Pharmacy and Pharmaceutical Sciences Commons^™

Identification Of Clinical, Laboratory And Genetic Covariates For Pharmacokinetics, Efficacy And Toxicity Of Sorafenib In Patients With Solid Tumors, Lokesh Jain

Theses and Dissertations

The goal of this research work was to understand the clinical-pharmacology based treatment approaches for sorafenib. Treatment with sorafenib is associated with high inter-patient variability in pharmacokinetic exposures, efficacy and toxicity. We explored the demographic, laboratory, clinical and pharmacogenetic factors to elucidate the sources of variability. In addition, we examined the impact of pharmacogenetic variation in VEGFR2, an important mediator of the VEGF pathway, on risk of prostate cancer. To support these investigations, (mainly single-dose) pharmacokinetic, pharmacogenetic, efficacy and toxicity information were collected from patients with solid tumors, enrolled in five phase I / II clinical trials at National Cancer …

Age-Related Differences In In-Vitro Sensitivity To Inhibition Of Human Red Blood Cell Acetylcholinesterase And Plasma Butyrylcholinesterase By The Cholinesterase Inhibitors Physostigmine (Phys), Pyridostigmine (Pyr), Donepezil (Don) And Galantamine (Gal), David Lee

Theses and Dissertations

Alzheimer’s disease (AD) is a chronic, progressive neurodegenerative disorder, characterized clinically by a progressive loss of memory, cognitive function, ability to care for oneself and psychiatric symptoms. First-line agents for the treatment of AD are ChE inhibitors (DON, GAL), whose modest clinical efficacy and the high incidence of dose-limiting toxicities limit their clinical utility. In addition to AD, ChE inhibitors (PYR) are used for other medical conditions, such as myasthenia gravis (MG). Furthermore, ChE inhibitors (PYR) are used by military personnel prophylactically if impending exposure to chemical warfare agents, e.g., soman, is suspected. The purpose of this research project was …

To Evaluate The Level Of Agreement Between Two Self-Reported Medication Adherence Scales And Prescription Refill Records In Older Adults, Priyanka Kakad

Theses and Dissertations

Objective: To evaluate the level of agreement between two self-reported medication adherence scales and prescription refill records in older adults. Design: Cross-sectional study Setting: Imperial Plaza; a retirement community located in Richmond, Virginia. Participants: 32 independent-living older adults, taking anti-hypertensive medications and filling their prescriptions at on-site Plaza Professional Pharmacy were recruited in the study. Methods: Participants’ 6 months refill records were obtained and Medication Possession Ration (MPR) was calculated. Participants were interviewed using Morisky Medication Adherence Scale (MMAS) & Brief Medication Questionnaire (BMQ). Kappa statistics was used to evaluate the level of agreement. Results: Poor level of agreement was …

Factors Influencing Placental Transfer Of Lopinavir: Binding, Uptake And Efflux, Abhishek Gulati

Theses and Dissertations

HIV protease inhibitors are an important component of Highly Active Antiretroviral Therapy used to treat HIV infected pregnant women. They have a low placental transfer and are highly plasma protein bound. The purpose of this thesis was to characterize the factors limiting placental passage and fetal exposure to lopinavir. These factors include lopinavir plasma protein binding and uptake, cellular binding, and efflux of lopinavir in the placental trophoblast cells. First, we determined the unbound fraction of lopinavir in cord blood and characterized the binding of lopinavir to α1-acid glycoprotein (AAG) and human serum albumin (HSA), and displacement by ritonavir. Serum …

The Use Of Lactobacillus In The Treatment Of Clostridium Difficile Infection In Hospitalized Adult Patients, Ali Alhammad

Theses and Dissertations

Objective To describe the use of Lactobacillus by hospitalized patients and to examine its relationship with various Clostridium difficile infection (CDI) related outcomes. Methods The characteristics of Lactobacillus users and non-users and the initiation of Lactobacillus with respect to initiation of antibiotic therapy and CDI treatment were described using national hospital discharge database. The relationships between Lactobacillus use and post-CDI length of stay, mortality, switch of CDI therapy, and readmission were analyzed. Results Lactobacillus users and non-users were different in most characteristics. Metronidazole and fluoroquinolones were the most frequently used antibiotics by Lactobacillus users. They were mainly CDI cases, used …

The Economic Impact Of Antimicrobial Resistance In Patients With Nosocomial Staphylococcus Aureus Bacteremia, Suzanne Phillips

Theses and Dissertations

Background: The proportion of nosocomial Staphylococcus infections caused by methicillin-resistant Staphylococcus aureus (MRSA) has increased from 22% in 1995 to 63% in 2004. Blood stream infections, more commonly referred to as bacteremias, represented the majority (75.5%) of hospital-onset MRSA cases. The economic impact of Staphylococcus aureus bacteremia merits investigation. Methods: This was a retrospective cohort analysis within Cerner HealthFacts data warehouse. Eligible patients were those who had Staphylococcus aureus bacteremia and were discharged between January 1, 2000, and December 31, 2006. Inclusion criteria include age > 18 years old and onset of infection > 48 hours post admission. The crude association was …

In Silico Whole Genome Association Scan For Murine Prepulse Inhibition, Bradley Todd Webb, Joseph L. Mcclay, Cristina Vargas-Irwin, Timothy P. York, Edwin J. C. G. Van Den Oord

Biomarker Research and Personalized Medicine Publications

Background

The complex trait of prepulse inhibition (PPI) is a sensory gating measure related to schizophrenia and can be measured in mice. Large-scale public repositories of inbred mouse strain genotypes and phenotypes such as PPI can be used to detect Quantitative Trait Loci (QTLs) in silico. However, the method has been criticized for issues including insufficient number of strains, not controlling for false discoveries, the complex haplotype structure of inbred mice, and failing to account for genotypic and phenotypic subgroups.

Methodology/Principal Findings

We have implemented a method that addresses these issues by incorporating phylogenetic analyses, multilevel regression with mixed …

Pulmonary Delivery Of Anorectic Gut Secreted Peptides For Appetite Suppression In Rats, Priya Nadkarni

Theses and Dissertations

This dissertation project aimed to demonstrate that pulmonary delivery of two anorectic gut secreted peptides, peptide YY (PYY) and oxyntomodulin (OXM) enabled food intake suppression and reduced body weight gain in rats via their systemic absorption from the lung and interaction with the brain. After PYY and OXM were administered to the lungs at varying doses, food intake and body weight gain were monitored in freely feeding rats. Significant 30-35 % food intake suppression was achieved for 4-6 h following pulmonary administration of endogenously active PYY3-36 and OXM1-37 at 0.80 and 0.50 mg/kg, respectively. Moreover, when administered daily for 7 …

In Vitro Models For Inhaled Corticosteroid (Ics) Aerosols: A Study Of Their Biopharmaceutics And Pharmacology, Deepika Arora

Theses and Dissertations

Lung cellular disposition and anti-inflammatory pharmacology of inhaled corticosteroids (ICSs) is complex, comprised of a cascade of aerosol deposition and dissolution, followed by cellular uptake for local pharmacological action. This project hypothesized that the kinetics of dissolution for certain ICS aerosols generated from inhaler products were kinetically rate-determined for their cellular uptake and local pharmacological action. A novel dissolution testing system was developed to determine the dissolution kinetics for the ICS aerosols. A total of 5 ICSs aerosols generated from 6 inhaler products were collected in 2.1-3.3 or 4.7-5.8 µm of aerodynamic diameters at 0.7-19.8 µg on filter membranes by …

Electrical Behavior Of Non-Aqueous Formulations: Role Of Electrostatic Interactions In Pressurized Metered Dose Inhalers (Pmdis), Reshma Kotian

Theses and Dissertations

Aerosol electrostatics is an important property of pharmaceutical aerosols. The electrostatic properties of pMDI aerosols have been shown to be a function of both formulation and packaging components. The modified ELPI enables measurement of aerosol charge as a function of particle size, and the simultaneous determination of the mass distribution using chemical analysis. However, in order to fully assess the cause and effects of aerosol electrostatics in terms of its biological and regulatory implications, it is necessary to understand the basic charging mechanisms inside the pMDI formulation.

Electrical resistivity and zeta potential measurements confirmed the presence of charged species within …

Impaired Clearance Of Methotrexate In Organic Anion Transporter 3 (Slc22a8) Knockout Mice: A Gender Specific Impact Of Reduced Folates, Adam L. Vanwert, Douglas H. Sweet

Pharmaceutics Publications

Purpose

To elucidate the role of the renal basolateral transporter, Oat3, in the disposition of methotrexate.

Materials and Methods

Chinese hamster ovary cells expressing mouse Oat3 were used to determine kinetics and specificity of inhibition of methotrexate transport. Methotrexate clearance was then examined in vivo in wildtype and Oat3 knockout mice.

Results

NSAIDs, ß-lactams, and uremic toxins inhibited mOat3-mediated methotrexate uptake by 70–100%, while folate, leucovorin, and 5-methyltetrahydrofolate inhibited transport by 25–50%. A Km of 60.6±9.3 μM for methotrexate transport was determined. Oat3 knockout mice exhibited reduced methotrexate-to-inulin clearance ratios versus wildtype. Male wildtype mice, but not knockouts or …

Effects Of Smoking And Gender On Tetrahydroisoquinolines And Beta-Carbolines In A Healthy Population And During Alcohol Detoxification, Satjit Singh Brar

Theses and Dissertations

The purpose of this investigation was to evaluate the effects of smoking and gender on 1) tetrahydroisoquinolines (TIQs) and beta-carbolines (BCs) in a population of healthy subjects and 2) TIQs in an alcohol-dependent population undergoing in-patient detoxification. Comparison in plasma TIQs between the populations was additionally conducted. To support the clinical investigations, a HPLC-FD method was developed and validated to assess plasma concentrations of BCs, harman and norharman, while a HPLC-ESI-MS/MS method was validated to quantify the TIQs, R/S-salsolinol along with dopamine. Forty-one young volunteers were recruited including 19 nonsmokers (NS), 11 light smokers (LS) and 11 heavy smokers (HS), …

Investigation Of Inosine And Hypoxanthine As Biomarkers Of Cardiac Ischemia In Plasma Of Non-Traumatic Chest Pain Patients And A Rapid Analytical System For Assessment, Don E. Farthing

Theses and Dissertations

Each year in the U.S., approximately 7-8 million patients with non-traumatic chest pain visit hospital emergency departments (ED) for medical evaluation. It is estimated that approximately 2-5% of these patients are experiencing acute cardiac ischemia, but due to the shortcomings of current test methods, they are incorrectly diagnosed and discharged without appropriate treatment provided, thus leading to poor patient outcome and potential medical malpractice litigation.The goals of this research were to evaluate plasma samples for potential biomarker(s) of acute cardiac ischemia prior to heart tissue necrosis, and to ultimately develop a rapid method for detection of the potential biomarker(s) in …

A Capillary-Based Microfluidic System For Immunoaffinity Separations In Biological Matrices, Michael Peoples

Theses and Dissertations

The analysis of biological samples in clinical or research settings often requires measurement of analytes from complex and limited matrices. Immunoaffinity separations in miniaturized formats offer selective isolation of target analytes with minimal reagent consumption and reduced analysis times. A prototype capillary-based microfluidic system has been developed for immunoaffinity separations in biological matrices with laser-induced fluorescence detection of labeled antigens or antibodies. The laboratory-constructed device was assembled from two micro syringe pumps, a microchip mixer, a micro-injector, a diode laser with fused-silica capillary flow cell, and a separation capillary column. The columns were prepared from polymer tubing and packed under …

Prediction Of In-Vivo Antimuscarinic Activity (Ama) By In-Vitro Receptor Binding Assessment And Pk/Pd Modeling For Prototypical Drugs, Taghrid Y. Obied

Theses and Dissertations

Purpose: To establish a tool, termed as antimuscarinic activity (AMA), to predict the incidence of antimuscarinic adverse events (AMAEs).Methods: A literature review, focused on drugs having off-target interaction with muscarinic receptors, was performed. Prototypical drugs olanzapine, diphenhydramine, paroxetine were selected for the analysis. Scopolamine and darifenacin were included as positive and negative controls, respectively. Physiochemical properties, pharmacokinetic data, and clinical incidence of AMAEs for the selected drugs were collected from reported literature. Extrapolation of literature data was carried-out to obtain exposure data. To determine the drugs muscarinic affinity (Ki values), experiments were performed using 3H-QNB and membrane suspensions of M1, …

Surgical Infection Society Guidelines For Vaccination After Traumatic Injury, Thomas R. Howdieshell, Daithi Heffernan, Joseph T. Dipiro

Publications from the Office of the Dean

Background: Recommendations for vaccination of injured patients against infection are evolving. Newly-recognized infections, safety considerations, changing epidemiology, and redefinition of patient groups at risk are factors that may influence vaccine development priorities and recommendations for immunization. However, recommendations must often be formulated based on incomplete data, forcing reliance on expert opinion to address some crucial questions. These guidelines provide evidence-based recommendations for the prevention or treatment of infectious morbidity and mortality after traumatic injury, such as soft tissue wounds, human or animal bites, or after splenectomy.

Methods: A panel of experts conducted a thorough review of published literature, …

Organic Anion And Cation Transporter Expression And Function During Embryonic Kidney Development And In Organ Culture Model Systems, Douglas H. Sweet, Satish A. Eraly, Kevin T. Bush, Sanjay K. Nigam

Pharmaceutics Publications

Background

Organic anion and cation transporters (OATs, OCTs and OCTNs) mediate the proximal tubular secretion of numerous clinically important compounds, including various commonly prescribed pharmaceuticals. Here, we examine the ontogeny of these transporters in rat embryonic kidney in detail, both in vivo and in two in vitro organ culture models of kidney development, whole embryonic kidney (WEK) culture and culture of induced metanephric mesenchyme (MM).

Methods

We used QPCR to determine expression levels of transporter genes in rat embryonic kidneys on each day of gestation from ed13 to ed18, in induced and un-induced MM, and on each day of one …

Interspecies Pharmacokinetic Scaling And Metabolism Of Alcohols And Glycols, Pankaj Gupta

Theses and Dissertations

Background: Despite the numerous pharmaceutical applications of alcohols andglycols, the interspecies differences with respect to their pharmacokinetics (PK) arepoorly understood. The aim of this research was to use in-vivo and in-vitro approaches to compare and model the PK characteristics across various species.Methods: Appropriate published in-vivo studies (in different species) foralcohols and glycols were carefully selected. PK analysis was performed using (a) noncompartmental analysis and (b) compartmental modeling to estimate relevant dose-independent PK parameters. Next, six alcohols (methanol, ethanol, 1 -propanol, 1 -butanol, 1-hexanol, and 1-octanol), two glycols (ethylene glycol and propylene glycol)and one secondary alcohol (2-propanol) were examined as in-vitro …

Characterization Of Perphenazine And Scopolamine Aerosols Generated Using The Capillary Aerosol Generator, Xihao Li

Theses and Dissertations

The characterization of perphenazine and scopolamine aerosols generated using the capillary aerosol generator (CAG) was reported. Variables including steady state power, the formulation vehicle, the drug concentration and the formulation flow rate were studied for their effects on the chemical stability and particle size of these drug aerosols.Stability-indicating HPLC and LC-MS assays were developed and validated for perphenazine and scopolamine, respectively. The chemical stability of each compound was investigated under a variety of stress conditions and the structure of degradation products was proposed.Perphenazine aerosols were generated from propylene glycol (PG) formulations with concentrations of 9, 48 and 90mM at formulation …

The Effect Of Variability In Substance Abuse And Dependence Terminology On Physicians' Prescribing Decisions, Lisa Rochelle Burroughs Phipps

Theses and Dissertations

Prescription drug abuse is a continuing problem in the United States. Educating physicians on issues related to prescription drug abuse is a key factor in preventing and treating this problem. High variability has been found in substance abuse terminology in the literature, textbooks, and FDA-approved product labeling. This dissertation describes a survey study designed to address how the variability in substance abuse terminology, specifically package inserts, affects the prescribing decisions made by physicians.A random sample of 1008 physicians currently licensed and residing in the Commonwealth of Virginia received a letter of explanation, a self-administered questionnaire, and a follow-up reminder and …

A 'Biorelevant' Approach For Accelerated In Vitro Release And In Vitro-In Vivo Relationship Of A Biodegradable, Naltrexone Implant, Sunil S. Iyer

Theses and Dissertations

Characterization of in vitro and in vivo drug release profiles constitutes an important step in developing and optimizing an effective, long acting delivery system for naltrexone. Accelerated in vitro methods are also important for quality assurance of manufactured dosage forms. For drug release testing of sustained release parenteral dosage forms, the modified USP Apparatus 4 (flow-through cell) has been recommended by the The Fédération Internationale Pharmaceutique/American Association of Pharmaceutical Scientists (FIP/AAPS) Guidelines. Details on such studies however, are generally not found in the literature. To incorporate 'biorelevance' to implant drug release studies, this research investigated an approach to apparatus design …

Length Of Hospital Stay, Delirium And Discharge Status Outcomes Associated With Anticholinergic Drug Use In Elderly Hospitalized Dementia Patients, Kelly J. Gauthier

Theses and Dissertations

Problem: There are a significant proportion of patients taking acetylcholinesterase inhibitors (ChEi) for cognitive dysfunction also taking medications with anticholinergic (ACh) properties that may counteract their effects. As the number of ACh medications, burden, increases so does the likelihood of an adverse outcome.Background: ACh medications are frequently used in the elderly population (Carnahan 2004) even those with dementia or AD (Roe et al., 2002; Giron et al., 2001; Altavela 2003; Gill et al., 2005; Kogut et al., 2005). Methods: Hospitalized patients > 65 years of age with dementia (AD, other dementias, or with inferred dementia based on ChEi or NMDA antagonist …

Small Molecules Binding To Serpins, Junaid Afridi

Theses and Dissertations

Serpins are a unique breed of proteins due to their enzymatic mechanism. Two systems were closely monitored during fluorescent binding studies, the ACT-CHY along with the AT:TRY interaction. Four different conformational variants of each system were studied including the native, cleaved, latent and complex forms. Three different fluorescent dyes were used to identify the conformations including ANS, TNS, and bis-ANS. SI studies and protease assays utilizing both Suc-AAPF-pNA and L-BAPNA were instrumental in determining conformations along with gel electrophoresis studies. The hydrophobic dyes bound to the different serpins with varying KD and ΔFmax due to structural variations among the conformers …

Clinical Pharmacology Of Ms-275, A Histone Deacetylase Inhibitor, Milin R. Acharya

Theses and Dissertations

The goal of this escalating single-dose phase I research study was to determine the safety, tolerability, pharmacokinetics, pharmacodynamics as well as in vitro metabolism and plasma protein binding of MS-275, a novel histone deacetylase inhibitor, in patients with solid tumors and lymphomas. A validated LC/MS assay was developed to quantitate MS-275 in plasma, human liver microsomes and urine. The pharmacokinetic (PK) evaluation was done using a non-compartmental approach. In-vitro plasma protein binding profile of MS-275 was characterized by a validated micro-equilibrium dialysis method. In vitro phase I and phase II hepatic metabolism of MS-275 were evaluated using human liver microsomes. …

The Influence Of Direct-To-Consumer Advertising: Who Will Talk To Their Doctor As A Result Of Prescription Drug Advertisement?, Hai Dubo Chen

Theses and Dissertations

OBJECTIVES: To identify the types of patients who talk with their physicians as a result of Direct-to-Consumer (DTC) advertising. METHODS: Data were taken from a national survey, "Public Health Impact of Direct-to-Consumer Advertising of Prescription Drugs, July 2001- January 2002", conducted by researchers from Harvard Medical School. Participants (n = 3000) were interviewed by telephone. We constructed a conceptual framework consisting of outcomes (3 types of physician visits), intervention (DTC experience) and five groups of explanatory factors (health beliefs, demographics, health status, socioeconomic status and market factors). Data were analyzed with three multivariate stepwise logistic regressions. The three dependent variables …

Evaluation Of The Pharmacokinetic-Pharmacodynamic Relationship, Metabolism And Plasma Protein Binding Of The Novel Antitumor Agent, 2-Methoxyestradiol (2me2), Following Oral Administration In Patients With Solid Tumors., Nehal Jagdish Lakhani

Theses and Dissertations

The goal of this study was to determine safety, tolerability and pharmacokinetics of 2ME2 in patients with solid tumors and determine maximum tolerated dose (MTD). The following hypotheses were tested: 1) 2ME2 will be well tolerated in clinic when given orally and will have quantifiable effects on the ex vivo markers of angiogenesis and apoptosis; 2) 2ME2 will exhibit linear pharmacokinetics; 3) Plasma protein binding will be extensive and linear; 4) Sulfation will be the major metabolic pathway for 2ME2.This was a phase I dose escalation study. Twenty patients with refractory solid tumors were enrolled. 2ME2 was administered orally starting …

A Nomogram For Valproic Acid And The Effect Of Missed Doses, Alaa M. Ahmad

Theses and Dissertations

Background. Clinicians are divided on dosing recommendations when a dose is delayed or missed. For a neuropsychiatric agent like valproic acid (VPA), rational dosing recommendations are of particular importance. VPA is subject to therapeutic monitoring using total concentrations. Due to non-linear binding of VPA to plasma proteins, current dose titration schemes for VPA are empirical. The objectives of this research were to 1- study the effect of missed/delayed doses on steady state concentrations of VPA and 2-design a nomogram that can be used for dose titration based on total VPA concentrations. Methods. 1- A simulation study was conducted to test …

The Surgical Infection Society Guidelines On Antimicrobial Therapy For Intra-Abdominal Infections: An Executive Summary, John E. Mazuski, Robert G. Sawyer, Avery B. Nathens, Joseph T. Dipiro, Moshe Schein, Kenneth A. Kudsk, Charles Yowler

Publications from the Office of the Dean

The Surgical Infection Society last published guidelines on antimicrobial therapy for intra-abdominal infections in 1992 (Bohnen JMA, et al., Arch Surg 1992;127:83-89). Since then, an appreciable body of literature has been published on this subject. Therefore, the Therapeutics Agents Committee of the Society undertook an effort to update the previous guidelines, primarily using data published over the past decade. An additional goal of the Committee was to characterize its recommendations according to contemporary principles of evidence-based medicine. To develop these guidelines, the Committee carried out a systematic search for all English language articles published between 1990 and 2000 related to …

Aminoglycosides For Intra-Abdominal Infection: Equal To The Challenge?, John A. Bailey, Katherine S. Virgo, Joseph T. Dipiro, Avery B. Nathens, Robert G. Sawyer, John E. Mazuski

Publications from the Office of the Dean

Background: Aminoglycosides, combined with antianaerobic agents, have been used widely for the treatment of intra-abdominal infection. However, some prospective randomized controlled trials and other data suggested that aminoglycosides were less efficacious than newer comparators for the treatment of these infections. We therefore performed a meta-analysis of all prospective randomized controlled trials utilizing aminoglycosides to reevaluate the efficacy of these agents for the treatment of intra-abdominal infection.

Methods: Published English-language prospective randomized controlled trials comparing aminoglycosides with other agents for treatment of intra-abdominal infection were identified by MEDLINE search. For each study, data were collected regarding the number of …

The Surgical Infection Society Guidelines On Antimicrobial Therapy For Intra-Abdominal Infections: Evidence For The Recommendations, John E. Mazuski, Robert G. Sawyer, Avery B. Nathens, Joseph T. Dipiro, Moshe Schein, Kenneth A. Kudsk, Charles Yowler

Publications from the Office of the Dean

Revised guidelines for the use of antimicrobial therapy in patients with intra-abdominal infections were recently developed by the Therapeutic Agents Committee of the Surgical Infection Society (Mazuski et al., Surg Infect2002;3:161-173). These were based, insofar as possible, on evidence published over the past decade. The objective of this document is to describe the process by which the Committee identified and reviewed the published literature utilized to develop the recommendations and to summarize the results of those reviews. English-language articles published between 1990 and 2000 related to antimicrobial therapy for intra-abdominal infections were identified by a systematic MEDLINE search and …