Medicinal Chemistry and Pharmaceutics Commons^™

Target-Directed Biosynthetic Evolution: Redirecting Plant Evolution To Genomically Optimize A Plant’S Pharmacological Profile, Dustin Paul Brown

Theses and Dissertations--Neuroscience

The dissertation describes a novel method for plant drug discovery based on mutation and selection of plant cells. Despite the industry focus on chemical synthesis, plants remain a source of potent and complex bioactive metabolites. Many of these have evolved as defensive compounds targeted on key proteins in the CNS of herbivorous insects, for example the insect dopamine transporter (DAT). Because of homology with the human DAT protein some of these metabolites have high abuse potential, but others may be valuable in treating drug dependence. This dissertation redirects the evolution of a native Lobelia species toward metabolites with greater activity …

Chemoenzymatic Studies To Enhance The Chemical Space Of Natural Products, Jhong-Min Chen

Theses and Dissertations--Pharmacy

Natural products provide some of the most potent anticancer agents and offer a template for new drug design or improvement with the advantage of an enormous chemical space. The overall goal of this thesis research is to enhance the chemical space of two natural products in order to generate novel drugs with better in vivo bioactivities than the original natural products.

Polycarcin V (PV) is a gilvocarcin-type antitumor agent with similar structure and comparable bioactivity with the principle compound of this group, gilvocarcin V (GV). Modest modifications of the polyketide-derived tetracyclic core of GV had been accomplished, but the most …

Utilization Of Placebo Response In Double-Blind Psychopharmacological Studies, Contextual Perspective, Margarita Olegovna Ashirova

Antioch University Dissertations & Theses

Placebo response has been an elusive phenomenon in the fields of medicine, medical research, and psychology. Even though it has been heavily utilized as a comparator treatment in double-blind psychopharmacological studies, the reliable definition and consistent understanding of placebo response are missing. In this contextual exploration, I outlined the state of current placebo response research and variable rates of placebo response reported in double-blind studies. I identified the gap in the literature—lack of consistent understanding of placebo response—that has led to a waste of resources by the psychopharmacological research industry. Further, I compared and contrasted the current inconsistent Western medical …

Islet Dysfunction In Diabetes, Syeda Khadija

Wayne State University Dissertations

Type 2 Diabetes [T2DM] is a chronic condition resulting from gradual failure of pancreatic beta cells to synthesize and secrete sufficient insulin to meet the metabolic demands and the inability of tissues [muscle, adipose and liver] to efficiently utilize the secreted insulin leading to an overall increase in blood glucose levels [hyperglycemia]. As indicated by recent estimates from the International Diabetes Federation, the prevalence of the disease in the year 2014 has risen to a record 387 million worldwide. The main objective of my project was to study the mechanisms involved in pancreatic beta cell dysfunction in diabetes, specifically in …

Development Of Clinically Relevant In Vitro Performance Tests For Powder Inhalers, Xiangyin Wei

Theses and Dissertations

While realistic in vitro testing of dry powder inhalers (DPIs) can be used to establish in vitro–in vivo correlations (IVIVCs) and predict in vivo lung doses, the aerodynamic particle size distributions (APSDs) of those doses and their regional lung deposition remains unclear. Four studies were designed to improve testing centered on the behavior of Novolizer®. Different oropharyngeal geometries were assessed by testing different mouth-throat (MT) models across a realistic range of inhalation profiles (IPs) with Salbulin® Novolizer®. Small and large Virginia Commonwealth University (VCU) and Oropharyngeal Consortium (OPC) models produced similar ranges for total lung dose in vitro (TLD …

Bioethanol: Feedstock Alternatives, Pretreatments,Lignin Chemistry, And The Potential For Green Value-Added Lignin Co-Products, Ruben Michael Ceballos, N. A. Batchenkova, M.K. Y. Chan, A. X. Duffing-Romero, A. E. Nelson, S. Man

Biological Sciences Faculty Publications and Presentations

Major challenges still exist in the cost-competitive production of cellulosic ethanol. Lignocellulose deconstruction using physiochemical pretreatments continues to be the most efficient way to remove lignin and expose cellulose for enzyme-mediated sugar reduction. Recent interest in the development of “value-added” lignin co-products and the desire to reduce the use of hazardous materials has prompted a resurgence of interest in alternative lignocellulosic feedstock and research into environment-friendly biological pretreatments. This article provides an overview of bioethanol processes and economics, standard and alternative feedstocks, physiochemical and biological pretreatments, and lignin chemistry. The chemistry and mode of action of ligninolytic and cellulolytic enzymes …

Phytochemical, Antioxidant And Antibacterialpotential Of Elaeagnus Kologa (Schlecht.) Leaf., Zoe Merculieff, Shubharani Ramnath, Seethalakshmi Madhukar Sankoli, Sivaram Venkataramegowda, Ganti S. Murthy, Ruben Michael Ceballos

Biological Sciences Faculty Publications and Presentations

Objective To screen different solvent extracts of Elaeagnus kologa (E. kologa) leaf to determine the phytochemicals, potent antioxidant and antibacterial activity to find out the possible source of applied pharmaceutical formulations. Methods Solvent extracts of leaf material were prepared using the Soxhlet apparatus. A study was performed on antioxidant activity of methanolic extract of leaf by 1-1-diphenyl-2-picrylhydrazyl method. The phenolic and flavonoid content of all the fractions were determined using high performance liquid chromatography. Leaves were also subjected to protein and carbohydrate test. Results The total phenols, flavonoids were found to be high in petroleum ether as compare to other …

Submonomer Synthesis And Structure-Activity Relationship Studies Of Azapeptide Inhibitors Of The Insulin Receptor Tyrosine Kinase, Lathamol A. Kurian

Seton Hall University Dissertations and Theses (ETDs)

Azapeptides are a class of peptide mimics (peptidomimetics), which have served as valuable tools for the development of peptide based therapeutic agents. The therapeutic promise of azapeptides has been correlated to its primary sequence modification which translates into bio-active secondary structures that improves the pharmacological properties of the native peptide sequence. More specifically, azapeptides contain a semicarbazide within the peptide backbone which restricts the peptide bond torsion angles (φ, ψ) into pre-organized b-turn secondary structures. Thus, azapeptides have been shown to stabilize bio-active b-turn secondary structures responsible for high affinity and selective binding to a target …

Statistical Analysis, Modeling, And Algorithms For Pharmaceutical And Cancer Systems, Bong-Jin Choi

USF Tampa Graduate Theses and Dissertations

The aim of the present study is to develop a statistical algorithm and model associ- ated with breast and lung cancer patients. In this study, we developed several statistical softwares, R packages, and models using our new statistical approach.

In the present study, we used the five parameters logistic model for determining the optimal doses of a pharmaceutical drugs, including dynamic initial points, an automatic process for outlier detection and an algorithm that develops a graphic user interface(GUI) program. The developed statistical procedure assists medical scientists by reducing their time in determining the optimal dose of new drugs, and can …

Chemical Profiling And Biological Activity Of Two Tunicate-Associated Marine Bacteria, Lyubina Yankova

Honors Scholar Theses

Marine natural products have recently been an increasingly abundant source of novel antibiotics. Given that there is an increasing resistance to current drug therapies, finding new sources such as marine natural products is essential. Tunicate-associated marine bacteria can be a significant source of antibacterial compounds. Two tunicates of the species Eudistoma were collected from Portobelo National Park on the Salmedina Reef of Panama in the Caribbean Sea. Bacteria associated with the tunicate were isolated, cultured, extracted, and fractionated. Fractions were tested against an array of clinically relevant bacterial pathogens in the BioMAP assay. Two fractions MB0086E and MB0088E demonstrated activity …

Big Pharma Is Hurt, Singapore Management University

Perspectives@SMU

Cutting down R&D inefficiency and restoring the trust of investors and consumers are key to curing the industry’s ills.

Nudging The Fda, W. Nicholson Price Ii, I. Glenn Cohen

Law Faculty Scholarship

[Excerpt] "The FDA’s regulation of drugs is frequently the subject of policy debate, with arguments falling into two camps. On the one hand, a libertarian view of patients and the health care system holds high the value of consumer choice. Patients should get all the information and the drugs they want; the FDA should do what it can to enforce some basic standards but should otherwise get out of the way. On the other hand, a paternalist view values the FDA’s role as an expert agency standing between patients and a set of potentially dangerous drugs and potentially unscrupulous or …

Site-Directed Mutagenesis Of Conserved Amino Acids Residues In N5-Carboxyaminoimidazole Ribonucleotide Mutase: Converting N5-Cair Mutase Into Aminoimidazole Ribonnucleotide Carboxylase & Developing A High-Throughput Screening Assay For The Discovery Of N5-Carboxyaminoimidazole Ribonucleotide Mutase, Zhiwen Shi

Wayne State University Theses

The de novo purine biosynthesis pathway plays a critical role in providing new purines to the cell. Previous studies have shown differences between the human and bacterial pathways which suggests that pathway may be a potential target for antibiotic drug discovery. Three critical enzymes are involved in the pathway divergence. In the bacterial pathway, N5-CAIR synthetase (PurK) first converts AIR to N5-CAIR, which is then transformed into CAIR catalyzed by the enzyme N5-CAIR mutase (Class I PurE). In the human pathway, AIR carboxylase (Class II PurE) catalyzes the direct conversion of AIR to CAIR. Class I and Class II PurEs …

Design Of Functional Dendrimer Nanocarriers And Their Formulations In Propellant-Based Inhalers For Pulmonary Drug Delivery, Lin Yang

Wayne State University Dissertations

This Dissertation focuses on addressing two of the major challenges in developing pressurized metered dose inhalers for pulmonary drug / gene delivery to and through the lungs. First challenge is to design biocompatible moieties for the steric stabilization of suspension formulations in HFO-based propellants. Using a combination of tools including ab initio calculation, molecular dynamics simulation and high pressure tensiometry, potential fluorocarbon-philic moieties were systematically screened. Surfactants with those chemistries as tail fragments were studied at the HFO|H2O interface for their ability to lower the interfacial tension at HFO|H2O interface. Selected surfactants were further optimized for surfactant balance by altering …

Species - Dependent Cardiac And Motor Responses To Cholinergic Stimulation In Daphnia Pulex And Daphnia Magna, Bryan James Hannan

Wayne State University Theses

The role of acetylcholine (ACh) in regulating the activity of the heart and `feeding current' driven by the beating thoracic appendages of Daphnia pulex and Daphnia magna was evaluated using acetylcholinesterase inhibitors (AChE-I) and muscarinic receptor agonists. Single animals, tethered to a stainless steel pin, were tested in a watertight aquatic chamber that allowed free movement of appendages and swimming antennae. Heart contraction rate and the rate of thoracic appendage beating were quantified optically by measuring fluctuating changes in light-intensity caused by movement. Physostigmine, neostigmine, oxotremorine, pilocarpine as well as nicotine were used to study ACh and AChE. Atropine was …

Development And Evaluation Of Plga-S-S-Peg Micelles Coencapsulating Curcumin Difluorinated And Paclitaxel For Synergistic Therapeutic Efficacy, Lakshmi Deepika Cheemalakonda

Wayne State University Theses

ABSTRACT

DEVELOPMENT AND EVALUATION OF PLGA-S-S-PEG MICELLES COENCAPSULATING CURCUMIN DIFLUORINATED AND PACLITAXEL FOR SYNERGISTIC THERAPEUTIC EFFICACY

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LAKSHMI DEEPIKA CHEEMALAKONDA

August 2014

Advisor: Dr. Joshua Reineke Major: Pharmaceutical Sciences Degree: Master of Science

Solid tumors like pancreatic tumor has unique property of forming a dense desmoplastic layer around the tumor cells making it difficult for the drug to transport across this layer. Multi drug resistance is also one of the major limitation of chemotherapy. Therefore the aim of this project was to make PLGA-SS-PEG micelles encapsulating CDF and paclitaxel for synergistic cancer therapy. CDF was found to have 16-fold better …

Functional Studies Of 5-Carboxyaminoimidazole Ribonucleotide Synthetase And Mutase From Thermotoga Maritima, Mingyang Zhao

Wayne State University Theses

De novo purine biosynthesis is divergent depending upon the organism. In bacteria, yeasts and plants, 5-aminoimidazole ribonucleotide (AIR) is converted to 4-carboxyaminoimidazole ribonucleotide (CAIR) by N5-carboxyaminoimidazole ribonucleotide (N5-CAIR) synthetase (PurK) and N5-CAIR mutase (Class I PurE). In animals, AIR is converted into CAIR by AIR carboxylase (Class II PurE). The distinction makes PurK and Class I PurE good targets in design of antimicrobial drugs. N5-CAIR is chemically unstable with t1/2 of about 0.9 minutes at pH 7.8 and 37 °C. If the production of N5-CAIR is not regulated relative to its conversion to CAIR, ATP utilization can rapidly become non-stoichiometric. …

Proteomic Discovery Of Protein Phosphatase 1 Catalytic Subunit Protein Interaction Partners In Human Skeletal Muscle, Zhao Yang

Wayne State University Theses

Protein Phosphatase 1 (PP1), a member of Serine/ Threonine Phosphatase family, targets its dephosphorylation activity on serine and threonine residues. As the catalytic subunit of PP1, PP1c can achieve its substrate specificity only by binding with PP1 regulatory subunits. Previous researches have shown that PP1c can involve in multiple functional regulation by associating with various interaction partners. Since serine/ threonine phosphorylation on the Insulin receptor substrate-1 (IRS1) may direct inactivation and degradation of IRS1, this phosphorylation activity is believed to be a source of Insulin Resistance. PP1 is hypothesized to dephosphorylate serine/ threonine site on IRS1, which may rescue the …

Comparative Study Of The Prevalence Of Psk41 In Heterogenous Vancomycin-Intermediate Staphylococcus Aureus Isolates Against Non- Heterogenous Vancomycin-Intermediate Staphylococcus Aureus Isolates And The Prevalence By Patient Severity, Poorva Mukund Divekar

Wayne State University Theses

COMPARATIVE STUDY OF THE PREVALENCE OF PSK41 IN HETEROGENOUS VANCOMYCIN-INTERMEDIATE STAPHYLOCOCCUS AUREUS ISOLATES AGAINST NON- HETEROGENOUS VANCOMYCIN-INTERMEDIATE STAPHYLOCOCCUS AUREUS ISOLATES AND THE PREVALENCE BY PATIENT SEVERITY

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POORVA DIVEKAR

December 2014

Advisor: Dr. Emily T. Martin

Major: Pharmaceutical Sciences

Degree: Master of Science

Earlier studies have reported that pSK41 plays an important role in the transfer of vancomycin resistance from Vancomycin-resistant Enterococci (VRE) to S. aureus. This transfer leads to the development of Vancomycin-resistant S. aureus (VRSA). Thirteen VRSA cases have been reported in the United States since 2002. To determine and compare the prevalence of pSK41 in hVISA isolates …

Synthesis And Characterization Of Brain Penetrant Prodrug Of Neuroprotective D264: Potential Disease Modifying Treatment Agent For Parkinson's Disease, Fahd Shamoon Dholkawala

Wayne State University Theses

Parkinson's disease (PD) is a complex neurodegenerative disorder with progressive loss of dopamanergic neurons in the substantia nigra region of the brain and accumulation of intracytoplasmic inclusions called `Lewy bodies'. PD is characterized by tremors, rigidity, slowness of movement, bradykinesia and postural imbalances. Although the etiology of PD is not well understood, it is well established that oxidative stress, mitochondrial dysfunction, alpha-synuclein aggregation play a central role in the pathogenesis of PD. Current treatment methods are based on symptomatic relief without addressing the underlying pathophysiological factors responsible for the disease. It is important to develop therapies which can address these …