Pharmaceutics and Drug Design Commons^™

Amine Containing Analogs Of Sulindac For Cancer Prevention, Bini Mathew, Judith V. Hobrath, Michele C. Connelly, R. Kiplin Guy, Robert C. Reynolds

Pharmaceutical Sciences Faculty Publications

Background:

Sulindac belongs to the chemically diverse family of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) that effectively prevent adenomatous colorectal polyps and colon cancer, especially in patients with familial adenomatous polyposis. Sulindac sulfide amide (SSA), an amide analog of sulindac sulfide, shows insignificant COX-related activity and toxicity while enhancing anticancer activity in vitro and demonstrating in vivo xenograft activity.

Objective:

Develop structure-activity relationships in the sulindac amine series and identify analogs with promising anticancer activities.

Method:

A series of sulindac amine analogs were designed and synthesized and then further modified in a “libraries from libraries” approach to produce amide, sulfonamide and N,N-disubstituted …

The Morality Of Compulsory Licensing As An Access To Medicines Tool, Margo A. Bagley

Faculty Articles

This Article contemplates the validity of theft rhetoric in relation to the right of countries to grant compulsory licenses from an unconventional perspective; that of biblical teachings on what it means to steal.

Part I describes the use of theft rhetoric in relation to IP infringement broadly and drug-patent compulsory licenses in particular.

Part II challenges the contention, suggested by theft rhetoric, that compulsory licenses are morally wrong as a form of stealing, by considering the meaning of theft in the context of its Judeo-Christian origins.

Part III considers the cogency of the accusation that the issuance of compulsory licenses …

Discovery Of New Antimicrobial Options And Evaluation Of Aminoglycoside Resistance Enzyme-Associated Resistance Epidemic, Selina Y. L. Holbrook

Theses and Dissertations--Pharmacy

The extensive and sometimes incorrect and noncompliant use of various types of antimicrobial agents has accelerated the development of antimicrobial resistance (AMR). In fact, AMR has become one of the greatest global threat to human health in this era. The broad-spectrum antibiotics aminoglycosides (AGs) display excellent potency against most Gram-negative bacteria, mycobacteria, and some Gram-positive bacteria, such as Staphylococcus aureus. The AG antibiotics amikacin, gentamicin, kanamycin, and tobramycin are still commonly prescribed in the U.S.A. for the treatment of serious infections. Unfortunately, bacteria evolve to acquire resistance to AGs via four different mechanisms: i) changing in membrane permeability to …

Development And Preclinical Evaluation Of Long-Lasting Cocaine Hydrolases For Cocaine Overdose And Cocaine Use Disorder Treatment, Ting Zhang

Theses and Dissertations--Pharmacy

Cocaine is a plant-based illicit drug commonly involved in substance use disorder. Although cocaine overdose and cocaine use disorders cause adverse health consequences to individuals and the economic burden on their family and society, there are no FDA (Food and Drug Administration) approved medications for treatment. Recently, it has been recognized that delivery of cocaine hydrolase (CocH) is a promising therapeutic strategy. Human butyrylcholinesterase (hBChE), the primary enzyme involved in cocaine metabolism in human, have advantages over other candidates for the development of CocH. Previous studies in our laboratory have designed and characterized hBChE mutants that have ~4,000-fold improved catalytic …

Using The Qbest Equation To Evaluate Ellagic Acid Safety Data: Generating A Qnoael With Confidence Levels From Disparate Literature, Cynthia Rose Dickerson

Theses and Dissertations--Pharmacy

QBEST, a novel statistical method, can be applied to the problem of estimating the No Observed Adverse Effect Level (NOAEL or QNOAEL) of a New Molecular Entity (NME) in order to anticipate a safe starting dose for beginning clinical trials. The NOAEL from QBEST (called the QNOAEL) can be calculated using multiple disparate studies in the literature and/or from the lab. The QNOAEL is similar in some ways to the Benchmark Dose Method (BMD) used widely in toxicological research, but is superior to the BMD in some ways. The QNOAEL simulation generates an intuitive curve that is comparable to the …

Scalable Feature Selection And Extraction With Applications In Kinase Polypharmacology, Derek Jones

Theses and Dissertations--Computer Science

In order to reduce the time associated with and the costs of drug discovery, machine learning is being used to automate much of the work in this process. However the size and complex nature of molecular data makes the application of machine learning especially challenging. Much work must go into the process of engineering features that are then used to train machine learning models, costing considerable amounts of time and requiring the knowledge of domain experts to be most effective. The purpose of this work is to demonstrate data driven approaches to perform the feature selection and extraction steps in …

Elucidation Of Substrate Binding Interactions For Human Organic Cation Transporters 1 (Slc22a1) And 2 (Slc22a2) Using In Silico Homology Modeling In Conjunction With In Vitro Site-Directed Mutagenesis And Kinetic Analysis, Raymond E. Lai

Theses and Dissertations

The organic cation transporters (OCTs) play a critical role in the absorption, distribution and elimination of many drugs, hormones, herbal medicines, and environmental toxins. Given the broad substrate specificity of OCTs, they fall victim to the high susceptibility for contributing to harmful drug-drug interactions. Further defining how human (h)OCTs mechanistically bind to its broad array of substrates will provide significant insight to the understanding and prediction of drug-drug interactions in polypharmacy patients and the advancement of future rational drug design for therapeutics targeting OCTs. The goal of the current study was to elucidate the critical amino acid residues for transporter-substrate …

Glycosaminoglycan Lyases In The Preparation Of Oligosaccharides, Alhumaidi B. Alabbas

Theses and Dissertations

Glycosaminoglycans are heterogeneous polysaccharides that mediate important biological functions. There has been considerable interest in deciphering the precise GAG sequences that are responsible for protein interactions. In fact, several GAG oligosaccharides have been discovered to date as targeting proteins with higher level of specificity. Yet, it has been difficult to develop GAG oligosaccharides as drugs. One of the key reasons for this state of art is that GAG synthesis is extremely challenging and is highly structure-specific. Thus, much of the biology and pharmacology of GAG remains unknown and unexploited to date.

An alternative approach is to prepare GAG oligosaccharides using …

Development And Validation Of A Semi-Physiological Pharmacokinetic (Pbpk) Model To Predict Systemic And Pulmonary Exposures After Intravenous, Oral Administration And Pulmonary Inhalation Of Selected Drugs, Budesonide, Tobramycin And Ciprofloxacin, In Humans, Bishoy Hanna

Theses and Dissertations

Using a semi-PBPK modeling/quantitative meta-analysis approach, this project investigated what factors affect pulmonary and systemic exposures of Budesonide (BUD), Tobramycin (TOB), and Ciprofloxacin (CIP) after inhalation:

Three structurally different pulmonary disposition models were developed for each drug, including pulmonary absorption (all three), excretion (TOB and CIP) and sequestration (TOB) in a peripheral and central lung compartment. Systemic disposition parameters were estimated using available human mean plasma (c_p(t)) and sputum (c_s(t)) concentration profiles after IV administration, and GI absorption parameters were estimated from these profiles after oral administration. Pulmonary disposition parameters were estimated from c_p(t) …

Evaluation Of A Drug Delivery System Based On Cyclodextrins For Cancer Therapy, Caroline Mendes

Doctoral

Due to the side-effects caused by regular chemotherapy, the development of drug delivery systems that can specifically target cancer cells and deliver the therapeutic dose is required. In this study, a folate-derivative of β-cyclodextrin has been studied as a vehicle for targeting folate receptors (FR) and delivering the chemotherapeutic drug methotrexate (MTX). FRs can be considered key cell membrane targets since they are commonly over-expressed in cancer cells and play an important role in cancer development and progression. Cyclodextrins (CDs) are cyclic oligosaccharides with a unique structure that allows them to form inclusion complexes with guest molecules, increasing their aqueous …

Aerosolized Surfactants: Formulation Development And Evaluation Of Aerosol Drug Delivery To The Lungs Of Infants, Susan Boc

Theses and Dissertations

The overall aim of this research project was to develop surfactant dry powder formulations and devices for efficient delivery of aerosol formulations to infants using the excipient enhanced growth (EEG) approach. Use of novel formulations and inline delivery devices would allow for more efficient treatment of infants suffering from neonatal respiratory distress syndrome and bronchiolitis.

A dry powder aerosol formulation has been developed using the commercial product, Survanta ® (beractant) and EEG technology to produce micrometer-sized hygroscopic particles. Spray drying and formulation parameters were initially determined with dipalmitoylphosphatidylcholine (DPPC, the dominant phospholipid in pulmonary surfactant), which produced primary particles 1 …

Current Approaches And New Developments In The Pharmacological Management Of Tourette Syndrome., Julio Quezada, Keith A. Coffman

Manuscripts, Articles, Book Chapters and Other Papers

Tourette syndrome (TS) is a neurodevelopmental disorder of unknown etiology characterized by spontaneous, involuntary movements and vocalizations called tics. Once thought to be rare, TS affects 0.3-1% of the population. Tics can cause physical discomfort, emotional distress, social difficulties, and can interfere with education and desired activities. The pharmacologic treatment of TS is particularly challenging, as currently the genetics, neurophysiology, and neuropathology of this disorder are still largely unknown. However, clinical experience gained from treating TS has helped us better understand its pathogenesis and, as a result, derive treatment options. The strongest data exist for the antipsychotic agents, both typical …

Detection And Quantification Of Glucuronidation Of Ursolic Acid (Ua) In Human Liver Microsomes (Hlms)., Kamola Tolliboeva, Philip M. Gerk

Undergraduate Research Posters

No abstract provided.

Design And Analysis Of Curcumin Conjugated Poly(Beta-Amino Ester) Networks For Controlled Release In Oxidative Stress Environments, Carolyn T. Jordan

Theses and Dissertations--Chemical and Materials Engineering

Oxidative stress, the imbalance of free radical generation with antioxidant defenses, leads to cellular inflammation, apoptosis and cell death. This compromised environment results in debilitating diseases, such as oral mucositis (OM), atherosclerosis, and ischemia/reperfusion injury. Antioxidant therapeutics has been a proposed strategy to ameliorate these imbalances and maintain homeostatic environments. However, the success of these approaches, specifically curcumin, has been limited due to characteristics such as hydrophobicity and high reactivity when released as bolus doses to contest to oxidative stress induced diseases. The development of a controlled release system to aid in protection of the antioxidant capacity of curcumin, as …

The Development Of Microfluidic Devices For The Production Of Safe And Effective Non-Viral Gene Delivery Vectors, Jason Matthew Absher

Theses and Dissertations--Chemical and Materials Engineering

Including inherited genetic diseases, like lipoprotein lipase deficiency, and acquired diseases, such as cancer and HIV, gene therapy has the potential to treat or cure afflicted people by driving an affected cell to produce a therapeutic protein. Using primarily viral vectors, gene therapies are involved in a number of ongoing clinical trials and have already been approved by multiple international regulatory drug administrations for several diseases. However, viral vectors suffer from serious disadvantages including poor transduction of many cell types, immunogenicity, direct tissue toxicity and lack of targetability. Non-viral polymeric gene delivery vectors (polyplexes) provide an alternative solution but are …

Clearance Concepts: Fundamentals And Application To Pharmacokinetic Behavior Of Drugs, Reza Mehvar

Pharmacy Faculty Articles and Research

Clearance concepts were introduced into the pharmacokinetics discipline in the 1970s and since then have played a major role in characterization of the pharmacokinetic behavior of drugs. These concepts are based on the relationship between organ extraction ratio or clearance and physiologic parameters such as the organ blood flow and the intrinsic capability of the eliminating organ to remove the free (unbound) drug from the body. Several theoretical models have been developed, which define these relationships and may be used to predict the effects of changes in the physiological parameters on various pharmacokinetic parameters of drugs, such as drug clearance. …

Discovery Of Natural Product Analogs Against Ethanol-Induced Cytotoxicity In Hippocampal Slice Cultures, Meredith A. Saunders-Mattingly

Theses and Dissertations--Psychology

An estimated 13.9% of Americans currently meet criteria for an alcohol (ethanol; EtOH) use disorder (AUD). While there are 4 medications approved by the Food and Drug Administration (FDA) to treat AUD, these treatments have demonstrated poor clinical efficacy. Our ongoing research program encompasses a multi-tiered screening of a natural product library and validation process to provide novel information about the mechanisms underlying EtOH-induced changes in neurobiology and to identify novel chemical scaffolds to be exploited in the development of pharmacological treatments for AUD in a rodent organotypic hippocampal slice culture model. Initial screens of several natural product compounds identified …

Comparative Analysis Of The Dissolution Performance Of Aspirin Tablets In The Usp Apparatus 2 And In A Minivessel Dissolution System, Annmarie C. Walker

Theses

Dissolution testing is a critical component of quality control procedures in the pharmaceutical industry in order to ensure that the final solid dosage forms have consistent dissolution properties. Dissolution tests are also routinely conducted to evaluate the in-vitro performance of solid dosage forms during pharmaceutical development, to aid in the behavior of formulations, and to optimize drug release from dosage forms.

The use of compendial dissolution test apparatus and techniques, such as the USP 2 (Paddle), to characterize the dissolution performance of oral drug delivery system is an established area of pharmaceutical science. However, this method is not always appropriate, …

Computational And Experimental Determination Of The Mixing Efficiency Of A Microfluidic Serpentine Micromixer, Siril Arockiam

Theses

In microfluidics, efficiency and mixing time are the greatest disadvantages. These parameters hinder the application of microfluidic devices for biochemical and immunological assays. However, once these disadvantages have been overcome by optimizing the parameters of the microfluidic device, it becomes the important analytical tool. In this experiment, various designs of microfluidic devices have been both simulated using COMSOL software, and experimentally verified to obtain the optimized parameter such as depth and velocity for better mixing efficiency. The COMSOL model has been validated by comparing the results with fluorescent images data of the experiment. The microfluidic device is built with Adhesive …

Novel Therapeutic Strategies For Treatment Of Castration-Resistant Prostate Cancer, Matthew A. Ingersoll

Theses & Dissertations

Prostate cancer (PCa) remains the most commonly diagnosed solid tumor and is the third leading cause of cancer-related death in United States men. While androgen deprivation therapy is the current standard-of-care treatment for metastatic PCa, most patients eventually relapse and develop castration-resistant (CR) tumors, for which there is currently no effective treatment. Therefore, synthesis of novel therapeutic agents and identification of alternative target proteins are necessary to improve treatment. Herein, I investigate the efficacy of novel imidazopyridine and statin derivatives as alternative therapeutic compounds. These molecules not only inhibit androgen receptor signaling, but also block activation of the AKT axis, …