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Articles 301 - 330 of 384
Full-Text Articles in Pharmacy and Pharmaceutical Sciences
Prediction Of Human Systemic, Biologically Relevant Pharmacokinetic Properties Based On Physicochemical Properties Of Calcium Channel Blockers, Tafif Abdullah Al
Prediction Of Human Systemic, Biologically Relevant Pharmacokinetic Properties Based On Physicochemical Properties Of Calcium Channel Blockers, Tafif Abdullah Al
Theses and Dissertations
This research explored quantitative relationships (QSPKR) between different molecular descriptors and pertinent, systemic PK properties for 14 calcium channel blockers (CCB). Physicochemical properties (PC) such as molecular weight (MW), molar volume (MV), calculated logP (clogP), pKa, calculated logD7.4 (clogD), % ionized at pH 6.3 and pH 7.4, hydrogen bond donors (HBD), hydrogen bond acceptors (HBA), and number of rotatable bonds (nRot) were chosen as possible predictor variables for systemic PK properties for CCB, obtained from pertinent literature, assessing the PK of CCB after intravenous administration to healthy humans. All PC properties and molecular descriptors were computed using ACD-solubility/DB 12.01. Total …
Preparation And Evaluation Of Deconstruction Analogs Of 7-Deoxykalafungin As Akt Inhibitors, Sudha Korwar
Preparation And Evaluation Of Deconstruction Analogs Of 7-Deoxykalafungin As Akt Inhibitors, Sudha Korwar
Theses and Dissertations
Pyranonaphthoquinone lactones have been recently found to be selective inhibitors of the serine-threonine kinase AKT/PKB. AKT/PKB plays a major role in tumorigenesis, hence these compounds have a great potential to act as anti-cancer agents. They act by a novel bioreductive alkylation mechanism of inhibition of AKT/PKB. In this work, 7-deoxykalafungin, a pyranonaphthoquinone lactone and its deconstruction analogs were synthesized. The structural features of the compounds necessary to inhibit AKT1 potently and selectively were determined. It was observed that compounds with a pyran ring were more potent in inhibiting AKT1. Conversely, flexible compounds were found to be weak inhibitors of AKT1. …
Towards Understanding The Mechanism Of Action Of Abused Cathinones, Rakesh Vekariya
Towards Understanding The Mechanism Of Action Of Abused Cathinones, Rakesh Vekariya
Theses and Dissertations
The dopamine transporter (DAT) mediates reuptake of dopamine from the synaptic cleft into the presynaptic terminus and plays a critical role in maintaining the normal function of dopaminergic neurons. DAT is the major target of widely abused psychostimulant drugs, including cocaine and amphetamine. DAT also figures into disease states, and it is a target for therapeutic drugs. It is known that cathinone and methcathinone, β-keto analogs of amphetamine and methamphetamine, respectively, produce pharmacological actions similar to amphetamine. Cathinone and methcathinone analogs are recently gaining in popularity on the clandestine market (e.g. ‘bath salts’). Cathinone and methcathinone analogs as well as …
Small Molecules As Negative Allosteric Modulators Of Alpha7 Nachrs, Osama Alwassil
Small Molecules As Negative Allosteric Modulators Of Alpha7 Nachrs, Osama Alwassil
Theses and Dissertations
Alpha7 Neuronal nicotinic acetylcholine receptors (nAChRs) are involved in essential physiological functions and play a role in disorders such as Alzheimer’s disease. MD-354 (3-chlorophenylguanidine; 21), the first small–molecule negative allosteric modulator (NAM) at alpha7 nAChRs, served as a lead in developing structure–activity relationships for NAMs at a7 nAChRs. MD-354 (21) also binds at 5-HT3 receptors. Analogs of MD-354 with structural features detrimental to 5-HT3 receptor affinity were evaluated in patch-clamp recordings and an aniline N-methyl analog resulted in a more potent and selective NAM than MD-354. A new N-methyl series of compounds was synthesized in which the 3-position was replaced …
Development And Comparison Of Risk-Adjusted Models To Benchmark Antibiotic Use In The University Healthsystem Consortium Hospitals, Omar Moh'd Musa Ibrahim
Development And Comparison Of Risk-Adjusted Models To Benchmark Antibiotic Use In The University Healthsystem Consortium Hospitals, Omar Moh'd Musa Ibrahim
Theses and Dissertations
Background. Infectious diseases societies recommend that hospitals risk-adjust their antimicrobial use before comparing it to their peers, a process called benchmarking. The purpose of this investigation is to apply and compare 3 risk-adjustment procedures for benchmarking hospital antibacterial consumption (AbC). Two standardization of rates procedures, direct and indirect standardization, are compared with one another as well as with regression modeling. Methods. Total aggregate adult AbC for 52 systemic antibacterial agents was measured in 70 hospitals that subscribed to the University HealthSystem Consortium Clinical Resource Manager database in 2009 and expressed as days of therapy (DOTs) per either 1000 patients days …
Synthesis And Biological Evaluation Of Second Generation Anibamine Analogues As Novel Anti-Prostate Cancer Agents, Shilpa Singh
Synthesis And Biological Evaluation Of Second Generation Anibamine Analogues As Novel Anti-Prostate Cancer Agents, Shilpa Singh
Theses and Dissertations
Prostate cancer is the most prevalent non-cutaneous cancer among men. Since the 19th century when Virchow first introduced the concept of inflammation in cancer, chemokines and their receptors have garnered a lot of interest. Chemokine receptor CCR5 has been especially implicated in many disease states and recently found to be over expressed in prostate cancer cell lines. Anibamine, a natural CCR5 antagonist discovered in 2004, has been found to have significant anti-prostate cancer activity at micromolar level. To optimize this compound and also discover a novel pharmacophore, exploration of the original structure was carried out. Significant modifications were made to …
Therapeutic Drug Monitoring Of Factor Viii Prophylaxis Using Its Plasma Coagulant Activity And Global Hemostasis Biomarkers: A Pharmacokinetic/Pharmacodynamic Pilot Study, Hawaj Maitham Al
Theses and Dissertations
Background: The current clinical practice of factor VIII (FVIII) prophylaxis revolves around converting patients with severe hemophilia A, hereafter simply referred to as hemophilia, phenotype (defined as plasma factor VIII coagulant activity [FVIII:C] <1 IU dL-1) to moderate hemophilia phenotype (defined as plasma FVIII:C from 1–5 IU dL-1). However, a wide inter-individual variation in bleeding tendency is observed despite changes in plasma FVIII:C (pharmacokinetic [PK] changes). Therefore, monitoring FVIII prophylaxis by global hemostasis biomarkers (pharmacodynamic [PD] response) can potentially be beneficial. Objective: To conduct appropriate PK/PD modeling using plasma FVIII:C and global hemostasis (platelet function and blood viscoelastic) biomarkers in severe hemophilia. Methods: Nine non-bleeding severe hemophiliacs (plasma FVIII:C <1 IU dL-1) with variant bleeding tendency (5 frequent bleeders and 4 infrequent bleeders) were infused with a recombinant factor FVIII (rFVIII) prophylactic dose (mean = 32.1 international units per kilogram [IU kg-1]). Blood was collected at baseline and 0.5-, 1-, 2-, 4-, 8-, 12-, 24- and 48-hours (h) post-dose for plasma FVIII:C, platelet function (platelet contractile force [PCF], clot elastic modulus [CEM] and force onset time [FOT]) and blood viscoelastic (reaction-time [R], kinetics-time [K] and maximum amplitude [MA]) biomarkers and activated partial thromboplastin time (aPTT). Non-compartmental analysis (NCA) was performed using standard methods. Compartmental analysis (CA) and PK/PD modeling were performed by non-linear regression. Correlation and analysis of variance (ANOVA) were used to explore the role of clinically relevant modifiers of bleeding tendency, as appropriate. ANOVA was used to assess inter-group differences in pertinent PK and PD parameters. P value <0.05 significance level was pre-specified for all statistical tests. Results: Mean (±SD) volume of distribution at steady state (Vss), total clearance (CLtot) and terminal half-life (t1/2) from NCA were 40.5 (±11.2) milliliter per kilogram (mL kg-1), 2.9 (±1.2) milliliter per hour per kilogram (mL h-1 kg-1) and 11.6 (±6.2) h, respectively. Mean (±SD) Vss and CLtot from the one-compartment body model (CA) were 39.6 (±8.9) mL kg-1 and 3.1 (±1.3) mL h-1 kg-1, respectively. The mean (±SD) baseline effect (E0) and slope from the PK/PD linear modeling were: for aPTT, 48.9 (±4.4) seconds (sec) and -0.025 (±0.009) second deciliter per international unit (sec dL IU-1), respectively; for PCF, 0.3 (±0.3) kilodynes (kdynes) and 0.008 (±0.004) kilodynes deciliter per international unit (kdynes dL IU-1), respectively; and for CEM, 0.0 (±0.0) kilodynes per square centimeter (kdynes cm-2) and 0.032 (±0.016) kilodynes deciliter per international unit per square centimeter (kdynes dL IU-1 cm-2), respectively. The mean (±SD) maximum effect (Emax) and half the maximum effective concentration (EC50) from the PK/PD sigmoidal Emax model were: for FOT, 70.1 (±16.9) % reduction and 87.8 (±31.4) IU dL-1 for FOT, respectively; for R, 74.9 (±26.0) % reduction and 68.5 (±28.4) IU dL-1, respectively; and for K, 73.2 (±36.4) % reduction and 67.2 (±29.0) IU dL-1, respectively. MA was not PK/PD modeled due to its low sensitivity. Conclusions: Plasma FVIII:C remained ≥1 IU dL-1 over the prophylactic interval. FOT and R were the most sensitive biomarkers at lower plasma FVIII:C. PCF and CEM were more sensitive than K and aPTT at lower plasma FVIII:C. MA was the least sensitive biomarker. Correlation and inter-group differences did not reach statistical significance (small sample size). These results may be used to assess risk of bleeding and dose-optimize FVIII prophylaxis in severe hemophilia.
Quantitative Analysis Of Multiple Charged Large Molecules In Human Or Rat Plasma Using Liquid Chromatography Tandem Mass Spectrometry, Matthew Halquist
Quantitative Analysis Of Multiple Charged Large Molecules In Human Or Rat Plasma Using Liquid Chromatography Tandem Mass Spectrometry, Matthew Halquist
Theses and Dissertations
Immunoassays have traditionally been employed for the determination of plasma concentration-time profiles for pharmacokinetic studies of therapeutic proteins and peptides. These ligand binding assays have high sensitivity but require significant time for antibody generation (1 to 2 years) for assay development. Despite high sensitivity, these assays suffer from cross-reactivity that can lead to inaccurate results. As an alternative to immunoassays, this dissertation was focused on the development and validation of assays that can be used for quantitative analysis of peptides or proteins in plasma using liquid chromatography tandem mass spectrometry (LC-MS/MS). Two approaches were considered for measurement of proteins and …
In Vitro Methods To Predict Aerosol Drug Deposition In Normal Adults, Renishkumar Delvadia
In Vitro Methods To Predict Aerosol Drug Deposition In Normal Adults, Renishkumar Delvadia
Theses and Dissertations
This research was aimed at the development and validation of new in vitro methods capable of predicting in vivo drug deposition from dry powder inhalers, DPIs, in lung-normal human adults. Three physical models of the mouth, throat and upper airways, MT-TB, were designed and validated using the anatomical literature. Small, medium and large versions were constructed to cover approximately 95% of the variation seen in normal adult humans of both genders. The models were housed in an artificial thorax and used for in vitro testing of drug deposition from Budelin Novolizer DPIs using a breath simulator to mimic inhalation profiles …
A Cellular Automata Model Of Enantiomer Interactions With Beta-Cyclodextrin, Desoi Darren
A Cellular Automata Model Of Enantiomer Interactions With Beta-Cyclodextrin, Desoi Darren
Theses and Dissertations
The binding mechanisms of molecules to cyclodextrins continues to be studied to better explain the interactions occurring. The majority of published models focus on one-to-one molecular binding thermodynamics to explain experimental results. They rely on physical concepts of energies and forces to guide the actions of molecules expressed mathematically in terms of differential and non-linear equations. These models are limited in scope due to their complexity and are not easily expanded to study many diverse analytes. Conversely, cellular automata uses simple mathematical idealizations of systems governed by deterministic and probabilistic rules that are easily adaptable to many types of molecular …
Predictors Of Carbapenem Resistant Gram-Negative Bacteria In A Consortium Of Academic Medical Center Hospitals, Mera Ababneh
Predictors Of Carbapenem Resistant Gram-Negative Bacteria In A Consortium Of Academic Medical Center Hospitals, Mera Ababneh
Theses and Dissertations
Background: Gram-negative resistance is a growing problem worldwide. It is generally believed that rates of resistant bacteria within a hospital are a function of antibiotic use, resistant organisms brought into the hospital, infection control efforts, and underlying severity of patient illness. The relative contribution of each to a particular resistance phenotype is unclear. P. aeruginosa is responsible for many hospital acquired infections and it may become resistant to carbapenems. In addition, newer threats to the future utility of the carbapenems are carbapenemase-producing K. pneumoniae Purpose: To determine if there is an association between the volume and composition of antibiotic use, …
Factors Influencing Pharmacists’ Decision To Report Adverse Events Related To Dietary Supplements, Ali M. Alhammad
Factors Influencing Pharmacists’ Decision To Report Adverse Events Related To Dietary Supplements, Ali M. Alhammad
Theses and Dissertations
Background: The increasing consumption of dietary supplements (DS) has drawn the attention of regulatory agencies, researchers and healthcare professionals. The US Food and Drug Administration (FDA) does not require premarketing assessment of DS considering them safe unless proven otherwise. However, the reporting rate of DS adverse events (DS-AE) is low. Objective: To describe pharmacists’ attitudes and knowledge of DS and DS information resources, and to determine the importance of selected attributes in pharmacists’ decisions to report a DS-AE. Methods: A convenience sample of practicing pharmacists in Virginia was surveyed using a web-based self-administered questionnaire. A conjoint analysis exercise was developed …
Designing Direct And Indirect Factor Xa Inhibitors, Rami Al-Horani
Designing Direct And Indirect Factor Xa Inhibitors, Rami Al-Horani
Theses and Dissertations
Anticoagulants are the basis for treatment and prevention of thrombotic diseases. The currently available medicines are associated with a wide range of adverse reactions that mandates developing new anticoagulants. Several lines of evidence support the superiority of factor Xa (FXa) as a promising target to develop novel anticoagulants. This work focuses on the design of direct and indirect FXa inhibitors using an interdisciplinary approach. As indirect FXa inhibitors, a focused library of tetrasulfated N–arylacyl tetrahydroisoquinoline (THIQ) nonsaccharide allosteric antithrombin activators was designed, synthesized, and biochemically evaluated to establish their structure–activity relationship (SAR). An N–arylacyl THIQ analog having carboxylate at position–3, …
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 …
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 …
“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 …
Utilization Patterns And Economic Impact Of Iv Iron And Erythropoiesis Stimulating Agents In Chronic Kidney Disease Patients: A Multi-Hospital Study, Avani Joshi
Theses and Dissertations
Background: Chronic kidney disease (CKD) affects approximately 20 million Americans and is the cause of significant morbidity and mortality. Anemia, common in CKD, develops early in the disease process. It contributes to increased risk of cardiovascular disease, hospitalization, mortality, and diminishes health-related quality of life. Intravenous iron and Erythropoiesis Stimulating Agents (ESAs) are recommended for anemia management in CKD. The utilization patterns of IV iron and ESA, and their impact on hospital costs and length of stay merits investigation. Objectives: There were five general objectives of this investigation. The rate and extent of utilization of IV iron in anemic CKD …