Pharmaceutics and Drug Design Commons^™

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 …

Chemical Properties, Biological Activities And Poisoning Treatment Of Novichok: A Review, Tesia Aisyah Rahmania, Bantari Wisynu Kusuma Wardhani, Editha Renesteen, Yahdiana Harahap

Pharmaceutical Sciences and Research

Novichok is an organophosphate compound found as a nerve agent chemical weapon. However, the information about its chemical properties, biological activities, and molecular interactions in the body are still protected under the “top secret” security clearance. Novichok, with the codes A230, A232 and A234, is a compound whose structure has been successfully determined. The compound is synthesized from a precursor through a nucleophilic substitution reaction. Novichok agents are considered more potent than VX gas and can be applied in unitary and binary forms. This compound has ability for the binding with acetylcholinesterase (AChE) due to inability of acetylcholine metabolism. AChE …

Validation Method For Simultaneous Analysis Of Betamethasone Dipropionate And Retinoic Acid In Cream Formulation By Ultra High-Performance Liquid Chromatography, Supandi Supandi, Umar Mansyur, Annisa Ananda Ranie, Linda Mazroatul Ulya

Pharmaceutical Sciences and Research

A simple, precise and rapid reverse phase UHPLC-PDA method has been developed and validated for the simultaneous analysis of betamethasone dipropionate (BTM) and retinoic acid (REA) in whitening cream dosage form. The mixture of betamethasone dipropionate (BTM) and retinoic acid (REA) was separated on Phenomenex Bonclone 10 C18 (150 mm x 3.9 mm) column. All separations were performed with a Dionex 3000 Photodiode Array (PDA) detector on 240 nm and 340 nm wavelength, column temperature at 40oC, and flow rate at 1.0 ml/min. The mobile phase was methanol-acetic acid 0.1% (85:15) with pH 5. The retention times of BTM and …

The Effect Of Ethanol Extract Of Punica Granatum Linn. Leaves On Lipid Profiles Of Dyslipidemic Rat, Neng Fisheri Kurniati, Afrillia Nuryanti Garmana, Lia Nurul Sakinah

Pharmaceutical Sciences and Research

It has been reported that peel of Punica granatum has antidyslipidemic activity. The aim of this research was to investigate the antidyslipidemic activity of Punica granatum leaf. The dried Punica granatum leaves were extracted with 96% ethanol. Rats were divided into several groups, which were normal, positive control, simvastatin at a dose of 10 mg/kg bw as reference group, and Punica granatum extract at a dose of 100 mg/kg. Before treatment, male Wistar rats were fed with high cholesterol chow for 3 months, and then plant extract was given for 4 weeks. Blood samples were collected at week 0, 12, …

Structural And Inhibitory Studies Of Enzymes Essential For Cell Wall And Ergothioniene Biosynthesis In Mycobacterium Tuberculosis, Thanuja D. Sudasinghe

Theses & Dissertations

Tuberculosis (TB) is one of the world’s oldest contagious diseases caused by Mycobacterium tuberculosis (M. tb). With the emergence and spread of drug-resistant M. tb strains, there is an urgent need to discover novel drugs and drug targets specifically against drug-resistant strains and dormant bacteria. This dissertation focuses on M. tbenzymes essential for the M. tb cell wall and ergothioneine biosynthesis. The M. tb cell wall acts as a protective barrier due to the presence of unique lipids and mycolic acids. Among these lipids, trehalose-dimycolate and mycolylarabinogalactan play a major role in constructing and maintaining the outer …

Development Of Once-A-Year Injectable Formulation Of Cabotegravir For Prevention And Treatment Of Hiv Infection, Tanmay Abhay Kulkarni

Theses & Dissertations

Long-acting cabotegravir (CAB) extends antiretroviral drug (ARV) dosing to monthly for maintenance of human immunodeficiency virus type one (HIV-1) suppression and to every other month for prevention of viral transmission. However, injection dose volumes, site reactions, and clinical oversights that are required remain obstacles towards broad usage. To meet these needs, surfactant coated hydrophobic and lipophilic CAB prodrugs were created with controlled prodrug dissolution, hydrolysis and drug tissue penetration. To such ends, fatty acid ester CAB nanocrystal prodrugs with 14, 18, and 22 added carbon chains were synthesized then nanoformulated as NMCAB, NM2CAB, and NM3CAB. These nanocrystal formulations were tested …

Development Of Macromolecular Prodrug Of Sinomenine For The Treatment Of Rheumatoid Arthritis, Roshni Mukundan

Theses & Dissertations

Inflammation is a natural response of the body to infections or any potential threat to the body. But, sometimes the immune system attacks its own body causing persistent inflammation leading to inflammatory diseases. One of the common chronic inflammatory diseases is rheumatoid arthritis (RA) which causes inflammation of the synovial membrane. The current treatments for RA are effective in controlling the symptoms but they come with severe side effects and economic burden. Further, the management of pain is still a problem with these drugs. Sinomenine is a natural alkaloid obtained from the Chinese medicinal plant Sinomenium acutum that has been …

Small Molecule Inhibitors Of Inflammatory Caspases-1, -4, And -5, Christopher D. Ahlers

DePaul Discoveries

Inflammatory caspases-1, -4, and -5 play critical roles in mediating the innate immune response to pathogen- and damage-associated molecular patterns. Caspase-1 produces the cytokine interleukin-1β (IL-1β), while caspases-4 and -5 activate the NOD-like receptor protein 3 inflammasome via the non-canonical pathway. Overactivation of these enzymes is associated with an increased risk for inflammatory diseases such as lupus, psoriasis, and rheumatoid arthritis. Small molecule inhibitors (SMIs) have been developed to attenuate the production of IL-1β, but unfavorable bioavailability and toxicity have provided an insurmountable barrier in clinical trials. This work is concerned with delivering an overview of current progress in the …

Development Of A Combined Feedforward-Feedback Quality Control System For Extended-Release Granules Using A Quality By Design Approach, Yuxiang Zhao

Electronic Theses and Dissertations

Objectives

For a fluid bed film coating process to consistently deliver quality products, its control system needs to be robust against the variability of input materials and environmental disturbances. Presently, limited studies have been reported to understand the effects and interactions of the material attributes, environmental variables, and process parameters on the product in vitro drug dissolution. A control system can be developed with a proper understanding of the coating process, by adjusting the process parameters in feedback and feedforward manners to compensate for the undesired effect caused by disturbances, and ensure consistent product quality.

Methods

The control system was …

Uplc-Ms/Ms Analysis Of The Michaelis-Menten Kinetics Of Cyp3a-Mediated Midazolam 1′- And 4-Hydroxylation In Rat Brain Microsomes, Devaraj Venkatapura Chandrashekar, Barent Dubois, Reza Mehvar

Pharmacy Faculty Articles and Research

Midazolam (MDZ) is a short-acting benzodiazepine with rapid onset of action, which is metabolized by CYP3A isoenzymes to two hydroxylated metabolites, 1′-hydroxymidazolam and 4-hydroxymidazolam. The drug is also commonly used as a marker of CYP3A activity in the liver microsomes. However, the kinetics of CYP3A-mediated hydroxylation of MDZ in the brain, which contains much lower CYP content than the liver, have not been reported. In this study, UPLC-MS/MS and metabolic incubation methods were developed and validated for simultaneous measurement of low concentrations of both hydroxylated metabolites of MDZ in brain microsomes. Different concentrations of MDZ (1–500 µM) were incubated with …

Design, Synthesis, And Evaluation Of A Novel Cytotoxic Peptide-Doxorubicin Conjugate Targeting Triple-Negative Breast Cancer, Elmira Ziaei

Pharmaceutical Sciences (PhD) Dissertations

The aim of this thesis was to design, synthesize, and characterize a novel peptide-doxorubicin conjugate, evaluate in vitro stability and cytotoxicity properties of the conjugate and study its mechanism for uptake into the triple-negative breast cancer (TNBC) cells. For the synthesis of the conjugate, first, doxorubicin (Dox) was conjugated to a highly efficient established cross-linker, MCC, to give an intermediate product, MCC-Dox. MCC-Dox was characterized using NMR spectroscopy, mass spectrometry, and RP-HPLC and purified for subsequent reaction. Second, the 11-mer peptide 18-4 (NH₂-CWxEAAYQrFL-CONH₂) with high proteolytic stability and specificity for breast cancer cells was reacted with …

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 …

Histone Deacetylases In Alcohol Associated Liver Disease., Srineil Bodduluri

Electronic Theses and Dissertations

Alcohol abuse is endemic worldwide and there is no FDA approved treatment for Alcohol-Associated Liver Disease (ALD). Many scholars have posited that targeting Histone Deacetylases (HDAC) may be therapeutic in ALD intervention. In this study, the changes in hepatic gene expression and immune phenotyping of mice undergoing chronic plus binge alcohol exposure was examined. The characterization of relative mRNA levels for all 18 HDAC were performed. Results showed decreased expression of the genes HDAC 1,7,9,10,11 and Sirtuin enzymes (SIRT) 3,4,5,7. Other pathways related to lipid metabolism as well as systemic inflammation and hepatic injury also exhibited significant changes. These altered …

Government As The First Investor In Biopharmaceutical Innovation: Evidence From New Drug Approvals 2010–2019, Ekaterina Galkina Cleary, Matthew J. Jackson, Fred D. Ledley

Natural & Applied Sciences Faculty Publications

The discovery and development of new medicines classically involves a linear process of basic biomedical research to uncover potential targets for drug action, followed by applied, or translational, research to identify candidate products and establish their effectiveness and safety.

This Working Paper describes the public sector contribution to that process by tracing funding from the National Institutes of Health (NIH) related to published research on each of the 356 new drugs approved by the U.S. Food and Drug Administration from 2010-2019 as well as research on their 218 biological targets.

Development Of Vaccines And Antivirals Against Zika Virus, Aryamav Pattnaik

School of Veterinary and Biomedical Sciences: Dissertations, Theses, and Student Research

The re-emergence of Zika virus (ZIKV), an arbovirus, poses a major global human health concern because of its ability to cause congenital abnormalities and neurological diseases. While many candidate vaccines and antiviral drugs are in the developmental pipeline, none have been approved for use against ZIKV infection. This dissertation describes the characterization of one vaccine and two antiviral drug candidates against ZIKV infection. A bacterial ferritin-based nanoparticle vaccine, termed zDIII-F, is designed to display multiple copies of ZIKV E protein domain III on its surface. These stable nanoparticles are shown to induce robust antibody-mediated protection against lethal ZIKV infection in …