Pharmaceutics and Drug Design Commons^™

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 …

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 …

Differential Effect Of Proinflammatory Cytokines On Corneal And Conjunctival Epithelial Cell Mucins And Glycocalyx, Kiumars Shamloo, Priya Mistry, Ashley Barbarino, Christopher Ross, Vishal Jhanji

Pharmacy Faculty Articles and Research

Purpose: Ocular surface mucins and glycocalyx are critical for providing ocular hydration as well lubrication and repelling pathogens or allergens. Elevated levels of tear proinflammatory cytokines in dry eye may have detrimental effect on mucins and glycocalyx. The present study tested the effect of proinflammatory cytokines IL-6, TNF-α, and IFN-γ on membrane-tethered mucins expression, glycocalyx, and viability of ocular surface epithelial cells.

Methods: Stratified cultures of human corneal and conjunctival epithelial cells were exposed to different concentrations of IL-6, TNF-α, and IFN-γ for 24 hours. The mucins gene and protein expressions were quantified by real-time polymerase chain reaction …

Engineering And Characterization Of Human Β-Defensin-3 And Its Analogues And Microcin J25 Peptides Against Mannheimia Haemolytica And Bovine Neutrophils, Harpreet Dhingra, Kamaljit Kaur, Baljit Singh

Pharmacy Faculty Articles and Research

Mannheimia haemolytica-induced bovine respiratory disease causes loss of millions of dollars to Canadian cattle industry. Current antimicrobials are proving to be ineffective and leave residues in meat. Antimicrobial peptides (AMPs) may be effective against M. haemolytica while minimizing the risk of drug residues. Cationic AMPs can kill bacteria through interactions with the anionic bacterial membrane. Human β-Defensin 3 (HBD3) and microcin J25 (MccJ25) are AMPs with potent activity against many Gram-negative bacteria. We tested the microbicidal activity of wild-type HBD3, three HBD3 peptide analogues (28 amino acid, 20AA, and 10AA) derived from the sequence of natural HBD3, and MccJ25 …

Modification And Antichlamydial Activity Evaluation On Dysregulators Of Cylindrical Proteases, Jiachen Feng

Theses & Dissertations

Chlamydia trachomatis infection is the most commonly reported sexually transmitted disease in the United States and the world. This pathogen can cause long-term health problems including blindness, pelvic inflammatory disease (PID) and ectopic pregnancy, which can be life-threatening if left untreated. To this day, there is no chlamydia-specific drug on the market. The standard treatment uses broad-spectrum antibiotics, which may affect regular functions of the commensal microbiota and leads to the development of bacterial resistance. Recently, a series of compounds based on Activators of Self-Compartmentalizing Proteases (ACP) was reported to show antichlamydial activity. Based on that scaffold, we prepared 21 …

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

Student Scholar Symposium Abstracts and Posters

Opioids such as morphine are important pain-relieving drugs but also carry a risk of harmful side effects including addiction. Morphine is active in both healthy and inflamed tissue, however, decreasing the pKa of the biochemically-active amine group can promote selective binding in the more acidic conditions of inflamed tissue and reduce harmful side effects associated with opioids. Herein, we explore the impact of fluorination on the pKa of fluoromorphine derivatives to identify which will bind selectively in inflamed tissue. Theoretical pKa values are determined at the M06-2X(SMD)/aug-cc-pVDZ level of theory to calculate the ΔGaq" …

Suppression Of Human Coronavirus 229e Infection In Lung Fibroblast Cells Via Rna Interference, Hamidreza Montazeri Aliabadi, Jennifer Totonchy, Parvin Mahdipoor, Keykavous Parang, Hasan Uludağ

Pharmacy Faculty Articles and Research

Despite extensive efforts to repurpose approved drugs, discover new small molecules, and develop vaccines, COVID-19 pandemic is still claiming victims around the world. The current arsenal of antiviral compounds did not perform well in the past viral infections (e.g., SARS), which casts a shadow of doubt for use against the new SARS-CoV-2. Vaccines should offer the ultimate protection; however, there is limited information about the longevity of the generated immunity and the protection against possible mutations. This study uses Human Coronavirus 229E as a model coronavirus to test the hypothesis that effective delivery of virus-specific siRNAs to infected cells will …

Label‑Free Spectral Imaging To Study Drug Distribution And Metabolism In Single Living Cells, Qamar Alshammari, Rajasekharreddy Pala, Nir Katzir, Surya M. Nauli

Pharmacy Faculty Articles and Research

During drug development, evaluation of drug and its metabolite is an essential process to understand drug activity, stability, toxicity and distribution. Liquid chromatography (LC) coupled with mass spectrometry (MS) has become the standard analytical tool for screening and identifying drug metabolites. Unlike LC/MS approach requiring liquifying the biological samples, we showed that spectral imaging (or spectral microscopy) could provide high-resolution images of doxorubicin (dox) and its metabolite doxorubicinol (dox’ol) in single living cells. Using this new method, we performed measurements without destroying the biological samples. We calculated the rate constant of dox translocating from extracellular moiety into the cell and …

[(Wr)8Wkβa]-Doxorubicin Conjugate: A Delivery System To Overcome Multi-Drug Resistance Against Doxorubicin, Khalid Zoghebi, Hamidreza Montazeri Aliabadi, Rakesh Kumar Tiwari, Keykavous Parang

Pharmacy Faculty Articles and Research

Doxorubicin (Dox) is an anthracycline chemotherapeutic agent used to treat breast, leukemia, and lymphoma malignancies. However, cardiotoxicity and inherent acquired resistance are major drawbacks, limiting its clinical application. We have previously shown that cyclic peptide [WR]₉ containing alternate tryptophan (W) and arginine (R) residues acts as an efficient molecular transporter. An amphiphilic cyclic peptide containing a lysine (K) residue and alternative W and R was conjugated through a free side chain amino group with Dox via a glutarate linker to afford [(WR)₈WKβA]-Dox conjugate. Antiproliferative assays were performed in different cancer cell lines using the conjugate and the …

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 …

Investigations On Novel Cyp26a1/B1 Inhibitor, Dx308: Using Atra Response As A Theraputic Target For Traumatic Brain Injury And Parkinson’S Disease, Jacob Morgan Leatherwood

Graduate Student Theses, Dissertations, & Professional Papers

Neurodegenerative diseases (NDs) take a wide spectrum of pathologies and have a tendency to present themselves later in life. Neurodegenerative diseases affect 6 million Americans annually with ~1 million currently living with Parkinson’s disease (PD). One of the greatest contributors to the pathogenesis of neurodegenerative diseases is the occurrence of a traumatic brain injury (TBI) during life.

All-trans-retinoic acid (atRA) is the active metabolite of Vitamin A. The retinoic acid pathway is known to be activated following TBI and is reduced in PD patients. Previous studies found a decrease in inflammation and behavioral deficits following administration of Vitamin …

Standardization Of E-Cigarette Research: Addressing The Analysis Of Total Nicotine And Free Base Nicotine In E-Cigarettes, Vinit Gholap

Theses and Dissertations

Electronic cigarettes (e-cigarettes) are one of the major sources of exposure to nicotine, an addictive chemical. Since 2016, the Food and Drug Administration (FDA) has started regulating these products under the Tobacco Control Act yet, specifications about the nicotine content in these products have not been established. In e-cigarettes, nicotine concentration ranges from 0 to >50mg/mL. Additionally, several e-cigarette related parameters have been identified which can affect nicotine delivery to users. Of these factors, nicotine forms (protonated and free base) have been found to play a significant role in nicotine absorption profiles yet, a limited and contradictory research is available …

Evaluation Of Antipsychotic Activity Of Ethanolic Bark Extract Of Myrica Esculenta In Rats, Biswash Sapkota, Ankit Acharya, Bishal Dangi, Annegowda Hv

Pharmaceutical Sciences and Research

The antipsychotic properties of Myrica esculenta stem bark were evaluated. The stem bark was collected, shade dried, and pulverized. Extraction was carried out with 70% ethanol by occasional shaking. Preliminary phytochemical screening of the extract was investigated in this study. Antipsychotic activity was evaluated against apomorphine-induced stereotypy using cook’s pole climbing apparatus and haloperidol-induced catalepsy models. Bioamine determination of noradrenaline and dopamine was also performed. The extract contains phytochemicals, including glycosides, flavonoids, volatile oils, proteins, saponins, phenolics, and tannins. The result showed decreased apomorphine-induced stereotyped behavior. This study reported significant dose-dependent potentiation of haloperidol-induced catalepsy in rats and a longer …

Pharmacological Characterization Of Novel Serotonin Transporter Inhibitors Identified Through Computational Structure-Based Virtual Screening, Michael Wasko

Electronic Theses and Dissertations

Depression is a mental health disorder affecting greater than 350 million people worldwide with roughly 7% of the United States population diagnosed as of 2017. The selective serotonin reuptake inhibitors (SSRIs) have been the mainstay of pharmacotherapies for depression for the last 40 years. The SSRIs target the serotonin transporter (SERT), a monoamine transporter (MAT) responsible for terminating serotonergic neurotransmission. The SSRIs are not perfect therapeutics and suffer from delayed response times, inconsistent efficacy among patients, and often produce intolerable side effects. Therefore, a strong need exists to develop new antidepressants that are more efficacious and have fewer adverse effects. …

Long-Acting Nanoformulated Antivirals For The Treatment And Prevention Of Hiv-1 And Hbv Infections, Dhruvkumar M. Soni Dr.

Theses & Dissertations

While antiretroviral therapy (ART) has revolutionized treatment and prevention of human immunodeficiency virus type one (HIV-1) infection, regimen adherence, viral mutations, drug toxicities, stigma and pill fatigue are limitations. These have led to the development of long acting (LA) ART. These include, but are not limited to, implantable devices, new chemical entities, prodrug modifications and nanoformulations. To these ends, this thesis focues on the transformation of nucleoside reverse transcriptase inhibitors (NRTIs) into LA parenterals, While elusive, data from our laboratories demonstrated that modifications to the PROdrug and nucleoTide technology (ProTide) enables improvements in drug apparent half-life and tissue and cell …

Great Expectations: Phosph(On)Ate Prodrugs In Drug Design—Opportunities And Limitations, Victoria Yan

Dissertations and Theses (Open Access)

Phosphate and phosphonates are chemical moieties with historical precedence in anticancer and antiviral nucleotide analogues. Synchronous to modern efforts identifying novel therapeutic targets in cancer, such chemical moieties are being investigated in the design of novel inhibitors with antineoplastic potential. A central challenge to the delivery of phosph(on)ate-containing drugs is their anionic character at physiological pH, which portends poor membrane permeability. This limitation has been successfully overcome through the use of prodrugs. When attached to the phosph(on)ate moiety, prodrugs mask the negative charge and easily enable cell permeability. Upon cellular entry, the promoieties are enzymatically or environmentally cleaved to unveil …

Celecoxib Loaded In-Situ Provesicular Powder And Its In-Vitro Cytotoxic Effect For Cancer Therapy: Fabrication, Characterization, Optimization And Pharmacokinetic Evaluation, Shady Swidan, Ali Nasr, Sameh Elhady, Noha Badawi

Pharmacy

Introduction: Several recent studies have shown that the role of cyclooxygenase 2 (COX-2) in carcinogenesis has become more evident. It affects angiogenesis, apoptosis, and invasion, and plays a key role in the production of carcinogens. It has also been reported that COX-2 inhibitors such as celecoxib (CLX) might play an effective role in preventing cancer formation and progression. Formulation of CLX into nanovesicles is a promising technique to improve its bioavailability and anticancer efficacy. Aim: The aim of this study is to optimize and evaluate the anticancer efficacy of CLX-loaded in-situ provesicular powder composed of surfactants and fatty alcohol-based novel …

Veru-111 As An Oral Tubulin Inhibitor Suppressing Triple-Negative Breast Cancer And Evaluation Of Novel Tubulin Inhibitors For Cancer Therapy, Shanshan Deng

Theses and Dissertations (ETD)

Triple negative breast cancer (TNBC) has aggressive clinical features strongly associated with poorer overall prognosis and higher mortality rates relative to other molecular subtypes. FDA-approved drugs, such as paclitaxel, are effective in treating TNBC. Yet, treatment failure is commonly observed due to the development of acquired chemoresistance, which remains a clinical challenge for TNBC therapy.

Model-Based Dose-Exposure-Response Assessment For Lead And Backup Spectinamide In A Mouse Model Of Tuberculosis, Santosh Janardan Wagh

Theses and Dissertations (ETD)

Despite decades of research, tuberculosis remains the oldest pathogen-based disease that is the leading cause of death from a single infectious agent. Among many anti-tubercular therapies under investigation, the semisynthetic compounds spectinamides are a promising novel class of anti-tuberculosis agents. One such lead candidate, spectinamide 1810, and backup spectinamide 1599 have demonstrated excellent efficacy, safety, and drug-like properties in various in vitro and in vivo assessments. The dose-ranging and dose fractionation studies were designed to characterize the dose-exposure-response relationship for lead and backup spectinamide in a mouse model of Mycobacterium tuberculosis infection. In this current study, we used 26 and …

Click-Free Synthesis Of A Multivalent Tricyclic Peptide As A Molecular Transporter, Sumit Kumar, Dindyal Mandal, Shaima Ahmed El-Mowafi, Saghar Mozaffari, Rakesh Kumar Tiwari, Keykavous Parang

Pharmacy Faculty Articles and Research

The cellular delivery of cell-impermeable and water-insoluble molecules remains an ongoing challenge to overcome. Previously, we reported amphipathic cyclic peptides c[WR]₄ and c[WR]₅ consisting of alternate arginine and tryptophan residues as nuclear-targeting molecular transporters. These peptides contain an optimal balance of positive charge and hydrophobicity, which is required for interactions with the phospholipid bilayer to facilitate their application as a drug delivery system. To further optimize them, we synthesized and evaluated a multivalent tricyclic peptide as an efficient molecular transporter. The monomeric cyclic peptide building blocks were synthesized using Fmoc/tBu solid-phase chemistry and cyclization in the …

Dermaseptin-Based Antiviral Peptides To Prevent Covid-19 Through In Silico Molecular Docking Studies Against Sars-Cov-2 Spike Protein, Taufik Muhammad Fakih

Pharmaceutical Sciences and Research

A pandemic coronavirus disease of 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has now been declared a global pandemic by the World Health Organization. The search for new drugs, especially by utilizing antiviral peptides is a very potential area. Through this study, protein-peptide docking and protein-protein docking simulations were conducted using in silico methods to identify, evaluate, and explore the molecular affinity and interaction of dermaseptin peptide molecules produced by frogs of the genus Phyllomedusa against the SARS-CoV-2 spike protein macromolecule, and its effect on attachment to the surface of the ACE-2 (Angiotensin Converting Enzyme-2) receptor. …

Prospects For Rnai Therapy Of Covid-19, Hasan Uludağ, Kylie Parent, Hamidreza Montazeri Aliabadi, Azita Haddadi

Pharmacy Faculty Articles and Research

COVID-19 caused by the SARS-CoV-2 virus is a fast emerging disease with deadly consequences. The pulmonary system and lungs in particular are most prone to damage caused by the SARS-CoV-2 infection, which leaves a destructive footprint in the lung tissue, making it incapable of conducting its respiratory functions and resulting in severe acute respiratory disease and loss of life. There were no drug treatments or vaccines approved for SARS-CoV-2 at the onset of pandemic, necessitating an urgent need to develop effective therapeutics. To this end, the innate RNA interference (RNAi) mechanism can be employed to develop front line therapies against …

Nih Funding For Research Underlying New Cancer Therapies, Ekaterina Galkina Cleary, Fred D. Ledley

Natural & Applied Sciences Faculty Publications

Contemporary discovery and development of cancer drugs are based on the model that investments in basic biomedical science will provide insights that can be translated into new cures. In the USA, basic research is primarily funded by the National Institutes of Health (NIH),1 which allocates half of its research budget to basic science,2 with smaller amounts contributed by philanthropy, academics, or industry.1 Basic science is formally defined as the “systematic study directed toward fuller knowledge or understanding of the fundamental aspects of phenomena and observable facts without specific application towards processes or products in mind”.3 However, science is often useinspired,4 …

Delivery For Hydrophobic Drugs For Treating Pancreatic Cancer, Saud Almawash

Theses & Dissertations

Purpose The aim of this study was to determine whether coadministration of hedgehog (Hh) pathway inhibitor cyclopamine (CYP) and microtubule stabilizer docetaxel (DTX) as polymer-drug conjugates, methoxy poly(ethylene glycol)-block-poly(2-methyl-2-carboxyl-propylenecarbonategraft- dodecanol-graft-cyclopamine) (P-CYP) and methoxy poly(ethylene glycol)-block-poly(2-methyl-2-carboxyl-propylene carbonate-graft-dodecanol-graft-docetaxel) (P-DTX) could synergistically inhibit orthotopic pancreatic tumor growth in NSG mice.

Methods P-DTX and P-CYP were synthesized from mPEGb- PCC through carbodiimide coupling reaction and characterized by 1H–NMR. The micelles were prepared by film hydration and particle size was measured by dynamic light scattering (DLS). Cytotoxicity, apoptosis and cell cycle analysis of P-DTX and P-CYP were evaluated in MIA PaCa-2 cells. In vivo efficacy …

Ocular, Neural, And Cellular Biodistribution Of Multifunctional Antioxidants, Damian Daszynski

Theses & Dissertations

Aging is a complex biological process which stems from a growing imbalance between the regenerative capacity of an organism and endogenous as well as exogenous damaging factors. This imbalance leads to the slow deterioration of individual cells, organs, and eventually the entire organism. The free radical theory of aging combines the evolutionary and mechanistic aspects of aging, postulating that the innate process is caused by deleterious, irreversible, and inevitable changes in biological systems caused by oxidative damage that accumulates over the lifespan. Evidence of this phenomenon is supported by the pathogenesis of age-related diseases, such as age-related macular degeneration and …

Phenylpyrazalopyrimidines As Tyrosine Kinase Inhibitors: Synthesis, Antiproliferative Activity, And Molecular Simulations, Bhupender S. Chhikara, Sajda Ashraf, Saghar Mozaffari, Nicole St. Jeans, Dindyal Mandal, Rakesh Kumar Tiwari, Zaheer Ul-Haq, Keykavous Parang

Pharmacy Faculty Articles and Research

N1-(α,β-Alkene)-substituted phenylpyrazolopyrimidine derivatives with acetyl and functionalized phenyl groups at α- and β-positions, respectively, were synthesized by the reaction of 3-phenylpyrazolopyrimidine (PhPP) with bromoacetone, followed by a chalcone reaction with differently substituted aromatic aldehydes. The Src kinase enzyme assay revealed modest inhibitory activity (half maximal inhibitory concentration, IC₅₀ = 21.7–192.1 µM) by a number of PhPP derivatives. Antiproliferative activity of the compounds was evaluated on human leukemia (CCRF-CEM), human ovarian adenocarcinoma (SK-OV-3), breast carcinoma (MDA-MB-231), and colon adenocarcinoma (HT-29) cells in vitro. 4-Chlorophenyl carbo-enyl substituted 3-phenylpyrazolopyrimidine (10) inhibited the cell proliferation of HT-29 and SK-OV-3 by 90% …

Coronavirus Disease 2019 (Covid-19), Matthew Dunbar

Pharmacy Student Scholarship

No abstract provided.

Measuring The Effects Of Lobinaline-N-Bioxide (419) On Alcohol Consumption, Nicotine Locomotor Sensitization, And Conditioned Place Preference In Mice And Rats, Cocanut M. Suhail

Theses and Dissertations--Medical Sciences

Objective: Novel drug 419 was examined to see the effect it has in vivo mice and rats on alcohol consumption, nicotine locomotor sensitization, and conditioned place preference (CPP) models regarding behavioral tests on dopamine transporter activity.

Methods: Mice and rats were used to see how they react to the drug 419 and control vehicle, in each of the models. The animals were assessed to pre- and post- drug administration of novel drug 419. We examined each model to see the association between how drug 419 will help with treating drug abuse.

Results: We found that in alcohol consumption model the …

Correlating The Physicochemical Properties Of Magnesium Stearate With Tablet Dissolution And Lubrication, Julie L. Calahan

Theses and Dissertations--Pharmacy

Magnesium stearate (MgSt) is the most commonly used pharmaceutical excipient and is present in over half the tablet formulations on the market. In spite of its popularity as an effective lubricant, it has been repeatedly recognized that there is significant variability between MgSt samples, which can cause inconsistent lubrication between batches of MgSt. The hypothesis of this research is that the batch-to-batch variability in tablet lubrication and dissolution observed in tablet formulations containing different MgSt samples can be correlated with differences in MgSt physicochemical properties (fatty acid salt composition, crystal hydrate form, particle size and surface area). Developing correlations between …

Novel Small Molecule Antifungals For Invasive Fungal Infections, Emily Dennis

Theses and Dissertations--Pharmacy

Human fungal pathogens cause a range of diseases from benign skin conditions (i.e., ringworm) to thrush, mucosal membrane infections, and life-threatening systemic infections including bloodstream infections (i.e., aspergillosis and candidiasis) and Cryptococcal meningitis. These systemic infections occur most often in immunocompromised individuals and have high mortality rates. Current antifungal agents used in the clinic belong to three main classes: the polyenes (e.g., amphotericin B (AmB)), the echinocandins (e.g., caspofungin (CFG)), and the azoles (e.g., fluconazole (FLC)). In addition, the antimetabolite pyrimidine analogue flucytosine is used in combination with AmB. The …