Pharmacy and Pharmaceutical Sciences Commons^™

Enzymology And Medicinal Chemistry Of N5-Carboxyaminoimidazole Ribonucleotide Synthetase : A Novel Antibacterial Target, Hanumantharao Paritala

Wayne State University Dissertations

N5-Carboxyaminoimidazole ribonucleotide synthetase (N5-CAIR synthetase), a key enzyme in microbial de novo purine biosynthesis, catalyzes the conversion of aminoimidazole ribonucleotide (AIR) to N5-CAIR. To date, this enzyme has been observed only in microorganisms, and thus, it represents an ideal target for antimicrobial drug development. Here we report structural and functional studies on the Aspergillus clavatus N5-CAIR synthetase and identification of inhibitors for the enzyme. In collaboration with Dr. Hazel Holden of the University of Wisconsin, the three-dimensional structure of Aspergillus clavatus N5-CAIR synthetase was solved in the presence of either Mg2ATP or MgADP and AIR. These structures, determined to 2.1 …

Preparation And Characterization Of Lyophilized Cyclodextrin Complexes Of A Hemisuccinate Ester Of Delta-9-Tetrahydrocannabinol For Transmucosal Delivery, Sampada Bhaskar Upadhye

Electronic Theses and Dissertations

Delta-9- Tetrahydrocannabinol (THC) is the primary active ingredient of the plant Cannabis sativa (marijuana), responsible for the majority of the pharmacological effects. The most promising clinical applications of THC approved by the Food and Drug Administration (FDA) are for the control of nausea and vomiting associated with chemotherapy and for appetite stimulation of AIDS patients suffering from anorexia and wasting syndrome. The only dosage form currently approved by FDA is an oral, soft gelatin capsule (e.g. Marinol®). In addition, orally administered THC from Marinol® has shown slow and variable absorption due to low oral solubility and first pass metabolism. Our …

Synthesis, Characterization And Biological Activity Of Copper (Ii) And Zinc (Ii) Complexes Of Thiosemicarbazones And Their N(4)-Substituted Derivatives Derived From 2,4-Dihydroxybenzaldehyde., Tan Kong Wai

Student Works (2010-2019)

Four thiosemicarbazones ligands (1-4) have been prepared with good yield by refluxing 2,4-dihydroxybenzaldehyde with thiosemicarbazide or N(4)-substituted thiosemicarbazide in ethanol or methanol. From these four ligands, 16 new ternary metal complexes (5-20) with the general formulation of M(B)L have been prepared from the reactions of metal acetates with 2,4-dihydroxybenzaldehyde N(4)-substituted thiosemicarbazone in the presence of N,N-heterocyclic base (M2+ = Zn2+ or Cu2+; B = 2,2'-bipyridine, (bpy); 1,10-phenanthroline, (phen); L2- = doubly deprotonated thiosemicarbazones = 2,4-dihydroxybenzaldehyde thiosemicarbazonato, (HT); 2,4-dihydroxybenzaldehyde 4-methylthiosemicarbazonato, (HM); 2,4-dihydroxybenzaldehyde 4-ethylthiosemicarbazonato, (HE) and 2,4-dihydroxybenzaldehyde 4-phenylthiosemicarbazonato, (HP)) These compounds have been characterized by elemental analyses, IR, UV-Vis, NMR and magnetic …

Prediction Of Human Systemic, Biologically Relevant Pharmacokinetic (Pk) Properties Based On Quantitative Structure Pharmacokinetic Relationships (Qspkr) And Interspecies Pharmacokinetic Allometric Scaling (Pk-As), Prajakta Badri

Theses and Dissertations

This research developed validated QSPKR and PK-AS models for predicting human systemic PK properties of three, preselected, pharmacological classes of drugs, namely opioids, β-adrenergic receptor ligands (β-ARL) and β-lactam antibiotics (β-LAs) using pertinent human and animal systemic PK properties (fu,, CLtot, Vdss, fe) and their biologically relevant unbound counterparts from the published literature, followed by an assessment of the effect of different molecular descriptors on these PK properties and on the PK-AS slopes for CLtot and Vdss from two species (rat and dog). Lipophilicity (log (D)7.4) and molecular weight (MW) were found to be the most statistically significant and biologically …

In-Vitro Metabolism And Protein Binding Of 5-Hmf, A Potential Antisickling Agent, Taghrid Obied

Theses and Dissertations

Purpose. 5-HMF is a potential antisickling agent forming a Schiff-adduct with hemoglobin (Hb). In-vitro studies were designed to identify the metabolic pathways of 5-HMF in human hepatic cytosol, to assess inter-species differences in its hepatic metabolism, and to predict in-vivo PK properties. Moreover, metabolism of 5-HMF in human RBCs was investigated. Finally, in-vitro studies were done to characterize 5-HMF binding kinetics with human Hb and albumin (HSA). Methods. NAD+ reduction was monitored at 340 nm in human hepatic cytosol for 5-HMF (26 mM) and prototypical ADH and ALDH substrates in the presence or absence of their inhibitors. Furthermore, concentration-dependency studies …

Novel Cinnamic Acid-Based Dehydropolymers For Emphysema: In Vitro And In Vivo Assessment Of Their Activities, Bhawana Saluja

Theses and Dissertations

Pulmonary emphysema is a serious worldwide illness, causing progressive and irreversible alveolar wall loss and difficulty in breathing. It is caused mostly by cigarette smoking. However, its unresolved complex and multiple pathogenic mechanisms have left this disease without effective pharmacotherapy. This project hypothesized that cinnamic acid-based dehydropolymers (DHPs), originally discovered as novel anti-coagulants, protect against emphysema through their potent triple inhibitory actions against oxidative stress, inflammation and elastase, some of the pathogenic mechanisms associated with this disease. Three in vitro inhibitory activity assays for oxidative stress, lung inflammation and neutrophil elastase (NE) were developed and used to identify the most …

Role Of Extended Release Quetiapine In The Management Of Bipolar Disorders, Martha Sajatovic

Faculty Scholarship

Atypical antipsychotics have become a widely utilized component of the bipolar disorder treatment armamentarium, with approximately 45% of bipolar patients prescribed atypicals. Over the last decade all atypical drugs except for clozapine have received a Food and Drug Administration (FDA) bipolar indication. In October 2008, the FDA approved quetiapine XR monotherapy for the treatment of acute depressive episodes of bipolar disorder and acute manic or mixed episodes in bipolar I disorder based on two placebo-control trials. Quetiapine was also approved as adjunct therapy with lithium and divalproex for the treatment of acute manic or mixed episodes as well as maintenance …

Inhibition Of Cholesterol Synthesis By Policosanol, Subhashis Banerjee

University of Kentucky Doctoral Dissertations

Cholesterol is an essential component of the cell, but excessive blood levels are a major risk factor for the development of atherosclerotic plaques that can lead to heart disease and stroke, the foremost cause of premature death in Western societies. Policosanol, a mixture of very long chain alcohols derived from sugarcane, has gained considerable attention among the public as safe and effective means to reduce blood cholesterol levels, a belief based on some early clinical studies. My research investigates one possible mechanism by which policosanol might decrease blood cholesterol levels: the inhibition of cholesterol synthesis in the liver. Previous studies …

Drug Release And Pharmacokinetic Properties Of Liposomal Db-67, Yali Liang

University of Kentucky Master's Theses

Sterically stabilized liposomes with saturated lipid as the major lipid component (DSPC:m-PEGDSPE were applied in DB-67 delivery. The drug retention in vitro and pharmacokinetic properties in vivo were investigated. Liposomal DB-67 was cleared faster from the circulation in the larger liposomes (~180 nm) than in the smaller ones (~120 nm), even though DB-67 was retained longer in smaller size liposomes in vitro. Liposomal DB-67 clearance was increased when cholesterol was present in the liposomal composition (40 mole %). It can be attributable to the faster drug release from cholesterol containing liposomes as compared to liposomes without cholesterol. Cholesterol free …

Alpha7 Nicotinic Acetylcholine Receptor Regulation In Experimental Neurodegenerative Disease, Christina Margaret Charriez

University of Kentucky Doctoral Dissertations

The α7 nicotinic acetylcholine receptor (nAChR) is involved in learning and memory, synaptic plasticity, neuroprotection, inflammation, and presynaptic regulation of neurotransmitter release. Alzheimer’s disease (AD), a neurodegenerative disease characterized by diminished cognitive abilities, memory loss, and neuropsychiatric disturbances, is associated with a loss of nAChRs. Similarly, traumatic brain injury (TBI) may result in long term neurobehavioral changes exemplified by cognitive dysfunction. Deficits in α7 nAChR expression have previously been shown in experimental TBI and may be related to cognitive impairment experienced in patients following TBI.

The purpose of this dissertation was to investigate changes in α7 nAChR expression in models …

Development Of Novel Ahr Antagonists, Hyosung Lee

University of Kentucky Doctoral Dissertations

Aryl hydrocarbon receptor (AHR) is a sensor protein, activated by aromatic chemical species for transcriptionally regulating xenobiotic metabolizing enzymes. AHR is also known to be involved in a variety of pathogenesis such as cancer, diabetes mellitus, cirrhosis, asthma, etc. The AHR signaling induced by xenobiotics has been intensively studied whereas its physiological role in the absence of xenobiotics is poorly understood. Despite a number of ligands of AHR have been reported thus far, further applications are still hampered by the lack of specificity and/or the partially agonistic activity. Thus, a pure AHR antagonist is needed for deciphering the AHR cryptic …

Modulation Of The Alpha-7 Nicotinic Acetylcholine Receptor Following Experimental Rat Brain Injury Improves Cellular And Behavioral Outcomes, Thomas Matt Woodcock

University of Kentucky Doctoral Dissertations

Traumatic brain injury (TBI) is a leading cause of death and long-term disability worldwide, and survivors are often left with cognitive deficits and significant problems with day to day tasks. To date, therapeutic pharmacological treatments of TBI remain elusive despite numerous clinical trials. An improved understanding of the molecular and cellular response to injury may help guide future treatment strategies. One promising marker for brain injury is the translocator protein (TSPO), which is normally expressed at a low level, but is highly expressed following brain damage and is associated with neuroinflammation. The isoquinoline carboxamide PK11195 binds selectively to the TSPO …

Pk/Pd Modelling Of Comb-Shaped Pegylated Salmon Calcitonin Conjugates Of Differing Molecular Weights, Sinead Ryan, Jesus Maria Frias, David H. Haddleton, David J. Brayden

Articles

Salmon calcitonin (sCT) was conjugated via cysteine-1 to novel combed-shaped end-functionalised poly(PEG) methyl ether methacrylate) (sCT-P) comb-shaped polymers, to yield conjugates of total molecular weights (MW) inclusive of sCT: 6.5, 9.5, 23 and 40 kDa. The conjugates were characterised by HPLC and their in vitro and in vivo bioactivity was measured by cAMP assay on human T47D cells and following intravenous (i.v.) injection to rats, respectively. Stability against endopeptidases, rat serum and liver homogenates was assessed. There were linear and exponential relationships between conjugate MW with potency and efficacy respectively, however the largest MW conjugate still retained 70% of E …

Isolation And Cultivation Of Equine Corneal Keratocytes, Fibroblasts And Myofibroblasts, Dylan G. Buss, Elizabeth A. Giuliano, Ajay Sharma, Rajiv R. Mohan

Pharmacy Faculty Articles and Research

Objective—To establish an in vitro model for the investigation of equine corneal wound healing. To accomplish this goal, a protocol to isolate and culture equine corneal keratocytes, fibroblasts and myofibroblasts was developed.

Animal material—Equine corneal buttons were aseptically harvested from healthy research horses undergoing humane euthanasia for reasons unrelated to this study. Slit-lamp biomicroscopy was performed prior to euthanasia by a board-certified veterinary ophthalmologist to ensure that all samples were harvested from horses free of anterior segment disease.

Procedure—Equine corneal stroma was isolated using mechanical techniques and stromal subsections were then cultured. Customized media at different culture conditions was used …