Pharmaceutics and Drug Design Commons^™

Selective And Brain-Penetrant Acss2 Inhibitors Target Breast Cancer Brain Metastatic Cells, Emily Esquea, Lorela Ciraku, Riley Young, Jessica Merzy, Alexandra Talarico, Nusaiba Ahmed, Mangalam Karuppiah, Anna Ramesh, Adam Chatoff, Claudia Crispim, Adel Rashad, Simon Cocklin, Nathaniel Snyder, Joris Beld, Nicole Simone, Mauricio Reginato, Alexej Dick

Kimmel Cancer Center Faculty Papers

Breast cancer brain metastasis (BCBM) typically results in an end-stage diagnosis and is hindered by a lack of brain-penetrant drugs. Tumors in the brain rely on the conversion of acetate to acetyl-CoA by the enzyme acetyl-CoA synthetase 2 (ACSS2), a key regulator of fatty acid synthesis and protein acetylation. Here, we used a computational pipeline to identify novel brain-penetrant ACSS2 inhibitors combining pharmacophore-based shape screen methodology with absorption, distribution, metabolism, and excretion (ADME) property predictions. We identified compounds AD-5584 and AD-8007 that were validated for specific binding affinity to ACSS2. Treatment of BCBM cells with AD-5584 and AD-8007 leads to …

Zinc-Containing Over-The-Counter Product Causing Sideroblastic Anemia And Neutropenia, Marshall Patrick Stagg, Jennifer Miatech, Baseera Majid, Ravali Polala

School of Medicine Faculty Publications

Sideroblastic anemia is characterized by anemia, granulocytopenia, and bone marrow findings of vacuolated precursors and ringed sideroblasts. Zinc-induced copper deficiency can present as sideroblastic anemia and neutropenia. We report the case of a previously healthy 74-year-old female who presented with newly discovered sideroblastic anemia as a result of an over-the-counter oral vitamin and mineral supplement. Serum analysis revealed increased zinc levels, decreased copper levels, and a decrease in ceruloplasmin. Bone marrow evaluation revealed ringed sideroblasts and cytoplasmic vacuolization in myeloid precursors. She demonstrated improvement in her hematologic profile with discontinuation of the over-the-counter product and administration of oral copper supplementation. …

Translational Pathways For Ultra Long-Acting Medicines For Chronic Disease: From Hiv To Substance Use Disorders, Suyash Sanjay Deodhar

Theses & Dissertations

Human immunodeficiency virus (HIV) and opioid use disorder (OUD) are among the top global public health challenges, with a significant overlap in the number of cases and higher mortality risks compared to the general population. Treatment and recreational opioid use lead to addictive disorders. Both conditions require repeated dosing of therapy where adherence to a strict lifelong regimen remains a major challenge. Notably, people living with HIV/AIDS (PLWHA) and struggling with opioid use disorders (OUD) show suboptimal adherence to antiretroviral drugs (ARVs). Also, the risk of transmitting HIV and other blood-borne infections through the sharing of needles and other injection …

Pharmacodynamic Effects Of Zsj-0228 On Complement Protein Deposition In The Kidneys Of Focal Segmental Glomerulosclerosis-Afflicted Mice., Braeden Pinkerton

Theses & Dissertations

Chronic inflammation, when left untreated, may result in significant morbidity and in severe cases, mortality. While glucocorticoids (GCs) are still being extensively used clinically as a class of very potent anti-inflammatory agents, they are also notorious for diverse adverse side effects. To mitigate these side effects, we have developed a polyethylene glycol (PEG)-based prodrug (ZSJ-0228) of dexamethasone (Dex). When tested on rodent models of Lupus Nephritis and Focal Segmental Glomerulosclerosis (FSGS), ZSJ-0228 was found to provide potent and sustained therapeutic efficacy without any detectable typical GC-associated side effects. Given ZSJ-0228’s transient renal exposure after systemic administration, it is yet to …

Assessment Of In-Vitro And In-Vivo Pre-Clinical Pharmacokinetics Of Epz015666; A Novel Small Molecule For Medulloblastoma Treatment, Pratiksha U. Kshirsagar

Theses & Dissertations

Group 3 medulloblastoma (MB) has the worst prognosis of the MB subgroups associated with elevated MYC expression and a 5-year survival rate of

Quantitation of EPZ was performed on a Shimadzu LC-MS/MS system utilizing electrospray ionization operated in positive mode. The validated assay was linear from 0.2 to 500 ng/mL. Metabolic stability studies demonstrated slow intrinsic clearance of EPZ in mouse and human liver microsomes, suggesting no CYP-mediated metabolism. Additionally, EPZ exhibited low binding affinity to plasma and brain proteins and high apparent permeability across artificial membranes, indicating efficient membrane penetration. Drug transporter studies identified EPZ as a substrate of …

Development Of Long-Acting Antiviral And Antimicrobial Prodrug Nanoformulations, Srijanee Das

Theses & Dissertations

Over the past decade, the global burden of infectious diseases has increased substantively, underscoring the need for more effective treatment strategies. However, the discovery and development of new drugs with desirable safety, pharmacokinetics, and efficacy is a time consuming and costly process with great uncertainty around success rate. As an alternative to new drug development, prodrugs and novel drug delivery systems have increasingly been explored. Both serve to overcome the drug development challenges. Such drug formulations that permit extended dosing intervals of potent native drugs serve multiple purposes by promoting patient adherence to in improving treatment outcomes. This is especially …

Investigation Of Avaren-Fc's Therapeutic Potential Against Ovarian Cancer., Katarina Lee Mayer

Electronic Theses and Dissertations

This thesis describes the investigation of Avaren-Fc (AvFc), a novel lectin-based therapeutic fusion protein consisting of the recombinant Avaren lectin and the Fc region of human IgG1, against ovarian cancer. AvFc possesses selectivity toward tumor associated N-linked high-mannose-type glycans. The present study demonstrates AvFc’s in vitro activity against OVCA cell lines via antibody-dependent cell-mediated cytotoxicity and its ability to extend the survival of mice challenged with murine ID8 OVCA cells after repeated systemic administration. Furthermore, AvFc treatment in this model was found to increase the presence of peritoneal leukocytes, suggesting a shift toward an improved antitumor immune response. Another key …

Electrochemical Modulation Of Surface Plasmon Wave To Investigate Dna-Based Sensing Platforms And Detection Of Sars-Cov2., Anil Sharma

Electronic Theses and Dissertations

This study offers a thorough comparative analysis of optical and electrical signaling strategies for assessing the electrochemical properties of different redox-labeled DNA-based biosensing platforms. In addition, it illustrates the development of an optical interrogation technique with electrochemical modulation of surface plasmon waves (ECM-SPW) as a route for analyzing and implementing DNA-based hybridization sensors. For those quantitative analyses, we chose a model sensing platform composed of a methylene blue (MB)-modified single-stranded DNA (ssDNA) signaling probe and an unlabeled capture ssDNA probe that complements the signaling probe. Two types of signaling probes were employed in this work: one with MB attached to …

Preclinical Stability Assessment Of Epicertin, A Biotherapeutic Candidate For Ulcerative Colitis Mucosal Healing., Wendy Michelle Kittle

Electronic Theses and Dissertations

EPICERTIN is a biotherapeutic candidate for mucosal healing in ulcerative colitis (UC), a major type of inflammatory bowel disease (IBD). Despite the critical role of mucosal healing in achieving successful remission of UC, there are currently no targeted mucosal healing agents available. EPICERTIN has previously demonstrated epithelial repair and mucosal healing activity in colon epithelial cells, murine colitis models, and tissue explants from IBD patients, highlighting its therapeutic potential to meet this unmet need for UC patients. The development of appropriate chemistry, manufacturing, and controls (CMC) data will facilitate our ultimate goal to bring EPICERTIN to the clinic for a …

Antioxidant Activities And Protective Effects Of Shorea Macrophylla Leaf And Bark Extracts, Salfarina Ramli, Nik Nor Sabrina Sukri, Nur Adhwa’ Faqihah Zulkifli, Donna Maretta Ariestanti, Chee Yan Choo, Hasseri Halim, Nurhuda Manshoor, Richard Johari James

Pharmaceutical Sciences and Research

Shorea macrophylla, also known as the ‘Engkabang’ tree or Light Red Meranti, is renowned for its role in reforestation efforts. Despite lacking records of traditional use, the reported biological activities of other species within the Shorea genus spark curiosity about the potential biological activities of this plant. Therefore, this study aims to explore the antioxidant capabilities of S. macrophylla leaf and bark extracts, along with their protective effects against oxidative stress using a brine shrimp model. In the evaluation of antioxidant potential, 2,2-diphenyl-1-picrylhydrazyl (DPPH) and ferric reducing antioxidant power (FRAP) assays were employed. Extracts were incubated in …

Mechanistic Study Of Antimicrobial Cyclic Peptide [R4w4] Antibacterial Effectiveness Against Methicillin-Resistant Staphylococcus Aureus (Mrsa), Ajayi Akinwale

Pharmaceutical Sciences (PhD) Dissertations

Antimicrobial peptides (AMPs) are being explored as a potential solution to combat antibiotic resistance, as they have shown promise in reducing susceptibility to antibiotics. This study explores if [R₄W₄] peptide is bacteriostatic or bactericidal using modified two-fold serial dilution and evaluates synergism of gentamicin and [R₄W₄] against Escherichia coli (E. coli) and Methicillin-resistant Staphylococcus aureus (MRSA) by checkered board assay. The MRSA resistant to [R₄W₄] and possibility with other antibiotics was evaluated with serial passage. Moreover, we investigated the mechanism of action of [R₄W_{4 …}

The Light Scattering Properties Of Amorphous Nanoparticles Formed By Poorly Soluble Drugs, Sarah Casella

Honors Scholar Theses

The research of amorphous drug formulations is an emerging field of study, which offers a promising strategy to improve the oral bioavailability of poorly water-soluble drugs. A critical aspect of amorphous solubility is the measurement of particle size and light diffraction, which is measured using dynamic light scattering (DLS). DLS is a technique used to characterize the size of colloidal dispersions, where a laser beam illuminates a suspension of particles or molecules undergoing Brownian motion. In this experiment, a procedure was developed utilizing DLS to investigate the similarities and differences in light diffraction properties of particles among three different poorly …

Synthesis Of Thermoresponsive Poly(N-Isopropyl Acrylamide) Based Core-Shell And Hollow Shell Nanogel With Tunable Core And Shell Thickness, Mohamad Hijazi, Molla R. Islam

Student Scholar Symposium Abstracts and Posters

Nanogels have emerged as a notably safer and more effective means for drug delivery, primarily due to their adjustable drug-loading capabilities. Hollow-core nanoparticles offer some unique properties that are desirable for drug delivery applications. Initially, silica core nanoparticles were synthesized using the Stöber process at different temperatures where Tetraethoxysilane (TEOS) undergoes hydrolysis in the presence of ethanol and then a condensation reaction to form silica nanoparticles. Scanning Electron Microscopy (SEM) and Optical Microscopy (OM) analysis revealed that the size of silica core particles varied with the synthesis temperature (300 nm at 30°C to 150 at 60°C). The core silica particles …

Transdermal Delivery Of Ketoprofen For Osteoarthritis Treatment And Management: A Literature Review On Current Progression, Dwi Asih Ramadhani, Yahdiana Harahap, Erny Sagita, Kartika Citra Dewi Permata Sari, Rr. Kirana Andranilla, Jessica Trisina, Gabriella Frederika Punu, Delly Ramadon

Pharmaceutical Sciences and Research

Arthritis, a diverse spectrum of joint disorders, is characterized by chronic pain and inflammation. Osteoarthritis (OA), the most prevalent form, leads to disabling pain, functional limitations, and reduced mobility. Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used for managing OA pain, with ketoprofen recognized as one of the effective options. However, oral administration of ketoprofen may cause gastrointestinal irritation. Addressing this issue, Transdermal Drug Delivery Systems (TDDS) emerge as a promising alternative route of administration. TDDS facilitates delivery of various drugs through the skin without undergoing first-pass metabolism. Recent studies have centered on enhancing ketoprofen’s transdermal delivery, particularly focusing on different …

Antioxidant, Tyrosinase Inhibition Activity, And In Vitro Spf Evaluation Of Pepino Fruit Extract (Solanum Muricatum Aiton) In Different Solvent Types And Concentrations, Nining Sugihartini, Girly Risma Firsty, Wahyu Kumil Laila, Sri Mulyaningsih, Ichwan Ridwan Rais

Pharmaceutical Sciences and Research

Solvent is a key factor that affects the effectiveness of active compound extraction from plant materials (simplisia). This study aimed to determine the optimal type and concentration of solvent used in the extraction of pepino fruit based on the parameter of antioxidant and tyrosinase inhibition activity, as well as Sun Protection Factor (SPF) value. The extraction was carried out using the maceration method with ethanol or ethyl acetate as the solvent, each at concentrations of 50%, 70%, and 96%, respectively. The antioxidant activity of the extracts was evaluated using the 1,1-diphenyl-2-picrylhydrazyl (DPPH) method. The inhibition of tyrosinase and …

Current Update Of Clinical Therapeutic Strategies For Colon-Targeted Delivery Systems, Risa Widiani Batubara, Fadlina Chany Saputri, Raditya Iswandana

Pharmaceutical Sciences and Research

Oral colon-targeted drug delivery systems represent a significant advancement offering both systemic and local therapeutic effects for a range of intestinal diseases, including irritable bowel syndrome, inflammatory bowel disease, colonic bacterial infections, and colorectal cancer. These systems facilitate the delivery of both small molecules and macromolecular compounds such as peptides, proteins, antibodies, oligonucleotides, RNA, and probiotics. This review provides an up-to-date exploration of the critical factors crucial for the effective design and development of drug delivery systems targeting the colon. The chosen strategy takes into account various aspects of colon physiology that influences the profile of drug release, absorption, dissolution, …

Broad-Spectrum Activity Of Membranolytic Cationic Macrocyclic Peptides Against Multi-Drug Resistant Bacteria And Fungi, Sandeep Lohan, Anastasia G. Konshina, Rakesh K. Tiwari, Roman G. Efremov, Innokentiy Maslennikov, Keykavous Parang

Pharmacy Faculty Articles and Research

The emergence of multidrug-resistant (MDR) strains causes severe problems in the treatment of microbial infections owing to limited treatment options. Antimicrobial peptides (AMPs) are drawing considerable attention as promising antibiotic alternative candidates to combat MDR bacterial and fungal infections. Herein, we present a series of small amphiphilic membrane-active cyclic peptides composed, in part, of various nongenetically encoded hydrophilic and hydrophobic amino acids. Notably, lead cyclic peptides 3b and 4b showed broad-spectrum activity against drug-resistant Gram-positive (MIC = 1.5–6.2 µg/mL) and Gram-negative (MIC = 12.5–25 µg/mL) bacteria, and fungi (MIC = 3.1–12.5 µg/mL). Furthermore, lead peptides displayed substantial antibiofilm action comparable …

Aspects Of Pharmaceutical Networks, Hannah Rita Joseph, Afia L. Rahaman, Kaya Wilson

ENGL 1102 Showcase

The theme of our anthology is different drugs and processes of drug usage in the result how the various aspects of the pharmaceutical companies. We analyze the quality of health that Americans receive from certain parts of the health care industry. We have focused on informing and analyzing the increase of insulin prices, and how that affects Americans everyday lives. The delivery methods of medical cannabis, how each method is effective, and how they are administered. As well as pharmaceutical scams and how it affects elderly people, who rely on medication.

Identification And Characterization Of Novel, Small Molecule Inhibitors Of Spermine Oxidase, Amelia Bryn Furbish

MUSC Theses and Dissertations

The major intracellular polyamines spermine and spermidine are abundant endogenous compounds that are essential for cellular growth and development. Dysregulation of polyamine metabolism has been implicated as a key mechanism of injury across multiple forms of clinically challenging pathologies. Of the enzymes within the polyamine pathway, the catabolic enzyme spermine oxidase (SMOX) is of particular interest as it is subject to induction in response to infection, neuronal excitotoxicity, ischemia, and oxidative stress. In addition to the loss of radical scavenging capabilities associated with spermine depletion, catabolism of spermine by SMOX results in the production of toxic byproducts, including H_{2 …}

Impact Of Blender Type On Tribocharging In Pharmaceutical Powders Using Surface Modified V-Blender, Ami Shah

Honors Scholar Theses

Powders are a vital component of the pharmaceutical industry as they provide the basis for many solid dosage forms like tablets and capsules. Although, when using powders a common challenge is electrostatic charge accumulation due to numerous particle-particle and particle-wall collisions. This accumulated charge can lead then to poor powder homogeneity and compromised powder flow properties. In this study, tribocharging of pharmaceutical powders was analyzed using various V-blenders and mixing times . The evaluated blenders include: Aluminum, Polyvinyl Chloride (PVC), and surface modified Aluminum-PVC. Using the blenders, the model drug, Ibuprofen, was processed for different time intervals such as 5, …