Medicinal and Pharmaceutical Chemistry Commons^™

Quadruped Gait And Regulation Of Apoptotic Factors In Tibiofemoral Joints Following Intra-Articular Rhprg4 Injection In Prg4 Null Mice, Daniel S. Yang, Edward E. Dickerson, Ling X. Zhang, Holly Richendrfer, Padmini N. Karamchedu, Gary A. Badger, Tannin A. Schmidt, Alger M. Fredericks, Khaled A. Elsaid, Gregory D. Jay

Pharmacy Faculty Articles and Research

Camptodactyly-arthropathy-coxa vara-pericarditis (CACP) syndrome leads to diarthrodial joint arthropathy and is caused by the absence of lubricin (proteoglycan 4—PRG4), a surface-active mucinous glycoprotein responsible for lubricating articular cartilage. In this study, mice lacking the orthologous gene Prg4 served as a model that recapitulates the destructive arthrosis that involves biofouling of cartilage by serum proteins in lieu of Prg4. This study hypothesized that Prg4-deficient mice would demonstrate a quadruped gait change and decreased markers of mitochondrial dyscrasia, following intra-articular injection of both hindlimbs with recombinant human PRG4 (rhPRG4). Prg4^−/− (N = 44) mice of both sexes were injected with rhPRG4 …

Acetaminophen, A Therapeutic Or An Extremely Toxic Remedy – A Review, Genica Caragea, Oana Avram, Andreea Pauna, Andreea Cristina Costea, Miruna Tudosie

Journal of Mind and Medical Sciences

When a new coronavirus appeared in the late 2019, identified as the cause of several cases of pneumonia in Wuhan, Paracetamol was initially reported to be the preferable antipyretic medication, choice which was detrimental to the use of other drugs. People have resorted to buying large stocks of Paracetamol and some have used it in large doses, regardless of the consequences. However, the Paracetamol (Acetaminophen) overdose remains the leading cause of death or transplantation due to acute liver failure in many parts of the world. This review aims at presenting the pharmacokinetics, the clinical signs, and the risk factors for …

Sars-Cov-2 Main Protease Inhibitors Repurposed For Hiv-1 Protease Binding, Jacob Minkkinen

CSB/SJU Distinguished Thesis

Severe acute respiratory syndrome (SARS-CoV-2) led to the COVID-19 global pandemic, with over 460 million cases of infection and over 6 million deaths since the start of the pandemic. SARS-CoV-2 is a retrovirus that utilizes a main protease (Mpro). Mpro is a catalytic cys/his protease. Several treatments were proposed to stop the pandemic including repurposing drugs to inhibit the Mpro. Another retrovirus that uses a protease is human immunodeficiency virus (HIV-1) which has been a global epidemic for 40 years and is a devastating disease that attacks the immune system. HIV-1 has infected 79.5 million people and has killed an …

The Development Of Inhibitors For Sars-Cov-2 Orf8, My Thanh Thao Nguyen

CSB/SJU Distinguished Thesis

An unexpected outbreak of SARS-CoV-2 caused a worldwide pandemic in 2020. Many repurposed drugs were tested, but there are currently only three FDA approved antivirals (Merck’s antiviral Molnupiravir, Pfizer’s antiviral Paxlovid, and Remdisivir).1 Most of the antiviral drugs tested SARS-CoV-2 main protease and RNA-dependent RNA polymerase. However, it is important to explore different drug targets of SARS-CoV-2 to prepare for the virus mutations of the future. This research looks at an alternative approach in which SARSCoV- 2 Open Reading Frame 8 (ORF8), which has been shown to be a rapidly evolving hypervariable gene, was chosen to be the protein of …

Prenatal Drug Exposure And Its Effects On Fetal Development: Clinical And Health Education Implications, Johanna Marie Olo Tapangan

Senior Honors Theses

Prenatal drug exposure is a common clinical phenomenon in pregnancy cases. Pregnancy is a fragile period of time for both the mother and the fetus. Therefore, strict drug regulation is important to ensure the safety and wellbeing of the developing fetus. Certain drugs, once thought to be safe, have been found to have detrimental effects on the normal development of functioning organ systems in the fetus. Current research has identified drugs that when taken during pregnancy can result in the onset of fetal physical abnormalities, impaired brain development, and disrupted organogenesis and organ function. Thalidomide, losartan, opioids, alcohol, and caffeine …

Antiviral Drug Development: Targeted Design And Broad Spectrum Approach, Claude Krummenacher

Faculty Scholarship for the College of Science & Mathematics

No abstract provided.

Amphiphilic Cell-Penetrating Peptides Containing Natural And Unnatural Amino Acids As Drug Delivery Agents, David Salehi, Saghar Mozaffari, Khalid Zoghebi, Sandeep Lohan, Dindyal Mandal, Rakesh Tiwari, Keykavous Parang

Pharmacy Faculty Articles and Research

A series of cyclic peptides, [(DipR)(WR)₄], [(DipR)₂(WR)₃], [(DipR)₃(WR)₂], [(DipR)₄(WR)], and [DipR]₅, and their linear counterparts containing arginine (R) as positively charged residues and tryptophan (W) or diphenylalanine (Dip) as hydrophobic residues, were synthesized and evaluated for their molecular transporter efficiency. The in vitro cytotoxicity of the synthesized peptides was determined in human epithelial ovary adenocarcinoma cells (SK-OV-3), human lymphoblast peripheral blood cells (CCRF-CEM), human embryonic epithelial kidney healthy cells (HEK-293), human epithelial mammary gland adenocarcinoma cells (MDA-MB-468), pig epithelial kidney normal cells (LLC-PK1), and human epithelial …

Combination Of Amphiphilic Cyclic Peptide [R4W4] And Levofloxacin Against Multidrug-Resistant Bacteria, Muhammad Imran Sajid, Sandeep Lohan, Shun Kato, Rakesh Kumar Tiwari

Pharmacy Faculty Articles and Research

Bacterial resistance is a growing global concern necessitating the discovery and development of antibiotics effective against the drug-resistant bacterial strain. Previously, we reported a cyclic antimicrobial peptide [R₄W₄] containing arginine (R) and tryptophan (W) with a MIC of 2.67 µg/mL (1.95 µM) against methicillin-resistant Staphylococcus aureus (MRSA). Herein, we investigated the cyclic peptides [R₄W₄] or linear (R₄W₄) and their conjugates (covalent or noncovalent) with levofloxacin (Levo) with the intent to improve their potency to target drug-resistant bacteria. The physical mixture of the Levo with the cyclic [R_{4 …}

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 …

Arkansas Women In Stem Conference Presentation: Investigations Of Salvia Officinalis Secondary Metabolites, Maria Ines Ines Dow

Arkansas Women in STEM Conference

Salvia officinalis or Sage (The “Salvation Plant”) is known to have various health benefits. Salvia officinalis has been known to treat menstrual cycle pains, gastroenteritis problems, improve liver function, as well as in applications for anticancer remedies and neurodegenerative diseases. This fragrant plant is most often found in the Mediterranean, Southeast Asia, and South America. This research aims to test the raw and vinegar-baked medicinal plant to investigate the change in its chemistry and its biological effect. The plant was purchased as dry leaves and stems. It was then grounded and extracted. The extractions were done via a Soxhlet extraction …

An Atypical Case Of Extreme Polypharmacy, Michael A. Veronin

Pharmacy Faculty Publications and Presentations

A commonly reported definition of polypharmacy is the numerical definition of 5 or more medications daily, and definitions have ranged from 2 or more to 11 or more medications. In this case report, an extreme case of polypharmacy is presented, highlighted by the inordinate number of drugs used over time throughout the patient’s care. A 48-year-old African American female with multiple comorbidities experienced a serious adverse drug event (ADE) prompting reporting to MedWatch, the US Food and Drug Administration’s adverse drug event reporting system. The patient’s concomitant medications included 146 drug entities, across 82 therapeutic drug categories. It is apparent …

Natural Phaeosphaeride A Derivatives Overcome Drug Resistance Of Tumor Cells And Modulate Signaling Pathways, Victoria Abzianidze, Natalia Moiseeva, Diana Suponina, Sofya Zakharenkova, Nadezhda Rogovskaya, Lidia Laletina, Alvin A. Holder, Denis Krivorotov, Alexander Bogachenkov, Alexander Garabadzhiu, Anton Ukolov, Vyacheslav Kosorukov

Chemistry & Biochemistry Faculty Publications

n the present study, natural phaeosphaeride A (PPA) derivatives are synthesized. Anti-tumor studies are carried out on the PC3, K562, HCT-116, THP-1, MCF-7, A549, NCI-H929, Jurkat, and RPMI8226 tumor cell lines, and on the human embryonic kidney (HEK293) cell line. All the compounds synthesized turned out to have better efficacy than PPA towards the tumor cell lines listed. Among them, three compounds exhibited an ability to overcome the drug resistance of tumor cells associated with the overexpression of the P-glycoprotein by modulating the work of this transporter. Luminex xMAP technology was used to assess the effect of five synthesized compounds …

Late-Stage Chemoenzymatic Installation Of Hydroxy-Bearing Allyl Moiety On The Indole Ring Of Tryptophan-Containing Peptides, Nagaraju Mupparapu, Lauren Brewster, Katrina F. Ostrom, Sherif I. Elshahawi

Pharmacy Faculty Articles and Research

The late-stage functionalization of indole- and tryptophan-containing compounds with reactive moieties facilitates downstream diversification and leads to changes in their biological properties. Here, the synthesis of two hydroxy-bearing allyl pyrophosphates is described. A chemoenzymatic method is demonstrated which uses a promiscuous indole prenyltransferase enzyme to install a dual reactive hydroxy-bearing allyl moiety directly on the indole ring of tryptophan-containing peptides. This is the first report of late-stage indole modifications with this reactive group.

“Hiccups” With Covid-19 Management, Yong W. Lee, Jacob Psomiadis, Sarah Akbani, Marvin Lopez-Medal, Aisha Miller

Advances in Clinical Medical Research and Healthcare Delivery

Hiccups, medically referred as singultus, is a condition that results from involuntary contraction of the diaphragm and intercostal muscles. Singultus is usually a self-limiting condition which typically lasts less than 48 hours but in rare cases, can persist greater than 48 hours. This is a case of a 48 year-old male who was prescribed dexamethasone for COVID-19 but developed intractable singultus for two weeks. Patient was unable to tolerate diet due to intractable singultus leading to vomiting. He underwent various non-pharmacological maneuvers and pharmacotherapy without resolution. Dexamethasone- induced hiccups have been reported as an under recognized side effect of dexamethasone. …

A Semi-Physiological Three-Compartment Model Describes Brain Uptake Clearance And Efflux Of Sucrose And Mannitol After Iv Injection In Awake Mice, Behnam Noorani, Ekram Ahmed Chowdhury, Faleh Alqahtani, Md Sanaullah Sajib, Yeseul Ahn, Ehsan Nozohouri, Dhavalkumar Patel, Constantinos Mikelis, Reza Mehvar, Ulrich Bickel

Pharmacy Faculty Articles and Research

Purpose

To evaluate a three-compartmental semi-physiological model for analysis of uptake clearance and efflux from brain tissue of the hydrophilic markers sucrose and mannitol, compared to non-compartmental techniques presuming unidirectional uptake.

Methods

Stable isotope-labeled [¹³C]sucrose and [¹³C]mannitol (10 mg/kg each) were injected as IV bolus into the tail vein of awake young adult mice. Blood and brain samples were taken after different time intervals up to 8 h. Plasma and brain concentrations were quantified by UPLC-MS/MS. Brain uptake clearance (K_in) was analyzed using either the single-time point analysis, the multiple time point graphical method, …

Inhibition Of Interferon-Gamma-Stimulated Melanoma Progression By Targeting Neuronal Nitric Oxide Synthase (Nnos), Shirley Tong, Maris A. Cinelli, Naglaa Salem El-Sayed, He Huang, Anika Patel, Richard B. Silverman, Sun Yang

Pharmacy Faculty Articles and Research

Interferon-gamma (IFN-γ) is shown to stimulate melanoma development and progression. However, the underlying mechanism has not been completely defined. Our study aimed to determine the role of neuronal nitric oxide synthase (nNOS)-mediated signaling in IFN-γ-stimulated melanoma progression and the anti-melanoma effects of novel nNOS inhibitors. Our study shows that IFN-γ markedly induced the expression levels of nNOS in melanoma cells associated with increased intracellular nitric oxide (NO) levels. Co-treatment with novel nNOS inhibitors effectively alleviated IFN-γ-activated STAT1/3. Further, reverse phase protein array (RPPA) analysis demonstrated that IFN-γ induced the expression of HIF1α, c-Myc, and programmed death-ligand 1 (PD-L1), in contrast …

A Pdk-1 Allosteric Agonist Neutralizes Insulin Signaling Derangements And Beta-Amyloid Toxicity In Neuronal Cells And In Vitro, Henry Querfurth, John Marshall, Keykavous Parang, Mengia S. Rioult-Pedotti, Rakesh Tiwari, Bumsup Kwon, Steve Reisinger, Han-Kyu Lee

Pharmacy Faculty Articles and Research

The Alzheimer’s brain is affected by multiple pathophysiological processes, which include a unique, organ-specific form of insulin resistance that begins early in its course. An additional complexity arises from the four-fold risk of Alzheimer’s Disease (AD) in type 2 diabetics, however there is no definitive proof of causation. Several strategies to improve brain insulin signaling have been proposed and some have been clinically tested. We report findings on a small allosteric molecule that reverses several indices of insulin insensitivity in both cell culture and in vitro models of AD that emphasize the intracellular accumulation of β-amyloid (Aβi). PS48, a chlorophenyl …

Channelopathy-Causing Mutations In The S45A/S45B And Ha/Hb Helices Of KCa2.3 And KCa3.1 Channels Alter Their Apparent Ca2+ Sensitivity, Razan Orfali, Young-Woo Nam, Hai Minh Nguyen, Mohammad Asikur Rahman, Grace Yang, Meng Cui, Heike Wulff, Miao Zhang

Pharmacy Faculty Articles and Research

Small- and intermediate-conductance Ca²⁺-activated potassium (K_Ca2.x and K_Ca3.1, also called SK and IK) channels are activated exclusively by a Ca²⁺-calmodulin gating mechanism. Wild-type K_Ca2.3 channels have a Ca²⁺ EC₅₀ value of ∼0.3 μM, while the apparent Ca²⁺ sensitivity of wild-type K_Ca3.1 channels is ∼0.27 μM. Heterozygous genetic mutations of K_Ca2.3 channels have been associated with Zimmermann-Laband syndrome and idiopathic noncirrhotic portal hypertension, while K_Ca3.1 channel mutations were reported in hereditary xerocytosis patients. K_Ca2.3_S436C and K_Ca2.3_V450L channels with …

Endothelial Nitric Oxide Synthase (Enos) And The Cardiovascular System: In Physiology And In Disease States, N Tran, T Garcia, M Aniqa, S Ali, A Ally, Surya M. Nauli

Pharmacy Faculty Articles and Research

Endothelial nitric oxide synthase (eNOS) plays a critical role in regulating and maintaining a healthy cardiovascular system. The importance of eNOS can be emphasized from the genetic polymorphisms of the eNOS gene, uncoupling of eNOS dimerization, and its numerous signaling regulations. The activity of eNOS on the cardiac myocytes, vasculature, and the central nervous system are discussed. The effects of eNOS on the sympathetic autonomic nervous system (SANS) and the parasympathetic autonomic nervous system (PANS), both of which profoundly influence the cardiovascular system, will be elaborated. The relationship between the eNOS protein with cardiovascular autonomic reflexes such as the baroreflex …

Formulation, Characterisation And Evaluation Of The Antihypertensive Peptides, Isoleucine-Proline-Proline And Leucine-Lysine-Proline In Chitosan Nanoparticles Coated With Zein For Oral Drug Delivery, Minna Khalid Danish, John P. Gleeson, David J. Brayden, Hugh Byrne, Jesus Maria Frias, Sinead Ryan

Articles

Isoleucine-Proline-Proline (IPP) and Leucine-Lysine-Proline (LKP) are food-derived tripeptides whose antihypertensive functions have been demonstrated in hypertensive rat models. However, peptides display low oral bioavailability due to poor intestinal epithelial permeability and instability. IPP and LKP were formulated into nanoparticles (NP) using chitosan (CL113) via ionotropic gelation and then coated with zein. Following addition of zein, a high encapsulation efficiency (EE) (>80%) was obtained for the NP. In simulated gastric fluid (SGF), 20% cumulative release of the peptides was achieved after 2 h, whereas in simulated intestinal fluid (SIF), ~90% cumulative release was observed after 6 h. Higher colloidal stability …