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Articles 1 - 16 of 16
Full-Text Articles in Medicine and Health Sciences
Development Of Dual-Pathway Inhibitors Of Raf/Mek/Erk And Pi3k/Akt Signaling Pathways., Sasha Fraser
Development Of Dual-Pathway Inhibitors Of Raf/Mek/Erk And Pi3k/Akt Signaling Pathways., Sasha Fraser
Theses and Dissertations
In the present study, we designed a new chemical template that contains an oxindole moiety as potential dual-pathway inhibitors of the Raf/MEK/ERK and PI3K/Akt signaling pathways. The design hypothesis is to evaluate whether the oxindole ring system will approximately orient functional groups in a similar manner to the thiazolidinedione moiety, and thus maintain biological activity as dual-pathway inhibitors of the Raf/MEK/ERK and PI3K/Akt signaling pathways. Furthermore, the oxindole ring will provide the flexibility to allow the introduction of various substituents on the oxindole moiety, thereby facilitating comprehensive SAR studies to further explore the biological activity.
Medication-Related Problems In Older Adults: A Focus On Underuse Of Warfarin And Warfarin-Antibiotic Interactions, Parinaz K. Ghaswalla
Medication-Related Problems In Older Adults: A Focus On Underuse Of Warfarin And Warfarin-Antibiotic Interactions, Parinaz K. Ghaswalla
Theses and Dissertations
The work presented in this dissertation focuses on two important medication-related problems in older adults, that is, untreated indication and drug-drug interactions, specifically with respect to a high-risk medication such as warfarin. Warfarin is a challenge to use in clinical practice due to its narrow therapeutic index, variability in dose-response and its interactions with numerous foods and drugs. This dissertation presents the research from two projects. In the first project the prevalence and predictors of warfarin use in nursing home (NH) residents with atrial fibrillation (AF), and use of secondary stroke prevention strategies was determined, in order to understand the …
Development Of A Novel Approach To Assess Qualitative And Quantitative Dynamics Associated With The Subcutaneous Or Intramuscular Administration Of Pharmaceuticals And Associated Parenteral Delivery Systems, Eric Edwards
Theses and Dissertations
There has been a significant increase in the number of injectable pharmaceutical products over the last decade that have been incorporated into unique delivery systems such as pen injectors, auto-injectors, or pre-filled syringes. The advancement of these delivery systems and the paradigm shift towards administration of injectables in the out-of-hospital or home setting have introduced variables that can affect the bioavailability of injectable drugs and potential pharmacologic outcomes. An approach that allows for the qualitative and quantitative dispersion assessment of an injectable at the moment of tissue deposition coupled with an assessment of systemic exposure parameters could provide substantial information …
Fluctuations And Instantons In Complex Landscapes: From Ligand Unbinding To Proton Transfer, Justin Elenewski
Fluctuations And Instantons In Complex Landscapes: From Ligand Unbinding To Proton Transfer, Justin Elenewski
Theses and Dissertations
Biophysical entities are complex systems systems with strong environmental coupling, dominated by fluctuations on a hierarchy of timescales. These properties confound simulation of ligand binding and catalysis, inflating the scale of the problem to one tractable only with a considerable outlay of resources. In an attempt to ameliorate this restriction, several techniques are developed to accelerate biomolecular simulations while collaterally lending physical insight. The first segment of this dissertation is concerned with directed simulations of ligand binding in a model system. Using the serum retinol binding protein as a prototype, the potential of mean force associated with ligand binding is …
Designing Allosteric Inhibitors Of Thrombin, Preetpal Sidhu
Designing Allosteric Inhibitors Of Thrombin, Preetpal Sidhu
Theses and Dissertations
Thrombin is a key enzyme of the coagulation cascade exhibiting important roles in both pro-coagulation and anti-coagulation processes. Most clinically used anticoagulant drugs, including polymeric heparin, warfarin, hirudin, argatroban and the recently approved dabigatran, aim to reduce thrombin activity. There are several binding domains on thrombin including the active site, anion-binding exosites I and II, and the sodium binding site. We hypothesized that thrombin may be better regulated through an allosteric process mediated by small molecules binding to either exosite I or II. An appropriately designed allosteric regulator that reduces the procoagulant signal in a finely tuned manner may maintain …
Effect Of Combined Oral Contraceptives On Insulin Clearance In Lean And Obese Pre-Menopausal Women, Vidya Moorthy
Effect Of Combined Oral Contraceptives On Insulin Clearance In Lean And Obese Pre-Menopausal Women, Vidya Moorthy
Theses and Dissertations
Introduction: Obese women are predisposed to greater risks of insulin resistance and compensatory hyperinsulinemia. Likewise, African-Americans, appear to be inherently insulin resistant and hyperinsulinemic even after controlling for obesity. Hyperinsulinemia has been attributed to insulin resistance and a compensatory insulin hyper-secretion by the pancreas, as well as decreased insulin clearance, notably in obesity. Pharmacological agents that may worsen insulin resistance/hyperinsulinemia in obese women is of clinical relevance. Previous data from our group suggested that combined oral contraceptives (COCs) may worsen insulin sensitivity particularly in obese women, but limited information on insulin clearance is available in obese women or African-American women. …
Water Molecules: A Closer Look At Their Behavior At Protein-Protein Interfaces And Their Contributions To The Docked Model Of Pyridoxal Kinase - Serine Hydroxymethyltransferase Complex, Mostafa H. Ahmed
Theses and Dissertations
The work in this thesis is divided into two aims. The first aim is to provide a detailed analysis of water molecules at protein-protein interfaces as well as quantifying their contributions with respect to different residue types. To achieve this aim a data set of 4741 water molecules abstracted from 179 high-resolution (≤ 2.30 Å) X-ray crystal structures of protein-protein complexes was analyzed with a suite of modeling tools based on HINT. The second aim is to observe the effect of adding interfacial water molecules in developing a model for the protein-protein interaction between pyridoxal kinase and serine hydroxymethyltransferase. This …
Quantifying Polypharmacy In Diabetes Patients In The U.S., Jing Tao
Quantifying Polypharmacy In Diabetes Patients In The U.S., Jing Tao
Theses and Dissertations
ix Objectives: To quantify polypharmacy and assess the socio-economic predictors of medication use and expenditure in diabetics. Methods: This study analyzed adult diabetes patients using a nationally representative sample in Medical Expenditure Panel Survey in 2006. Top ten most highly utilized drug classes were identified. Descriptive statistics were used to portray the patients’ medication utilization and spending. Generalized linear models were conducted to assess the socio-economic variants in drug use and spending. Results: On average, a diabetes patient had 45 prescriptions in 2006, for total annual spending of $3,161. A diabetes patient used drugs from 3.43 classes within top ten …
Analysis And Fingerprinting Of Glycosaminoglycans, Joseph King
Analysis And Fingerprinting Of Glycosaminoglycans, Joseph King
Theses and Dissertations
Heparin is a complex mixture of sulfated polysaccharides derived from animals and one of the oldest drugs in use. While an efficacious anticoagulant, heparin is beset by side effects and pharmacokinetic difficulties. Low molecular weight heparins (LMWH) are made by depolymerizing unfractionated heparin (UFH) and present improvements in these areas. However, they still retain a phenomenally high level of complexity due to their polydispersity and the introduction of non-native structural features. This makes the structural characterization LMWHs a daunting task. This work details the development of a novel capillary electrophoretic (CE) method for fingerprinting LMWHs. Since their complexity normally results …
Sythesis And Biological Screening Of A Series Of Novel Chemokine Receptor Ccr5 Antagonists, Soundarya Vaithianathan
Sythesis And Biological Screening Of A Series Of Novel Chemokine Receptor Ccr5 Antagonists, Soundarya Vaithianathan
Theses and Dissertations
The chemokine receptor CCR5 has been implicated in the pathogenesis of cancers and AIDS. A series of novel piperidine derivatives were designed, synthesized, and evaluated as CCR5 antagonists. The ability of the new ligands to inhibit the increment of intracellular calcium level stimulated by endogenous ligand CCL5 was measured in the calcium mobilization assay as an indication of its CCR5 receptor antagonism. The anti-proliferation assay was performed to measure the ability of these new compounds to inhibit the proliferation of prostate cancer cell lines, PC-3 and M12. A new lead compound has been identified which showed micromolar level of inhibition …
Synthesis Of A Library Of Sulfated Small Molecules, Shrenik Mehta
Synthesis Of A Library Of Sulfated Small Molecules, Shrenik Mehta
Theses and Dissertations
The discovery of heparin in 1916 resulted in a huge impact on the practice of medicine. Heparin has played a major role in alleviating thrombotic disorders and has also exhibited effects on almost every major system in the human body. Over the past few decades, more and more heparin-protein interactions have come to light. It is implicated to modulate several important processes such as cell growth and differentiation, inflammatory response, viral infection mechanism etc. More interesting is the observation that these interactions are considerably specific with regard to oligosaccharide sequences which have specific spatially oriented sulfate groups modulating the responses. …
Impact Of Medicare Part D Coverage Gap On Beneficiaries' Adherence To Prescription Medications, Urvi Desai
Impact Of Medicare Part D Coverage Gap On Beneficiaries' Adherence To Prescription Medications, Urvi Desai
Theses and Dissertations
INTRODUCTION: Medicare Part D provides prescription drug coverage to seniors through a benefit plan with a major deductible inserted in the middle. It is important to study the extent to which this structure affects seniors’ adherence to prescription medications. Therefore, this study had the following objectives: (1) To identify characteristics of beneficiaries reaching and not reaching the coverage gap, (2) To study the entry and exit times from the coverage gap, (3) To study the impact of a complete gap in coverage on beneficiaries’ adherence to prescription medications, (4) To study the impact of a partial gap in coverage on …
Application Of Pharmacometric Methods To Improve Pediatric Drug Development, Mallika Lala
Application Of Pharmacometric Methods To Improve Pediatric Drug Development, Mallika Lala
Theses and Dissertations
Pharmacometrics is a quantitative science that is rapidly changing the landscape of drug development, and particularly so for the pediatric population. The motivation behind the research underlying this dissertation is to contribute towards the improvement of pediatric drug development by the astute application of pharmacometric methods. Two distinct research areas have been focused upon: 1- improving pediatric pharmacokinetic (PK) trial design and 2- improving pediatric dosing of warfarin by using a genetics-based dosing regimen. The first project examined in detail the feasibility of and simulation-based methodology for implementing a recent regulatory PK quality standard. The focus was on designing pediatric …
“Clicked” Bivalent Multifunctional Ligands In Alzheimer’S Disease., Ronak Gandhi
“Clicked” Bivalent Multifunctional Ligands In Alzheimer’S Disease., Ronak Gandhi
Theses and Dissertations
Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by beta-amyloid (Aβ) aggregation/oligomerization, biometal dyshomeostasis, oxidative stress, and neuroinflammation. The multifactorial nature of AD may indicate the therapeutic potential of multifunctional ligands that tackle various risk factors simultaneously as effective AD-modifying agents. This notion is further supported by the fact that while numerous AD-modifying agents targeting one single risk factor have been developed and a number of them entered clinical trials, none of them has been successfully approved by the FDA. Furthermore, neuronal cell membrane/lipid rafts (CM/LR) have been demonstrated to associate with all the indicated risk factors, indicating that this …
Synthesis, Screening And Cocrystallization Of Adenosine Based Inhibitors With Methyltransferases, Ermc' And Ksga, Matthew Baker
Synthesis, Screening And Cocrystallization Of Adenosine Based Inhibitors With Methyltransferases, Ermc' And Ksga, Matthew Baker
Theses and Dissertations
Antibiotic resistance threatens to throw mankind back into an era when infectious disease was the predominant cause of death. In an effort to mitigate this danger, we targeted ErmC’ and KsgA. Both methylate N6-adenosine of ribosomal RNA, though each serve different roles in their bacterial host. ErmC’ dimethylates A2058 on 23S rRNA, conferring resistance to MLSB antibiotics (macrolides, lincosamides, streptogramin B). KsgA aids in ribosome assembly, binding inactive 30S until dimethylating A1518/A1519 of 16S rRNA. Like most methyltransferases, ErmC’ and KsgA use cofactor S-adenosylmethionine (SAM) as their methyl source, which binds adjacent to their specific adenosine substrate. ErmC’ inhibitors could …
Biochemical Evaluation Of Lignin-Like Molecules, Jay Thakkar
Biochemical Evaluation Of Lignin-Like Molecules, Jay Thakkar
Theses and Dissertations
Current anticoagulants carry a serious risk of bleeding complications. In addition, narrow therapeutic index, drug interactions, immunological reactions, toxicity and high cost to benefit ratio limits the effective use of these drugs in patients with thrombotic conditions.Heparin is the most widely used anticoagulant. We hypothesized that one of the major drawback of heparins, its non-specific interaction with the plasma proteins arises as a result of negative charges. To reduce these non-specific interactions, our laboratory designed sulfated low molecular weight lignin (LMWL) like biomacromolecules, which were found to be direct inhibitors of thrombin and factor Xa, acting through a unique exosite-2 …