Pharmacy and Pharmaceutical Sciences Commons^™

Mass Spectrometry Directed Pre-Clinical Studies Of Asthma Candidate Midd0301 And Its Analogs, Md Shadiqur Rashid Roni

Theses and Dissertations

ABSTRACTMASS SPECTROMETRY DIRECTED PRE-CLINICAL STUDIES OF ASTHMA CANDIDATE MIDD0301 AND ITS ANALOGS by Md Shadiqur Rashid Roni The University of Wisconsin-Milwaukee, 2021 Under the Supervision of Professor Alexander (Leggy) Arnold

Asthma is one of the most prevalent global health problems. More than 25 million Americans are suffering from asthma and their symptoms especially in children are not well controlled with current medications. The current therapeutic options to control symptoms are limited and are commonly based on inhaled corticosteroids. There are several reasons for uncontrolled asthma symptoms that includes steroid resistance, improper use of inhalers and very few orally available medications. …

Sex Differences And Neuroimmune Effects Of Microglial Response In The Mesolimbic Reward Pathway In Nicotine Substance Use Disorder, Erin Leigh Anderson

Theses and Dissertations

Smoking remains the leading cause of morbidity and mortality in the United States, with less than 5% of smokers attempting to quit succeeding. This is due to the unpleasant withdrawal symptomology, which includes affective symptoms, such as irritability, weight gain, anxiety, and severe craving among others, as well as the cognitive effects, such as difficulty concentrating. This low smoking cessation success rate is also thought to be due to the long-lasting sensitization of nicotinic acetylcholine receptors (nAChRs) leading to long-term neuroadaptations in the brain’s reward system and alterations in synaptic plasticity that occur following chronic nicotine exposure and withdrawal. Glial …

Variations In Er Stress And Unfolded Protein Response Predict Disease Susceptibility, Youwen Zhang

Theses and Dissertations

Numerous studies linked endoplasmic reticulum (ER) stress and unfolded protein response (UPR) to physiological responses to stress and various human pathologies, including metabolic disorders. Although variability in stress responses among individuals has been widely recognized, how such variations in the UPR affect susceptibility to diseases remains unknown. Using outbred deer mice as a model, we explored the consequences of the differential propensity to UPR at the transcriptomic, cellular, and organismic level.

Initially, we analyzed the correlation between several UPR-related genes in primary fibroblasts, at the whole transcriptome level, after ER stress induction. The analysis of correlated transcripts revealed that their …

The Development Of Novel Cdk8 And Cdk19 Inhibitors And Degraders As Potential Anti-Cancer Agents, Li Zhang

Theses and Dissertations

CDK8 and its homolog CDK19 are essential for transcription regulation and their dysregulation has been identified in numerous diseases, especially in cancers. CDK8 and CDK19 have been implicated in cancer development through their kinase activity and kinase independent functions. Despite the existing CDK8/19 inhibitors, there is still a need to develop novel CDK8/19 inhibitors with improved potency and PK profile. It is also necessary to develop CDK8/19 degraders that are able to eliminate the kinase-independent functions. Although two CDK8-degrading PROteolysis Activating Chimeras (PROTACs) have been reported, they have limited CDK8 degradation efficacy and no effect on CDK19. PROTACs with improved …

Age-Dependent Increase In Tyrosine Level Depletes Tyrosyl-Trna Synthetase And Causes Neuronal Oxidative Dna Damage In Alzheimer’S Disease, Megha Jhanji

Theses and Dissertations

Alzheimer’s disease (AD) is the most common form of dementia, and it currently affects more than 50 million people worldwide. Much of the population develop late-onset AD after 65 and constitute more than 95% of the cases. Currently, there is no definitive cure or way to slow down the progression of this disease that addresses the neurodegeneration and loss of cognitive functions. Although the underlying cause of AD is still unknown, the “amyloid cascade hypothesis” attributed it to the aggregation of amyloid beta (AU+03B2) peptides and has been the focus for targeting most disease-modifying drugs in clinical trials. However, emerging …

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 …

Market Segmentation And Targeted Messaging To Improve Hpv Vaccine Intentions In The College Aged Population, Ashley Caitlin Godwin

Theses and Dissertations

Background: Human Papillomavirus (HPV) is a sexually transmitted infection that can lead to 6 different types of cancer, including cervical, vaginal, vulvar, penile, anal, and oropharyngeal cancer. Every year in the United States, nearly 35,000 cancer cases are estimated to be caused by HPV infection. While catch-up HPV vaccination is recommended through age 26 for those not previously vaccinated, only 21.5% of adults age 18-26 have completed the recommended number of HPV vaccine doses as of 2018. Many interventions have been tested to increase vaccination rates, and one such intervention, framed messaging, has shown promise in increasing intention to vaccinate. …

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 …

Retrospective Review Of Pharmacist Delivered Employee Medication Therapy Management (Mtm) Visits, Atuobi N. Yiadom Pharmd

Theses and Dissertations

Medication therapy management (MTM) services are evolving, and through collaborative practice agreements with providers, pharmacists are in a unique position to use their knowledge and skills to improve therapeutic outcomes for patients. Studies have shown that employer provided MTM services can lead to reduced spending on employer healthcare plan costs and improve overall health outcomes for beneficiaries of the MTM program. CentraCare offers MTM programs for their employees and their beneficiaries, but the program is underutilized due to lack of awareness and limited ambulatory care pharmacists to provide MTM services. This project covers ambulatory care pharmacists' role in improving employee …

Metabolites Profiling Of Coffee Seeds In Context To Their Origin, Processing And Gut Microbiota Interaction, Amr Abdelwareth

Theses and Dissertations

Coffee is among the most consumed beverages worldwide, with the present study to focus on the aroma and non-volatiles composition associated with coffee seeds processing, brewing methods and gut microbiota interaction. The study uncovered a large number of primary and secondary metabolites in diverse coffee products consumed in the Middle East in the context of its origin, roasting, and blends and microbiota mediated biotransformation products. First, aroma of authentic coffee specimens of Coffea arabica and Coffea robusta alongside with commercial products consumed in the Middle East were analyzed using HS-SPME coupled to GC-MS and modelled using multivariate data analyses (MVA). …

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 …

Design And Synthesis Of Macrocyclic Peptide Braf-Wt Dimerization Inhibitors For The Treatment Of Metastatic Melanoma, Chad Mulloy Beneker

Theses and Dissertations

In cases of metastatic melanoma, BRAF is frequently mutated to the V600E oncoprotein causing uncontrolled cell proliferation driven by the MAPK-ERK pathway. There are several BRAF inhibitors, such as vemurafenib, which are FDA approved, but patients treated with these Type-I kinase inhibitors frequently observe relapse under mutant RAS and BRAF-wt conditions due to paradoxical activation. The mechanism of this resistance occurs through binding of the inhibitor to BRAF-wt initiating conformational changes which leads to BRAF dimerization. Once in the dimerized state, the inhibited monomer induces allosteric transactivation of the second monomer. This drug-induced activation of BRAF in cells with mutant …

Panaxynol’S Pharmacokinetic Properties And Its Mechanism Of Action In Treating Ulcerative Colitis, Hossam Sami Tashkandi

Theses and Dissertations

Panaxynol (PA) is a polyacetylene that was found to be an abundant active ingredient in American ginseng (AG). Pharmacokinetics (PK) studies of PA were conducted to determine how the body reacts to it by using liquid chromatography-tandem mass spectrometry (LC-MS/MS) to measure PA’s concentration. In vitro, PA’s clearance by microsome metabolism is a moderate 48.1 minutes. In vivo, CD-1® mice were treated with PA by intravenous (IV) injection or orally (PO). Concentrations of PA were measured in plasma and tissue using LC-MS/MS. Also, PA has a high bioavailability of 50.4% and a moderate half-life of 5.9 hours. In addition, mice …

Evaluation Of The Anticancer Potential Of Alchemilla Vulgaris Extract Against Human Neuroblastoma Cells, Yomna Moqidem

Theses and Dissertations

Neuroblastoma is one of the most challenging pediatric tumors that present heterogeneity in prognosis and survival despite intensive treatment protocols. Therefore, there is an urge to develop novel and more potent anticancer drugs. Medicinal plants have recently gained worldwide attention due to their variable activities, wide availability, and cost-efficiency. Accordingly, this study attempted to identify novel plant extracts that could show potential anticancer properties against neuroblastoma. In this study, Alchemilla vulgaris (A.vulgaris) ethyl acetate extract was prepared and evaluated for its anticancer potential against SH-SY5Y Human neuroblastoma cell line. The Phenolic content of the prepared extract was characterized …

The Antioxidant And Antimicrobial Activities Of Cornsilk Extract Encapsulated In Polysaccharide Nanoparticles, Maryam Mady

Theses and Dissertations

Corn silk possess antibacterial and antioxidant activities due to its phenolic compounds but they are of low bioavailability that requires some innovative techniques to develop such active ingredients in a safe and less toxic manner. Accordingly, silk extract SE was encapsulated in chitosan nanoparticles CS NPs, which is a natural and abundant polymer derived from chitin. Among 15 experimental trials via design expert software, the optimum formula of SE x\CS NPs was prepared at 800 rpm, 5hrs. on magnetic stirrer, and by CS: TPP ratio was 2.5:1. Then SEM showed the majority of particles size diameter in the range of …

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 …

Self-Emulsified Nanoemulsion As Permeation Enhancer And Its Application For Intranasal Delivery Of Insulin, Kanyaphat Bunchongprasert

Theses and Dissertations

This study aimed to investigate the permeation enhancing property and safety of self-emulsified nanoemulsion (SEN) and use these findings to enhance insulin absorption through the nasal route.

The first part of the project was to identify the factors affecting cytotoxicity and permeation enhancement of SEN on Madin-Darby Canine Kidney (MDCK) cells, a widely used paracellular model. Twenty-six fatty acid esters (FAEs) commonly used in SEN were investigated. Among the FAEs (mono-, di-, and triesters), fatty acid monoesters (FAME) are the main excipient causing cytotoxicity and opening tight junction. The cytotoxicity of FAME in SEN was reduced with the presence of …

Development Of Nanoliposomes For The Treatment Of Braf V600e Mutated Parent And Vemurafenib-Resistant Melanoma, Yige Fu

Theses and Dissertations

Melanoma is one of the most aggressive and deadliest types of skin cancer. Currently, off-target toxicities and the rapid resistance development of metastatic melanoma mainly restrict the efficiency of the treatments. This thesis presents efforts towards developing liposomes to address current problems of BRAF-mutant metastatic melanoma.

EphA2-Receptor Targeted PEGylated Nanoliposomes for the Treatment of BRAF V600E Mutated Parent and Resistant Melanoma

In order to address off-target toxicities of the targeted therapy of MEK inhibitor trametinib (TMB), we developed a physically stable EphrinA1-mimicking peptide (YSA) anchored TMB-loaded PEGylated nanoliposomes (YTPLs). The YTPLs were evaluated in BRAFV600E-mutated parent cell lines (A375 and …

Development And Characterization Of Bilayer Abuse Deterrent Extended Release Tablet Using Various Model Drugs For Opioids Overdose Crisis, Ankit Soni

Theses and Dissertations

The objective of present study is to develop bilayer abuse-deterrent extended-release tablets (ADERTs) using various model drugs for opioids overdose crisis. Bilayer ADERTs using various model drugs were fabricated by direct compression; consists of extended-release drug layer and pH modifying layer. To develop extended-release layer, various hydrophilic polymers evaluated for their abuse deterrent potential. Based on significantly higher viscosity at 100RPM and lower syringe-ability data, it was found that HPMC K100M could be used as abuse deterrent polymer. Along HPMC K100M, various diluents were evaluated for their abuse deterrent potential. Tablet formulations prepared with various type of diluents using metformin …

Qbd Approach For Development Of Ivermectin-Loaded Gastro Retentive Sustained Release Tablets As Mass Drug Administration For Malaria Transmission Control, Zhangjie Xi

Theses and Dissertations

Malaria is a life-threatening disease with a high prevalence worldwide. Mass drug administration (MDA) of ivermectin have been shown to prevent the transmission of malaria. The objective of this investigation is to develop ivermectin-loaded gastro retentive sustained release tablets (GRSRTs), which have the potential to avoid not only frequent administration of MDA but also fluctuation of ivermectin in systemic circulation. Based on the outcomes from screening various materials to be the suitable matrix forming polymer and bio-adhesive polymer mixture of GRSRTs, HPMC K100M, Carbopol 934p and sodium alginate:chitosan (1:1) were selected as formulation variables. Eight formulations of ivermectin-loaded GRSRTs were …

Exploring Efficacy Of An Anti-Malarial Nanomedicine In Non-Small Cell Lung Cancer Treatment, Vineela Parvathaneni

Theses and Dissertations

New drug and dosage form development faces significant challenges, especially in oncology, due to longer development cycle and associated scale-up complexities. Repurposing of existing drugs with potential anti-cancer activity into new therapeutic regimens provides a feasible alternative. In this project, amodiaquine (AQ), an anti-malarial drug, has been explored for its anti-cancer efficacy through formulating inhalable nanoparticulate systems using high-pressure homogenization (HPH) with scale-up feasibility and high reproducibility. A 32 multifactorial design was employed to better understand critical processes and formulation parameters so as to ensure product quality with improved anticancer efficacy in non-small cell lung cancer (NSCLC). Optimized AQ loaded …

Design And Synthesis Of Non-Xanthone Structural Analogs Of Α-Mangostin, Maryam Foroozmehr

Theses and Dissertations

α-Mangostin belongs to a class of polyphenolic compounds called xanthones. The potential pharmacological effects such as anti-bacterial and anti-cancer effects of α-mangostin have made it an important natural product for medicinal chemistry evaluation. During this thesis research, we have designed and synthesized a series of non-xanthone analogs of α-mangostin for medicinal chemistry evaluation. A commercially available starting material, methyl-4-methoxysalicylate was used to synthesize these non-xanthone analogs. The analogs were designed as more flexible derivatives compared to the tricyclic motif within α-mangostin yet retain the hydroxybenzoate scaffold. Through a one-pot chemical synthesis, with relatively high yield (70%), we prepared eight different …

Double-Coated Biodegradable Poly (Butyl Cyanoacrylate) Nanoparticulate Delivery Systems For Brain Targeting Of Doxorubicin Via Oral Administration, Neeraj Kaushal

Theses and Dissertations

Primary brain cancer cells grow within the brain or cancer cells can metastasis from different site of the body into brain. The major hurdle in the treatment of brain cancer is the presence of blood-brain barrier (BBB). Additionally, acquired multidrug-resistant (MDR) impedes the success of long-term chemotherapy. Therefore, the objective of this investigation is to evaluate the brain targeting potential of orally administered poly(butyl cyanoacrylate) nanoparticulate delivery systems (PBCA-NPDS), double-coated with Tween 80 and polyethylene glycol (PEG) 20000 for brain delivery of doxorubicin, that does not cross the BBB by itself. And, evaluate the MDR reversal potential of PBCA-NPDS. Doxorubicin-loaded …