Other Pharmacy and Pharmaceutical Sciences Commons^™

Elucidating Proteasome Catalytic Subunit Composition And Its Role In Proteasome Inhibitor Resistance, Kimberly C. Carmony

Theses and Dissertations--Pharmacy

Proteasome inhibitors bortezomib and carfilzomib are FDA-approved anticancer agents that have contributed to significant improvements in treatment outcomes. However, the eventual onset of acquired resistance continues to limit their clinical utility, yet a clear consensus regarding the underlying mechanisms has not been reached.

Bortezomib and carfilzomib are known to target both the constitutive proteasome and the immunoproteasome, two conventional proteasome subtypes comprising distinctive sets of catalytic subunits. While it has become increasingly evident that additional, ‘intermediate’ proteasome subtypes, which harbor non-standard mixtures of constitutive proteasome and immunoproteasome catalytic subunits, represent a considerable proportion of the proteasome population in many cell …

Acute Kidney Injury In Patients Treated With Vancomycin And Piperacillin-Tazobactam: A Retrospective Cohort Analysis, Wilbur Cliff Rutter

Theses and Dissertations--Pharmacy

Empiric antimicrobial therapy often consists of the combination of Gram-positive coverage with vancomycin (VAN) and Gram-negative coverage, specifically an anti-pseudomonal beta-lactam, such as piperacillin-tazobactam (PTZ). Nephrotoxicity is commonly associated with VAN therapy; however, recent reports demonstrate increasing nephrotoxicity rates among patients treated with the combination of VAN and PTZ. This study evaluated the effect of the VAN/PTZ combination on acute kidney injury (AKI), as defined by the RIFLE criteria, compared to VAN and PTZ monotherapies.

Overall, 11,650 patients were analyzed, with 1,647 (14.1%) AKI cases occurring. AKI was significantly more frequent in the VAN/PTZ group (21%) compared to either monotherapy …

Clinical Outcomes Associated With Time To Antimicrobial Therapy Change From Vancomycin To Daptomycin In Staphylococcal Bacteremia, Sarah J. Tennant

Theses and Dissertations--Pharmacy

Background: Staphylococcus aureus is an aerobic, Gram positive commensal organism that is capable of causing a wide spectrum of disease. This study contributes to previously published literature regarding daptomycin versus vancomycin use in S. aureus bacteremia (SAB).

Methods: Adult patients admitted between 2010 and 2014, billed for ICD-9 code V09.0, 038.11, 038.12, 041.11, or 041.12, and received vancomycin and daptomycin were included in this retrospective analysis. Patients were stratified by time to change in antibiotics from vancomycin to daptomycin to the early switch (1-3 days), intermediate switch (4-7 days), or late switch (8 days or later) group. The primary outcome …

Quantitative Analysis Of 5-Chloro-2-Methoxy-N-[2-(4-Sulfamoylphenyl)Ethyl]Benzamide (Glyburide Analogue, Ga) In Mouse Plasma And Whole Blood Using A Micro-Extraction And Liquid Chromatography-Tandem Mass Spectrometry, Ankit Zalavadia

Theses and Dissertations

Pharmacokinetic evaluation of 5-chloro-2-methoxy-N-[2-(4- sulfamoylphenyl)ethyl]benzamide in mouse plasma demanded for a suitable bioanalytical method. No reported bioanalytical method exists to-date that can quantify concentration of this compound in any biological matrix. The purpose of this study was 1) to develop and validate a new bioanalytical method using a micro-extraction and LC-MS/MS to quantify the target analyte in mouse plasma and 2) to partially validate the method in whole blood. A bioanalytical method was developed and validated in both matrices for a linear concentration range of 2-1000 ng/ml. For both matrices, the reverse predicted concentration of calibration standards (-8.95% to 12.16% …

Using Semiphysiologically-Based Pharmacokinetic (Semi-Pbpk) Modeling To Explore The Impact Of Differences Between The Intravenous (Iv) And Oral (Po) Route Of Administration On The Magnitude And Time Course Of Cyp3a-Mediated Metabolic Drug-Drug Interactions (Ddi) Using Midazolam (Mdz) As Prototypical Substrate And Fluconazole (Flz) And Erythromycin (Ery) As Prototypical Inhibitors, Mengyao Li

Theses and Dissertations

The purpose of the project was to investigate the impact of IV and PO routes difference for MDZ, a prototypical CYP3A substrate, and two CYP3A inhibitors (CYP3AI) -FLZ and ERY-, on the magnitude and time course of their inhibitory metabolic DDI.

Individual semi-PBPK models for MDZ, FLZ and ERY were developed and validated separately, using pharmacokinetic (PK) parameters from clinical/in-vitro studies and published physiological parameters. Subsequently, DDI sub-models between MDZ and CYP3AIs incorporated non-competitive and mechanism-based inhibition (MBI) for FLZ and ERY, respectively, on hepatic and gut wall (GW) CYP3A metabolism of MDZ, using available in-vitro/in-vivo information. Model-simulated MDZ …

The Synthesis And Applications Of [2.2]Paracyclophane Derivatives, Craig Hicks

Doctoral

This work concerns the preparation of novel [2.2]paracyclophane derivatives intended for use as asymmetric ligands and investigations into surface coatings prepared from [2.2]paracylophanes. This begins with a general introduction to enantioselective synthesis, followed by a review of relevant reported ligands based on the [2.2]paracyclophane framework and their applications. Next is described the preparation of novel ligands based on the [2.2]paracyclophane structure. Starting with the preparation of a range of mono and disubstituted [2.2]paracyclophanes, including several novel analogues, this moves on to investigating resolution procedures where a novel method for the preparation of enantiopure 4-bromo[2.2]paracyclophane is described. The coupling of prepared …

An Analysis Of Psychologist Postdoctoral Psychopharmacology Training Materials For Critiques Of Neurobiological Hypotheses Of Depression's Etiology, Critical Analyses Of The Dsm's Rigor, And For Consumer/Survivor/Ex-Patient Content., Chris William Nicholas Rowe

Antioch University Dissertations & Theses

There is widespread agreement that neurobiology plays a role in psychological distress and that psychiatric diagnosis and associated psychopharmacological interventions can be helpful. However, there are also unresolved issues surrounding the limits of empirical support for current diagnostic criteria, shortcomings in neurobiological explanations of psychopathology, and unanswered questions about the mechanism, safety, and efficacy of psychiatric medications. This has implications for treatment errors which can precipitate negative socio-economic and health consequences, particularly for vulnerable groups like the Consumer/Survivor/Ex-Patient (c/s/x) population. It is for these reasons that the training psychologists receive to prescribe should, in addition to integrating the critiques of …

Multiple Sirna Delivery Against Cell Cycle And Anti-Apoptosis Proteins Using Lipid-Substituted Polyethylenimine In Triplenegative Breast Cancer And Non-Malignant Cells, Manoj B. Parmar, Bárbara E. Arteaga Ballesteros, Timothy Fu, Remant Bahadur Kc, Hamidreza Montazeri Aliabadi, Judith C. Hugh, Raimar Löbenberg, Hasan Uludag

Pharmacy Faculty Articles and Research

Conventional breast cancer therapies have significant limitations that warrant a search for alternative therapies. Short-interfering RNA (siRNA), delivered by polymeric biomaterials and capable of silencing specific genes critical for growth of cancer cells, holds great promise as an effective and more specific therapy. Here, we employed amphiphilic polymers and silenced the expression of two cell cycle proteins, TTK and CDC20, and the anti-apoptosis protein survivin to determine the efficacy of polymer-mediated siRNA treatment in breast cancer cells as well as side effects in non-malignant cells in vitro. We first identified effective siRNA carriers by screening a library of lipid-substituted polyethylenimines …

Examination Of The Pharmacodynamics And Pharmacokinetics Of A Diclofenac Poly(Lactic-Co-Glycolic) Acid Nanoparticle Formulation In The Rat, Sam Harirforoosh, Kelsi O. West, Derek E. Murrell, James W. Denham, Peter C. Panus, Greg A. Hanley

Pharmacy Faculty Articles and Research

OBJECTIVE: Nonsteroidal anti-inflammatory drugs (NSAIDs) are assembled into two categories; cyclooxygenase (COX-1) sparing inhibitors of COX-2 and non-selective NSAIDs. Diclofenac (DICLO) is a non-selective NSAID that has been linked to serious side effects including gastric ulcers and renal injury. In this study, we examine the effect of poly(lactic-co-glycolic) acid nanoformulation on DICLO-associated adverse events and pharmacokinetics using a nanoparticle (NP) formulation previously developed in our laboratory.

MATERIALS AND METHODS: Rats were administered a single dose of methylcellulose (VEH), blank NP, DICLO (10 mg/kg), or a DICLO-NP suspension equivalent to the DICLO dose. Urinary and blood parameters were measured …

Assessment Of Celecoxib Poly(Lactic-Co-Glycolic) Acid Nanoformulation On Drug Pharmacodynamics And Pharmacokinetics In Rats, Sam Harirforoosh, Kelsi O. West, Derek E. Murrell, James W. Denham, Peter C. Panus, Greg A. Hanley

Pharmacy Faculty Articles and Research

OBJECTIVE: Celecoxib (CEL) is a nonsteroidal anti-inflammatory drug (NSAID) showing selective cycloxygenase-2 inhibition. While effective as a pain reducer, CEL exerts some negative influence on renal and gastrointestinal parameters. This study examined CEL pharmacodynamics and pharmacokinetics following drug reformulation as a poly(lactic-co-glycolic) acid nanoparticle (NP).

MATERIALS AND METHODS: Rats were administered either vehicle (VEH) (methylcellulose solution), blank NP, 40 mg/kg CEL in methylcellulose, or an equivalent NP dose (CEL-NP). Plasma and urine (over 12 hrs) samples were collected prior to and post-treatment. The mean percent change from baseline of urine flow rate along with electrolyte concentrations in plasma …

Development Of A Novel In Vivo Corneal Fibrosis Model In The Dog, K. M. Gronkiewicz, Elizabeth A. Giuliano, K. Kuroki, F. Bunyak, Ajay Sharma, L. B. C. Teixeira, C. W. Hamm, R. R. Mohan

Pharmacy Faculty Articles and Research

The aim of this study was to develop a novel in vivo corneal model of fibrosis in dogs utilizing alkali burn and determine the ability of suberanilohydroxamic acid (SAHA) to inhibit corneal fibrosis using this large animal model. To accomplish this, we used seven research Beagle dogs. An axial corneal alkali burn in dogs was created using 1 N NaOH topically. Six dogs were randomly and equally assigned into 2 groups: A) vehicle (DMSO, 2 μL/mL); B) anti-fibrotic treatment (50 μM SAHA). The degree of corneal opacity, ocular health, and anti-fibrotic effects of SAHA were determined utilizing the Fantes grading …

Epigenetic Modification Prevents Excessive Wound Healing And Scar Formation After Glaucoma Filtration Surgery, Ajay Sharma, Govindaraj Anumanthan, Marcos Reyes, Huiyi Chen, Jason W. Brubaker, Saad Siddiqui, Suneel Gupta, Frank G. Rieger, Rajiv R. Mohan

Pharmacy Faculty Articles and Research

PURPOSE. The purpose of this study was to determine the efficacy of suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor (HDACi), in prevention of excessive wound healing and scar formation in a rabbit model of glaucoma filtration surgery (GFS).

METHODS. A rabbit model of GFS was used. Rabbits that underwent GFS received balanced salt solution, or SAHA (50 lM), or mitomycin C (0.02%). Clinical scores of IOP, bleb vascularity, and slit-lamp examination were performed. On postoperative day 14, rabbits were killed and the bleb tissues were collected for evaluation of tissue fibrosis with hematoxylin and eosin, Masson trichrome, a-smooth muscle …

Application Of Organ Clearance To Estimation Of The In Vivo Hepatic Extraction Ratio, Reza Mehvar

Pharmacy Faculty Articles and Research

Organ clearance, which has been derived from the organ blood flow and extraction ratio (E), has been extensively used by clinical pharmacologists to explain the pharmacokinetics of many drugs in health and disease. For example, the extent of hepatic clearance or E (E_h) of drugs would determine their response to changes in the liver blood flow and/or activities of the metabolizing enzymes. Although E_h may be obtained directly by cannulating internal blood vessels, the method is invasive. Therefore, indirect methods have been used to estimate E_h from the peripheral blood concentration-time data after intravascular administration of …

Molecular Mechanisms Of Suberoylanilide Hydroxamic Acid In The Inhibition Of Tgf-Β1-Mediated Canine Corneal Fibrosis, Kristina M. Gronkiewicz, Elizabeth A. Giuliano, Ajay Sharma, Rajiv R. Mohan

Pharmacy Faculty Articles and Research

Objective—To investigate molecular mechanisms mediating anti-fibrotic effect of SAHA in the canine cornea using an in vitro model. We hypothesized that SAHA attenuates corneal fibrosis by modulating Smad-dependent and, to a lesser extent, Smad-independent signaling pathways activated by TGF-β1, as well as matrix metalloproteinase (MMP) activity.

Methods—Cultured canine corneal fibroblasts (CCF) were incubated in the presence/absence of TGF-β1 (5ng/ml) and SAHA (2.5μM) for 24hrs. Western blot analysis was used to quantify non-phosphorylated and phosphorylated isoforms of Smad2/3, p38 MAP kinase (MAPK), ERK1/2 and JNK1. Real-time PCR and zymography were utilized to quantify MMP1, MMP2, MMP8 and MMP9 mRNA expression and …

Phenylephrine Versus Ephedrine: Safest Vasopressor For The Neonate During Caesarean Section, James S. Hale Jr.

Doctoral Projects

One of the most common side effects of spinal anesthesia is the development of hypotension. Data collected has determined that 80% of parturients that undergo spinal anesthesia for this mode of delivery experience hypotension (Chestnut et al., 2014).

Hypotension, if sustained and severe, can lead to fetal hypoxia, neonatal depression or injury, and decreased uteroplacental perfusion. Hypotension can also cause severe health issues for the parturient including apnea, altered level of consciousness, cardiac arrest, and pulmonary aspiration. This systematic review of the literature was conducted to determine whether the administration of phenylephrine or ephedrine was safer for the neonate to …

Predicting Human Drug Toxicity And Safety Via Animal Tests: Can Any One Species Predict Drug Toxicity In Any Other, And Do Monkeys Help?, Jarrod Bailey, Michelle Thew, Michael Balls

Laboratory Experiments Collection

Animals are still widely used in drug development and safety tests, despite evidence for their lack of predictive value. In this regard, we recently showed, by producing Likelihood Ratios (LRs) for an extensive data set of over 3,000 drugs with both animal and human data, that the absence of toxicity in animals provides little or virtually no evidential weight that adverse drug reactions will also be absent in humans. While our analyses suggest that the presence of toxicity in one species may sometimes add evidential weight for risk of toxicity in another, the LRs are extremely inconsistent, varying substantially for …

Evaluating The Impact Of Pharmacist Health Education On The Perceptions Of The Pharmacist’S Role Among Women Living In A Homeless Shelter, Laura V. Tsu, Kelsey Buckley, Sarah Nguyen, Jennifer Kohn

Pharmacy Faculty Articles and Research

Objectives: To determine the impact of pharmacist-provided educational seminars on the participant’s perception of the pharmacist’s role in providing women’s health education. Secondary objectives include the participant’s level of perceived benefit from the information provided during each presentation, as well as determining characteristics of participants who are interested in attending seminars.

Methods: This is a prospective study conducted within a homeless women’s shelter in Phoenix, Arizona. Pharmacists and pharmacy students provided 10 monthly educational seminars on topics related to women’s health. Participants completed a pre- and post-seminar survey regarding their perceptions of the presentations and pharmacists.

Results: …

Pharmacists On The Front Lines Of Polypharmacy: The Individualized Medication Assessment And Planning (Imap) Project To Improve Medication Use In Senior Adults With Cancer, Ginah Nightingale Pharmd, Bcop, Laura T. Pizzi Pharmd, Mph, Emily Hajjar Pharmd, Bcps, Bcacp, Cgp, Elizabeth Pigott, Margaret Wang, Shannon Doherty, Kristine Swartz Md, Andrew Chapman Do, Facp

Population Health Matters (Formerly Health Policy Newsletter)

No abstract provided.

The Flaws And Human Harms Of Animal Experimentation, Aysha Akhtar

Experimentation Collection

Nonhuman animal (“animal”) experimentation is typically defended by arguments that it is reliable, that animals provide sufficiently good models of human biology and diseases to yield relevant information, and that, consequently, its use provides major human health benefits. I demonstrate that a growing body of scientific literature critically assessing the validity of animal experimentation generally (and animal modeling specifically) raises important concerns about its reliability and predictive value for human outcomes and for understanding human physiology. The unreliability of animal experimentation across a wide range of areas undermines scientific arguments in favor of the practice. Additionally, I show how animal …

Monitoring Of Outpatient Parenteral Antimicrobial Therapy (Opat) And Implementation Of Clinical Pharmacy Services At A Community Hospital Infusion Unit, Punit J. Shah, Scott Bergman, Donald Graham, Stephanie Glenn

SIUE Faculty Research, Scholarship, and Creative Activity

Background: In 2004, the Infectious Diseases Society of America (IDSA) published monitoring guidelines for outpatient parenteral antimicrobial therapy (OPAT), but no assessment of their utilization has been reported. We evaluated adherence to these recommendations by physicians at infusion centers and then piloted a program of supervision of monitoring by pharmacists.

Methods: Phase I: We performed a retrospective case-control study of patients who received OPAT over one year at two hospital infusion centers. Controls were patients treated by an infectious diseases (ID) physician, and cases were those without an ID physician. Patients were excluded if they received fewer than …