Pharmaceutics and Drug Design Commons^™

Daclizumab (Zinbryta®): An Emerging Therapy For The Treatment Of Relapsing-Remitting Multiple Sclerosis, Morgan Homan, Sunitha Jones, Michaela Louden, Molly Wheeler, Anh Dao Le, Lindsey Peters

Pharmacy and Wellness Review

Multiple sclerosis (MS) is an autoimmune disorder of the central nervous system characterized by the deterioration of the myelin sheath, causing axonal damage which leads to debilitating symptoms. Most therapies for the treatment of MS, including daclizumab, primarily target relapsing-remitting multiple sclerosis (RRMS), a form of MS where patients experience periods of exacerbated symptoms as well as intermittent periods of remission. Daclizumab is a humanized monoclonal antibody that is administered as a once monthly subcutaneous injection. The SELECT trilogy of trials have been instrumental in providing safety and efficacy data for daclizumab. The DECIDE study was the first randomized controlled …

Lipid Based Nanoparticles As A Novel Treatment Modality For Hepatocellular Carcinoma: A Comprehensive Review On Targeting And Recent Advances, Khaled Mahmoud, Shady Swidan, Mohamed A. El-Nabarawi, Mahmoud H. Teaima

Pharmacy

Liver cancer is considered one of the deadliest diseases with one of the highest disease burdens worldwide. Among the different types of liver cancer, hepatocellular carcinoma is considered to be the most common type. Multiple conventional approaches are being used in treating hepatocellular carcinoma. Focusing on drug treatment, regular agents in conventional forms fail to achieve the intended clinical outcomes. In order to improve the treatment outcomes, utilizing nanoparticles—specifically lipid based nanoparticles—are considered to be one of the most promising approaches being set in motion. Multiple forms of lipid based nanoparticles exist including liposomes, solid lipid nanoparticles, nanostructured lipid carriers, …

Variants Associated With Bedaquiline (Bdq) Resistance Identified In Rv0678 And Efflux Pump Genes In Mycobacterium Tuberculosis Isolates From Bdq Naïve Tb Patients In Pakistan, Dania Khalid Saeed, Sadia Shakoor, Safina Abdul Razzak, Zahra Hasan, Saba Faraz Sabzwari, Zahida Azizullah, Akber Kanji, Asghar Nasir, Samreen Shafiq, Najia Karim Ghanchi, Rumina Hasan

Department of Pathology and Laboratory Medicine

Background: Mutations in the Rv0678, pepQ and atpE genes of Mycobacterium tuberculosis (MTB) have been reported to be associated with reduced antimycobacterial susceptibility to bedaquiline (BDQ). Resistance conferring mutations in treatment naïve MTB strains is likely to have implications for BDQ based new drug regimen that aim to shorten treatment duration. We therefore investigated the genetic basis of resistance to BDQ in MTB clinical isolates from BDQ naïve TB patients from Pakistan. In addition, mutations in genes associated with efflux pumps were investigated as an alternate mechanism of resistance.
Methods: Based on convenience sampling, we studied 48 MTB clinical isolates …

The Use Of Advanced Spectral Imaging To Reveal Nanoparticle Identity In Biological Samples, Qamar A. Alshammari, Rajasekharreddy Pala, Ayan K. Barui, Saud O. Alshammari, Andromeda M. Nauli, Nir Katzir, Ashraf M. Mohieldin, Surya M. Nauli

Pharmacy Faculty Articles and Research

Nanoparticles (NPs) have been used in drug delivery therapies, medical diagnostic strategies, and as current Covid-19 vaccine carriers. Many microscope-based imaging systems have been introduced to facilitate detection and visualization of NPs. Unfortunately, none can differentiate the core and the shell of NPs. Spectral imaging has been used to distinguish a drug molecule and its metabolite. We have recently integrated this technology to a resolution of 9 nm by using artificial intelligence-driven analyses. Such a resolution allowed us to collect many robust datapoints for each pixel of an image. Our analyses could recognize 45 spectral points within a pixel to …

Three Waves: The United States Opioid Crisis, Ryan B. Santoro

Senior Scholars Papers in Science, Technology, and Society

The past two and a half decades have witnessed widespread suffering, addiction, and death at the hands of the opioid crisis. This paper analyzes the crisis through a series of time periods, broken down into “waves.” Drawing upon primary material in relation to OxyContin advertisements in the 1990’s, this research takes aim at the origin of widespread opioid abuse disorder. By building upon analysis done on the Sackler Family, Purdue Pharma, heroin abuse, fentanyl overdoses, the COVID-19 pandemic and opioids and addiction in modern pop culture, this thesis shows how despite constant change in public policy, the opioid crisis continues …

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

Theses and Dissertations--Pharmacy

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

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

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

Theses and Dissertations--Pharmacy

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

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

Theses and Dissertations--Pharmacy

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

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

Theses and Dissertations--Pharmacy

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

Liposomal Technologies To Improve Gene Delivery, David Nardo Padron

Theses and Dissertations--Pharmacy

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

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

Theses and Dissertations--Pharmacy

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

Putative Mechanisms Underlying The Antidepressant Actions Of Ketamine: A Review And Study Proposal, Tristan Reece

CMC Senior Theses

Major Depressive Disorder (MDD) is a highly debilitating and common psychiatric disorder that affects over 250 million people globally; it is among the most financially and emotionally burdensome illnesses in the world. Currently approved antidepressants are suboptimal in their efficacy and latency of therapeutic action. In contrast, single administrations of sub-anesthetic ketamine have been shown to rapidly alleviate depressive symptoms within hours, even in treatment-resistant patients. Ketamine is believed to exert these effects by increasing glutamatemediated neurotransmission and promoting rapid neurotrophic factor release, restoring the integrity of neural circuits that are compromised in depression. However, uncertainty surrounding its specific antidepressant …

Exploiting Modulation Of The Blood-Brain And Blood-Tumor Barrier Permeability By Translational Focused Ultrasound For Therapeutic Delivery To Cns Metastases, Tasneem A. Arsiwala

Graduate Theses, Dissertations, and Problem Reports (ETD)

Transcranial low-intensity focused ultrasound is a unique technology to modulate the integrity of tight endothelial junctions and transiently increase BBB/BTB permeability to enhance therapeutic delivery. Despite promising early studies, present literature lacks agreement on key experimental conditions, which restricts our knowledge and the technique's widespread translation. This dissertation first provides a critical review of the current gaps in knowledge regarding the universal use of LiFUS in preclinical and clinical use. We then identify key parameters for translational and predictable opening of the BBB using a 3T MRI coupled with a clinical device. Our investigation highlights that passive permeability of the …

Ero1Α Promotes Tumorigenesis In Egfr Driven Nsclc, Brennan D. Johnson

Graduate Theses, Dissertations, and Problem Reports (ETD)

Non-Small Cell Lung Cancer (NSCLC) is a pulmonary malignancy most commonly associated with smoking, or exposure to asbestos or Radon. Approximately, 1.6 Million deaths occur each year due to lung cancer. Lung Cancer is categorized by two main types, Small Cell Lung Cancer (SCLC) and NSCLC. NSCLC accounts for approximately 85% of all lung cancer cases and is subdivided into three sub-categories: Adenocarcinoma, the most common and leading cause of death in the United States; Squamous Cell Carcinoma (SCC), and Large Cell Carcinoma. Though NSCLC treatment regimens have shown increasing clinical benefit over the last two decades with targeted therapies. …

The Water Solubility Of Ursolic Acid Complexes At Different Choline Concentrations, Sera Lim, Renjie Zhan, Phillip M. Gerk

Undergraduate Research Posters

No abstract provided.

Modified Ysk12-Mend-Sirna In Dendritic Cells For Cancer Immunotherapy, Syed S. Alam

Undergraduate Research Posters

Tumors may induce tolerogenesis through signaling dendritic cells to produce tolerogenic molecules, such as indoleamine 2, 3-dioxygenase 1 (IDO1). Tumor-associated immunosuppression is associated with higher mortality in patients. Small interfering RNA (siRNA) has been shown to silence specific target genes in the target cell. The siRNA associated with these genes could support a gene knockdown of these immunosuppressors and reduce mortality. Delivery of these therapeutic nucleic acids is difficult in vivo because siRNA is easily broken down inside the cell and the bloodstream through present nucleases. Use of liposome polymers has been reviewed extensively in literature. YSK12-C4, a lipid nanoparticle …

The Benefits Of Astaxanthin To Improve Pain Relief In Patients With Painful Diabetic Neuropathy: An Open-Label, Randomized Controlled Trial, Rizaldy Taslim Pinzon, Mary Rose Angelina Budi Harsana

Pharmaceutical Sciences and Research

Treatment of diabetic neuropathy is still carried out by providing symptomatic therapy, which only improves ± 50% of the total symptoms felt by patients, but does not tackle the underlying causes of the disease. Astaxanthin is a potent antioxidant, anti-inflammatory, and anti-diabetic carotenoid that could be an additional treatment option. We aimed to measure the effectiveness of administering astaxanthin as an additional therapy to improve the impact of pain and discomfort experienced daily by diabetes mellitus patients with painful diabetic neuropathy. We conducted a randomized experimental study with an open label design of 36 patients who had been diagnosed with …

Comparative Analytical Study Of Phytochemicals In Selected Antidiabetic Medicinal Plant Seeds In Sri Lanka, Gowri Rajkumar, Mihiri Rangika Jayasinghe, Vinotha Sanmugarajah

Pharmaceutical Sciences and Research

Medicinal plants are universally used in the management of various diseases in different medical practices. A varied diversity of compounds extracted from plants may show anticancer, antibacterial, and antidiabetic activities. Comparative laboratory studies and scientific approach of efficacy related to phytochemicals found in medicinal plants in Sri Lanka have not been reported yet. This study aims to evaluate the phytochemicals in selected four different plant seeds such as Syzygium cumini (L.) Skeels, Brassica alba (L.) Rabenh, Trigonella foenum-graecum L. and Nigella sativa L., which are used in the management of diabetes mellitus in Sri Lanka. The ethanol extracts of …

Biologic Tnf-Α Inhibitors Reduce Microgliosis, Neuronal Loss, And Tau Phosphorylation In A Transgenic Mouse Model Of Tauopathy, Weijun Ou, Joshua Yang, Juste Simanauskaite, Matthew Choi, Demi M. Castellanos, Rudy Chang, Jiahong Sun, Nataraj Jagadeesan, Karen D. Parfitt, David H. Cribbs, Rachita K. Sumbria

Pharmacy Faculty Articles and Research

Background

Tumor necrosis factor-α (TNF-α) plays a central role in Alzheimer’s disease (AD) pathology, making biologic TNF-α inhibitors (TNFIs), including etanercept, viable therapeutics for AD. The protective effects of biologic TNFIs on AD hallmark pathology (Aβ deposition and tau pathology) have been demonstrated. However, the effects of biologic TNFIs on Aβ-independent tau pathology have not been reported. Existing biologic TNFIs do not cross the blood–brain barrier (BBB), therefore we engineered a BBB-penetrating biologic TNFI by fusing the extracellular domain of the type-II human TNF-α receptor (TNFR) to a transferrin receptor antibody (TfRMAb) that ferries the TNFR into the brain via …

The Use Of Natural Polymers In Formation Of Polyelectrolyte Complexation, Niharika Lal, Athira Nair, Navneet Verma

Bulletin of Faculty of Pharmacy Cairo University

In recent years, great advances have been made towards the development of various techniques for novel drug delivery systems. These techniques focus on the rate of drug delivery, duration of action and site of action. One of such technique in fabricating novel drug delivery system is the use of polymers in development of in-situ drug delivery systems. Polymers used as carriers have revolutionized over the years. The formation of a polymer complex with other oppositely charged polymers resulted in the formation of polyelectrolyte complexes, which possess unique physicochemical properties with high biocompatibility. The polyelectrolyte's themselves are characterized as cationic, anionic …

Development Of A Bamlanivimab Infusion Process In The Emergency Department For Outpatient Covid-19 Patients, Danny Pham, Sandy Wong, Christina T. Nguyen, Stephen C. Lee, Kimberly J. Won

Pharmacy Faculty Articles and Research

The coronavirus disease 2019 (COVID-19) pandemic has prompted the creation of new therapies to help fight against the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Bamlanivimab is a SARS-CoV-2 monoclonal antibody that is administered as an intravenous infusion to ambulatory patients with mild or moderate COVID-19, but a concern that arose was deciding the optimal location for patients to receive the medication. This report describes the development and implementation of a bamlanivimab infusion center in the emergency department of three hospitals in Orange County, California, shortly after bamlanivimab received emergency use authorization. As a result, a total of 601 …

Ketamine As A Treatment Modality For Treatment-Resistant Depression, Tracy Wulff, Shen Cao

Physician Assistant Capstones, 2020-current

Many recent studies have demonstrated the ability of ketamine, an NMDA receptor antagonist, to produce antidepressant effects that may be effective in helping reduce treatment-resistant major depression. In particular, three double-blinded randomized control trials have been conducted to assess the viability and effectiveness of this medication for treatment. This systematic literature review will analyze these studies and determine if the overall research indicates that ketamine is useful in improving depression as measured by the Montgomery–Asberg Depression Rating Scale (MADRS)¹.

Objective: Assess the effectiveness of IV Ketamine in reducing treatment-resistant major depressive disorder as measured by the Montgomery–Asberg …

Development Of A Muc16-Targeted Near-Infrared Antibody Probe For Fluorescence-Guided Surgery Of Pancreatic Cancer, Madeline T. Olson

Theses & Dissertations

Pancreatic cancer (PDAC) is an extremely lethal disease with an overall survival rate of 10%. Surgery remains the only potentially curative treatment option, but resections are complicated by infiltrative disease, proximity of critical vasculature, peritumoral inflammation, and dense stroma. Surgeons are limited to tactile and visual cues to differentiate cancerous tissue from normal tissue. Furthermore, translating preoperative images to the intraoperative setting poses additional challenges for tumor detection, and can result in undetected and unresected lesions. Thus, PDAC has high rates of incomplete resections, and subsequently, disease recurrence. Fluorescence-guided surgery (FGS) has emerged as a method to improve intraoperative detection …

Delivery Of Sirna With Drugs Targeting Polyamine Metabolism As Combinational Cancer Treatment, Ao Yu

Theses & Dissertations

Cancer has been a major public health issue worldwide for years and is the second leading cause of death in the United States. Important barrier must be broken to extend the life expectancy in every country. The standard care for cancer causes severe side effects which affects patients’ physical health and quality of life. Polyamines are highly related with the cell proliferation and apoptosis. Dysregulated polyamine metabolism in cancer leads to increased polyamine concentration in neoplastic cells. Thus, polyamine metabolism for cancer therapy can be an intriguing target. However, the heterogeneity affecting key cancer pathways poses significant challenges for effective …

Computational Design Of Β-Fluorinated Morphine Derivatives For Ph-Specific Binding, Makena Augenstein, Nayiri Alexander, Matthew Gartner

Student Scholar Symposium Abstracts and Posters

Molecular extension and dissection techniques are used to design a morphine derivative that promotes selective binding in inflamed tissue due to its lower pH while avoiding dangerous activation in the brain. Morphine is used to treat pain associated with inflammation. While being effective analgesics, opioids carry the risk of central side effects, including addiction, respiratory depression, and sedation. Opioids are agonists that bind to the μ-opioid peptide receptor (MOR) within central and peripheral nerves and act via a G-protein coupled receptor pathway.

Deprotonation of the tertiary amine induces a negative charge on the nitrogen, discouraging binding at physiological pH (pH=7.4). …

Characterizing And Overcoming Resistance To Aminomethylspectinomycins In Gram-Negative Bacteria, Nisha Das

Theses and Dissertations (ETD)

Spectinomycin (SPC) is a broad-spectrum aminocyclitol antibiotic. Its use in agriculture has led to widespread resistance in enteric bacteria, necessitating the development of more effective analogs. Aminomethyl spectinomycins (amSPC) are modified spectinomycins with increased potency against many bacterial species. These species include Legionella pneumophila, which harbors a chromosomally encoded aminoglycoside modifying enzyme (AME). In this study, we follow up on this observation and examine the extent to which the amSPCs are substrates for AMEs through adenylation (ANTs) and phosphorylation (APH). APH(9)-Ia and ANT(3")(9) were expressed in E. coli BL21(DE3) and purified using the Ni-affinity chromatography. The ability of AMEs to …

The Concentration Of Brain Homogenates With The Amicon Ultra Centrifugal Filters, Joshua Yang, Rachita K. Sumbria

Pharmacy Faculty Articles and Research

Accurately measuring the brain concentration of a neurotherapeutic is critical in determining its pharmacokinetic profile in vivo. Biologics are potential therapeutics for neurologic diseases and biologics fused to an antibody targeting a transcytosis receptor at the Blood-Brain Barrier, designated as antibody-biologic fusion proteins, are Blood-Brain Barrier penetrating neurotherapeutics. The use of sandwich immunosorbent assays to measure concentrations of antibody-biologic fusion proteins in brain homogenates has become increasingly popular. The raw brain homogenate contains many proteins and other macromolecules that can cause a matrix effect, potentially interfering with the limit of detection of such assays and reduce the overall sample …

Discovery Of Pyrazolopyridine Derivatives Dually Targeting Inflammation And Proliferation In Colorectal Cancer Cell Lines: In-Silico Drug Design Approach, Zahra Kassem, Raghida Bou Merhi, Doaa Issa

BAU Journal - Health and Wellbeing

Elimination of inflammation represents a promising strategy for cancer prevention and treatment since cancer and inflammation are related. The combined use of anti-inflammatory agents and cancer therapy is a focal point. In this frame, pyrazolopyridine derivatives DZ-BAU2021-6 and DZ-BAU2021-14, developed in BAU Labs, having promising anti-proliferative activity on colon cancer cells HCT-116 and HT-29 with notable IC50 values and remarkable CDK2 inhibitory effect, were in-silico tested. As an approach to dual anti-inflammatory anticancer potential, their binding modes and energies on the active site of crystalline structure of CDK2 and COX2, (1HCK and 3LN1), respectively were explored. Their physicochemical and pharmacokinetic …

Listening To Current Practice: Patient Involvement In The Pharmaceutical Packaging Design Process, Giana Carli Lorenzini, Annika Olsson, Andreas Larsson

Journal of Applied Packaging Research

Multiple functional challenges in the use of pharmaceutical packaging reveal a great need of packaging to be designed inclusively. This study investigates patient involvement in the pharmaceutical packaging design process by analysing interview data from representatives of the pharmaceutical and packaging industry. Four main themes related to patient involvement were uncovered: patient expertise levels, patient involvement modes, factors encouraging patient involvement, and factors discouraging patient involvement. Passive patient involvement modes were found to be dominant due to regulations and a traditional perspective regarding physical testing. However, active patient involvement modes were identified, motivated by empathy and understanding of the lives …

Valproic Acid Autoinduction: A Case-Based Review, Sean Bennett, Mujeeb U. Shad

School of Medicine Faculty Research

Although valproic acid (VPA) induces the metabolism of multiple other drugs, the clinical reports of VPA autoinduction are rare. A comprehensive literature search yielded only one published case series, which provided the rationale to conduct a review of the published cases along with a new case of VPA autoinduction. Although there may be myriad of reasons for lack of published cases of VPA autoinduction, potential underreporting may be one of the core reasons. Lack of understanding into the highly complex metabolism of VPA may also make it difficult to recognize and report VPA autoinduction. However, it is important to mention …