Pharmacy and Pharmaceutical Sciences Commons^™

Elaboration Of Diquinanes To Access Trifunctional Angular Triquinanes And Designed Dna Polymerase Α Inhibitors, Spencer M. Webber

University of the Pacific Theses and Dissertations

Natural products are of great significance to the pharmaceutical industry in the development of new drugs. Diquinane or bicyclo[3.3.0]octane is a conspicuous structural unit existing in the carbo-frameworks of a wide range of natural products such as alkaloids and terpenoids. These diquinane-containing molecules not only exhibit intriguing architectures, but also showcase a broad spectrum of significant bioactivities, which draw widespread attention from the global synthetic community. A more specific group of compounds containing a diquinane moiety with one extra 5-membered ring are called the angular triquinanes.In this work, we have developed a general synthetic scheme to the angular triquinanes. We …

Development Of Nano Formulations Of Lipophilic Platinum Complexes Against Lung Cancer, Zizhao Xu

University of the Pacific Theses and Dissertations

Lung cancer remains a leading cause of death worldwide and urges the development of more effective and safer treatment options. Conventional platinum-based drugs like cisplatin, while effective, are associated with significant systemic toxicity, particularly nephrotoxicity. Nano formulations, such as liposomal and micellar delivery systems, represent a promising approach to enhance the anticancer activity and reduce the toxicity of platinum complexes.

This study develops and evaluates novel miriplatin-loaded nano formulations for lung cancer therapy. We prepared and screened various liposomal and micellar formulations of miriplatin by either thin-film hydration or co-solvent evaporation, which identified a number of formulations with appropriate sizes …

An Empirical Predictive Model For Determining The Aqueous Solubility Of Bcs Class Iv Drugs In Amorphous Solid Dispersions, Sridivya Raparla

University of the Pacific Theses and Dissertations

Poor aqueous solubility persists as a significant challenge in the pharmaceutical industry.Ongoing research aims to enhance the solubility of drugs to deliver them more effectively. Amorphous solid dispersion (ASD) is a widely used solubility enhancement technique. The absence of a specific model to predict compound solubility from ASDs resulted in a trial-and- error approach to studying solubility enhancement and makes it a laborious and time-consuming process. Predictive models could streamline this process and accelerate the development of oral drugs with improved aqueous solubilities. This study aimed to develop a predictive model to estimate the solubility of a compound from the …

Impact Of Drug-Polymer Interactions On Stability In Simvastatin-Based Amorphous Solid Dispersions, Charina Lampa

University of the Pacific Theses and Dissertations

This study aimed to investigate the drug-polymer interactions between simvastatin (SIM) and three polymers [PVP-VA, HPMC-AS, and Soluplus® (SOL)] in amorphous solid dispersions (ASDs) prepared by hot melt extrusion (HME), and to understand the implications on physical stability. ASDs are of significant interest within the pharmaceutical industry for improving drug bioavailability. However, the amorphous nature of a drug in an ASD presents physical stability challenges. Utilizing novel applications of accessible tools such as ATR-FTIR or DSC aid in understanding the mechanisms of stabilization which are critical to the rational design of ASDs. ASDs were prepared using HME and were characterized …

Evaluation Of Human Stem Cell-Derived Neurons In 2d And 3d Cultures For Neurodevelopmental Studies, Epilepsy Disease Modeling And Drug Discovery, Hamed Salmanzadeh-Dozdabi

University of the Pacific Theses and Dissertations

Human stem cells have revolutionized the study of early neural development, offering a powerful tool to investigate the complex processes involved in the formation of the nervous system. In this study, the human pluripotent stem cell line, TERA2.cl.SP12, was utilized to derive neuroglial cells and to determine their differentiation and functional maturation up to one year in culture; this model was then investigated as a new tool for the study of neurodevelopmental toxicity, for seizure modeling and as a screening method for the investigation of new anticonvulsants. Immunocytochemistry experiments determined that non-differentiated cells expressed the stem cell marker Oct-3/4 and, …

Targeting Ribonucleotide Reductase For Breast Cancer Treatment, Nahid Sultana

University of the Pacific Theses and Dissertations

Breast cancer is the second most common type of cancer in the world. Hormone receptor (HR) positive breast cancer (BC) is a prevalent disease accounting for approximately 2 million new cases globally. Almost 70-80% of breast cancer patients are women with a positive score for the estrogen receptor (ER). Triple-negative breast cancer (TNBC) which have a negative score for estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor type 2 (HER2) is considered an aggressive histological breast cancer subtype with limited treatment options.Frequently, doxorubicin (DOXO)-based chemotherapy is utilized in this patient population due to the lack of …

Incorporating Glutamic Acid-Valine-Citrulline Linker In Trifunctional Molecules Targeting Psma Ensures Enhanced Stability, Safety, And Efficacy In Mouse Model Of Prostate Cancer, Toufiq Ul Amin

University of the Pacific Theses and Dissertations

This project describes the development of a new antitumor therapeutic platform that combines the benefits of small-molecule drug conjugates (SMDCs) and antibody drug conjugates (ADCs). Valine-citrulline (VCit) dipeptide linkers are popular cathepsin B cleavable ADC linkers. Due to its instability in mouse serum, translating efficacy data from mouse to human is more difficult. It has been reported that replacing the VCit linker with glutamic acid-valine-citrulline (EVCit) improves ADC stability in mouse serum. The effect of the EVCit linker on the stability of SMDCs has not been reported so far. In a xenograft mouse model of prostate cancer, we found that …

Investigation Of Cdk8 Inhibitor Q-12 Effects On Cdk8 And Cdk8 Substrates In Triple Negative Breast Cancer Cell Line Mda-Mb-468, Shengxi Li

University of the Pacific Theses and Dissertations

Cyclin-dependent kinases (CDKs) and cyclins (Cyclins) are the core molecules in the regulation mechanism of the entire cell cycle. Cell cycle dysregulation is a common feature of human cancers, and inhibitors of cyclin-dependent kinases (CDKs) play a crucial role in cell cycle control and are one of the most promising areas of cancer therapy. We aspired to use our cyclin-dependent kinase 8 (CDK8) inhibitor, Q-12, as a probe for biomarker discovery for CDK8 inhibitor sensitive tumor types. Q-12 shows potent inhibition of cell viability and induction of apoptosis process in some triple-negative breast cancer (TNBC) and colorectal cancer cell lines …

Optimization Of The Structure Of Ttr Ligands For Half-Life Extension (Tlhe), Guanming Jiang

University of the Pacific Theses and Dissertations

Many potential therapeutic agents face challenges for their clinical development due to short circulation half-life. As a result, prolonging the half-life of therapeutic drugs in circulation while preserving their hydrophilicity and small size will be a key step toward more effective and safe pharmacological molecules. Our lab developed a new approach for enhancing the safety and efficacy of therapeutic agents. By endowing therapeutic agents with a hydrophilic small molecule (a derivative of the clinical candidate, AG10) which reversibly binds to the serum protein transthyretin (TTR), the half-life of the therapeutic agent should be extended by binding to the TTR in …

Expression Of Mouse Full-Length Aryl Hydrocarbon Receptor And Human Aryl Hydrocarbon Receptor Ligand Binding Domain In Pichia Pastoris, Yiyuan Wang

University of the Pacific Theses and Dissertations

Aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that regulates biological responses to planar aromatic hydrocarbon. AHR activates gene transcription by binding to its corresponding enhancer with its partner-aryl hydrocarbon receptor nuclear translocator (ARNT). In addition, this receptor has been shown to regulate xenobiotic-metabolizing enzymes such as cytochrome P450. AHR exists widely in body tissues and affects bioactivation of carcinogenic compounds, T cell differentiation, fatty acid synthesis, cell proliferation, hematopoietic stem cell differentiation, respiratory reactivity, and insulin sensitivity. Although the precise mechanism illustrating the endogenous AHR function remains unclear, there has been intense interest in exploring AHR as a …

Optimizing The Human Aryl Hydrocarbon Receptor (Hahr) Expression In Pichia Pastoris, Junyu Qian

University of the Pacific Theses and Dissertations

The aryl hydrocarbon receptor (AHR) is a transcription factor which heterodimerizes with the aryl hydrocarbon receptor nuclear translocator (Arnt) to regulate downstream gene transcription. For the purpose of studying the crystal structure of human aryl hydrocarbon receptor (hAHR), it is essential to obtain abundant amount of pure recombinant protein.Basing on the benefits of using P. pastoris system to produce recombinant protein, including appropriate folding, secretion of interest proteins to the external environment of the cell, and easier purification process of protein due to the its limited production of endogenous secretory proteins [1], our lab chose P. pastoris yeast as the …

Peripherally Restricted Delivery System Provides Insights On The Role Of Cns In Precipitating Opioid-Induced Constipation, Dengpan Liang

University of the Pacific Theses and Dissertations

A serious opioid crisis is affecting public health and economics, eroding people’s quality of life. 80% of patients who receive opioids suffer from adverse effects such as Opioid-induced constipation (OIC). However, there is no efficient medicine for these adverse effects. Notably, mainstream theory supports that analgesia effects are mainly controlled by CNS while OIC is predominately controlled by peripheral. In addition, the sites of action of opioid was based on the assumption that mu-opioid receptor antagonists (PAMORAs), did not cross the blood-brain barrier (BBB). Unfortunately, the BBB crossing of PAMORAs mislead the understanding of the role of the central nervous …

Thermodynamic Mechanisms Of Helix Stabilization In A Model Peptide And Protein, Ryan Murray

University of the Pacific Theses and Dissertations

Biologics are large, complex therapeutic agents generally produced from living organisms. One group of biologics is peptide/protein based. Biological agents offer unique advantages over traditional therapeutics including longer half-lives, higher specificity, greater efficacy, and reduced off-target effects. However, protein/peptide based drugs suffer from both delivery and stability issues. The higher order of protein structures (secondary, tertiary, etc.) derive ~80% of their conformational stability from paltry hydrophobic effects, with net stabilization of 5-15 kcal/mole observed for many proteins. Loss of conformational stability can lead to increased aggregation, precipitation, and degradation; and reduced activity and side effects. To increase stability and improve …

Peripherally Restricted Opioid Conjugates And Its Use As Pharmacological Probes And Potential Therapeutics, Md Tariqul Haque Tuhin

University of the Pacific Theses and Dissertations

Opioid-induced constipation (OIC) is one of the major adverse effects of opioid analgesics used by millions of patients each year. While progress has been made, there remains a significant unmet medical need in the treatment of OIC. Major gaps remain in our understanding of the role of the gastrointestinal tract and central nervous system (CNS) in precipitating OIC. For the last four decades, numerous investigations to study the sites of action of opioid analgesics have utilized peripherally acting mu-opioid receptor antagonists (PAMORAs), which have been incorrectly believed to have limited penetration across the blood-brain barrier (BBB). Several preclinical and clinical …

The Vagabond Flourine Atom Revisited: Dissociative Photoionization Of Tri- And Pentafluoropropene, Jessica K. De La Cruz

University of the Pacific Theses and Dissertations

Photoelectron Photoion Coincidence (PEPICO) Spectroscopy studies on two unsaturated hydrofluorocarbons (HFCs), also known as hydrofluoroolefines (HFOs), are presented here. Previously, the Sztáray group has studied the dissociation of trans-1,3,3,3-tetrafluoroprop-1-ene (ElixClean), which is a fourth-generation refrigerant and propellant and has lower global warming potential than its precursors. My study is an extension of the ElixClean study as it aims to explore how the different number of fluorine atoms impact the dissociation reactions of these molecules. Both 3,3,3-trifluoropropene (TFP) and cis-1,2,3,3,3- pentafluoropropene (PFP) are also utilized as propellants and refrigerants.Measurements were carried out with remote access to the CRF-PEPICO (combustion reactions followed …

Post-Translational Modification And Degradation Mechanisms Of The Aryl Hydrocarbon Receptor, Yujie Yang

University of the Pacific Theses and Dissertations

The aryl hydrocarbon receptor (AHR) is a transcription factor first discovered to be activated by exogenous ligands, such as dioxins, and helps promote downstream gene (e.g. CYP1A1) transcription to metabolize the toxicants. With the reports of various AHR targets genes, the expression levels and activities of AHR have been implicated in many physiological and pathological situations. Understanding how AHR protein level is regulated would provide more information to target AHR. AHR stays in the cytosol in the absence of ligand in a complex with HSP90, p23 and XAP2. After ligand activation, AHR translocates into the nucleus, fulfilling its transactivation function …

Bayesian-Derived Vancomycin Auc24h Threshold For Nephrotoxicity In Special Populations, Dan Ho

University of the Pacific Theses and Dissertations

A Bayesian-derived 24-hour area under the concentration-time curve over minimum inhibitory concentration from broth microdilution (AUC24h/MICBMD) ratio of 400 to 600 is recommended as the new monitoring parameter for vancomycin to optimize efficacy and minimize nephrotoxicity. The AUC24h threshold of 600 mg*h/L for nephrotoxicity was extrapolated from studies that assessed the general population. It is unclear if this upper threshold is consistent or varies when used in special populations such as critically ill patients, obese patients, patients with preexisting renal disease, and patients on concomitant nephrotoxins.The purpose of this study is to investigate the generalizability of the proposed vancomycin AUC24h …

Harnessing Transthyretin To Enhance The In Vivo Half-Life Of Human Interleukin-2 (Il-2), Fang Liu

University of the Pacific Theses and Dissertations

Protein therapeutics are available as cytokines, clotting factors, enzymes, hormones, growth factors, antibodies et al. They have been shown to be effective in treating a variety of important human diseases. Since human insulin was approved as the first recombinant protein therapeutic, this field has experienced rapid growth. One of the biggest challenges for protein therapeutics in clinical application is their short half-life. Except for monoclonal antibodies, which have serum half-life for weeks, most of the protein therapeutics have half-lives ranging from minutes to hours. Kidney filtration, proteasome degradation and liver metabolism are the main factors that attribute to their short …

Development Of Miriplatin-Loaded Nanoparticles Against Non-Small Cell Lung Cancer, Zhongyue Yuan

University of the Pacific Theses and Dissertations

Lung cancer claims the highest mortality and the second-most estimated new cases among all oncological diseases [1]. Non-small cell lung cancer (NSCLC) accounts for approximately 85% of all newly diagnosed lung cancers [2]. Approximately 40% of newly diagnosed lung cancer patients are stage IV. For stage IIIB/IV NSCLC, cytotoxic combination chemotherapy is standard first-line chemotherapy. A regimen of platinum (cisplatin or carboplatin) plus paclitaxel, gemcitabine, docetaxel, vinorelbine, irinotecan, or pemetrexed is the recommended clinical treatment [3].

Cisplatin is the first-generation platinum-based anti-cancer drug. Although cisplatin is much more effective than other platinum drugs at the same dosage [4], accumulating reports …

Multicellular Spheroids Of A549 And A549-Irfp As An In Vitro Model Of Lung Cancer, Xinyu Pei

University of the Pacific Theses and Dissertations

Lung cancer is the second most common cancer in both men and women around the world, and 85% of it is non-small cell lung cancer (NSCLC). It is estimated that in 2020, there will be 228,820 cases of lung cancer and 135,720 deaths from lung (American Cancer Society, 2020). The prognosis of lung cancer is poor (

Traditionally, the most commonly used in vitro method for screening therapeutic drugs is monolayer cell cultures, which are reproducible, convenient and of low cost. However, monolayer cell culture models are unable to reproduce many properties of in vivo solid tumors such as the …

Midazole-Based Ph-Sensitive Convertible Liposomes For Anticancer Drug Delivery, Ruiqi Huang

University of the Pacific Theses and Dissertations

Solid tumors possess biological features that are different from those in healthy tissues, which provides opportunities of anticancer treatment by nanomedicines. Due to the presence of the fenestrated tumor vasculatures, nanomedicines can selectively accumulate in tumor tissues by the enhanced permeability and retention (EPR) effect. The acidic pH in tumor interstitium (pH 6.0-7.0) also provides a promising mechanism to trigger the nanomedicines to promote the cellular uptake of cargo drugs. The previously reported stealth liposomes coated with PEG are known to accumulate in tumors owing to their prolonged circulation time. The PEG coating on liposomes can hinder serum protein adsorption …

Role Of Polymer Physicochemical Properties On In Vitro Mucoadhesion, Qing Zhang

University of the Pacific Theses and Dissertations

Polymers with mucoadhesive properties are universally used in the development of mucoadhesive drug delivery system. Their physicochemical properties as well as the mechanisms related to their adhesive actions draw great attention for the modification of mucoadhesive properties.

In this study, relationships between physicochemical properties of hydroxypropyl methylcellulose (HPMC) compacts and mucoadhesive performance were investigated. Different commercial grades of HPMC (K3, E3, E5, E50, K4M, E4M and K15M) were prepared into compacts, and their surface hydrophilicity and hydration behavior were characterized. The in vitro mucoadhesive performance was determined by the tension strength between the compacts and different regions of mucous membrane …

Development Of Lipid-Based Nano Formulations Of Miriplatin Against Lung Cancer, Zizhao Xu

University of the Pacific Theses and Dissertations

Cancer is the second leading cause of death and is responsible for approximately 9.6 million deaths worldwide in 2018. Among all oncological diseases, lung cancer claims the highest mortality (male: 23.5%; female: 22%) and the second most new cases (male: 13%; female: 12%) in the US. Approximately 40% of newly diagnosed lung cancer patients are in the advanced stage IV, for which platinum-based chemotherapy is the first-line treatment, either by itself or in combination with surgery or radiotherapy.

Cisplatin, the first-generation platinum-based anticancer chemotherapeutic agent, has the highest potency against lung cancer but carries many severe adverse effects. Cisplatin also …

Studies On The Size And Non-Planarity Of Aromatic Stacking Moiety On Conformation Selectivity And Thermal Stabilization Of G-Quadruplexes, Mandeep Singh

University of the Pacific Theses and Dissertations

Targeting DNA has the advantage over proteins for cancer remediation because of the fewer copies of the ligands required for the desired therapeutic effect. Traditionally, covalent DNA binders like alkylating agents have been used to induce genetic instability through the formation of DNA lesions and strand breaks, leading to cellular apoptosis. The primary drawback of this treatment is the non-specific binding that affects both cancerous and non-cancerous cells. G-quadruplexes are the DNA secondary structures that are present in abundance near the promoter regions of the oncogenes and are involved in the regulation of their activities. A ligand-mediated stabilization of G-quadruplexes …

Testing A Modified Model Of Stress Process For Understanding Quality Of Life Among Informal Caregivers And Assessing Their Formal Service Use, Nilesh V. Gangan

Electronic Theses and Dissertations

Informal caregivers provide timely care to family members who are disabled or have a chronic condition that requires close monitoring or constant assistance. To provide adequate support to informal caregivers there is a need to assess ways to improve their quality of life (QOL) and understand how formal services can be improved. This dissertation strives to extend the knowledge available for policy makers by examining the factors that can be targeted by policy makers to improve QOL of informal caregivers as well as the factors that enable the use of formal services provided to support informal caregivers. The psychometric properties …

Cheminformatic Approach For Deconvolution Of Active Compounds In A Complex Mixture - Phytoserms In Licorice, Manal Mohammad Alhusban

Electronic Theses and Dissertations

ABSTRACT After the validation of our in silico models by using the previous knowledge in this area the alerting phytochemicals from two Glycyrrhiza species (G. glabra and G. uralensis) were clustered. Exhaustive computational mining of licorice metabolome against selected endocrinal and metabolic targets led to the discovery of a unique class of compounds which belong to the dihydrostilbenoids (DHS) class appended with prenyl groups at various positions. To the best of our knowledge this interesting group of compounds has not been studied for their estrogenic activities or PXR activation. In addition some of the bis-prenylated DHS have been reported to …

Fabrication Of Topical Film Forming Polymeric Solution For Pain Management, Maha Hani Alkurdi

Electronic Theses and Dissertations

FFS were developed by varying the type and content of the film forming polymer. The resulting formulations were evaluated according to favorable film characteristics in vitro and ex vivo drug release profiles. Eudragit E100 was identified as a suitable release matrix for ketoprofen. In the case of diclofenac Na; however the ex vivo permeation study results failed to show a characteristic release profile for either the test formulation or the marketed formulation VOLTAREN® Gel. Nevertheless the presented work provided a rationalized way for the development and evaluation of FFS and investigated their potential as delivery systems for ketoprofen and diclofenac …

Valuation Of Mentorship In Pharmacy Education And The Impact Of Perceived Personal Relevance, Ashley Stubblefield Crumby

Electronic Theses and Dissertations

Mentorship is an important component of personal and professional development for student pharmacists. This research measured the value of mentorship in this population examined potential influencing factors and the likelihood to participate in a mentoring relationship and identified preferences for the mentoring relationship. Data collection involved survey self-report of student pharmacists (P1-P4) at four participating universities. An adapted 29-item Mentoring Functions Scale (MFS) was used to measure value with functions divided into career and psychosocial categories. The highest ranked mentoring functions were psychosocial with an average score of 9 or greater on the 10-point scale. Perceived personal relevance measured using …

Pharmacy Value-Based Incentive Programs: An Evaluation Of Health Plan Strategies, Pharmacist Attitudes, And Financial Impact On Retail Stores, Tristen H. Jackson

Electronic Theses and Dissertations

Since the Affordable Care Act (ACA) in 2012 health plans serving Medicare beneficiaries have begun receiving sizeable incentives (>$1B) for demonstrating high ratings to quality performance scores in CMS’s Medicare star ratings program. Several of the quality measures can be directly impacted by retail pharmacists (e.g. medication adherence measures) resulting in health plans implementing programs designed to incentive retail pharmacies to work toward improving their own performance related to quality measures. While awareness of these value-based incentive (VBI) programs is growing there is still a significant lack of research which elucidates the nature of these programs and the potential …

Comparative Assessment Of Safety And Quality Of Tinospora Species-Tinospora Crispa And Tinospora Sinensis, Abidah Parveen

Electronic Theses and Dissertations

Tinospora crispa Miers ex Hook.f. & Thomson and Tinospora sinensis (Lour.) Merr. (Menispermaceae) are two species that have morphological similarities which makes distinction between the two of critical importance because T. crispa has been reported to cause hepatotoxicity. Comparative morpho-anatomy of the leaves and stems of Tinospora species indigenous to south and southeast Asia was undertaken to elaborate their distinguishing pharmacognostic features. Chemical characterization of the secondary metabolites of the two species may aid in elucidating their chemical diversity and hence help to resolve safety and quality issues. Phytochemical investigation of the stems led to the isolation of nineteen compounds …