Pharmacy and Pharmaceutical Sciences Commons^™

Risk Factors For Postoperative Cognitive Dysfunction In Older Adults Undergoing Major Noncardiac Surgery, Osama Shoair

Theses and Dissertations

Background: Postoperative cognitive dysfunction (POCD) is a deterioration in cognitive function that occurs after surgery as measured by neuropsychological tests. The purpose of this study was to determine the incidence and risk factors for POCD in older adults three months after major noncardiac surgery. Methods: This is a prospective study of patients aged 65 years and older who underwent major noncardiac surgery. Patients’ cognitive function was assessed before and three months after surgery using a computerized neurocognitive battery. Blood samples were withdrawn from patients before surgery to identify patients with high level of C-reactive protein (CRP), and patients who had …

Understanding Molecular Interactions: Application Of Hint-Based Tools In The Structural Modeling Of Novel Anticancer And Antiviral Targets, And In Protein-Protein Docking, Hardik Parikh

Theses and Dissertations

Computationally driven drug design/discovery efforts generally rely on accurate assessment of the forces that guide the molecular recognition process. HINT (Hydropathic INTeraction) is a natural force field, derived from experimentally determined partition coefficients that quantifies all non-bonded interactions in the biological environment, including hydrogen bonding, electrostatic and hydrophobic interactions, and the energy of desolvation. The overall goal of this work is to apply the HINT-based atomic level description of molecular systems to biologically important proteins, to better understand their biochemistry – a key step in exploiting them for therapeutic purposes. This dissertation discusses the results of three diverse projects: i) …

Acute Pharmacological Treatment Given To Older Adults With Acute Myocardial Infarction: A Nationwide Emergency Department Study, 1992-2010, Maryam S. Alowayesh

Theses and Dissertations

OBJECTIVES: To determine the pattern and predictors of use of antiplatelet agents and beta-blockers given in the emergency department (ED) to older adults with acute myocardial infarction (AMI) and its effects on in-hospital mortality and length of hospital stay (LOS) and to determine the effect of computerized ED guideline reminders on their utilization. METHODS: A cross-sectional study using the National Hospital Ambulatory Medical Care Survey (NHAMCS) ED data for years 1992 to 2010 was conducted. Patients were included if they had an admission diagnosis of AMI (ICD-9-CM code 410.xx) and were ≥55 years. Survey logistic regression was used to examine …

Development Of Antagonists Targeting Chemokine Receptor Ccr5 And The Chemokine Receptor Ccr5 – Mu Opioid Receptor Heterodimer, Christopher Kent Arnatt

Theses and Dissertations

The chemokine receptor CCR5 (CCR5) plays an integral role within the inflammatory network of cells. Importantly, CCR5 is a mediator in several disease states and can be targeted using small molecule antagonists. Within this work, CCR5’s role in prostate cancer and HIV/AIDS has been exploited in order to develop potential therapeutics and probes. First, a series of novel compounds was designed by using pharmacophore-based drug design based upon known CCR5 antagonists and molecular modeling studies of the CCR5 receptor’s three-dimensional conformation. Once synthesized, these compounds were tested for their CCR5 antagonism and their anti-proliferative effects in several prostate cancer cell …

Kinetic And Thermodynamic Studies Of Thrombin Inhibitors, Aziz May Abdel

Theses and Dissertations

Sulfated low molecular weight lignins (LMWLs), CDSO3 and FDSO3, designed recently as macromolecular mimetics of heparin, were found to exhibit potent anticoagulant activity. Small molecules based on the same scaffold, SBD and SBT, showed promising thrombin inhibition. We were able to address the mechanism of the inhibition using Michaelis-Menten kinetics. All the molecules were found to be allosterically impairing thrombin activity using either noncompetitive or uncompetitive mechanism. Absence of competition with hirugen, an exosite 1 ligand, and competition with polymeric heparin points to exosite 2 as the site of interaction for these inhibitors. Yet mixed competition results with other exosite …

Positive Allosteric Modulators Of Alpha4beta2 Neuronal Nicotinic Receptors: Synthesis And In Vitro Studies, Atul Jain

Theses and Dissertations

des-Formylflustrabromine (dFBr), isolated from the marine organism Flustra foliacea, is the first selective, positive allosteric modulator (PAM) of α4β2 nicotinic acetylcholine receptors that potentiates the action of the neurotransmitter acetylcholine (ACh). Most agonists for this receptor population are not selective and can activate other nACh receptors. A selective PAM, which activates α4β2 nACh receptors only in the presence of ACh, might find application in the treatment of of various neurological diseases such as Alzheimer’s disease or autism. dFBr was examined and found to produce a biphasic dose-response curve over a wide concentration range (i.e., potentiation at low concentration, but inhibition …

Impacts Of Black Box Warning, National Coverage Determination, And Risk Evaluation And Mitigation Strategies On The Inpatient On-Label And Off-Label Use Of Erythropoiesis-Stimulating Agents, Arpamas Seetasith

Theses and Dissertations

Background: FDA black box warning, Risk Evaluation and Mitigation Strategies (REMS), and CMS national coverage determination (NCD) aim to reduce inappropriate use of erythropoiesis-stimulating agents (ESAs) that are widely used in anemic patients. Previous studies have not linked specific safety interventions to changes in ESA utilization patterns in the inpatient settings nor assessed such interventions on off-label use of the drugs. Ineffectiveness of the intervention and lag time between such interventions and the observed change in clinical practice could lead to serious clinical outcomes. In addition, such interventions may unintentionally reduce on-label and some off-label use of ESAs considered “appropriate” …

Design, Syntheses, And Biological Evaluation Of 14-N-Substituted Naltrexone Derivatives As Opioid Receptor Ligands, Orgil Elbegdorj

Theses and Dissertations

Opium, the dried resin obtained from the unripe seedpods of the poppy flower, has been used for medicinal and euphoric purposes since ancient times. Morphine, the main active ingredient of opium, and other clinically useful opioid analgesics all mediate their effects through activating the mu opioid receptor. Studies involving the mu opioid receptor knockout mice showed that the interaction with the mu opioid receptor is also responsible for many notorious side effects associated with these drugs including dependence and addiction. Therefore, selective antagonists for the mu opioid receptor are needed to study its function in drug abuse and addiction. Previously, …

Defining A Simplified Pharmacophore For Simocyclinone D8 Inhibition Of Dna Gyrase, Lauren Gaskell

Theses and Dissertations

The type II topoisomerase subfamily of enzymes has been clinically targeted by the widely used, broad-spectrum quinolone class of antibacterials. Due to emerging drug-resistant strains of bacteria, the quinolones’ effectiveness is threatened. The natural product simocyclinone D8 (SD8) has shown the ability to inhibit the type II topoisomerase, DNA gyrase, even when mutated to be resistant to the quinolones. In order to determine the pharmacophore required for SD8 binding to DNA gyrase, 16 compounds were synthesized. These compounds were then tested by surface plasmon resonance for their ability to inhibit the DNA – DNA gyrase binding interaction. It was found …

Effects Of Dna Damage And Cdk Inhibitors On The Nucleoli, Vineet Garg

Theses and Dissertations

The nucleolus is the primary site of ribogenesis and consists of three compartments, namely, fibrillar center (FC), dense fibrillar component (DFC) and granular component (GC). Recent studies have observed a novel structure distinct from these three compartments which forms in the nucleolus upon DNA damage called Intranucleolar body (INoB). Previous studies in our laboratory have found INoBs forming in HT1080 fibrosarcoma cell lines after ectopic overexpression of damage-inducible cell cycle inhibitor p21. This INoB formation has been observed to be decreased by Senexin A which is an inhibitor of transcription regulating kinases CDK8/CDK19.

Here we show that INoB formation correlates …

A Novel Approach To The Design Of Selective Inhibitors For Cell Cycle Cyclin Dependent Kinases, Tracy Perkins

Theses and Dissertations

CDK2/cyclin A and CDK4/cyclin D1 are proven targets for cancer drug discovery. The development of novel CDK inhibitors, with high selectivity, are being investigated by targeting the cyclin binding groove (CBG) located on the cyclin, the regulatory subunit of CDK. The CBG is a shallow area that is involved in signaling and the inhibition of cell cycle CDKs via endogenous tumor suppressors. Currently, non-peptidic inhibitors are being developed based on the recognition amino acid sequence, HAKRRLIF, of the C-terminal peptide sequence of the CDK inhibitor p21WAF1. Computational design and the utilization of non-natural amino acids are being proposed to identify …

K+ Channels And Beta3 Adrenergic Receptors As New Pharmacological Targets For Overactive Bladder Treatment, Serge Amani Yao Afeli

Theses and Dissertations

Overactive bladder (OAB) is a pathophysiological condition which is characterized by the urinary bladder's failure to achieve proper storage of urine. OAB has a tremendous impact on the patient's quality of life by disturbing his sleep, work, and sexual activity. About 17% of Americans are affected with this disease and most patients experience symptoms of urgency, frequent urination, and abnormally elevated detrusor smooth muscle (DSM) contractility. Despite, numerous attempts to treat the disorder in the past with antimuscarinics and now with beta3 adrenergic receptors (beta3-AR agonists), OAB still remains a serious public health issue because the long term efficacy of …

Bioassay Guided Fractionation Of American Ginseng. A Hexane Fraction Of American Ginseng Suppresses Colitis And Associated Colon Cancer. Mechanism Of Action., Deepak Poudyal

Theses and Dissertations

Inflammatory Bowel Disease (IBD) [Ulcerative colitis (UC) and Crohn's Disease (CD)] is a group of chronic disorders of unknown etiology characterized by inflammation in the gastrointestinal tract associated with a high colon cancer risk. UC is characterized by periods of active disease ("flare-ups"), followed by periods when the disease is inactive ("remission"). The end result is an abnormal immune response with repeated episodes of colonic inflammation. Conventional treatment of UC by aminosalicylates, TNFα inhibitors, and steroids have modest effects, and come with a high risk of side effects including dyspeptic symptoms, gastric ulceration and sometimes hospitalization and deaths. Because of …

Assessment Of The Feasibility Of Co-Administration Of Phenolic Dietary Compounds With Phenylephrine To Increase Its Bioavailability, Zhenxian Zhang

Theses and Dissertations

R-(-)-Phenylephrine (PE) is the most commonly used nonprescription oral nasal decongestant in the United States. It is a selective α1-adrenergic receptor agonist and has many years of safe usage. However, the efficacy of PE is controversial, due to its extensive pre-systemic metabolism, which leads to low and variable oral bioavailability (38 ± 9%, mean ± SD). Sulfation plays a very important role in pre-systemic metabolism of PE. The sulfation of PE occurs at its phenolic group, which is the preferred structural feature of many sulfotransferase (SULT) substrates. Compounds with phenolic groups have similar structures to PE, which may share the …

In-Vitro Pk/Pd Profiling And Modeling Of The Anti-Sickling Agents, 5-Hydroxymethyl Furfural (5-Hmf) And Novel Synthetic Allosteric Effectors Of Hemoglobin (Aeh) In Human Whole Blood, Apurvasena Parikh

Theses and Dissertations

Introduction. 5-HMF and novel INN-compounds are left-shifting AEH, shown to have anti-sickling action by forming transiently covalent Schiff-base adducts with hemoglobin (Hb), thereby increasing the Hb O2-affinity. They are hypothesized to be substrates for aldehyde dehydrogenase (ALDH) in the liver and red blood cells (RBC). Methods. Biopharmaceutical assessments were made for AEH, using calculated physicochemical properties. Their in-vitro hepatic metabolism (mediated by ALDH) was characterized using hepatic cytosol, and in-vitro-in-vivo extrapolations (IVIVE) were made. Inter-species differences in hepatic cytosolic ALDH activity were investigated using acetaldehyde as a model substrate in different mammalian species. Time- and concentration-dependent in-vitro disposition of 5-HMF …

Association Between Concomitant Use Of Bisphosphonates And Serotonin Reuptake Inhibitors And Increased Risk Of Osteoporotic-Related Fractures: Among Community-Dwelling Postmenopausal Women, Abner Nyandege

Theses and Dissertations

Osteoporosis and depression are prevalent among older postmenopausal women 65 years or older. Bisphosphonates (BPs) and selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs) are commonly used medications to treat these conditions. Inhibitory effects of BPs on osteoclasts are responsible for the reduction in fracture risk. SSRIs, however, are associated with increased fracture risk through decreasing osteoblasts and increasing osteoclastic activity. These effects of SSRIs could attenuate the beneficial effects of BPs. This dissertation describes the concomitant use of BPs and SSRIs among postmeopausa women and reports findings from examining the association between concomitant use of BPs …

Prevalence Of Anti-Diabetic And Antilipidemic Medications In Children And Adolescents Treated With Atypical Antipsychotics In A Virginia Medicaid Population, Della Varghese

Theses and Dissertations

Objective: To determine if the prevalence of anti-diabetic and antilipidemic medication use among children treated with atypical antipsychotics is higher than those not treated with antipsychotics. Methods: Virginia Medicaid beneficiaries (2-17 years) continuously enrolled from August 1, 2010 to July 31, 2011 with at least two prescription claims for atypical antipsychotics were the exposed group. All other subjects during the study period were the non-exposed group. Prevalence of anti-diabetic and antilipidemic medication use in both groups were computed and compared using Chi-square test (α=0.05). Results: A total of 299,593 and 4,922 subjects were identified as the non-exposed and exposed groups, …

Kinetics And Mechanisms Of Accumulation For Liposomal Ciprofloxacin Into Rat Alveolar Macrophages, Sayeed Mossadeq

Theses and Dissertations

The kinetics and mechanism of accumulation for liposomal ciprofloxacin (Lipo-CPFX) into the rat alveolar macrophage NR8383 cells were studied in vitro, in comparison to unformulated ciprofloxacin (CPFX). Upon incubation with CPFX or Lipo-CPFX, cellular drug accumulation was determined from the cell lysates or efflux was from the extracellular media by fluorescence-HPLC. The accumulation for Lipo-CPFX reached the asymptotic values at ≥ 2 hours, which was a result of uptake and efflux. The uptake appeared to be due to liposomes, mediated via cellular energy-independent mechanism like lipid fusion. In contrast, the efflux appeared to be due to ciprofloxacin, partly cellular energy-dependent, …

In Vitro Lung Epithelial Cell Transport And Anti-Inflammatory Activity For Liposomal Ciprofloxacin, Ruba Darweesh

Theses and Dissertations

Liposomal ciprofloxacin (Lipo-CPFX) is being developed for inhalation, with a goal of sustaining the therapeutic activity, compared to unformulated ciprofloxacin (CPFX). However, the kinetics and mechanism of its sustained local lung retention and pharmacological activity are yet to be fully characterized. This project hypothesized that Lipo-CPFX enables slower and sustained lung epithelial transport and uptake, compared to CPFX, thereby producing prolonged local pharmacological actions. The human bronchial epithelial Calu-3 cells were used as monolayers to characterize the kinetics and mechanism of transport and/or uptake, and to assess the effects of such slow kinetics for Lipo-CPFX on its inhibition against lipopolysaccharide …

The Economic Burden Of Opioid Poisoning In The United States And Determinants Of Increased Costs In Opioid Poisoning, Timothy Inocencio

Theses and Dissertations

Introduction: Opioid poisoning has been rapidly increasing in the past decade, and has been driven in large part due to increases in opioid prescribing. This has been accompanied by intervention efforts aimed at preventing and reversing opioid poisoning through naloxone prescription programs. Current literature have not quantified the economic burden of opioid poisoning. Understanding this information can help inform these efforts and bring light to this growing problem. In addition understanding various determinants of increased costs can help to identify the types of populations more likely to have greater costs. Main Objectives: The objectives are 1) to quantify the economic …

Medication-Related Problems Experienced By Patients During Transitions To Assisted Living, Deanna Flora

Theses and Dissertations

Medication reconciliation is a systematic and comprehensive review of medication regimens during care transitions aiming to prevent adverse drug events. Poorly executed transitions negatively impact patient welfare and cause financial burden. Medication-related problems (MRPs) experienced during transitions to an assisted living facility (ALF) were evaluated. Data was collected from pharmacy records for transitions to an ALF over three months, including demographics, medications, potentially inappropriate medications, and MRPs. MRPs were categorized and summarized using descriptive statistics. Forty-five patients (71% female) experienced 59 transitions. Average age was 85.6 years. Median length of stay away from the ALF was three days. There were …

The Role Of Megalin In The Transport Of Aminoglycosides Across Human Placenta, Amal Akour

Theses and Dissertations

Background: Intra-amniotic infections (IAIs) are common complications of labor and delivery. If inadequately treated, these infections can lead to significant morbidity and mortality in the mother and the fetus. Intrapartum aminoglycoside (AG) administration is recommended for the management of IAIs. AGs are known to cross the placenta and achieve bactericidal concentrations in fetal serum. However, the highest and most persistent fetal levels are achieved in renal tissue. So, the fetus may be vulnerable to the nephrotoxic effects of AGs. Megalin, a 600 kDaendocytic receptor, is responsible for the uptake of AGs into renal proximal tubular epithelial cells. This receptor is …

Costs And Use Of Oral Anti-Cancer Medications Among Senior Medicare Part D Beneficiaries, Nantana Kaisaeng

Theses and Dissertations

Oral cancer drugs are branded and expensive medications that generally do not have generics available. The restrictions of the Medicare Part D program, including the coverage gap and high cost-sharing, and the high cost of oral chemotherapy may lead to patients’ non-adherence to medication. Few studies have examined the cost and utilization of oral anti-cancer medications. This study will be the first to examine the costs associated with the use of oral anti-cancer medications and the impact of cost-sharing and type of prescription drug subsidy on medication discontinuation in the Medicare Part D elderly population. Objectives: To determine the usage …

A New Approach To Dried Blood Spot Analysis For Newborn Screening Using High Resolution Liquid Chromatography Tandem Mass Spectrometry, John H. Miller Iv

Theses and Dissertations

The primary purpose of newborn screening is to quickly identify children that are at risk of having a specific disorder in order to start treatment, prevent early death and reduce the chances of permanent physical or mental damage. The current and widely accepted approach used for identification of metabolism disorders involves a flow injection analysis with mass spectrometry detection of acylcarnitines and amino acids. Although this approach is widely accepted and has shown to be sufficient for identification of multiple metabolism disorders the method is not fully quantitative and results often have to be confirmed by second-tier tests. The primary …

Capture And Characterization Of Dioxygen Reactive Intermediates In Cyp51 Catalysis, Gareth Kent Jennings

Theses and Dissertations

The cytochromes P450 (CYPs) are a superfamily of biological catalysts that are ubiquitous throughout the biological domain. CYPs are heme-b containing monooxygenases which oxidize substrates with the help of accessory redox partners. CYP substrates include endogenous compounds required for many biological functions and homeostasis, such as steroids, as well as the majority of clinically used drugs and environmental xenobiotics. The majority of studies that have been performed to date are on P450cam (CYP101) from Pseudomonas putida. Of the numerous reactions catalyzed by CYPs, unactivated carbon-carbon bond cleavage, is one of particular versatility. Being unique in their catalytic mechanisms, the C-C …

Influence Of Electrostatic Charge Upon The Deposition Behavior Of Pharmaceutical Aerosols Within Cascade Impactors, Megha Mohan

Theses and Dissertations

Cascade impactors, routinely used for in vitro particle size characterization of pharmaceutical aerosols, are calibrated using dilute, charge-neutralized, monodisperse aerosols. But pharmaceutical aerosols are known to generate concentrated, inherently charged, polydisperse aerosol clouds. A computational model of the Andersen Cascade Impactor (ACI) suggested that the presence of charge on aerosol particles may influence their deposition within the ACI, but experimental validation of the model is warranted. This dissertation investigates the influence of electrostatic charge upon the deposition behavior of aerosols within cascade impactors, to address the impact of charge on particle size characterization. The influence of applied charge upon the …

Discovery And Biophysical Characterization Of Allosteric Inhibitors Of Factor Xia (Fxia), Malaika Argade

Theses and Dissertations

Thrombosis is one of the leading causes of mortality and morbidity that is associated with myocardial infarction, stroke and pulmonary embolism. Anti-thrombotic agents which intend to reduce the occurrence and severity of thrombosis usually target the enzymes of the coagulation cascade. FXIa, a 160 kDa homodimer is gaining popularity of late as a potential target for anti-thrombotic agents due to its relative safety. A number of inhibitors which target the active site of FXIa have been reported but to our knowledge there have been no inhibitors which act via an allosteric mechanism. The aim of this project was to screen …

Α2-Adrenoceptor And 5-Ht3 Serotonin Receptor Ligands As Potential Analgesic Adjuvants, Genevieve Alley

Theses and Dissertations

There continues to be a need for more effective analgesics. The α2-adrenoceptor (AR) agonist clonidine is an analgesic whose use is severely limited by undesirable side effects. meta-Chlorophenylguanidine (MD-354), an agent developed in our laboratory, selectively potentiates the antinociceptive effects of clonidine in a biphasic manner. Mechanistic studies suggest that both 5-HT3 receptor and α2-AR mechanisms are involved. To further evaluate mechanisms underlying the analgesia-potentiating effect of clonidine by MD-354, pharmacological studies using more established 5-HT3 receptor agonists: meta-chlorophenylbiguanide (mCPBG) and centrally-acting SR57227A, and non-selective α2-adrenoceptor ligand TDIQ, administered alone and in combination with clonidine, were conducted in mouse antinociceptive …

Assessment Of The Role Of Solute Carrier Drug Transporters In The Systemic Disposition Of Fluoroquinolones: An In Vitro - In Vivo Comparison, Aditi Mulgaonkar

Theses and Dissertations

Fluoroquinolones (FQ) are broad-spectrum charged antimicrobials exhibiting excellent tissue/fluid permeation. Thus, FQ disposition depends essentially on active transport and facilitative diffusion. Although most early transporter studies investigating renal elimination of FQs have focused on apical efflux of FQs from renal proximal tubule cell (RPTC) into urine, their basolateral uptake mechanism(s) from blood into RPTC (i.e., first step to tubular secretion) has not yet been explored in detail. Renally expressed SLC22 members: organic anion (OATs) and cation (OCTs) transporters are known to transport such small organic ionic substrates (molecular weight ~400 Da). Hence it is of interest to explore the role …

In Vitro In Vivo Methods And Pharmacokinetic Models For Subcutaneously Administered Peptide Drug Products, Amit Somani

Theses and Dissertations

Over the last several years, injectable drugs have been a growing area for the treatment of various therapeutic conditions and they are projected to comprise an even larger proportion among the drugs that will be available in the years to come. The injectable drugs are administered by various routes such as intramuscular (IM), intravenous (IV), subcutaneous (SC) and others, however, the majority of these drugs are administered subcutaneously. Even though subcutaneous delivery has been utilized for a number of years, very little is known about the processes governing the absorption of macromolecules from the interstitial space; and the resulting impact …