rats were implanted subcutaneously either with placebo or 17 β-estradiol pellets (60 days release, 1.5mg/pellets). The plasma analytes for metabolic parameters and …

A Xenopus Oocyte Model System To Study Action Potentials, Aaron Corbin-Leftwich, Hannah E Small, Helen H Robinson, Carlos A. Villalba-Galea, Linda M Boland

School of Pharmacy Faculty Articles

Action potentials (APs) are the functional units of fast electrical signaling in excitable cells. The upstroke and downstroke of an AP is generated by the competing and asynchronous action of Na+- and K+-selective voltage-gated conductances. Although a mixture of voltage-gated channels has been long recognized to contribute to the generation and temporal characteristics of the AP, understanding how each of these proteins function and are regulated during electrical signaling remains the subject of intense research. AP properties vary among different cellular types because of the expression diversity, subcellular location, and modulation of ion channels. These complexities, in addition to the …

Regulation Of Kv2.1 Channel Inactivation By Phosphatidylinositol 4,5-Bisphosphate., Mayra Delgado-Ramírez, José J De Jesús-Pérez, Iván A Aréchiga-Figueroa, Jorge Arreola, Scott K Adney, Carlos A. Villalba-Galea, Diomedes E Logothetis, Aldo A Rodríguez-Menchaca

School of Pharmacy Faculty Articles

Phosphatidylinositol 4,5-bisphosphate (PIP2) is a membrane phospholipid that regulates the function of multiple ion channels, including some members of the voltage-gated potassium (Kv) channel superfamily. The PIP2 sensitivity of Kv channels is well established for all five members of the Kv7 family and for Kv1.2 channels; however, regulation of other Kv channels by PIP2 remains unclear. Here, we investigate the effects of PIP2 on Kv2.1 channels by applying exogenous PIP2 to the cytoplasmic face of excised membrane patches, activating muscarinic receptors (M1R), or depleting endogenous PIP2 using a rapamycin-translocated 5-phosphatase (FKBP-Inp54p). Exogenous PIP2 rescued Kv2.1 channels from rundown and partially …

Development Of Novel Phenanthroline And Thiazole Orange Derived G-Quadruplex Ligands And Telomerase Inhibitors, Siwen Wang

University of the Pacific Theses and Dissertations

The end of the human chromosome is protected by telomeres which contain a special tandem guanine-rich DNA sequence, 5’-TTAGGG. The length of telomeres is shortened during cell replications, and its length limits the replication capacity of cells. Telomerase is over-expressed in 85–90% of cancer cells, responsible for extending the telomere length in cancer cells. Guanine-rich DNA sequence can self-assemble into unique G-quadruplex structures that interfere with the extension of telomeres by telomerase. Therefore, DNA G-quadruplex has recently received much attention because of its important regulatory functions in telomerase-mediated cancerization. The formation of G-quadruplex requires monovalent cations (Na+ and K+) or …

Determining The Role Played By Aryl Hydrocarbon Receptor (Ahr) In The Colon Carcinoma Tumor Model, Poonam Yakkundi

University of the Pacific Theses and Dissertations

Aryl hydrocarbon receptor (AHR), commonly known as an environmental sensor involved in the metabolism and elimination of xenobiotic substances, is also an important modulator in the development and functioning of the immune system. AHR expression is varied in the T cell subsets with the highest expression in T-helper 17 and T regulatory cells. Work from many researchers has suggested that AHR can act as a tumor promoter or a tumor suppressor depending on the tumor type. Our goal is to understand the role played by AHR in MC38 syngeneic colon carcinoma tumor model. In the absence of AHR, MC38 tumor …

Rational Design Of Peptides Binding Towards Human Pd-L1 Using Knob-Socket Model, Xingchen Zha

University of the Pacific Theses and Dissertations

Programmed death-ligand 1 (PD-L1) is a type 1 transmembrane protein that has been reported to play a vital role in mediating suppressed immunity. The interaction between PD-L1 and PD-1 delivers a negative signal that reduces the proliferation of these T cells and induces apoptosis at the same time. Antibodies that can block the Programmed death-ligand 1 (PD-L1) on tumor cells have been shown to alleviate cancer-induced immunosuppression. While antibodies have a great potential in various therapeutic uses, many drawbacks such as the high cost of production, huge molecular size, and poor permeability impose restrictions on the extensive use of full-length …

Bimetallic Complexes: The Fundamental Aspects Of Metal-Metal Interactions, Ligand Sterics And Application, Michael Bernard Pastor

University of the Pacific Theses and Dissertations

Metal containing complexes have been used to catalyze various organic transformations for the past few decades. The success of several mononuclear catalysts led to transition metal catalysts used in pharmaceuticals, environmental, and industrial processes. While mononuclear complexes have been used extensively, bimetallic systems have received far less attention. Bimetallic or polynuclear sites are commonly found in metalloenzymes that perform elegant transformation in biological systems, underlying their significance. Inorganic chemists take inspiration from nature and design model bimetallic complexes to further study this cooperativity effect. A bimetallic platform offers many structural and functional differences such as the identity of the metal …

Peptide-Drug Conjugate For Her2-Targeted Drug Delivery, Yan Wang

University of the Pacific Theses and Dissertations

Recent strategies for anticancer drug design have been focused on utilizing antibody as a drug or targeted moiety for targeted drug delivery. Antibody−drug conjugates (ADCs) have become a promising new class of targeted therapeutic agents for treatment of cancer. ADCs are designed to preferentially direct a cytotoxic drug to a cell-surface antigen recognized by an antibody. However, there are some challenges in developing ADCs, such as limited solid tumor penetration, high manufacturing costs and antibody-drug stoichiometry. Smaller molecules such as peptides have been shown to specifically bind to cancer related targets. These peptides can be used to form peptide-drug conjugates …

Investigations On Cancer Cell Biological Effects Of Cdk8 Inhibitor Q-12, Zhixin Lu

University of the Pacific Theses and Dissertations

Over the past two decades, protein kinases have been intensively investigated as targets to treat neoplastic diseases. Many protein kinase inhibitors not only have therapeutic potential but are becoming invaluable reagents for the study of cell signaling.

We aspired to use our Cyclin-Dependent Kinase 8 inhibitor, Q-12, as a probe for biomarker discovery for CDK8 inhibitor sensitive tumor types. Q-12 shows potent inhibition of cell viability and induction of apoptosis process in some triple-negative breast cancer and colorectal cancer cell lines in vitro. Western blot results indicate that the reduction of STAT1 phosphorylation could be a robust indicator of CDK8 …

Design And In Vitro Characterization Of Lipids With A Ph-Sensitive Conformational Switch And Their Liposomes For Anticancer Drug Delivery, Shen Zhao

University of the Pacific Theses and Dissertations

The traditional anticancer drugs are distributed in vivo through systemic blood circulation with a very small portion reaching the tumor site. Targeted drug delivery systems are developed in efforts to concentrate the drug molecules in the tissue of interest while reducing the drug distribution to healthy tissues to reduce the side effects. Liposomes are colloidal systems composed of amphiphilic molecules that assemble into vesicle structures in aqueous media. They are common carriers for targeted drug delivery with the advantages of low toxicity, low immunogenicity and the ability of encapsulating both lipophilic and hydrophilic drugs.

Prior research indicated the advantages of …

Mechanistic Study Of P23-Mediated Aryl Hydrocarbon Receptor Expression, Beverly Pappas

University of the Pacific Theses and Dissertations

The aryl hydrocarbon receptor (AHR) is a ligand-activated signaling molecule which is involved in diverse biological functions ranging from cancer metastasis to immune regulation. This receptor forms a cytoplasmic complex with Hsp90, p23, and XAP2. We have previously reported that down-regulation of p23 triggers degradation of the AHR protein, uncovering a potentially dynamic event which controls the cellular AHR levels without ligand treatment. Here we investigate the underlying mechanisms for this p23 effect using wild-type HeLa and the p23 knockdown HeLa cells. Reduction of the Hsp90 and XAP2 contents, however, did not affect the AHR protein levels, implying that this …

Computational Methods In Biomolecules:Study Of Hydrophilic Interactions In Protein Folding & Constant-Ph Molecular Simulation Of Ph Sensitive Lipid Morc16, Wei Zhang

University of the Pacific Theses and Dissertations

Water molecules play a significant role in biological process and are directly involved with bio-molecules and organic compounds and ions. Recent research has focused on the thermal dynamics and kinetics of water molecules in solution, including experimental (infrared spectroscopy and Raman spectroscopy) and computational (Quantum Mechanics and Molecular Dynamics) approaches. The reason that water molecules are so unique, why they have such a profound influence on bio-activity, why water molecules show some anomalies compared to other small molecules, and where and how water molecules exert their influence on solutes are some of the areas under study. We studied some properties …

Influence Of The Estrous Cycle And Female Sex Hormones On Ghb Toxicokinetics, Hao Wei

University of the Pacific Theses and Dissertations

Gamma-Hydroxybutyrate (GHB) is an endogenous short-chain fatty acid formed from Gamma-aminobutyric acid (GABA). Clinically, GHB is marketed in the United States as Xyrem to treat narcolepsy with cataplexy and in Europe for the treatment of alcohol withdrawal and narcolepsy. However, the illicit use and abuse of GHB occurs due to its sedative/hypnotic and euphoric effects. Monocarboxylate transporters (MCTs and SMCTs) are integral membrane proteins that control the bidirectional transport of endogenous substrates including lactate, acetate and pyruvate. They have also been found to transport and mediate the clearance and distribution of GHB. MCTs demonstrate a wide tissue distribution, including brain, …

Synthesis Of Ag10 Analogs And Optimization Of Ttr Ligands For Half-Life Enhancement (Tlhe) Of Peptides, Raghavendra Jampala

University of the Pacific Theses and Dissertations

The misassembly of soluble proteins into toxic aggregates, including amyloid fibrils, underlies a large number of human degenerative diseases. Cardiac amyloidosis, which is most commonly, caused by aggregation of Immunoglobulin (Ig) light chains or transthyretin (TTR) in the cardiac muscle, represent an important and often underdiagnosed cause of heart failure. TTR-mediated amyloid cardiomyopathies are chronic and progressive conditions that lead to arrhythmias, biventricular heart failure, and death. As no Food and Drug Administration-approved drugs are currently available for treatment of these diseases, the development of therapeutic agents that prevent TTR-mediated cardiotoxicity is desired. AG10 is a potent and selective kinetic …

Fragment-Based Excitonic Coupled-Cluster Theory For Large Chemical Systems, Yuhong Liu

University of the Pacific Theses and Dissertations

Accurate energetic modeling of large molecular systems is always desired by chemists. For example, ligand-protein binding simulations and enzymatic catalysis studies all involve with a small energy difference. The energetic accuracy depends largely on a proper handling of electronic correlations. Molecular mechanics (MM) methods deliver a parameterized Newtonian treatment to these problems. They show great capability in handling large calculations but give only qualitatively good results. Quantum mechanics (QM) methods solve Schrödinger equations and exhibit much better energy accuracy, though the computational cost can be prohibitive if directly applied to very large systems.

Fragment-based methods have been developed to decompose …

Investigating Secondary Structure Features Of Yap1 Protein Fragments Using Molecular Dynamics (Md) And Steered Molecular Dynamics (Smd) Simulations, Ferdiemar Cardenas Guinto Jr.

University of the Pacific Theses and Dissertations

Molecular dynamics (MD) is a powerful tool that can be applied to protein folding and protein structure. MD allows for the calculation of movement, and final position, of atoms in a biomolecule. These movements can be used to investigate the pathways that allow proteins to fold into energetically favorable structures. While MD is very useful, it still has its limitations. Most notable, computing power and time are of constant concern.

Protein structure is inherently important due to the direct link between the structure of a protein and its function. One of the four levels of protein structure, the secondary structure, …

The Rational Investigation Of Anti-Cancer Peptide Specificity Using The Knob-Socket Model, Shivarni Patel

University of the Pacific Theses and Dissertations

Cancer has been a pervasive and deadly problem for many years. No treatments have been developed that effectively destroy cancer cells while also keeping healthy cells safe. In this work, the knob-socket construct is used to analyze two systems involved in cancer pathways, the PDZ domain and the Bcl-BH3 complex. Application of the knob-socket model in mapping the packing surface topology (PST) allows a direct analysis of the residue groups important for peptide specificity and affinity in both of these systems. PDZ domains are regulatory proteins that bind the C-terminus of peptides involved in the signaling pathway of cancer progression. …

Solubility Enhancement Of Model Compounds, Lavanya Pitani

University of the Pacific Theses and Dissertations

Solubility is the amount of solute in the solvent system at phase equilibrium with certain temperature and pressure. Many of the new chemical entities are lipophilic molecules that require techniques to enhance solubility. Solubility enhancement can be achieved by either physical and/or chemical modification of the drug. Various techniques are available for solubility enhancement of poorly soluble drugs include particle size reduction, salt formation, solid dispersions, use of surfactants, prodrug, crystal modification, etc.

In this study, the three model drugs belong to BCS class II and IV having low solubility with a certain range of physicochemical properties were studies in …

Clinical Factors Associated With Hepatitis C Treatment Selection In A Veterans Affairs Population, Carly Anne Ranson

University of the Pacific Theses and Dissertations

Background: Hepatitis C virus is currently the most common chronic blood borne pathogen in the United States, with only half of those infected aware of their condition. The cost for treatment is higher with Harvoni® (ledipasvir/sofosbuvir) than Viekira Pak® (ombitasvir/paritaprevir/ritonavir and dasabuvir). With finite resources available to treat patients, it is important to understand which clinical factors may influence treatment selection decisions.

Methods: The study is a 12-month medical record review within the Veterans Affairs (VA) system to evaluate significant relationships between selected clinical and sociodemographic factors and HCV treatment selection with either Harvoni® or Viekira Pak®. Clinical and demographic …

Liposome-Coated Magnesium Phosphate Nanoparticle For Delivery Of Cytochrome C Into Lung Cancer Cells A549, Weizhou Yue

University of the Pacific Theses and Dissertations

Proteins are large biomolecules that have great therapeutic potential in treating many human diseases. However, chemical/enzymatic degradation, denaturation, and poor penetration into cells are some of the challenges for clinical use of intracellular proteins.

Previously, our group has developed cationic lipid-coated magnesium phosphate nanoparticle (LP MgP NP-CAT) formulations to enhance the intracellular delivery of the negatively charged protein catalase. The goal of the current research is to develop a formulation to deliver cytochrome c (CytC), a positively charged protein into lung cancer cells A549. Specifically, this thesis research prepares and tests liposome-coated magnesium phosphate nanoparticle for delivery of cytochrome c …

Preclinical Evaluation Of Ag10 For Therapeutic Use Against Familial Amyloid Cardiomyopathy And Its Application In Various Other Technologies, Mark Russell Miller

University of the Pacific Theses and Dissertations

Transthyretin (TTR) amyloidosis is a progressive, fatal disease in which deposition of amyloid derived from either mutant or wild-type TTR causes severe organ damage and dysfunction. TTR cardiomyopathy is an infiltrative, restrictive cardiomyopathy characterized by progressive left and right heart failure. Familial amyloid cardiomyopathy (FAC) is driven by pathogenic point mutations in the TTR gene that destabilize the TTR tetramer, prompting its dissociation into dimers and monomers, with subsequent misfolding, aggregation and deposition of toxic TTR amyloid aggregates in the myocardium. The most prevalent mutation that causes FAC is the V122I variant, carried by 3.4% of African Americans, that increases …

Sexual Dimorphism In Rat Vascular Function Of Type I And Type Ii Diabetes: Role Of Edrfs, Roshanak Rahimian

Science Seminar Series

Dr. Roshanak Rahimian, professor of physiology and pharmacology in the Thomas J. Long School of Pharmacy and Health Sciences will tell us about her work on understanding the mechanisms underlying the interaction of sex and diabetes in vasculature.

Over the past decade, diabetes and obesity have reached epidemic levels in developed countries, and has become one of the most serious and challenging health problems in the 21st century. Several studies suggest that diabetes affects male and female vascular beds differently. However, the mechanisms underlying the interaction of sex and diabetes in vasculature remain to be investigated. We have shown that …

Pharmart: The Art Of Bringing Faculty, Librarians, And Students Together, Mickel Paris, Edward L. Rogan, R. Stark, Cassie Etter, Kate Dopkins

University Libraries Librarian and Staff Presentations

No abstract provided.

Retigabine Holds Kv7 Channels Open And Stabilizes The Resting Potential, Aaron Corbin-Leftwich, Sayeed M. Mossadeq, Junghoon Ha, Iwona Ruchala, Audrey Han Ngoc Le, Carlos A. Villalba-Galea

School of Pharmacy Faculty Articles

The anticonvulsant Retigabine is a KV7 channel agonist used to treat hyperexcitability disorders in humans. Retigabine shifts the voltage dependence for activation of the heteromeric KV7.2/KV7.3 channel to more negative potentials, thus facilitating activation. Although the molecular mechanism underlying Retigabine's action remains unknown, previous studies have identified the pore region of KV7 channels as the drug's target. This suggested that the Retigabine-induced shift in voltage dependence likely derives from the stabilization of the pore domain in an open (conducting) conformation. Testing this idea, we show that the heteromeric KV7.2/KV7.3 channel has at least two open states, which we named O1 …

Editorial: Phosphoinositides And Their Phosphatases: Linking Electrical And Chemical Signals In Biological Processes, Susy C. Kohout, Carlos A. Villalba-Galea

School of Pharmacy Faculty Articles

No abstract provided.

Predicting Aqueous Solubility Of Pharmaceutical Agents By Solid Dispersion Prepared By Solvent Evaporation Method, Karthik Reddy Patlolla

University of the Pacific Theses and Dissertations

Solubility of active pharmaceutical agents is a crucial process that determines drug absorption and ultimately its bioavailability. Many of the new therapeutically beneficial compounds discovered are lipophilic requiring various solubility enhancement strategies to improve their solubility. Among these strategies, solubility enhancement using solid dispersions is a leading method. To obtain a desirable increase in the solubility of a poorly-soluble compound, a good understanding of the molecular descriptors influencing the enhancement of solubility is essential. Therefore, the major research objective was to determine the descriptors which significantly influence the solubility enhancement by solid dispersions. After enhancing the solubility of selected poorly-soluble …

Healthcare Provider Utilization And Patient Outcomes: The Call For Enhanced Coordinated Care For Medicare Beneficiaries, Yvonne Mai, Rajul A. Patel, Suzanne M. Galal, Sian M. Carr-Lopez, Joseph A. Woelfel

School of Pharmacy Faculty Presentations

Background: The use of complementary and alternative medicine (CAM) and other non-physician health care providers (dentists, optometrists, etc.) has steadily increased in the United States; however, the associated outcomes reported in the Medicare population is limited.

Objective: To evaluate the utilization of different healthcare providers by Medicare beneficiaries and assess resultant patient outcomes.

Methods: Fourteen outreach events targeting Medicare beneficiaries were conducted throughout Northern/Central California during the 2014 open enrollment period. Trained student pharmacists (working under licensed pharmacist supervision) provided beneficiaries with comprehensive medication therapy management (MTM) services. During each intervention, demographic, quality-of-life, health behavior, and health provider/service utilization data …

Medication Adherence Behaviors Of Medicare Beneficiaries, Sian M. Carr-Lopez, Allen Shek, Janine Lastimosa, Rajul A. Patel, Joseph A. Woelfel, Suzanne M. Galal, Berit Gundersen

School of Pharmacy Faculty Articles

Background: Medication adherence is crucial for positive outcomes in the management of chronic conditions. Comprehensive medication consultation can improve medication adherence by addressing intentional and unintentional nonadherence. The Medicare Part D prescription drug benefit has eliminated some cost barriers. We sought to examine variables that impact self-reported medication adherence behaviors in an ambulatory Medicare-beneficiary population and to identify the factors that influence what information is provided during a pharmacist consultation.Methods: Medicare beneficiaries who attended health fairs in northern California were offered medication therapy management (MTM) services during which demographic, social, and health information, and responses to survey questions regarding adherence …

A Collaborative Approach To Combining Service, Teaching, And Research, Suzanne M. Galal, Sian M. Carr-Lopez, Seth Gomez, Van Duong, Caitlin Mizoshiri, Lauren Ujihara, Tina H. Tran, Rajul A. Patel, Joseph A. Woelfel

School of Pharmacy Faculty Articles

Objective. To describe a faculty-student collaborative model and its outcomes on teaching, service, and scholarship.

Design. A Medicare Part D elective course was offered that consisted of classroom and experiential learning where pharmacy students participated in community outreach events to assist Medicare beneficiaries with Part D plan selection. The course training was expanded to include medication therapy management (MTM) and the administration of immunizations. At the completion of the course, students collaborated with faculty members on research endeavors.

Evaluation. During the first 6 years of this course, the class size more than doubled from 20 to 42 students, and all …

Cost Variability Of Suggested Generic Treatment Alternatives Under The Medicare Part D Benefit, Rajul A. Patel, Mark P. Walberg, Emily Tong, Florence Tan, Ashley E. Rummel, Joseph A. Woelfel, Sian M. Carr-Lopez, Suzanne M. Galal

School of Pharmacy Faculty Articles

BACKGROUND: The substitution of generic treatment alternatives for brand-name drugs is a strategy that can help lower Medicare beneficiary out-of-pocket costs. Beginning in 2011, Medicare beneficiaries reaching the coverage gap received a 50% discount on the full drug cost of brand-name medications and a 7% discount on generic medications filled during the gap. This discount will increase until 2020, when beneficiaries will be responsible for 25% of total drug costs during the coverage gap.

OBJECTIVE: To examine the cost variability of brand and generic drugs within 4 therapeutic classes before and during the coverage gap for each 2011 California stand-alone …