Other Pharmacy and Pharmaceutical Sciences Commons^™

Specificity Of Interaction Of Antimicrobial Peptide With Cell Membrane, Srishhti Kumar Jha

Pharmaceutical Sciences (MS) Theses

Antimicrobial resistance (AMR) is an increasing global health threat due to its rising incidence worldwide. Resistant microbial infections have become difficult to treat and pose serious risks to patients. In 2019, AMR was responsible for approximately 1.27 million deaths globally, with numbers continuing to rise. The World Health Organization (WHO) has highlighted the urgent need for new antibiotics with novel mechanisms of action and low toxicity to combat this issue. Antimicrobial peptides (AMPs) represent a promising solution. These peptides exhibit broad-spectrum antimicrobial activity and rapid killing kinetics, reducing the likelihood of resistance development. AMPs primarily target bacterial cell membranes. Their …

Functional Characterization Of The C-Terminal Cholinesterase-Like (Chel) Domain Of The Thyroid Hormone Precursor Protein, Berenice Morales-Rodriguez

Pharmaceutical Sciences (MS) Theses

Vertebrate life is unsustainable without thyroid hormones. The only known precursor for thyroid hormone synthesis is thyroglobulin (Tg), composed of upstream regions I-II-III and a C-terminal cholinesterase-like (ChEL) domain, which bears 47% similarity to acetylcholinesterase (AChE). Mutations in Tg cause congenital hypothyroidism, the most common congenital endocrinopathy affecting 1 in 2,000-4,000 newborns, with a varying degree of phenotypic manifestations. Tg protein, regulated by TSH, is secreted to the lumen of thyroid follicles, where thyroxine (T₄) is formed primarily at the N-terminus, and triiodothyronine (T₃) is formed primarily in the ChEL domain. Previous in vitro studies indicated …

Proteomic Identification Of Hemp (Cannabis Sativa) Seeds By Tandem Mass Spectrometry And Evaluation Of Cytotoxic Activity, Taran Harris

Pharmaceutical Sciences (MS) Theses

Hemp (Cannabis sativa) has a long history of use globally as a source of traditional medicine, spiritual enlightenment, and recreational enjoyment. While it was commonly consumed for both medical and recreational purposes in the United States, it was classified as a Schedule 1 drug in 1937, severely restricting its use and research opportunities. Although hemp itself lacks psychoactive properties, Cannabis sativa flowers contain THC, the compound responsible for its psychotropic effects. This restriction hindered quality research into cannabis and its constituents. The study employed techniques, including top-down proteomics, size exclusion chromatography, affinity chromatography, high-resolution ESI QTOF LC/MS/MS, and …

Influence Of Human And Viral Il-6 On Kshv Infection In Human Tonsil Lymphocytes, Wajd Zakir

Pharmaceutical Sciences (MS) Theses

Infection of B cells by the lymphotropic gamma-herpesvirus Kaposi sarcoma-associated herpesvirus (KSHV) causes Multicentric Castleman Disease, Primary Effusion Lymphoma, and the newly-identified inflammatory syndrome designated KICS. Despite proven connections to lymphoproliferative disorders, little is known about how KSHV invades the human immune system or the early events governing infection in B lymphocytes. IL-6 signaling plays a critical role in KSHV-mediated disease, where elevated hIL-6 levels are positively associated with KSHV viral load and disease progression. This dynamic is even more complex due to the co-existence of human IL-6 (hIL6) and KSHV-encoded viral IL-6 (vIL6) in these diseases. Although the impact …

Analyzing Functional Interactions Of Designed Peptides By Nmr Spectroscopy, Wonsuk Choi

Pharmaceutical Sciences (MS) Theses

The development of small peptide-based therapeutics can be accelerated by the knowledge of relationships between the peptide structure and its functional interactions. Here, we report the analysis of two groups of synthetic peptides designed for two applications – broad bactericidal action and inhibition of protein-protein interactions in human cells. Novel amphiphilic peptides designed for antibacterial application incorporated arginine as cationic amino acids and non-natural amino acids that have aromatic side chains with similar hydrophobic properties as tryptophan. The interaction of lead cyclic peptides and their linear analogs with a phospholipid bilayer mimicking a bacterial membrane was studied using nuclear magnetic …

Design, Synthesis, And Evaluation Of Oleyl-Wrh Peptides For Sirna Delivery, Mrigank S Rai

Pharmaceutical Sciences (MS) Theses

The delivery of nucleic acid therapeutics across various cell membranes has always been one of the major challenges. Cell-penetrating peptides (CPPs) containing arginine (R), tryptophan (W), and histidine (H) have been promising for siRNA delivery. Therefore, to enhance siRNA delivery and efficient silencing of the STAT3 gene, herein, we hypothesized to use of fatty acylation with oleyl chain to our newly designed cell-penetrating peptide (WRH) to evaluate their silencing efficiency in breast and ovarian cancer cells. Therefore, the oleyl conjugated (WRH)_n (n=1-4) peptides were synthesized using Fmoc/tBu solid-phase peptide chemistry, followed by purification using Reverse-Phase High-Performance Liquid Chromatography (RP-HPLC), …

Cyclic And Linear Peptides Containing Tryptophan And Arginine Residues As Cell-Penetrating Peptides And Antifungal Agents, Khushbu Bhakta

Pharmaceutical Sciences (MS) Theses

Here, we synthesized a novel group of linear and cyclic amphiphilic peptides containing different sequences of arginine (R) and tryptophan (W) residues. The peptides included a class of cyclic peptides, [R3W3]2, [R3WRW]2, [RWW]4, [WRR]4, [RWRW3]2, and the corresponding linear peptides, (R3WRW)2, (RWW)4, (WRR)4, (RWRW3)2. The peptides were examined as potential molecular transporters and cell-penetrating peptides (CPPs), and their efficiency in delivering cell-impermeable compounds was compared with [WR]5. The peptides showed no significant cytotoxicity in different cell lines (MDA-MB-231, SK-OV-3, and HEK-293) at a concentration of 1 µM and after 3 h of incubation time. The uptake of fluorescence-labeled cargo molecules …

An Economic And Regulatory Analysis Of Breast Cancer Drugs Approved By The Us Food And Drug Administration, Abdullah Althomali

Pharmaceutical Sciences (MS) Theses

Introduction

Breast cancer is the most common cancer among women and the leading cause of cancer death among women worldwide. The pharmacological options for breast cancer include chemotherapy, hormone therapy, targeted therapy, and immunotherapy, which are used for the prevention or treatment of breast cancer. This study assessed trends in FDA approvals and prices at the market entry of new drugs indicated for breast cancer in the period 1980-2022. The study also evaluated the factors associated with the price of the new breast cancer drugs at market entry.

Material and Methods

Regulatory data were collected from the FDA website, and …

Renal Toxicity Warnings And Precautions Of Drugs Marketed In The Us, Mohammad Al Ghamdi

Pharmaceutical Sciences (MS) Theses

INTRODUCTION: The use of drugs can lead to renal adverse effects prompting the need to include warnings and precautions on medication labels. Studies evaluating renal warnings and precautions need to be improved. This study assessed the characteristics of FDA renal toxicity warnings and precautions included in the labels of drugs approved by the FDA and marked in the US. The study also evaluated the potential factors of including a boxed warning on a drug label.

METHODS: We extracted the labels of human prescription drugs with renal toxicity boxed warnings and warnings and precautions from the “FDA Label: Full-Text Search of …

Design, Synthesis, And Evaluation Of N-Methylated H2r2w4, Talal Alrubaie

Pharmaceutical Sciences (MS) Theses

Antimicrobial peptides (AMPs) are potential candidates for developing antibiotics against multidrug-resistant bacteria. We have recently developed a potent cyclic AMP containing histidine (H), arginine (R), and tryptophan (W) residues named [H₂R₂W₄]. This peptide showed antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) and Staphylococcus aureus (SA) with a minimum inhibitor concentration (MIC) of 3.1 μg/mL and a MIC of 6.2 μg/mL for Escherichia coli (E. coli). However, it displayed a mild cytotoxicity with cell viability of approximately 80% against normal human lung cells (MRC-5) and ~60% against normal human kidney cells (HEK-293) at the …

The Development Of A Novel Peptide-Drug Conjugate For Treating Triple-Negative Breast Cancer, Phi-Phung Than

Pharmaceutical Sciences (MS) Theses

Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype with poor prognosis and is difficult to treat. A diagnosis of TNBC means that the three most common types of receptors known to fuel most breast cancer growth–estrogen, progesterone, and HER2– are not present in the cancer tumors. Since the tumor cells lack necessary receptors, common treatments like hormone therapies and targeted HER2 drugs are ineffective. The use of chemotherapies in treating TNBC is an effective option instead. However, chemotherapies are not selective, thus they cause severe side effects such as cardiotoxicity, myelosuppression, alopecia and gastrointestinal problems. A peptide-drug conjugate …

Role Of Macrophages In Ocular Surface Fibrosis, Alyanna Corpuz

Pharmaceutical Sciences (MS) Theses

The present study is designed to investigate whether irradiation as used for conditioning regimen to ablate recipient’s diseased bone marrow prior to transplantation could trigger macrophage activation and polarization and whether macrophages could cause the transdifferentiation of ocular surface fibroblasts into myofibroblasts, thus contributing to oGVHD-associated fibrosis.

Bone marrow cells were cultured in M-CSF to obtain M0 macrophages, which were subsequently polarized into M1 and M2 phenotypes using IFN-g + LPS and IL-4, respectively.

The macrophages were exposed to 7 Gy radiation. The effect of irradiation on macrophage activation markers, phagocytosis, and apoptosis was assessed using real-time PCR, confocal microscopy, …

Approvals And Prices Of Systemic Antibiotics In Saudi Arabia And The United States, Saad Alharthi

Pharmaceutical Sciences (MS) Theses

Introduction

Antibiotics is one of the therapeutic classes with the highest level of consumption in the world. Despite the global diffusion of antibiotics, their availability and prices vary by country. This study assessed differences in the availability and prices of systemic antibiotics marketed in the United States (US) and Saudi Arabia and evaluated the factors associated with the differences in prices of systemic antibiotics marketed in both countries.

Material and Methods

We collected regulatory data from the US Food and Drug Administration (FDA) and the Saudi Food and Drug Authority (SFDA), the National Average Drug Acquisition Cost (NADAC) and the …

Effects Of Nnos Inhibitors On Melanoma-Induced Immunosuppression, Kate Alison Lozada

Pharmaceutical Sciences (MS) Theses

The incidence of cutaneous melanoma (CM) rises despite advances in immunotherapy and targeted therapy. Studies have shown that interferon-gamma (IFN-γ), a pro-tumorigenic cytokine in CM, induces the expression of programmed death-ligand 1 (PD-L1), leading to the escape of melanoma cells from immunosurveillance. Our previous study suggests that neuronal nitric oxide synthase (nNOS)-mediated nitric oxide (NO) signaling is crucial for melanoma progression and forms a mechanistic rationale behind nNOS inhibition as a novel treatment strategy for CM. An additional study demonstrated that IFN-γ interacts with nNOS signaling in melanoma and novel nNOS inhibitors (nNOSi) effectively diminished the induction of PD-L1 post …

Cyclic And Linear Cell-Penetarating Peptides Composed Of Tryptophan (Ww) And Arginine (Rr) Residues As Molecular Transporters, Lois Kim

Pharmaceutical Sciences (MS) Theses

The cell membrane has polar and negative charged characteristics and separates the inside of cells from the outside environment, and only allows small molecules to go into the cell to protect them from toxic substances. However, cell membrane characteristics make it difficult for polar and negatively-charged molecules to interact and penetrate the membrane. The delivery of cell impermeable compounds, such as phosphopeptides and siRNA, across the cell membrane remains a challenge. Previous studies in Dr. Parang’s laboratory have shown that cyclic peptides composed of tryptophan (W) and arginine (R) amino acids [WR]₅ have higher cellular uptake than the corresponding …

Content And Activity Of Cytochrome P450 3a In Rat Brain Microsomes And Mitochondria, Nouf Alshammari

Pharmaceutical Sciences (MS) Theses

The potential contribution of CYP3A in brain microsomes and mitochondria is crucial to designing appropriate therapeutic strategies and preventing toxicities. Until recently, there has been limited data reported in the literature with respect to CYP3A activity and its expression in the brain tissue. The reason for this limitation is most likely the relatively low level of CYP3A in the brain tissue. To this end, the primary purpose of this study is to develop a CYP3A functional assay in rat brain mitochondria and microsomes to determine the Michaelis-Menten kinetics of the formation of CYP3A-mediated hydroxylated metabolites of midazolam by UPLC-MS/MS. We …

Investigating Hybrid Cyclic/Linear And Linear Peptides As Vehicles For Nucleic Acid Delivery, Abdulelah Alhazza

Pharmaceutical Sciences (MS) Theses

Small interfering RNA (siRNA) and Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/CRISPR-associated Protein 9 (Cas9) are advanced biotechnological approaches that have been able to temporarily downregulate gene expression through post-transcription RNA interference or permanently knockdown a protein via creating a mismatch in DNA, respectively. Nucleic acids are anionic and hydrophilic molecule, which cannot enter the cell through passive diffusion and/or interaction with the cell membrane. Cell-penetrating peptides (CPPs) offer a unique carrier for nucleic acid delivery, where positively charged components of CPP bind to the negatively charged nucleic acid and the hydrophobic components enhance the interaction with cell membrane, and …

Cost-Effectiveness Analysis Of Tisagenlecleucel, Blinatumomab, And Clofarabine For Treatment Of B-Cell Precursor Acute Lymphoblastic Leukemia, Kamron Lotfi

Pharmaceutical Sciences (MS) Theses

Acute lymphoblastic leukemia (ALL) is a common type of adolescent and young adult leukemia in the United States (U.S.). Patients who are refractory or relapsed after receiving two or more lines of systemic therapy have the option of taking tisagenlecleucel. Due to the high cost of this treatment, a cost-effectiveness analysis was performed to assess the treatments for tisagenlecleucel, clofarabine combination, and blinatumomab. Objectives

The objective of this study is to evaluate the cost-effectiveness of tisagenlecleucel; clofarabine, etoposide, cyclophosphamide; and blinatumomab for the treatment of relapse- refractory ALL for adolescents and young adults from the U.S. health care payer perspective. …

Hybrid Cyclic-Linear Cell-Penetrating Peptides Containing Alternative Positive And Hydrophobic Residues As Molecular Transporters, Sorour Khayyatnejad Shoushtari

Pharmaceutical Sciences (MS) Theses

The cell membrane properties create a significant obstacle in intracellular delivery of cell-impermeable and negatively charged molecules. Amphiphilic cyclic peptides containing alternative arginine and tryptophan such as [WR]₅ have been shown to enhance the transport of cargo molecules across the cell membrane. Herein, we report the synthesis and biological evaluation of a novel series of hybrid cyclic-linear peptides containing alternative positive and hydrophobic amino acids on the ring and side-chain [(RW)₅]K(RW)_X (X=1-5) to compare their molecular transporter efficiency. The peptides were synthesized through Fmoc solid-phase peptide synthesis. Final compounds were purified by a reversed-phase HPLC (High …

Establishing The Role Of Dc-Sign And Glycoprotein H For Kshv Entry In B Lymphocytes, Nancy Palmerin

Pharmaceutical Sciences (MS) Theses

Kaposi sarcoma-associated herpesvirus, also known as KSHV or HHV-8, is an emerging pathogen and the causative agent of multiple cancers in immunocompromised patients. KSHV is known to cause four types of malignancies: endothelial-based Kaposi Sarcoma (KS), two rare B cell- based lymphomas; Primary effusion lymphoma, Multicentric Castleman’s disease and a recently characterized inflammatory disorder called KSHV-associated inflammatory cytokine syndrome(KICS). Unfortunately, all of the diseases associated with KSHV infection are fatal, and to this day there is no known cure. The purpose of this study is to understand the viral entry process of KSHV in tonsil-derived B lymphocytes. This study will …

Characterization Of The Growth Factor Receptor Network Oncogenes In Lung Cancer, Ashley Duche

Pharmaceutical Sciences (MS) Theses

Lung cancer remains the leading cause of cancer related deaths worldwide, reportedly contributing to 1.8 million of the 10.0 million mortalities documented in the year 2020. Although advancements have been made in therapeutics and diagnostic methods, formulation of effective treatments and development of drug resistance continues to be a challenge. These challenges arise from our lack of understanding of intricate signaling pathways, such as the Growth Factor Receptor Network (GFRN), which contributes to complex lung tumor heterogeneity allowing for drug resistance development. In this study, gene expression signatures of six GFRN oncogenes overexpressed in human mammary epithelial cells (HMECs) were …

Modulation Of Antibacterial Activity And Cytotoxicity In Amphipathic Cyclic Peptide [R4w4] Using Histidine Substitution, Ryan Stueber

Pharmaceutical Sciences (MS) Theses

Antibiotics have been the gold standard frontline defense against bacterial infections for decades. At the same time, these infecting bacteria have continued to evolve to resist developed antibiotics in an almost endless cycle. As such, we aim to take an alternative approach utilizing antimicrobial peptides (AMPs) as a means to end this cycle. [R4W4] is among known AMPs that demonstrated antimicrobial activity against methicillin-resistant staphylococcus aureus (MRSA) with a minimum inhibitory concentration (MIC) of 2.67 μg/mL. This peptide had notably effective antimicrobial activity, especially relative to linear (R4W4). However, it displayed a concerning level of cytotoxicity; eliciting a human embryonic …

The Development Of A Cancer-Targeting Peptide-Drug Conjugate For The Treatment Of Melanoma, Cassandra Dill

Pharmaceutical Sciences (MS) Theses

Cancer is an ongoing global pandemic which has caused a dramatic shift in research priorities. One of the most aggressive and difficult to treat has invariably remained metastatic melanoma. Although encompassing only 4% of overall skin cancer diagnoses, chances for recovery were slim until recent revolutionary development of immunotherapy adding to its regimen spectrum. This is due to its resistance to many standard-of-care treatment methods, along with its relatively high-metastatic potential. Within the past decade, eight new targeted and immune checkpoint inhibitors have gained FDA approval. The median life survival has increased significantly from 9 months to over 2 years …

Amphiphilic Cell-Penetrating Peptides Containing Natural And Unnatural Amino Acids As Drug Delivery Tools And Antimicrobial Agents, David Salehi

Pharmaceutical Sciences (MS) Theses

Cell-penetrating peptides containing arginine as positively charged residues and tryptophan or diphenylalanine as hydrophobic residues were synthesized. The synthesis was accomplished through the Fmoc solid-phase peptide synthesis in the presence of HBTU and DIPEA. The side-chain protected linear peptides were cleaved from the resin and cyclized in the presence of DIC and HOAt in the solution phase overnight. MALDI-TOF mass spectrometry was used to characterize the peptides.

The cytotoxicity of the synthesized peptides was determined in CCRF-CEM (human, lymphoblast peripheral blood), and HEK-293 (human, embryonic epithelial kidney healthy) cells using the MTS assay. A concentration of 10 µM was found …

Design And Evaluation Of Peptide Lipid-Associated Nucleic Acids (Planas) For Sirna And Crispr/Cas9 Delivery And Protein Silencing, Ryley Hall

Pharmaceutical Sciences (MS) Theses

Breast cancer affects 1 in 8 women in the United States. The American Cancer Society has estimated that in 2020 about 276,480 new cases of invasive breast cancer will be diagnosed in women. Cancer research has taken a turn in the last several decades to focus on new approaches to combat the disease. This project focuses on two approaches, siRNA and CRISPR/Cas9 that can have potential applications in cancer research.

The first approach is a specific type of RNA interference (RNAi) that has been pursued due to its therapeutic potential in cancer research. In short, siRNA delivery is a method …

Effect Of Diabetes Mellitus On Ocular Surface Tight Junctions And Glycocalyx, Saleh M. Alfuraih

Pharmaceutical Sciences (MS) Theses

Introduction: Diabetes mellitus is the disease of the century that affects many body organs. In the eye, diabetes mellitus causes retinopathy, cataract, glaucoma, papillopathy, and ocular surface disease. Ocular surface abnormalities in patients of diabetes mullites include impairment of corneal epithelial barrier function, conjunctival defects, increased incidence of corneal and conjunctival infections and higher prevalence of dry eye disease. Impairment of tight junctions and glycocalyx, which are critical for ocular surface barrier function, may underlie these diabetes-associated ocular surface defects. Therefore, the present study was designed to investigate the effect of high glucose exposure and type I diabetes mellitus on …

Role Of Protein Phosphatase-2a In Regulating Monocyte Activation By Soluble And Crystalline Uric Acid In Gout, Sandy Elsayed

Pharmaceutical Sciences (MS) Theses

Gout is a chronic inflammatory disease caused by the phagocytosis of monosodium urate monohydrate (MSU) crystals by monocytes/macrophages resulting in downstream expression and production of interleukin-1 beta (IL-1β) and chemokines. The activation of monocytes by MSU crystals involves the priming of monocytes with danger signals e.g. lipopolysaccharide (LPS) or soluble uric acid (UA), crystal phagocytosis and subsequent NLRP3 inflammasome activation and conversion of pro-IL-1β to active IL-1β. Protein-phosphatase-2A (PP2A) is a serine/threonine phosphatase that plays an important role in cell growth and inflammation. The prodrug Fingolimod (FTY720) and its phosphorylated active metabolite (p-FTY720) activate intracellular PP2A. We hypothesized that monocyte …

The Development Of Novel Apurinic/Aprymidinic Endonuclease/Redox-Factor 1 Inhibitors For The Treatment Of Human Melanoma, Bella Sharifi

Pharmaceutical Sciences (MS) Theses

Apurinic/apyrimidinic DNA repair endonuclease-1 (APE1), first recognized as an important DNA excision repair enzyme, is also known as Redox Factor-1 (Ref-1) involved in the activation of many nuclear transcription factors in both redox-dependent and independent manner. It has been well-documented that the overexpression of APE/Ref-1 contributes to the development of chemo-resistance and is associated with tumor progression in many human malignancies [1].

Our previous study in melanoma demonstrated that the development of novel inhibitors targeting the redox regulation domain of APE/Ref-1 is a promising strategy for melanoma treatment. To date, limited successes have been reported in developing novel …

Gender Differences In Opioid Prescribing Patterns Among Adults In The Us, Salena Marie Preciado

Pharmaceutical Sciences (MS) Theses

This project aims to evaluate gender differences in opioid prescribing in ambulatory care and emergency department settings. The retrospective analysis of opioid prescribing rates in the US included all adult medical visits from 2006-2016. Data was collected from two nationally representative surveys, The National Ambulatory Medical Care Survey (NAMCS) and the National Hospital and Ambulatory Medical Care Survey (NHAMCS). Eligible patients were at least 18 years old on the date of the visit. Bivariate and multivariate analysis were used to identify factors associated with opioid prescribing.

Rates of opioid prescribing increased for both men and women over the study period. …

Trends In Prices Of Insulin Marketed In The Us, Hana Althobaiti

Pharmaceutical Sciences (MS) Theses

INTRODUCTION: Diabetes mellitus is one of the most prevalent and costly chronic diseases in the United States (US). The healthcare and drug cost of diabetes has risen steadily and the increase in patients’ out-of-pocket drug expenditures are associated with a reduction in treatment adherence. The objectives of this study were to assess trends in insulin products prices in the period January 1983-July 2019, and to compare the price, acquisition costs and reimbursement amount of insulins available in the US.

DATA AND METHODS: Data of insulin products marketed in the US during the period January 1983-July 2019 was derived from the …