Chemicals and Drugs Commons^™

Design, Synthesis And Pharmacological Characterization Of Potential Mu Opioid Receptor Selective Ligands, Abhishek S. Kulkarni

Theses and Dissertations

Selective Mu Opioid Receptor (MOR) antagonists possess immense potential in the treatment of opioid abuse/addiction. Utilizing the “message-address” concept, our laboratory reported a novel, reversible, non-peptide MOR selective antagonist 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[(4՛-pyridyl)carboxamido]morphinan (NAP). Molecular modeling studies revealed that the selectivity of NAP for the MOR is because of a π-π stacking interaction of its pyridine ring with the Trp318residue in theMOR. Pharmacological characterization showed that NAP is a P-glycoprotein substrate, thereby limiting its use in the treatment of opioid abuse/addiction. Thus, to modify NAP, we replaced the pyridine ring with its isosteric counterpart thiophene. Isosteric replacement …

Discovery Of Selective Probes Targeting Rna Polymerase I, Xiao Tan

Theses and Dissertations--Chemistry

RNR Polymerase I (RNA Pol I) is a “factory” that orchestrate the transcription of ribosomal rRNA for constructing ribosomes as a primary workshop for protein translation to sustain cell growth. Misregulation of RNA Pol I can cause uncontrolled cell proliferation, which leads to the development of cancer. Yeast (Saccharomyces cerevisiae) is a valuable model system to study RNA Pol I. Recently, the X-ray crystal structure of the yeast homologue of RNA Pol I was elucidated, offering the structural basis to selectively target this transcriptional machinery. The approach to selective RNA Pol I targeting was to disrupt the interaction …

In Vitro Metabolism Of The Synthetic Cannabinoids Px-1, Px-2, Px-3 And A Comparison Of Their Clearance Rates In Human Liver Microsomes, Travon Cooman

Graduate Theses, Dissertations, and Problem Reports (ETD)

Detection of SCs in body fluids continue to be a challenge because of limited metabolism data, lack of standards and reference mass spectrometry data. In vivo and in vitro experiments help elucidate metabolite markers for novel psychoactive substances and can prompt synthesis of standards to verify proposed metabolites. In this study, metabolism of three SCs N-(1-amino-1-oxo-3-phenylpropan-2-yl)-1-(5-fluoropentyl)-1H-indole-3-carboxamine (PX-1), N-(1-amino-1-oxo-3-phenylpropan-2-yl)-1-(5-fluropentyl)-1H-indazole-3-carboxamide (PX-2), and N-(1-amino-1-oxo-3-phenylpropan-2-yl)-1-(cyclohexylmethyl)-1H-indazole-3-carboxamide (PX-3) were investigated using human liver microsomes. Previous studies showed PX-3 as the most potent CB1 and CB2 receptor agonist.

Half-life and clearance data were acquired using liquid chromatography- tandem mass spectrometry. Metabolite elucidation was performed using liquid chromatography …

An Open-Label, Single-Dose Study To Evaluate The Safety, Tolerability, Pharmacokinetics, And Pharmacodynamics Of Cinacalcet In Pediatric Subjects Aged 28 Days To < 6 Years With Chronic Kidney Disease Receiving Dialysis., Winnie Y. Sohn, Anthony A. Portale, Isidro B. Salusky, Hao Zhang, Lucy L. Yan, Bella Ertik, Shahnaz Shahinfar, Edward Lee, Bastian Dehmel, Bradley A. Warady

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: Calcimimetics, shown to control biochemical parameters of secondary hyperparathyroidism (SHPT), have well-established safety and pharmacokinetic profiles in adult end-stage renal disease subjects treated with dialysis; however, such studies are limited in pediatric subjects.

METHODS: In this study, the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of cinacalcet were evaluated in children with chronic kidney disease (CKD) and SHPT receiving dialysis. Twelve subjects received a single dose of cinacalcet (0.25 mg/kg) orally or by nasogastric or gastric tube. Subjects were randomized to one of two parathyroid hormone (PTH) and serum calcium sampling sequences: [(1) 2, 8, 48 h; or (2) …

Vibrational Characterization Of Granulosa Cells From Patients Affected By Unilaterial Ovarian Endometriosis: New Insights From Infrared And Raman Microspectroscopy, Valentina Notarstefano, Giorgia Gioacchini, Hugh Byrne, Carlotta Zaca, Eleni Sereni, Lisa Vaccari, Andrea Borini, Oliana Carnevali

Articles

Endometriosis is a chronic gynaecological disease characterised by the presence of endometrial cells in extra-uterine regions. One of the main factors impacting on the fertility of women affected by endometriosis is the poor oocyte quality. Granulosa Cells (GCs) regulate oocyte development and maintain the appropriate microenvironment for the acquisition of its competence; hence, the dysregulation of these functions in GCs can lead to severe cellular damages also in oocytes. In this study, luteinized GCs samples were separately collected from both ovaries of women affected by Unilateral Ovarian Endometriosis and analysed by infrared and Raman microspectroscopy. The spectral data were compared …

Rapid Identification Of Phospholipase A2 Transcripts From Snake Venoms, Ying Jia, Pablo Olvera, Frida Rangel, Bianca Mendez, Samir Reddy

School of Integrative Biological & Chemical Sciences (Formerly Dept. of Biology)

Phospholipase A₂ (PLA₂) is a major component in snake venoms and it is found in many different isoforms. To identify transcripts encoding different PLA₂ isoforms, we developed a simple, rapid procedure. Total RNA was extracted from the venoms of three cottonmouth snakes and two diamondback rattlesnakes, and further reverse-transcribed into complementary DNA (cDNA). Using one pair of cottonmouth PLA₂-specific primers and Reverse Transcription Polymerase Chain Reaction (RT-PCR) technique, we identified 27 unique full-length PLA₂ transcripts, including nine sequences identical to the previously documented ones in the database and one novel GIII-like PLA_{2 …}

Regenerative Potential Of Mesenchymal Stem Cell Derived Exosomes, Andrew P. Wong

Theses and Dissertations

Bone defects are a pervasive complication arising from many clinical conditions, both mechanical and pathological. Current treatments for large bony defects focus on applying bone grafts or synthetic materials to the defect area. Cell-based—and especially stem-cell—therapies have advanced greatly thanks to increasing attention focused on their ability to generate new tissues in situ with biomechanical properties approaching that of native tissue, but they suffer from their own shortcomings as well. Exosomes have been shown to play critical roles in cell-signaling and tissue regeneration and are therefore potentially ideal therapeutic vehicles for treating bone defects. Exosomes are small microvesicles counted amongst …

Pharmacodynamics Of Monoamine Transporter Releasing Agents And Reuptake Inhibitors, Alexa Holloway

Theses and Dissertations

Ligands of the human monoamine transporters encompass a wide range of both illicit and therapeutic drugs that act upon neural circuitry related to reward, motivation, and the processing of salient stimuli. The present study utilizes two methods for analyzing transporter substrates and inhibitors in order to characterize activity and assess potency. The first measures transient changes in intracellular calcium as a surrogate for transporter activity by harnessing the electrical coupling of monoamine transporters and L-type calcium channels. This is used to analyze novel chimera of the strong hDAT inhibitors methylphenidate and ��-PPP in order to assess the contribution of specific …

Structure-Activity Relationship Studies Of Synthetic Cathinones And Related Agents, Rachel A. Davies

Theses and Dissertations

Synthetic cathinones and related agents represent an international drug abuse problem, and at the same time an important class of clinically useful compounds. Structure-activity relationship studies are needed to elucidate molecular features underlying the pharmacology of these agents. Illicit methcathinone (i.e., MCAT), the prototype of the synthetic cathinone class, exists as a racemic mixture. Though the differences in potency and target selectivity between the positional and optical isomers of synthetic cathinones and related agents have been demonstrated to have important implications for abuse and therapeutic potential, the two MCAT isomers have never been directly compared at their molecular targets: the …

Eralpha Isoforms Modulate The Tumorigenicity Of 24r,25(Oh)2d3 In Estrogen-Responsive Cancer, Anjali Verma

Theses and Dissertations

Over 200,000 cases of breast cancer are diagnosed every year. Nearly 20% of these patients supplement their diets with some form of vitamin D. This high frequency of vitamin D supplement use may be due in part to research suggesting that cancer patients with higher serum vitamin D₃ levels have better prognoses than patients with low serum vitamin D_3. However, double-blind clinical trials on the efficacy of vitamin D₃ supplementation in breast cancer have been inconclusive. A recent meta-analysis showed evidence of reduced cancer recurrence in patients taking vitamin D₃ supplements who had ‘estrogen receptor positive’ …

Improving Dopamine Monitoring With Ncam And The Effects Of Intranasal Oxytocin On Dopamine Signaling In The Rat Brain, Darren Earl Ginder

EWU Masters Thesis Collection

Dopamine (DA) is a neurohormone highly involved in learning and memory. Oxytocin (OXT), another neurohormone, has also been implicated in learning and memory. Fast-scan cyclic voltammetry (FSCV) is a method used for the real-time examination of DA neurotransmission in the brain. Implanting FSCV electrodes is an invasive technique that likely results in an inflammatory response (i.e. gliosis) that can restrict FSCV recording of DA signals. Neural cell adhesion molecule (NCAM) may reduce gliosis and potentially improve the ability of FSCV electrodes to monitor DA signaling. Chapter 1 Methods: FSCV electrodes were coated with NCAM and implanted in the rat brain. …

Characterization Of The Microbial Phosphonate-Activating Pntc Enzymes, Kyle Rice

Theses and Dissertations (Comprehensive)

New strategies are urgently needed to combat infectious diseases in an era of rising antibiotic resistance. Furthermore, an emerging appreciation for the human microbiome’s role in maintaining health motivates discovery of species-specific antibiotics that minimally disrupt our native bacterial communities. Small molecule modifications to bacterial cell surfaces represent a potentially rich source of new targets for next generation antibiotics, as these molecules mediate virulence and evasion of the host immune response. Phosphocholine (PCho) is a rare cell surface modification that contributes to virulence, and modifications with phosphonates like 2-aminoethylphosphonate (AEP) are even more unusual and therefore provide opportunities for species- …

Targeting Lipoprotein Biogenesis: Considerations Towards Antimicrobials, Toufic El Arnaout, Tewfic Soulimane

Articles

Decades have passed without approval of a new antibiotic class. Several companies have recently halted related discovery efforts because of multiple obstacles. One promising route under research is to target the lipoprotein maturation pathway in light of major recent findings and the virulence roles of lipoproteins. To support the future design of selective drugs, considerations and priority-setting are established for the main lipoprotein processing enzymes (Lgt, LspA, and Lnt) based on microbiology, biochemistry, structural biology, chemical design, and pharmacology. Although not all bacterial species will be similarly impacted by drug candidates, several advantages make LspA a top target to pursue …

Development And Ex Vivo Characterization Of Enteric Coated Chitosan Beads For Crohn’S Disease Management, Craig Mendonca

University Scholar Projects

Drug delivery is the process of transporting a drug to its site of action. It includes controlled delivery, where the drug is released at the tissue in a regulated manner. Additionally, it includes targeted delivery, where the drug is aimed at a specific tissue or region to avoid unwanted side effects (that would occur if the drug were distributed throughout the body). A cellulose acetate phthalate coated chitosan bead was developed as a formulation for controlled and targeted release of dexamethasone to the ilium and colon. This formulation was determined to be effective in delaying dexamethasone release until the formulation …

The Effects Of Inhibiting Pi3k On Tumor Suppressor Gene P53 And Cell Proliferation, Kelsi Peters

Undergraduate Theses and Capstone Projects

When the cell surface molecule, Human EGF Receptor (HER2), is overexpressed, the cell can become cancerous. MDA-MB-453 is an established breast cancer cell line made cancerous by HER2 overexpression. This mutation that causes HER2 overexpression affects the cell signaling pathway of phosphoinositide 3-kinase (PI₃K), Akt, MDM2, and p53. We predicted that PI₃K would be inhibited with the compound, LY294002, sending signals for Akt and MDM2 to be deactivated in MDA-MB-453 cells. Deactivated MDM2 signals for p53 to be activated. P53 is a tumor suppressor protein that exists in low quantities in normal cells, but when damage …

Unlocking The Mysteries Of Weed And Mexico, Eddy Martinez

Capstones

An American biotech firm named Phylos Bioscience is interested in entering the Mexican marijuana market once it legalizes. Before it can do that, it must deal with the Mexican government and a conservative society.

https://eddymartinezcunyedu.atavist.com/figuring-out-the-mysteries-of-weed-and-mexico

Coordinated Unmanned Aircraft System (Uas) And Ground-Based Weather Measurements To Predict Lagrangian Coherent Structures (Lcss), Peter J. Nolan, James Pinto, Javier González-Rocha, Anders Jensen, Christina N. Vezzi, Sean C. C. Bailey, Gijs De Boer, Constantin Diehl, Roger Laurence Iii, Craig W. Powers, Hosein Foroutan, Shane D. Ross, David G. Schmale Iii

Mechanical Engineering Faculty Publications

Concentrations of airborne chemical and biological agents from a hazardous release are not spread uniformly. Instead, there are regions of higher concentration, in part due to local atmospheric flow conditions which can attract agents. We equipped a ground station and two rotary-wing unmanned aircraft systems (UASs) with ultrasonic anemometers. Flights reported here were conducted 10 to 15 m above ground level (AGL) at the Leach Airfield in the San Luis Valley, Colorado as part of the Lower Atmospheric Process Studies at Elevation—a Remotely-Piloted Aircraft Team Experiment (LAPSE-RATE) campaign in 2018. The ultrasonic anemometers were used to collect simultaneous measurements of …

Design, Synthesis, And Evaluation Of C5 Substituted Carbapenem Antibiotics To Counter Resistant Pathogens, Noora Mohammed S.A Al-Kharji

Chemistry Theses and Dissertations

The 21st century has seen a dramatic acceleration in the evolution of bacterial resistance. Many classes of commercial antibiotics, including most current commercial β-lactams, were structurally optimized to counter 20th century pathogens. The carbapenems represent the most potent and broadest spectrum of the β-lactams, representing crucial last line agents to treat lifethreatening infections. While the 21st century has seen the appearance of carbapenem-resistant strains, the basic substitution pattern of commercial carbapenem antibiotics has remained constant, other than minor modifications at the C2 position. This research will investigate whether substitution at an atypical carbapenem position, the C5 position, can improve the …

Clinical Pharmacology Of Tisagenlecleucel In B-Cell Acute Lymphoblastic Leukemia., Karen Thudium Mueller, Edward Waldron, Stephan A. Grupp, John E. Levine, Theodore W. Laetsch, Michael A. Pulsipher, Michael W. Boyer, Keith August, Jason Hamilton, Rakesh Awasthi, Andrew M. Stein, Denise Sickert, Abhijit Chakraborty, Bruce L. Levine, Carl H. June, Lori Tomassian, Sweta S. Shah, Mimi Leung, Tetiana Taran, Patricia A. Wood, Shannon L. Maude

Manuscripts, Articles, Book Chapters and Other Papers

PURPOSE: Tisagenlecleucel is an anti-CD19 chimeric antigen receptor (CAR19) T-cell therapy approved for the treatment of children and young adults with relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL).

PATIENTS AND METHODS: We evaluated the cellular kinetics of tisagenlecleucel, the effect of patient factors, humoral immunogenicity, and manufacturing attributes on its kinetics, and exposure-response analysis for efficacy, safety and pharmacodynamic endpoints in 79 patients across two studies in pediatric B-ALL (ELIANA and ENSIGN).

RESULTS: Using quantitative polymerase chain reaction to quantify levels of tisagenlecleucel transgene, responders (N = 62) had ≈2-fold higher tisagenlecleucel expansion in peripheral blood than nonresponders ( …

December 2018, Randy Curry, Cindy Brooks

RURAL ROCKS

Rural Rocks, the Rural Health Network newsletter by the SWOSU College of Pharmacy