Medicine and Health Sciences Commons^™

Tunable Dual-Phase Dual-Drug Delivery System Using A Plga Microparticle/Pva Hydrogel Composite, Timothy John Eck

Theses and Dissertations

Current drug-eluting coatings have demonstrated controlled long-term, sustained release but have only tried to mitigate short-term burst release as a negative side effect. For applications like wound healing, there is a need for a drug-eluting coating which is adjustable in both short- and long-term release, independent of each other. We present a tunable dual-phase dual-drug delivery coating composed of drug-loaded polymer microparticles and drug-loaded hydrogel which can control short term and long term release individually in this study. This coating was created using lidocaine and dexamethasone encapsulated in poly(D,L-lactide-co-glycolide) particles combined with lidocaine- and dexamethasone-loaded poly(vinyl alcohol) hydrogel. Hydrogel drug …

To Decipher Genomic Evolution Of Dengue Virus And To Probe The Activation Mechanism Of A Her2 Directed Chimeric Antigen Receptor Toward Computer Aided Drug Design (Cadd), Mariya Hryb

Theses and Dissertations

This study encompasses three significant chapters focusing on diverse yet interconnected aspects of pharmaceutical research. Chapter 1 delves into the complexities of drug development, emphasizing the challenges and the pressing need for advanced technologies to streamline the process. Computational methods like Computer-Aided Drug Design (CADD) extend their scope beyond small molecules, aiding in the design of intricate biomolecules vital for biomedical advancements, especially in immunotherapy. Chapter 2 introduces the Near-Neutral Balanced Selectionist Theory (NNBST) validated through analysis of Dengue virus evolution. The unique features observed align with NNBST, surpassing existing theories. This approach offers a deeper understanding of viral evolution …

Behavioral Effects Of Novel Treatments For Pain Using Different Pathways, Danya M I Aldaghma

Theses and Dissertations

Pain is defined as an unpleasant sensation that is mostly caused by a stimulus from our surroundings. This sensation has the potential to become a significant concern, disrupting daily activities, and diminishing overall quality of life. However, it could also hold significant importance as it serves as a protective mechanism. Pain acts as an alarm system for the human body, alerting it to potentially harmful situations where tissues may be at risk of damage1. Despite the considerable advancements in pain treatment and the extensive knowledge scientists possess regarding the pathophysiology and pathways of pain, numerous medications aimed at alleviating pain …

Artemisinin And Its Derivatives Reactions: Characterization Of The Reaction Products Using Lc/Tof Ms, Kogila Vijayan

Theses and Dissertations

Artemisinin (ART) is a sesquiterpene lactone and a popular malaria drug with potential anticancer properties. In this work, LC/TOF MS was used to investigate the reaction of ART with DNA bases and estradiol. ART-deoxyadenosine and ART-deoxycytidine interactions were studied in the presence of Fe (II) ions. ART-deoxyadenosine and ART-deoxycytidine reaction mixtures gave chromatographic signatures that remained unchanged at room temperature but grew after incubation at 37°C. The change in temperature from room temperature to 37°C was the main driver of adduct formation in these reactions. ART was found to react with Fe (II) ions as observed from several new chromatographic …

Substance Use Disorders And The Behavioral Effects Of Novel And Existing Compounds, Sarah Uribe

Theses and Dissertations

These investigations aimed to study the effects of experimental compounds for use in treating and preventing substance use disorders, particularly opioid use disorder (OUD) and alcohol use disorder (AUD). Identifying and testing potential medications for these two diseases is critical since current FDA-approved medications are only modestly effective, and addiction continues to spread. We previously demonstrated that co-administration of morphine and MP-III-024 produced synergistic effects in hot plate and von Frey assays. This study evaluated whether MP-III-024 also produced synergistic effects in behavioral tests sensitive to the side effects of morphine. Our findings suggest that co-administration of morphine and MP-III-024 …

Selective Small Molecule Targeting Of Mcl-1 In Multiple Myeloma, Omar S. Al Odat

Theses and Dissertations

Multiple Myeloma (MM) is a deadly blood malignancy, characterized by the uncontrolled proliferation of aberrantly differentiated plasma cells. MM is challenging to diagnose and treat, accounting for approximately 12% of hematologic malignancies. The overexpression of anti-apoptotic group of Bcl-2 family proteins, particularly Myeloid cell leukemia 1 (Mcl-1), play a critical role in the pathogenesis of MM. The overexpression of Mcl-1 is associated with drug resistance and overall poor prognosis. Thus, inhibition of the Mcl-1 protein is an attractive therapeutic strategy against myeloma cells. Over the last decade, the development of selective Mcl-1 inhibitors has seen remarkable advancement. In this project, …

Behavioral Effects Of Novel Treatments For Pain And Alcohol Use Disorder, Christa Marie Donegan

Theses and Dissertations

Opioid use disorder (OUD) and alcohol use disorder (AUD) are pressing public health problems in the United States that require new pharmacotherapies to be explored. Current FDA-approved treatment options for these two disorders are only moderately effective. Thus, there is a demand for the identification of new targets for drug development. Previous research initiatives have shown that when morphine is co-administered with the novel imidazodiazepine, MP-III-024, synergistic effects in models of analgesia and antinociception are produced. Our research efforts were concerned with understanding if morphine in combination with MP-III-024 produced synergistic effects in measures of undesirable pharmacological responses: opioid side …

Fabrication And Comparative Study Of Horizontal And Vertical Electrospun Protein-Polysaccharide Nanofiber Biomaterials, Ashley Rivera-Galleti

Theses and Dissertations

The use of biocompatible and biodegradable composite materials for biomedical applications has attracted the attention of many researchers in the past few years. In this study, we fabricated nanofibers of silk fibroin and cellulose and its derivatives to amalgamate their unique properties into a single material. The production of these nanofibers via electrospinning is of particular interest, and whereas several studies have been done on normal nanofibers, the formation of branched nanofibers is an exciting area not currently explored. Blend solutions are formed by dissolving silk and cellulose/cellulose acetate in formic acid separately and mixing to achieve the desired ratios. …

Investigation Of The Role Of Hydrophobic Amino Acids On The Structure-Activity Relationship In Ponericin L1 From Neoponera Goeldii, Nicholas Patrick Schifano

Theses and Dissertations

Due to the increase prevalence of antimicrobial resistance (AMR) antibiotic alternatives have been of great interest. Antimicrobial peptides (AMPs) and polymers like polymethacrylates that mimic AMPs are two non-traditional antimicrobial agents that have been investigated thoroughly over the years as a potential solution to the AMR problem. This study will further the understanding of the L1 peptide by investigating the role hydrophobic amino acids have on the antimicrobial activity. Biophysical and microbiological techniques were utilized to show that the L1 hydrophobic derivative showed enhanced binding to anionic lipid bilayers while maintaining low hemolytic activity. This study also elucidates the effect …

Endeavors Toward Novel Synthetic Roadmaps In The Synthesis Of Pertinent Pharmacological Molecular Scaffold Moieties, Justin David Horgan

Theses and Dissertations

One of the main goals in the GML lab group is the development of novel, economical, and environmentally friendly organic methods for the synthesis of pharmacologically relevant molecular moieties. The most salient pieces of data to the GML lab group members, reading dependable organic journals, are finding organic moieties that are largely unexplored, finding organic moieties which various research groups are having difficulty synthesizing, and finding complex organic procedures to key organic structures that can be easily reduced, or reconstructed, into novel methods that are more economical and environmentally friendly. By looking at these unexplored molecules, as well as hard …

The Exploration Of Novel Synthetic Methods Of Biologically Relevant Nitrogen And Halogen Containing Molecules, Rebekah Erin Strong

Theses and Dissertations

Visible light has become a highly useful, and regarded, tool to the organic chemist. The additions and transformations of an abundance of molecules can be achieved with the use of visible light and photocatalysts, when appropriate. More specifically compounds that contain nitrogen, halogens, or both are highly useful structures in nearly every chemical industry. They are elements found in naturally occurring molecules and have the capacity to mimic biologically active and relevant structures. This makes them useful targets for pharmaceutical compounds. Bromine and chlorine can act as leaving groups; this property makes molecules with these elements reactive and thus able …

Protein-Based Nanofibers And Thin Films For Drug Delivery Applications, Christopher R. Gough

Theses and Dissertations

Corn zein and silk are both widely available, easy to extract proteins making them valuable replacements for synthetics. Zein and silk are also promising biomaterials in several applications. This work explores the use of both proteins as drug delivery vehicles by loading 1-Dimensional micro-nanofibers and 2-Dimensional thin films with model drugs or the topical therapeutic sodium citrate. Using a formic acid solvent, powdered zein protein or silk fibers were dissolved into solution and then casted into 2D films or spun into 1D fibers through air-spraying. During dissolution, therapeutic products are added. SEM images showed that fibers maintain their small diameter …

Computational Study Of Drug Interactions Of Receptors, Specifically Glycoprotein D Of Human Herpes Virus 1 And Dopamine D4 Receptor, Griffin Fountain

Theses and Dissertations

This thesis introduces computer-aided drug design methods in Chapter 1 and discuss their applications on two receptors in Chapters 2 and 3: Glycoprotein D (gD) of Herpes Simplex Virus 1 (HSV-1) and Dopamine Receptor D4 (DRD4). The Herpes Simplex Virus is a human pathogen that develops unpleasant cold sores around the body, most commonly around the mouth, neck or genitals area. Currently there is no cure or vaccine that can eliminate this virus. Glycoprotein D (gD) is a viral ligand for host cell receptors such as nectin -1. This interaction mediates the entry of HSV-1. In chapter 2, we used …

Behavioral Analysis Of Conditions And Treatments Affecting Movement And Nociception, Indu Mithra Madhuranthakam

Theses and Dissertations

This thesis work includes three projects. First part deals with the investigation of novel D2 receptor ligands in Prepulse inhibition. The goal of this study is to establish a relationship between dopamine receptor antagonists and agonists and prepulse inhibition which can then serve as a working model for an in-vivo efficacy of novel dopamine D2 drugs. The second part of the thesis work deals with Niemann pick disease type C. Niemann pick disease type C is a progressive genetic disorder that is characterized by the lysosomal accumulation of lipids which causes neurodegeneration, dementia, ataxia, and death. NPC1_nmf164 mutant mice …

Efforts Toward Novel Methods For The Synthesis Of Stereochemically-Dense Pharmacologically Relevant Scaffolds, Lauren Nicole Tumbelty

Theses and Dissertations

Nitrogen is the most common pure element, present in nearly all relevant chemical compounds. It is an essential component of the building blocks of life such as proteins, nucleic acids, amino acids and adenosine tri-phosphate. There is a naturally occurring exchange between living organisms and the atmosphere which begins with the process of fixation. Although nitrogen is naturally abundant, the strength of the triple bond in atmospheric nitrogen prevents its applicability in organic synthesis. Therefore, the development of methods to place synthetic nitrogen into heteroatomic compounds plays an important role in the development of pharmacologically relevant scaffolds. Contained within this …

Synthesis And Cytotoxicity Of Trisubstituted Imidazoles, Venkata Agasthya Kasibotla

Theses and Dissertations

Aza heterocyclic compounds are an important class of organic compounds that play a major role in medicinal chemistry. Majority of the heterocyclic motifs such as imidazoles, triazoles, piperazines etc. act as building blocks for synthesizing active pharmaceutical ingredients. Several pharmaceutical drugs include these motifs due to their varying physicochemical properties, which enable them to exhibit wide range of pharmacological activities ranging from anti-fungal, anti-neoplastic, anti-helmintic, anti-microbial etc. Owing to their electron rich ring system, imidazole and piperazine based motifs have become an attractive target for design and development of novel chemical structures as new drugs. In the current study, we …

Experimental Pharmacotherapies In Models Of Alcohol Addiction, Mousumi Akter Sumi

Theses and Dissertations

The USA faces $220 billion economic loss and eighty thousand deaths per year due to alcohol abuse while affecting more than 15 million people, making it the third largest life-style related cause of death. The U.S. FDA has approved four medications namely, disulfiram, acamprosate, oral naltrexone, and injectable long-acting naltrexone. These existing drugs are trashed with side effects, have a low success rate, indicating a demand for new potential drugs. We studied the effects of the CB1 negative allosteric modulator, PSNCBAM-1, and the dopamine D4 receptor antagonist, L-745,870 in mouse models of alcohol addiction. PSNCBAM-1 did not significantly reduce CPP …

Investigation Of The Sequence-Structure-Activity Relationship In Ponericin L1 From Neoponera Goeldii & Synergistic Interactions Of Ionic Liquids And Antimicrobials To Improve Efficacy, Alexandria S. Senetra

Theses and Dissertations

Non-traditional antimicrobials have been an area of great interest due to the increasing prevalence of antimicrobial resistance (AMR) in bacteria. Antimicrobial peptides (AMPs) & ionic liquids (ILs) are two examples that have been investigated as a potential solution. Most AMPs are naturally derived & exhibit high selectivity against bacterial targets over host cells. The venom-derived peptide, ponericin L1 from Neoponera goeldii, was used to investigate the role of cationic residues & net charge on peptide activity. Using both in vitro & microbiological methods, L1 peptide & derivatives exhibited an alpha-helical conformation with enhanced binding to lipid vesicles containing anionic lipids …

Searching For New Medications For The Treatment Of Alcohol Use Disorder, Harley M. Buechler

Theses and Dissertations

Alcohol use disorder (AUD) affects more than 15 million people in the United States. Current pharmacotherapeutic treatments for AUD are only modestly effective, necessitating the identification of new targets for medications development. In this study, the effects of the D4 receptor antagonist, L-745,870, and the CB1 negative allosteric modulator, PSNCBAM-1, were both tested for effects in ethanol conditioned place preference (CPP) and oral ethanol self-administration. Food-restricted adult male mice were trained in operant chambers to nose poke for delivery of rewards, trained on ascending concentrations of alcohol with descending concentrations of Ensure and water, until the mixture self-administered was 8% …

Searching For New Analgesics Without Addiction Risks, Mohammad Atiqur Rahman

Theses and Dissertations

Opioids are widely used to treat acute and chronic pain. But opioid addiction to these compounds can cause social and life-threatening health problems, including the risk of overdose. In this thesis, I evaluated IBNtxA (3-iodobenzoyl naltrexamine), a novel mu opioid receptor (MOR) agonist structurally related to the classical MOR antagonist naltrexone, in drug discrimination studies in order to better understand its subjective effects and more thoroughly its abuse liability. IBNtxA represents an intriguing lead compound for preclinical drug development specifically targeting MOR splice variants, potentially creating effective analgesics with reduced side effects. These results indicate that IBNtxA produces potent antinociception …

Synthesizing Modified Polymeric Nanoparticles For Biofilm Inhibition, Antibiotic Encapsulation, And Specific Targeting Against Pseudomonas Aeruginosa, Logan Schnorbus

Theses and Dissertations

Widespread usage of antibiotics is a growing concern due to antibiotic resistance development in bacteria. This is due to common use of antibiotics in agricultural, livestock, and clinical usage. Antibiotic resistance is developing at a rate in which it is outpacing new drugs on the market. New strategies in drug development are necessary to combat the increasing resistance. We designed several motifs of sugar-modified nanoparticles to inhibit the biofilm formation of Pseudomonas aeruginosa.

P. aeruginosa is an opportunistic pathogenic bacterium that is responsible for common life-threatening infection in hospitals. This gram-negative opportunistic pathogenic bacterium infects hosts with compromised immune systems …

An In Silico Study Of Small Molecule Anti-Cancer Agents Targeting Dna G-Quadruplexes, Holli-Joi Sullivan

Theses and Dissertations

Free ligand binding molecular dynamic simulations are a powerful tool used to probe the ligand binding process, mechanism and pathway and the insight gained can help expedite the early stages of drug discovery. Using these methods, we model the binding of two small molecule anti-cancer agents BRACO19 and CX-5461 to a variety of DNA G-quadruplexes (G4s) and a DNA Duplex. The first study focuses on the binding of BRACO19 to three different topological folds (parallel, anti-parallel and hybrid) of the human telomeric G4s. Our detailed analysis identified the most stable binding modes were end stacking and groove binding for the …

Prediction Of Drug-Drug Interaction Potential Using Machine Learning Approaches, Joseph Scavetta

Theses and Dissertations

Drug discovery is a long, expensive, and complex, yet crucial process for the benefit of society. Selecting potential drug candidates requires an understanding of how well a compound will perform at its task, and more importantly, how safe the compound will act in patients. A key safety insight is understanding a molecule's potential for drug-drug interactions. The metabolism of many drugs is mediated by members of the cytochrome P450 superfamily, notably, the CYP3A4 enzyme. Inhibition of these enzymes can alter the bioavailability of other drugs, potentially increasing their levels to toxic amounts. Four models were developed to predict CYP3A4 inhibition: …

Synthesizing Galactose Modified Polymeric Nanoparticles For Biofilm Inhibition Of Pseudomonas Aeruginosa, Tyler R. Flockton

Theses and Dissertations

Treating patients with antibiotics is becoming harder with the increase in antibiotic resistance. This is due to the widespread antibiotic use in clinical and agricultural settings. With antibiotic resistance outpacing new drugs making it to the market, developing new options to treat bacterial infections is and will be important. We created sugar modified nanoparticles to inhibit the biofilm formation of Pseudomonas aeruginosa.

P. aeruginosa is a gram-negative opportunistic pathogen that infects its host that has a compromised immune system. This makes it one of the most significant bacterial infection in hospitals. P. aeruginosa uses biofilms as an attack mechanism …

Synthesis Of Betulinic Acid Via Baylis-Hillman Reaction, Sai Krishna Kommineni

Theses and Dissertations

Betulin is readily isolated from the bark of birch trees using simple extraction techniques and this molecule as well as its derivatives (eg. betulinic acid) exhibit impressive levels of biological activity. While it is naturally available and shows selective toxicity towards certain cancers, betulin suffers from a general lack of solubility in aqueous conditions. In this regard, we took up a project involving the synthesis of conjugates of betulin with improved solubility characteristics and we were able to identify a series of compounds that showed cytotoxicity against breast and pancreatic cancer cells.

This thesis describes our efforts on the development …

Development Of Functionalized Imidazoles As Potential Therapeutical Agents, Drew Christopher Morgan

Theses and Dissertations

Imidazoles are heterocyclic small molecules that play a major role in medicinal chemistry and drug discovery. There are several drugs in the market which contain imidazoles as the pharmacophore. Metronidazole, an imidazole containing compound, is a prominent antibiotic and antiprotozoal medication used for the treatment of a variety of infections such as amoebiasis, trichomoniasis, bacterial vaginosis, etc. The current work involves the synthesis of small molecule libraries of imidazoles derived from metronidazole using Baylis-Hillman (BH) reaction. BH reaction is a carbon-carbon bond forming reaction and involves the coupling of aldehydes or imines with activated alkenes such as acrylates, acrolein, or …

Functionalized Heterocyclics As Potential Therapeutics, Anupama Indukuri

Theses and Dissertations

Heterocyclic compounds play an important role in pharmaceutical drug development. Several natural products and biologically active compounds contain heterocyclic motifs in them. Multicomponent coupling reactions offer an excellent platform for the synthesis of diverse libraries of heterocyclic compounds. We have been working on the synthesis of novel heterocyclic small molecules utilizing reactions such as Baylis-Hillman reaction, Passerini reaction, Click reaction, reductive amination aldol condensation, etc.

In the current project, we prepared three series of heterocyclic compounds using Passerini and Baylis-Hillman reactions as key steps. Owing to the importance of heterocyclic chemistry in drug discovery and the ease of synthesis, the …

Medications Development For Drug Addiction And Other Neuropsychiatric Disorders, Ariful Islam

Theses and Dissertations

Drug addiction and abuse especially opiate and psychostimulant abuse is a national and global crisis. IBNtxA (3-iodobenzoyl naltrexamine) is a novel mu opioid receptor (MOR) agonist, a naloxone derivative, structurally related to the classical MOR antagonist naltrexone. Recent studies suggest IBNtxA preferentially signals through truncated MOR splice variants, producing a unique pharmacological profile resulting in potent analgesia with reduced side effects. It has been found that M. vaccae has immunoregulatory effects that can prevent stress-induced exaggeration of neuroinflammation in the brain. The purpose of our pilot study is to develop medication for addiction and neuropsychiatric disorders. According to our purpose, …

Modification And Characterization Of Chloro-Sugar Derivatives As Anti-Bacterial Agents, Mansi Jani

Theses and Dissertations

Sucralose is an artificial sugar substitute which is most commonly used sweetener among other artificial sweeteners. It is derived from sucrose through a complex chemical process that selectively substitutes three atoms of chlorine for three hydroxyl groups on sucrose molecule, which have shown some inhibition of bacterial growth in gut. The goal of the project was to substitute halide in sucralose in a way that it sustains potential anti-bacterial activity along with sweetening effect, which can be then incorporated into mouthwash formulation. Sucralose is very stable molecule and it also has other physico-chemical advantages which are suitable for our anticipated …

An In Silico Study Of G Protein-Coupled-Receptor Activation, Specifically In The Corticotropin Releasing Factor Receptor And The Glucagon-Like Peptide Receptor, Nicolas Angelo Scorese

Theses and Dissertations

The drug discovery process is an extremely long and expensive process that modern computational methods help to alleviate. Through the use of computational methods, we provide information and insight into the activation methods of class B GPCRs so that future drugs can be developed to have less side effects. The first study focuses on the corticotropin releasing factor receptor, which is a good drug target for anxiety and depression. A mechanism of activation was theorized which focuses less on molecular switches (as has been the focus of several papers) and more on large scale conformation at the intracellular region of …