Pharmaceutics and Drug Design Commons^™

Design Of Kappa Opioid Receptor Agonists For Potential Treatment Of Multiple Sclerosis, Lindsay Kornberger

Theses and Dissertations--Pharmacy

Multiple Sclerosis (MS) is a neurodegenerative disease of the central nervous system characterized by demyelination and neuroinflammation. There is currently no cure for MS. There is a critically unmet need for the development of pharmacotherapies that can induce remyelination promoting both repair and recovery. The kappa opioid receptor (KOR) has been identified as a potential target for the development of remyelinating pharmacotherapies. KOR activation has been shown to promote functional recovery and remyelination preclinically. However, typical KOR agonists like U50,488 have limitations such as sedation and dysphoria limiting their use. This necessitates further development of new KOR agonists that maintain …

Investigating The Use Of Mpges-1 Inhibitors For The Treatment Of Abdominal Aortic Aneurysms, Lauren M. Weaver

Theses and Dissertations--Pharmacy

The cardiovascular field is still searching for a treatment for abdominal aortic aneurysms (AAA). This inflammatory disease is a deadly, permanent ballooning of the aortic artery. It often goes undiagnosed until a late stage where associated rupture has a high mortality rate. Surgery is the only option available to patients, but it is risky. There are currently no FDA-approved pharmacological treatments for AAA available. Historically, drugs that have been examined in interventional clinical trials for treatment of AAA were repurposed therapeutics. Novel treatments have been unable to reach the clinic, stalling out in pre-clinical studies. Exceedingly few murine studies have …

Effectiveness Of A Long-Acting Cocaine Hydrolase In Metabolizing Cocaine And Its Physiologically Active Metabolites, Linyue Shang

Theses and Dissertations--Pharmacy

Cocaine is a widely abused, hepatotoxic drug without an FDA-approved pharmacotherapy specific for cocaine addiction or overdose. Cocaine-induced toxicity in animals and humans is due to its multiple physiological effects on the central nervous system, cardiovascular system, etc. The toxicity of cocaine is highly complex, as its metabolites also contribute to the toxicity. Notably, the combination of cocaine and alcohol is common among drug users and can produce additional metabolites. Some of the metabolites are more toxic than cocaine itself. Hence, to develop an ideal therapeutic candidate, the candidate should not only account for cocaine but should also detoxify other …

Self-Assembled Ternary Polypeptide Nanoparticles With Improved Biostability For Drug Delivery In Cancer Therapy, Preye Mike Agbana

Theses and Dissertations--Pharmacy

Cancer remains a real and present threat to global health. In the United States, according to cancer statistics, almost 40% of people will be diagnosed with cancer at some point in their lifetime. Conventional chemotherapy has become the mainstay for cancer treatment option. However, chemotherapeutic agents are plagued with problems such as poor aqueous solubility, chemical degradation, Bio instability, and off-site toxicity due to non-specificity. New drug modalities are needed to tackle the ever-growing burden on cancer. In recent times, the promise of nanotechnology has aided to develop drug delivery vehicles to facilitate the administration of potent chemotherapeutics. Nanoformulations such …

Optimization Of Orally Bioavailable Inhibitors Of Defective In Cullin Neddylation 1 (Dcn-1), Leah Kovalic

Theses and Dissertations--Pharmacy

Ubiquitin (UB) and ubiquitin-like protein (UBL) pathways have emerged as important targets for oncology drug discovery based on the success of proteasome inhibitors (bortezomib or carfilzomib), E3 inhibitors, and the NEDD8 E1 inhibitor pevonedistat (MLN42924). Chemical inhibitors have also proven to be useful probes for identifying and dissecting multifactor UB and UBL regulatory networks. Toward this end, we have pursued approaches to target NEDD8 ligation to Cullins, through developing small molecule inhibitors of DCN1 (defective in Cullin Neddylation 1). DCN1 was discovered as a potentiating RBX1-dependent NEDD8-ligation, through recognizing the acetylated N-terminal methionine of the NEDD8 E2s UBE2M and UBE2F. …

Design And Synthesis Of Small Molecular Inhibitors Of Dcn1-Ube2m Interaction, Tucker J. Moseley

Theses and Dissertations--Pharmacy

Over the last century, advancements in medicine have been made to improve cancer patients' outcomes. The discovery of new druggable targets is essential to achieving this goal. Defective in Cullin Neddylation 1 is a proven oncogenetic driver that may lead to better clinical outcomes when targeted. In efforts to further improve a series of novel small molecular inhibitors of the DCN1 and UBE2M protein-protein interaction, the Guy lab has designed and synthesized 26 new compounds. These compounds were designed to specifically target the UBE2M N-Acetyl sub-pocket on DCN1 that was not occupied by compounds previously described in the literature.

Building Tools For Improved Modulation Of The Human Gabaa Receptor, A Central Nervous System Target For The Treatment Of Anxiety, Garrett Edward Zinck

Theses and Dissertations--Pharmacy

In the U.S., anxiety is recognized as an increasing range of mentally and physically debilitating psychiatric health disorders with significant economic repercussions. Over the last 20 years, several novel anti-anxiety therapies have entered the drug development pipeline, but none have made it to market.

The work in this dissertation focused on structurally modifying valerenic acid (VA), a structurally unique carboxylated sesquiterpene acid found in Valeriana officinalis. VA is putatively reported to have allosteric modulatory activity of the human GABA_A receptor, a ligand-gated ion channel responsible for attenuating neurotransmissions. Structural modeling of VA’s GABA_A receptor interaction suggests that …

Studies Toward The Development Of An Improved Countermeasure For Synthetic Opioid Overdose, Sidnee L. Hedrick

Theses and Dissertations--Pharmacy

One of the most prominent opioid analgesics in the United States is the high potency agonist fentanyl. It is used in the treatment of acute and chronic pain and as an anesthetic adjuvant. When used inappropriately, however, ingestion of just a few milligrams of fentanyl or other synthetic opioid can cause opioid-induced respiratory depression (OIRD), often leading to death. Currently, the treatment of choice for OIRD is the opioid receptor antagonist naloxone. Recent reports, however, suggest that higher doses or repeated dosing of naloxone (due to recurrence of respiratory depression) may be required to fully reverse fentanyl-induced respiratory depression, rendering …

Investigating The Physical Stability Of Amorphous Pharmaceutical Formulations, Travis W. Jarrells

Theses and Dissertations--Pharmacy

Amorphous formulations, including amorphous solid dispersions (ASDs), consisting of the active pharmaceutical ingredient (API) intimately mixed in a polymeric matrix, are an attractive formulation approach to improve drug delivery, dissolution, and solubility. However, an amorphous API in an ASD is in a higher energy state compared to the crystalline drug and results in most ASDs being inherently unstable. The polymer helps to stabilize the amorphous drug against crystallization such that the resulting homogenous mixture maintains its solubility advantage relative to the crystalline form. One challenge of ASDs is that the presence of impurities including crystals or residual solvent, variations in …

Response Of Dopaminergic System To Cocaine Exposure, Recovery After Cocaine Abstinence, And Impact Of A Long-Acting Cocaine Hydrolase, Jing Deng

Theses and Dissertations--Pharmacy

Cocaine produces its physiological effects by targeting multiple proteins in the central nervous system, particularly by binding with dopamine transporter (DAT) to block the normal dopamine (DA) recycling process. This process along with the pleasure feeling would wear off shortly after the abstinence from the drug. However, chronic cocaine use is associated with neuroadaptations in the dopaminergic system, including increases in the density of DAT on plasma membrane of dopaminergic neurons. Given the critical role of DAT in neurotransmission, various studies have been carried out on animal models to learn its structure, function, and distribution. Long-standing evidence supports that DAT …

Liposomal Technologies To Improve Gene Delivery, David Nardo Padron

Theses and Dissertations--Pharmacy

Lipid based nanoparticles (LBNs) are used in myriad applications in medicine from small molecule drug delivery to mRNA vaccines. A major contributing factor to the development of the field has been the ongoing development of novel compounds that retain the functionality of natural lipids but expand upon them through inclusion of functional moieties that can be applied to specific scientific and biomedical questions. In the body of this dissertation, an extensive overview of LBNs is provided, focusing primarily on their use in immune modulation. The research presented herein begins with the synthesis of a novel class of lipids based on …

Development Of Accurate And Efficient Computational Methodologies For Predicting Protein-Ligand And Protein-Protein Binding Free Energies, Alexander Hamilton Williams

Theses and Dissertations--Pharmacy

Computational modeling is an invaluable tool in the drug discovery process either for small ligand or protein therapeutics. The widespread availability of protein X-Ray Crystal and Cryo-Electron Microscopy (Cryo-EM) structures has allowed for more accurate molecular dynamics (MD) simulations that are not reliant on methods such as homology modeling, which may produce structures that require significant computational time to demonstrate their stability. In this thesis we describe several novel methodologies for the computationally efficient modeling of protein/ligand and protein/protein complexes that may be employed within both large-scale virtual screenings and lead compound optimization. These methodologies may also be utilized in …

Understanding The Impact Of Solvents In Oral Solid Dosage Formulation And Process Development, Matthew Kyle Defrese

Theses and Dissertations--Pharmacy

The successful delivery of chemical compounds for the purpose of therapeutic treatments and prophylactics is a substantial undertaking in modern drug development. Notably, the adoption of high throughput screening techniques has led to the proliferation of poorly water soluble and/or highly potent molecules which further complicate development activities. Spray dried amorphous solid dispersions are an increasingly important formulation strategy to overcome solubility issues while wet granulation approaches are the method of choice for the preparation of highly potent APIs in oral solid dosage forms.

A common connection between these critical techniques is their reliance on solvent-based processing that can often …

Correlating The Physicochemical Properties Of Magnesium Stearate With Tablet Dissolution And Lubrication, Julie L. Calahan

Theses and Dissertations--Pharmacy

Magnesium stearate (MgSt) is the most commonly used pharmaceutical excipient and is present in over half the tablet formulations on the market. In spite of its popularity as an effective lubricant, it has been repeatedly recognized that there is significant variability between MgSt samples, which can cause inconsistent lubrication between batches of MgSt. The hypothesis of this research is that the batch-to-batch variability in tablet lubrication and dissolution observed in tablet formulations containing different MgSt samples can be correlated with differences in MgSt physicochemical properties (fatty acid salt composition, crystal hydrate form, particle size and surface area). Developing correlations between …

Novel Small Molecule Antifungals For Invasive Fungal Infections, Emily Dennis

Theses and Dissertations--Pharmacy

Human fungal pathogens cause a range of diseases from benign skin conditions (i.e., ringworm) to thrush, mucosal membrane infections, and life-threatening systemic infections including bloodstream infections (i.e., aspergillosis and candidiasis) and Cryptococcal meningitis. These systemic infections occur most often in immunocompromised individuals and have high mortality rates. Current antifungal agents used in the clinic belong to three main classes: the polyenes (e.g., amphotericin B (AmB)), the echinocandins (e.g., caspofungin (CFG)), and the azoles (e.g., fluconazole (FLC)). In addition, the antimetabolite pyrimidine analogue flucytosine is used in combination with AmB. The …

Phase Behavior Of Amorphous Solid Dispersions: Miscibility And Molecular Interactions, Kanika Sarpal

Theses and Dissertations--Pharmacy

Over the past few decades, amorphous solid dispersions (ASDs) have been of great interest to pharmaceutical scientists to address bioavailability issues associated with poorly water-soluble drugs. ASDs consist of an active pharmaceutical ingredient (API) that is typically dispersed in an inert polymeric matrix. Despite promising advantages, a major concern that has resulted in limited marketed formulations is the physical instability of these complex formulations. Physical instability is often manifested as phase heterogeneity, where the drug and carrier migrate and generate distinct phases, which can be a prelude to recrystallization. One important factor that dictates the physical stability of ASDs is …

Pharmacokinetic And Pharmacodynamic Evaluation Of Cocaine Hydrolases For The Treatment Of Cocaine Overdose And Cocaine Addiction Using Rodent Models, Xirong Zheng

Theses and Dissertations--Pharmacy

Overdose and addiction are two medical complications of cocaine abuse. To date, there is no FDA approved pharmacotherapy specific for cocaine abuse. Cocaine hydrolases (CocHs) have been extensively investigated for its potential in anti-cocaine therapy. Previous studies have demonstrated that CocHs efficiently hydrolyze cocaine to generate biologically inactive metabolites both in vivo and in vitro. However, it has not been studied whether there is gender difference in the therapy using CocHs. In addition, the effectiveness of CocHs is unknown for treating cocaine toxicity when alcohol is co-administered.

The main purpose of this dissertation is to characterize and evaluate efficient …

Mechanisms And Thermodynamics Of The Influence Of Solution-State Interactions Between Hpmc And Surfactants On Mixed Adsorption Onto Model Nanoparticles, Salin Gupta Patel

Theses and Dissertations--Pharmacy

Nanoparticulate drug delivery systems (NDDS) such as nanocrystals, nanosuspensions, solid-lipid nanoparticles often formulated for the bioavailability enhancement of poorly soluble drug candidates are stabilized by a mixture of excipients including surfactants and polymers. Most literature studies have focused on the interaction of excipients with the NDDS surfaces while ignoring the interaction of excipients in solution and the extent to which the solution-state interactions influence the affinity and capacity of adsorption. Mechanisms by which excipients stabilize NDDS and how this information can be utilized by formulators a priori to make a rational selection of excipients is not known.

The goals of …

Discovery Of Novel Pharmacotherapeutics For Substance Use Disorders, Na-Ra Lee

Theses and Dissertations--Pharmacy

Substance use disorders are serious health concerns in the United States. Furthermore, the National Survey on Drug Use and Health reports a continuous increase in substance use disorders in the United States during the last 10 years. However, there are not many effective pharmacotherapeutics available for substance use disorders. The current dissertation is focused on research aimed at discovering pharmacotherapeutics for substance use disorders. First part of dissertation focused on discovering methamphetamine (METH) use disorder therapeutics targeting specific mechanism of METH action on dopaminergic neurons. The second part of dissertation focused on opioids and cocaine use disorder therapeutics targeting rewarding …

Investigation Of Factors Influencing Protein Stability In Lyophilized Formulations Using Solid-State Nmr Spectroscopy, Ashley Lay-Fortenbery

Theses and Dissertations--Pharmacy

Many proteins are unstable in solution and must be formulated in the solid state. This has led to an increase in the use of lyophilized dosage forms. Lyophilization is a complicated processing method consisting of three major steps: freezing, primary drying, and secondary drying. This can lead to several formulation stability challenges including changes in ionization within the matrix, phase separation of the protein drug from added stabilizers, sufficient mobility within the system for movement of reactive species and protein side chains, and crystallization of excipients upon storage. Solid-State Nuclear Magnetic Resonance Spectroscopy (SSNMR) is used to characterize many important …

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 …

Effects Of Core And Shell Modification To Tethered Nanoassemblies On Sirna Therapy, Steven Rheiner

Theses and Dissertations--Pharmacy

siRNA therapy is an emerging technique that reduces protein expression in cells by degrading their mRNAs via the RNA interference pathway (RNAi). Diseases such as cancer often proliferate due to increased protein expression and siRNA therapy offers a new method of treatment for those diseases. Although siRNA therapy has shown success in vitro, it often fails in vivo due to instability in the blood stream. To overcome this limitation, delivery vehicles are necessary for successful transfection of siRNA into target cells and cationic polymers have been widely studied for this purpose. However, complexes between siRNA and delivery vehicles made …

Development Of Diverse Size And Shape Rna Nanoparticles And Investigation Of Their Physicochemical Properties For Optimized Drug Delivery, Daniel L. Jasinski

Theses and Dissertations--Pharmacy

RNA nanotechnology is an emerging field that holds great promise for advancing drug delivery and materials science. Recently, RNA nanoparticles have seen increased use as an in vivo delivery system. RNA was once thought to have little potential for in vivo use due to biological and thermodynamic stability issues. However, these issues have been solved by: (1) Finding of a thermodynamically stable three-way junction (3WJ) motif; (2) Chemical modifications to RNA confer enzymatic stability in vivo; and (3) the finding that RNA nanoparticles exhibit low immunogenicity in vivo.

In vivo biodistribution and pharmacokinetics are affected by the physicochemical …

Halo- And Solvato-Fluorochromic Polymer Nanoassemblies For Cancer Theranostics, Derek Alexander Reichel

Theses and Dissertations--Pharmacy

Theranostics is an emerging treatment approach that combines diagnostics with therapy in order to personalize treatment regimens for individual patients and decrease cancer mortality. Previously, nanoparticles entrapping conventional fluorescent dyes were developed for cancer theranostics, but fluorescent nanoparticles did not allow clinicians to significantly improve cancer treatments.

The use of fluorescent dyes that are sensitive to solvent acidity (halo-fluorochromism) and polarity (solvato-fluorochromism) may overcome the limitations of fluorescent nanoparticles and improve cancer therapy by enabling researchers to detect chemical properties within the nanoparticle core environment. The model halo- and solvato-fluorochromic dye Nile blue was attached to the core of nanoscale …

Development Of Cocaine Hydrolase For Therapeutic Treatment Of Cocaine Abuse, Xiabin Chen

Theses and Dissertations--Pharmacy

Cocaine abuse is a world-wide public health and social problem without a U.S. Food and Drug Administration (FDA)-approved medication. An ideal anti-cocaine medication would accelerate cocaine metabolism producing biologically inactive metabolites by administration of an efficient cocaine-specific exogenous enzyme. Recent studies in our lab have led to discovery of the desirable, highly efficient human cocaine hydrolases (hCocHs) that can efficiently detoxify and inactivate cocaine without affecting normal functions of central nervous system (CNS). Preclinical and clinical data have demonstrated that these hCocHs are safe for use in humans and effective for accelerating cocaine metabolism. However, the actual therapeutic use of …

Rna Nanotechnology For Next Generation Targeted Drug Delivery, Fengmei Pi

Theses and Dissertations--Pharmacy

The emerging field of RNA nanotechnology is developing into a promising platform for therapeutically application. Utilizing the state-of-art RNA nanotechnology, RNA nanoparticles can be designed and constructed with controllable shape, size for both RNA therapeutics and chemical drug delivery. The high homogeneity in particle size and ease for RNA therapeutic module conjugation, made it feasible to explore versatile RNA nanoparticle designs for preclinical studies.

One vital module for therapeutic RNA nanoparticle design is RNA aptamer, which can enable the RNA nanoparticles find its specific target for targeted drug delivery. A system of screening divalent RNA aptamers for cancer cell targeting …

Investigating Mechanisms Determining Cancer Cell Sensitivity To Carfilzomib And Novel Strategies To Overcome Resistance, Lin Ao

Theses and Dissertations--Pharmacy

Proteasome inhibitors (PIs) are a class of FDA-approved anti-cancer agents which includes the first-generation PI bortezomib (BTZ) and second-generation carfilzomib (CFZ). Drug resistance is a major challenge in PI therapy with no solution currently available. While a few resistance mechanisms had been proposed for BTZ, little was known about CFZ resistance before the start of our studies. In this dissertation work, we investigated multiple mechanisms contributing to CFZ resistance—alterations in the drug transporter activity, metabolic stability, and proteasome activity profiles—and evaluated potential strategies to overcome CFZ resistance.

We observed marked upregulation of the drug efflux transporter P-glycoprotein (P-gp) in our …

Rna As A Unique Polymer To Build Controllable Nanostructures For Nanomedicine And Nanotechnology, Hui Li

Theses and Dissertations--Pharmacy

RNA nanotechnology is an emerging field that involves the design, construction and functionalization of nanostructures composed mainly of RNA for applications in biomedical and material sciences. RNA is a unique polymer with structural simplicity like DNA and functional diversity like proteins. A variety of RNA nanostructures have been reported with different geometrical structures and functionalities. This dissertation describes the design and construction of novel two-dimensional and three-dimensional self-assembled RNA nanostructures with applications in therapeutics delivery, cancer targeting and immunomodulation. Firstly, by using the ultra-stable pRNA three-way junction motif with controllable angles and arm lengths, tetrahedral architectures composed purely of RNA …