Pharmacy and Pharmaceutical Sciences Commons^™

Structure, Synthesis And Biological Activity Of Harmful Algal Bloom Toxins From Karlodinium Sp. And Exploration Of Microbial Derived Natural Products, Amanda Leigh Waters

Electronic Theses and Dissertations

This work features natural products isolated from both the marine and microbial environments. Part I focuses on the elucidation of toxins from harmful algal blooms (HAB). The HAB dinoflagellate Karlodinium veneficum produces a harmful suite of molecules identified as the karlotoxins (KmTx) that have been implicated in massive fish kills pan-globally. Nine new karlotoxin congeners were isolated from various Karlodinium blooms around the world and utilizing the structure of KmTx2 were characterized using overlaid 2D NMR techniques. Due to the contrasting conformational differences between KmTx and the closely related amphidinols, the absolute configuration of KmTx was further evaluated by extensive …

Intranasal Delivery Of Therapeutics Targeted To Csf And Brain, Prashanth Manda

Electronic Theses and Dissertations

Blood-brain barrier and blood-cerebrospinal fluid barrier limit the systemic delivery of therapeutics to the brain and cerebrospinal fluid (CSF) respectively. Therapeutic agents targeting CNS are currently being administered by invasive routes which are not patient compliant and do not allow frequent administration. Intranasal delivery of therapeutics to target CSF and brain is a noninvasive route of administration which is patient compliant and allows frequent administration. In the current study, the plausibility of delivering ziconotide and cefotaxime to CSF and brain respectively via intranasal pathway using barrier modulating agents like chitosan was investigated. The ability of chitosan to enhance the permeation …

Secondary Metabolite Production By An Endophytic Bacillus Sp. From Platanus Occidentalis, Michael C. James

Electronic Theses and Dissertations

Endophytes are bacterial and fungal microbes that live inside of plant tissue without causing disease. Endophytes have applications in many industries including the pharmaceutical and food industries as producers of natural products. This potential was demonstrated by investigating the natural product production from a Bacillus amyloliquefaciens endophyte of Platanus occidentalis using a combination of MALDI-IMS, LC-MS, MS-MS, and NMR methods, by purifying nicotianamine from soy flour, and by reviewing natural product inhibitors of the hepatitis C virus (HCV). The secondary metabolite production of the endophytic B. amyloliquefaciens was investigated under a variety of fermentation conditions. It was discovered that the …

A Comprehensive Review Of Malaria With An Emphasis On Plasmodium Resistance, Lindsay O. Thomas

Honors Theses

Malaria is a disease that is caused by the Plasmodium genus. It is endemic in tropical areas. There are multiple drugs used for prophylaxis and treatment. However, the parasites have developed resistance towards most antimalarial pharmaceuticals. The pharmaceutical industry is generating new antimalarial pharmaceuticals, but the rate of new Plasmodium resistance is much faster.

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 …

Role Of Micro Rna 148/152 Family In Cancer Progression, Anusha Chaparala

Theses and Dissertations

Micro RNA are small single stranded RNA that regulate the expression of various genes. MiRNA guide the mRNA disintegrating RISC complex to the complimentary sequence in the target mRNA. Each micro RNA has multiple targets and can play a different biological role depending on the population of targets at the particular stage of the cell or a physiological state. Several miRNA show elevated or decreased levels of expression in various cancers because of their role in tumor initiation and progression. MiRNA belonging to mir148/152 family are examples of such MicroRNA. This family includes miR148a, miR148b and miR152. MiR148a and miR152 …

Rat Hippocampal Responses Up To 90 Days After A Single Nanoceria Dose Extends A Hierarchical Oxidative Stress Model For Nanoparticle Toxicity, Sarita S. Hardas, Rukhsana Sultana, Govind Warrier, Mo Dan, Peng Wu, Eric A. Grulke, Michael T. Tseng, Jason M. Unrine, Uschi M. Graham, Robert A. Yokel, D. Allan Butterfield

Chemistry Faculty Publications

Ceria engineered nanomaterials (ENMs) have very promising commercial and therapeutic applications. Few reports address the effects of nanoceria in intact mammals, let alone long term exposure. This knowledge is essential to understand potential therapeutic applications of nanoceria in relation to its hazard assessment. The current study elucidates oxidative stress responses in the rat hippocampus 1 and 20 h, and 1, 7, 30 and 90 days following a single systemic infusion of 30 nm nanoceria. The results are incorporated into a previously described hierarchical oxidative stress (HOS) model. During the 1-20 h period, increases of the GSSG: GSH ratio and cytoprotective …

Beta-Blockers Act Through Clathrin-Dependent Internalization And Egfr Transactivation To Promote Erk Phosphorylation, Taiwo Ajumobi

Graduate Thesis Collection

For cardiovascular diseases such as high blood pressure, angina pectoris, and left ventricle hypertrophy; long-term activation of beta-adrenergic receptors is strongly linked to the progression of these diseases. A class of antagonistic drugs that target betaadrenergic receptors are collectively called beta-blockers. These drugs are commonly used to reduce the inotropic and chronotropic effects of beta-adrenergic receptor activation. This past decade has revealed that beta-blockers and other ligands are capable of functional selectivity at receptors. Functional selectivity describes the ability of ligands acting at 0 protein-coupled receptors (OPCRs) to preferentially activate or inhibit different signal transduction pathways. The studies on beta-adrenergic …

A Service Learning Experience For Pharmacy Students Involving Unwanted Medication Collection, Patricia L. Darbishire

IMPACT Symposium

This poster outlining a serve learning experience of students in Purdue’s pharmacy program was presented at the IMPACT Symposium 2014.

Identifying Oncogenic Drivers In Nsclc Cells Harboring Egfr Kinase Domain Mutation With Resistance To Egfr Tki And Mesenchymal Phenotype, Yandi Gao

Master's Theses

EGFR kinase domain mutant NSCLC cells are exquisitely dependent on mutant EGFR for cell survival and proliferation. Patients with mutant EGFR respond well to the EGFR inhibitors. However, acquired drug resistance greatly limits the efficacy of the treatment. About 15% of the resistant tumors present an evidence of epithelial to mesenchymal transition (EMT). We hypothesize that the induction of mesenchymal promotes aberrant upregulation of other oncogenic drivers to replace the oncogenic mutant EGFR.

We observed overexpression of CXCR7 in NSCLC models of acquired resistance to EGFR TKI with mesenchymal phenotype. Additionally, our studies demonstrate that ectopically overexpressing CXCR7 in EGFR …

Investigation Of Pharmaceutical Mass Transfer Phenomena Using Molecular Dynamics Simulations, Yi Gao

Dissertations

Molecular dynamics (MD) simulation has been widely used in understanding the physical basis of the structure and function of biological macromolecules. However, its application in pharmaceutical research is still at an early stage. This dissertation attempts to establish the use of MD simulation in studying several important pharmaceutical mass transfer processes. The three-series study included (1) the understanding of drug crystal dissolution at molecular level, (2) the elucidation of an unique mechanism for facile polymorphic transformation of crystalline drugs in solutions, and (3) the determination of drug-polymer interactions at water-crystal interface and the implications to crystallization inhibition.

A drug crystal …

Hydropathic Interactions And Protein Structure: Utilizing The Hint Force Field In Structure Prediction And Protein‐Protein Docking., Mostafa H. Ahmed

Theses and Dissertations

Protein structure predication is a field of computational molecular modeling with an enormous potential for improvement. Side-chain geometry prediction is a critical component of this process that is crucial for computational protein structure predication as well as crystallographers in refining experimentally determined protein crystal structures. The cornerstone of side-chain geometry prediction are side-chain rotamer libraries, usually obtained through exhaustive statistical analysis of existing protein structures. Little is known, however, about the driving forces leading to the preference or suitability of one rotamer over another. Construction of 3D hydropathic interaction maps for nearly 30,000 tyrosines extracted from the PDB reveals their …

Synthetic, Sulfated, Lignin-Based Anticoagulants, Akul Mehta

Theses and Dissertations

Chemoenzymatically synthesized low molecular weight lignin polymers have been previously found to be potent inhibitors of a number of serine proteases via allosteric mechanisms targeting heparin binding sites. Herein, we describe the creation of synthetic sulfated β-O4 lignin (SbO4L) polymer, which is more homogenous compared to previous lignins with respect to its inter-monomeric linkage. SbO4L is a selective inhibitor of thrombin and plasmin. SbO4L was found to act via a unique mechanism targeting thrombin exosite 2 in a manner similar to platelet glycoprotein Ibα (GPIbα). Advanced hemostasis and thrombosis assays demonstrated that SbO4L acts via a dual mechanism: as an …

Evaluation Of The Allometric Exponents In Prediction Of Human Drug Clearance, Da Zhang

Theses and Dissertations

Background. Allometric scaling (AS) is widely used in predicting human clearance (CL) based on animal data. Substantial prediction errors have been commonly observed and various modifications to AS have not provided a broad reliable improvement. In this study, an extensive data set was assembled including animal and human systemic CL and physiochemical properties. The allometric exponents were calculated based on multiple species AS and single-species AS methods. The correlations between the allometic exponents and physiochemical properties were evaluated in an attempt to find covariates that may explain the inter-compound variability in the allometric exponents. Lastly, the statistical approaches in analyzing …

Prediction Of Human Systemic, Biologically Relevant Pharmacokinetic (Pk) Properties Using Quantitative Structure Pharmacokinetic Relationships (Qspkr) And Interspecies Pharmacokinetic Allometric Scaling (Pk-As) Approaches For Four Different Pharmacological Classes Of Compounds, Gopichand Gottipati

Theses and Dissertations

This research developed and validated QSPKR models for predicting in-vivo human, systemic biologically relevant PK properties (i.e., reflecting the disposition of the unbound drug) of four, preselected, pharmacological classes of drugs, namely, benzodiazepines (BZD), neuromuscular blocking agents (NMB), triptans (TRP) and class III antiarrhythmic agents (AAR), as well as PK allometric scaling (PK-AS) models for BZD and NMB, using pertinent human and animal systemic PK information (fu, CLtot, Vdss and fe) from published literature. Overall, lipophilicity (logD7.4) and molecular weight (MW) were found to be the most important and statistically significant molecular properties, affecting biologically relevant systemic PK properties, and …

Reversed-Phase Ion-Pairing Ultra Performance Liquid Chromatography-Mass Spectrometry In Characterization Of Glycosaminoglycans, Alhumaidi Alabbas

Theses and Dissertations

Glycosaminoglycans (GAGs) are a family of linear bio-polysaccharides, which are heterogeneously modified with negatively charged sulfate and carboxylate groups. They are located on every cell surface, extracellular matrix or intracellular space in the body. GAGs are composed of alternating units of an amino sugars (glucosamine or galactosamine) and hexuronic acid/hexose (iduronic acid, glucoronic acid/ or galactose), which are linked by glycosidic bonds with different geometries. In recent years, GAGs have attracted considerable interest. GAGs play vital roles in fundamental biological processes, such as hemostasis, angiogenesis, cell signaling, growth and differentiation. Thus, GAGs contribute to a number of diseases such as …

Development Of Bivalent Ligands Targeting The Putative Ccr5-Mor Heterodimer, Thomas Raborg

Theses and Dissertations

Chemokine receptor CCR5 (CCR5) is a G-protein coupled receptor (GPCR) predominantly expressed on leukocytes, or white blood cells.1–3 During inflammation, the body releases chemokines that bind to receptors such as CCR5 and attract leukocytes to the area of inflammation, leading to an immunological response.1 CCR5 is also an important receptor in the human immunodeficiency virus's (HIV-1) invasion of host cells, as CCR5 acts as a co-receptor that facilitates HIV-1 viral entry.4,5 The continued destruction of leukocytes as a result of HIV-1 viral entry produces a disease state called acquired immunodeficiency syndrome (AIDS).5 Of note, this receptor is also expressed on …

A Route To Discover Small Molecule Inhibitors Of Psaa, A Potential Target For Streptococcus Pneumoniae, Ahmad J. Obaidullah

Theses and Dissertations

Due to the development of multidrug resistance in Streptococcus pneumoniae, research has begun to define new drug targets for pneumonia therapy. Different research groups have identified a lipoprotein, PsaA that is important for pneumonia virulence. PsaA is a manganese transporter that is required for bacterial virulence and growth. We have employed computer modeling to virtually screen a small-molecule database for inhibition of PsaA function by targeting the metal binding pocket, performing receptor-based virtual screening and molecular docking and scoring to identify potential inhibitors of PsaA function. We have developed an assay for screening compounds, including the use of a PsaA …

The Effect Of Sleep Medication Use And Poor Sleep Quality On Risk Of Falls In Community-Dwelling Older Adults, Yaena Min

Theses and Dissertations

The work presented in this dissertation focuses on the association between sleep medication use, poor sleep, and falls in community-dwelling adults 65 years or older. Sleep complaints and the consumption of medications to aid sleep are common in older adults. Psychotropic medications, such as sedative hypnotics, are associated with risk of falls in older adults. However, very few studies have assessed the impact of poor sleep and sleep medication use on the risk of falls in community-dwelling older adults. In the first project, a cross-sectional analysis of the Health and Retirement Study (HRS) 2010 data was conducted to determine the …