Pharmacy and Pharmaceutical Sciences Commons^™

Identifying Cancers For Cdk8/19 Inhibitor Therapy, Igor Roninson, Balázs Győrffy, Zachary T. Mack, Alexander A. Shtil, Michael S. Shtutman, Mengqian Chen, Eugenia Broude

Faculty Publications

CDK8 and CDK19 Mediator kinases are transcriptional co-regulators implicated in several types of cancer. Small-molecule CDK8/19 inhibitors have recently entered or are entering clinical trials, starting with breast cancer and acute myeloid leukemia (AML). To identify other cancers where these novel drugs may provide benefit, we queried genomic and transcriptomic databases for potential impact of CDK8, CDK19, or their binding partner CCNC. sgRNA analysis of a panel of tumor cell lines showed that most tumor types represented in the panel, except for some central nervous system tumors, were not dependent on these genes. In contrast, analysis of clinical samples for …

Effects Of Human Dopamine Transporter (Dat) Mutations And Novel Allosteric Modulatory Compounds In Disrupting Hiv-1 Tat-Dat Protein Interaction, Pamela Marie P. Quizon

Theses and Dissertations

More than 37 million people are living with HIV worldwide. Despite the widespread use of antiretroviral therapy (ART), up to 70% of HIV-positive individuals suffer from cognitive and behavioral deficits collectively known as HIV-associated neurocognitive disorders (HAND). HIV-mediated damage to the dopaminergic system is a mediating factor in HAND. Dopamine (DA) transporter (DAT)-mediated reuptake is essential for maintaining DA homeostasis. Because most ART cannot efficiently cross the blood-brain barrier (BBB), the brain serves as a viral reservoir that facilitates the spread of infection to microglia and astrocytes. Infected cells shed viral proteins such as Tat, which plays a critical role …

Glia Responsivity In Nicotine Dependence, Adewale Oluwamuyiwa Adeluyi

Theses and Dissertations

Neurons are the primary research target in the exploration and development of novel smoking cessation pharmacotherapies over the years. These research efforts have led to the discovery and development of three FDA-approved smoking cessation aids – nicotine replacement therapy, varenicline, and bupropion, each of which have quantifiable success as smoking cessation aids. However, relapse is still very common and smoking cessation is successful in less than 5% of quit attempts, making paramount the development of novel therapeutics. One untapped therapeutic target are glia, particularly, astrocytes and microglia, which are active participants in the neuroplastic events underlying drug addiction.

First, we …

Investigating The Neural Correlates Of Nicotine Withdrawal Phenotypes In Mice: Involvement Of Creb-Dependent Nrg3-Erbb4 Signaling In Mediating Anxiety-Like Behavior, Miranda Fisher

Theses and Dissertations

Addiction to nicotine and the ability to quit smoking are influenced by genetic factors. Therefore, it is important to understand how genes and drugs of abuse mechanistically impact each other. One well-characterized protein responsible for regulating both response to drugs and gene expression is the transcription factor cAMP response element-binding protein (CREB). Work from our lab indicates that hippocampal specific alterations in CREB signaling and synaptic plasticity underlie certain nicotine withdrawal (WD) phenotypes in a region-specific manner. We found that CREB deletion in the ventral hippocampus (VH), a region known for regulation of mood and emotion, results in amelioration of …

Torsades De Pointes And Qt Prolongation Associations With Antibiotics: A Pharmacovigilance Study Of The Fda Adverse Event Reporting System, Chengwen Teng Pharm.D., Ph.D., Elizabeth A. Walter, Daryl Kevin S. Gaspar, Obiageri O. Obodozie-Ofoegbu, Christopher R. Frei

Faculty Publications

Introduction: Macrolides, linezolid, imipenem-cilastatin, fluoroquinolones, penicillin combinations, and ceftriaxone are known to be associated with Torsades de pointes/QT prolongation (TdP/QTP). Other antibiotics may also lead to TdP/QTP, but no study has systemically compared TdP/QTP associations for many available antibiotics.

Objectives: The objective of this study was to evaluate the association between TdP/QTP and many available antibiotics using the FDA Adverse Event Report System (FAERS).

Methods: FAERS reports from January 1, 2015 to December 31, 2017 were analyzed. The Medical Dictionary for Regulatory Activities (MedDRA) was used to identify TdP/QTP cases. We calculated the Reporting Odds Ratios (RORs) …

Clostridium Difficile Infection Risk With Important Antibiotic Classes: An Analysis Of The Fda Adverse Event Reporting System, Chengwen Teng Pharm.D., Ph.D., Kelly R. Reveles, Obiageri O. Obodozie-Ofoegbu, Christopher R. Frei

Faculty Publications

Introduction: Antibiotic use is an important risk factor for Clostridium difficile infection (CDI). Prior meta-analyses have identified antibiotics and antibiotic classes that pose the greatest risk for CDI; however, CDI epidemiology is constantly changing and contemporary analyses are needed.

Objectives: The objective of this study was to evaluate the association between CDI and important antibiotic classes in recent years using the FDA Adverse Event Report System (FAERS).

Methods: FAERS reports from January 1, 2015 to December 31, 2017 were analyzed. The Medical Dictionary for Regulatory Activities (MedDRA) was used to identify CDI cases. We computed the Reporting Odds Ratios (RORs) …

Comparison Of Quetiapine Abuse And Misuse Reports To The Fda Adverse Event Reporting System With Other Second-Generation Antipsychotics, Kirk E. Evoy, Chengwen Teng Pharm.D., Ph.D., Victor G. Encarnacion, Brian Frescas, John Hakim, Stephen Saklad, Christopher R. Frei

Faculty Publications

Background:

Methods:

Cellular Localization Of Rad51d Mutant Proteins And The Application Of Art To Increase Scientific Literacy In America, Claire L. Chabot

Senior Theses

Ovarian cancers are the leading cause of death from cancer of the female reproductive system. Approximately 50% of ovarian cancers have defects in the homologous recombination (HR) DNA repair pathway that is required for the repair of DNA double-stranded breaks. The status of HR genes, such as BRCA1, BRCA2, and the RAD51 family, contributes to ovarian cancer development as well as treatment decisions regarding chemotherapy, radiation, and immunotherapy. The overarching goal of this project is to identify new insights into HR that can integrate with Precision Medicine Initiatives and align with the goals of the Cancer Moonshot 2020 Program. I …

A Baker's Dozen Of Top Antimicrobial Stewardship Intervention Publications In 2017, Daniel B. Chastain, David B. Cluck, Kayla R. Stover, Katherine T. Lusardi, Ashley Marx, Sarah Green, Carmen Faulkner-Fennell, Michelle Turner, Elias B. Chahine, P Brandon Bookstaver, Christopher M. Bland

Faculty Publications

With an increasing number of antimicrobial stewardship-related articles published each year, attempting to stay current is challenging. The Southeastern Research Group Endeavor (SERGE-45) identified antimicrobial stewardship-related peer-reviewed literature that detailed an "actionable" intervention for 2017. The top 13 publications were selected using a modified Delphi technique. These manuscripts were reviewed to highlight the "actionable" intervention used by antimicrobial stewardship programs to provide key stewardship literature for training and teaching and identify potential intervention opportunities within their institutions.

The Pharmabiotic For Phenylketonuria: Development Of A Novel Therapeutic, Chloé Elizabeth Lebegue

Senior Theses

Phenylketonuria, now known as phenylalanine hydroxylase (PAH) deficiency, is a genetic disorder of metabolism affecting approximately one in every 15,000 infants born in the United States. Patients have nonfunctional PAH enzyme secondary to one or more genetic mutations. The enzyme deficit results in destructive supraphysiologic blood phenylalanine levels upon consumption of the essential dietary amino acid phenylalanine. Current standards of care mitigate signs and symptoms of the disorder, but do not approach a cure. The methods for creating a prototype pharmabiotic as an innovative treatment strategy for PAH deficiency are described herein.

DNA molecular cloning techniques were utilized to engineer …

Utility Of Combination Antimicrobial Therapy In Adults With Bloodstream Infections Due To Enterobacteriaceae And Non-Fermenting Gram-Negative Bacilli Based On In Vitro Analysis At Two Community Hospitals, Rachel Foster, Casey Troficanto, P. Brandon Bookstaver, Joseph Kohn, Julie Ann Justo, Majdi Al-Hasan

Faculty Publications

This study examined the utility of combination therapy for bloodstream isolates of Enterobacteriaceae and non-fermenting Gram-negative bacilli (NFGN) from adults at two community hospitals from January 2010 through to June 2015. Changes to in vitro antimicrobial susceptibilities by adding ciprofloxacin or gentamicin to third-generation cephalosporins (3GC) were examined overall and in patients with risk factors for 3GC resistance. Overall ceftriaxone susceptibility among Enterobacteriaceae was 996/1063 (94%) and 247/295 (84%) in patients with 3GC resistance risk factors. Susceptibilities increased marginally by adding ciprofloxacin or gentamicin (mean difference 2.4% (95% CI 1.5, 3.4) and 3.0% (95% CI 2.0, 4.0), respectively, overall and …

Role Of Transcription-Regulating Kinase Cdk8 In Colon Cancer Metastasis, Jiaxin Liang, Mengqian Chen, Eugenia Broude, Igor Roninson

Faculty Publications

No abstract provided.

Rhabdomyolysis Associations With Antibiotics: A Pharmacovigilance Study Of The Fda Adverse Event Reporting System (Faers), Chengwen Teng Pharm.D., Ph.D., Courtney Baus, James P. Wilson, Christopher R. Frei

Faculty Publications

Introduction: Daptomycin, macrolides, trimethoprim-sulfamethoxazole, linezolid, fluoroquinolones, and cefdinir are known to be associated with rhabdomyolysis. Other antibiotics may also lead to rhabdomyolysis, but no study has systemically compared rhabdomyolysis associations for many available antibiotics.

Objectives: The objective of this study was to evaluate the association between rhabdomyolysis and many available antibiotics using the FDA Adverse Event Report System (FAERS).

Methods: FAERS reports from January 1, 2004 to December 31, 2017 were included in the study. The Medical Dictionary for Regulatory Activities (MedDRA) was used to identify rhabdomyolysis cases. Reporting Odds Ratios (RORs) and corresponding 95% confidence intervals (95%CI) for the …

Bloodstream Infection Due To Piperacillin/Tazobactam Non-Susceptible, Cephalosporin Susceptible Escherichia Coli: A Missed Opportunity For De-Escalation Of Therapy, Leah Carlisle, Julie Ann Justo, Majdi N. Al-Hasan

Faculty Publications

An increasing number of reports describing Escherichia coli isolates with piperacillin/tazobactam resistance, despite retained cephalosporin susceptibility, suggest further emergence of this phenotypic resistance pattern. In this report, a patient with metastatic breast cancer presented to medical care after two days of chills, nausea, vomiting, reduced oral intake, and generalized weakness. Blood and urine cultures grew E. coli as identified by rapid diagnostics multiplex PCR and MALDI-TOF, respectively. The patient continued to manifest signs of sepsis with hypotension and tachypnea during the first three days of hospitalization despite empirical antimicrobial therapy with intravenous piperacillin/tazobactam. After in vitro antimicrobial susceptibility testing demonstrated …

Multidisciplinary Authorship Among Infectious Diseases Society Of America Clinical Practice Guidelines: Examining The Contributions Of Infectious Diseases Pharmacists, Lauren K. Freeman, Jasmine N. Lindsay, Sarah Elizabeth Davis, Brian F. Norman, April W. Thompkins, Vera P. Luther, Christopher A. Ohl, P Brandon Bookstaver

Faculty Publications

We describe the proportion of pharmacist representation among current and corresponding prior editions of Infectious Diseases Society of America (IDSA) clinical practice guidelines (CPGs). Pharmacist representation was 13% and 21% in previous and current editions, respectively, increasing significantly since 2011. We advocate for continued collaborations between IDSA and pharmacy organizations to enhance multidisciplinary representation in CPGs.

The Role Of Cdk8 In Metastatic Growth Of Colon Cancer, Jiaxin Liang

Theses and Dissertations

Unresectable hepatic metastases of colon cancer poorly respond to existing therapies and are a major cause of colon cancer lethality. Transcription- regulating Mediator kinase CDK8, an early clinical stage drug target, is amplified or overexpressed in many colon cancers and CDK8 expression correlates with shorter patient survival. Here we show that CDK8 inhibition does not generally suppress proliferation of CDK8-overexpressing colon cancer cells but nevertheless CDK8 knockdown by shRNA or CDK8 kinase inhibition by a selective small-molecule drug candidate suppresses metastatic growth of mouse and human colon cancer cells in the liver. This effect is due at least in part …

Ubiquitin Receptor Rpn13 Mediates The Inhibitory Interaction Of Diphenyldihaloketones Clefma And Ef24 With The 26s Proteasome, Geeta Rao, Gregory Nkepang, Jian Xu, Hooman Yari, Hailey Houson, Chengwen Teng Pharm.D., Ph.D., Vibhudutta Awasthi

Faculty Publications

The proteasome is a validated target in drug discovery for diseases associated with unusual proteasomal activity. Here we report that two diphenyldihaloketones, CLEFMA and EF24, inhibit the peptidase activity of the 26S proteasome. The objective of this study was to investigate interaction of these compounds with the proteasome and identify a putative target within the protein components of the 26S proteasome. We employed standard fluorogenic peptide-based proteasome activity assay for trypsin-like, chymotrypsin-like, and caspase-like activities of human purified 26S proteasome in cell-free conditions. GFPu-1 and HUVEC cells were used as proteasome reporter cells. Direct binding studies used purified 19S, 20S, …

Impact Of Outpatient Vs Inpatient Absssi Treatment On Outcomes: A Retrospective Observational Analysis Of Medical Charts Across Us Emergency Departments, P Brandon Bookstaver, Timothy C. Jenkins, Edward Stenehjem, Shira Doron, Jack Brown, Shannon H. Goldwater, Carlos Lopes, Angela Haynes, Chuka Udeze, Yifan Mo, Patrick Gillard, Yan Liu, Katelyn Keyloun

Faculty Publications

Background: The objective of this study was to characterize treatment of patients with acute bacterial skin and skin structure infections (ABSSSIs) and describe the association between hospital admission and emergency department (ED) visits or readmissions within 30 days after initial episode of care (IEC). Methods: This was a retrospective, observational, cohort study of adults with ABSSSI who presented to an ED between July 1, 2012, and June 30, 2013. Patient, health care facility, and treatment characteristics, including unplanned ED visits or readmissions, were obtained through manual chart review and abstraction. Adjusted logistic regression analysis examined likelihood of all-cause unplanned ED …

Evaluation Of Pharmacy Students’ Tendency To Self-Medicate, Rebekah Lee Crandall, Danielle O'Neal

Senior Theses

Objective: To investigate whether the tendency to self-medicate increases as students progress though the pharmacy curriculum.

Design: An online survey was administered through Survey Monkey by a link sent to the email addresses of students who attended the South Carolina College of Pharmacy/ University of South Carolina College of Pharmacy (SCCP/USC-COP) during the 2017-2018 school year.

Methods: Self-medication was defined as the use of over-the-counter (OTC) medications, medications prescribed to another person, and recreational (i.e. alcohol, tobacco) or illicit substances for therapeutic purposes. The primary outcome was the likelihood of each class of pharmacy students to self-medicate based on a …

A Novel Mir-375-Hoxb3-Cdca3/Dnmt3b Regulatory Circuitry Contributes To Leukemogenesis In Acute Myeloid Leukemia, Laixi Bi, Bin Zhou, Haiying Li, Licai He, Chunjing Wang, Zhonggai Wang, Liqing Zhu, Mengqian Chen, Shenmeng Gao

Faculty Publications

Background: Acute myeloid leukemia (AML) is a heterogeneous group of hematopoietic malignancies due to sophisticated genetic mutations and epigenetic dysregulation. MicroRNAs (miRNAs), a class of small non-coding RNAs, are important regulators of gene expression in all biological processes, including leukemogenesis. Recently, miR-375 has been reported to be a suppressive miRNA in multiple types of cancers, but its underlying anti-leukemia activity in AML is largely unknown. Methods: Quantitative reverse transcriptase PCR (qRT-PCR) was used to measure the expression of miR-375 and HOXB3 in leukemic cells and normal controls. Targets of miR-375 were confirmed by western blot and luciferase assay. Phenotypic effects …

The Effects Of Stand-Alone Prescription Drug Plans On Health Care Utilizations, Expenditures And Medication Adherence Among Elderly Medicare Beneficiaries, Jing Yuan

Theses and Dissertations

Since the implementation of Medicare Part D in 2006, a growing body of evidence has shown that Medicare Part D might offset the total healthcare spending by improving the use of prescription drugs. However, little is known about the impact of different types of Part D plans – Stand-alone Prescription Drug Plan (PDPs) and Medicare Advantage Prescription Drug Plan (MA-PDs) – on health care utilizations and expenditures. This dissertation examined the association between the effect in PDPs on health care utilizations as well as expenditures, and medication adherence among elderly Medicare beneficiaries, compared to MA-PDs. Data was pooled from 2006-2010 …

Kv7 Channels Of The Urinary Bladder Smooth Muscle: Functional Roles And Therapeutic Potential, Aaron Provence

Theses and Dissertations

Overactive bladder (OAB) is a pervasive and debilitating condition for which effective therapeutic modalities are lacking. As potential novel pharmacological targets for lower urinary tract dysfunction, our recent studies have demonstrated voltage-gated KV7 channels (KV7.1-KV7.5) to be functionally expressed in detrusor smooth muscle (DSM) of the urinary bladder. Nonetheless, the specific roles of individual KV7 channel subtypes remains poorly understood. Using Western blot, immunocytochemistry, isometric DSM tension recordings, ratiometric fluorescence Ca2+ imaging, and patch-clamp electrophysiology, we demonstrated expression and key physiologic roles for the KV7.2/KV7.3 channels in guinea pig DSM using the novel and selective KV7.2/KV7.3 channel opener N-(2-Chloro-5-pyrimidinyl)-3,4-difluorobenzamide (ICA-069673). …

Mechanisms Of Rad51d-Dependent Repair Of Dna And Telomere Damage Induced By Interstrand Crosslinking Agents And Thiopurines, Nicole M. Reilly

Theses and Dissertations

Mutations in homologous recombination (HR) genes increase genomic instability, an enabling characteristic of cancer. However, the status of these same genes can also determine chemotherapy outcomes. RAD51D is a breast and ovarian cancer susceptibility gene that is an important component of HR. Mammalian cells defective for RAD51D have extensive chromosomal aberrations and are more sensitive to the interstrand crosslink-inducing agent mitomycin C (MMC) and the thiopurine 6-thioguanine (6TG). Previously, the RNF138 E3 ubiquitin ligase was identified to promote RAD51D ubiquitination, and loss of RNF138 also increased cellular sensitivity to MMC. Ubiquitination assays were used to show that a 3-ubiquitin modification …

Mechanism Of Action Of American Ginseng And Its Components In The Treatment Of Ulcerative Colitis, Anusha Chaparala

Theses and Dissertations

Inflammatory bowel diseases (IBD), mainly ulcerative colitis (UC), Crohn’s disease (CD), are chronic, idiopathic, inflammatory diseases of the gastrointestinal tract affecting millions of people worldwide. The incidence of IBD is steadily increasing in the modern world due to changes in dietary habits and other environmental influences that originated from industrialization. The etiology is poorly understood but is believed to be a combination of genetic predisposition, environmental factors, and overactive immune system. UC is characterized by inflammation and ulceration of colonic mucosa and rectum and has a higher incidence than CD. Aside from severely affecting the quality of life of the …

Clostridium Tertium Peritonitis And Concurrent Bacteremia In A Patient With A History Of Alcoholic Cirrhosis, S. Scott Sutton, Mark Jumper, Ansal Shah, Babatunde Edun

Faculty Publications

Spontaneous bacterial peritonitis (SBP) is a recognized cause of morbidity and mortality in cirrhotic patients. Enterobacteriaceae have been isolated from the majority of peritonitis cases and the gram negative aerobe Escherichia coli is the most commonly isolated organism. Anaerobic organisms are rarely isolated because of the high oxygen tension in ascetic fluid. We report a patient with a history of alcoholic cirrhosis who developed SBP and concurrent bacteremia with the anaerobe Clostridium tertium. The patient was successfully treated with intravenous antibiotics and was discharged home on oral ciprofloxacin. This case report is unique in that it is the fourth …

Application Of Fluoroquinolone Resistance Score In Management Of Complicated Urinary Tract Infections, Ansal Shah, Julie Ann Justo, P Brandon Bookstaver, Joseph Kohn, Helmut Albrecht, Majdi N. Al-Hasan

Faculty Publications

The fluoroquinolone resistance score (FQRS) predicts the probability of fluoroquinolone resistance with good discrimination. The score has been derived from patients with bloodstream infections caused by Gram-negative bacteria and is based on fluoroquinolone use within the past 6 months, among other clinical and health care exposure criteria. This study aims to examine the utility of the FQRS in patients with complicated urinary tract infections (cUTI) and determine whether extension of prior fluoroquinolone use to 12 months improves model discrimination. Adults with cUTI at Palmetto Health in central South Carolina, USA, from 1 April 2015 through 31 July 2015 were prospectively …

Inhibition Of Cdk8 Mediator Kinase Suppresses Estrogen Dependent Transcription And The Growth Of Estrogen Receptor Positive Breast Cancer, Martina S. Mcdermott, Alexander A. Chumanevich, Chang-Uk Lim, Jiaxin Liang, Mengqian Chen, Serena Altilia, David Oliver, James M. Rae, Michael Shtutman, Hippokratis Kiaris, Balázs Győrffy, Igor Roninson, Eugenia Broude

Faculty Publications

Hormone therapy targeting estrogen receptor (ER) is the principal treatment for ER-positive breast cancers. However, many cancers develop resistance to hormone therapy while retaining ER expression. Identifying new druggable mediators of ER function can help to increase the efficacy of ER-targeting drugs. Cyclin-dependent kinase 8 (CDK8) is a Mediator complex-associated transcriptional regulator with oncogenic activities. Expression of CDK8, its paralog CDK19 and their binding partner Cyclin C are negative prognostic markers in breast cancer. Meta-analysis of transcriptome databases revealed an inverse correlation between CDK8 and ERα expression, suggesting that CDK8 could be functionally associated with ER. We have found that …

Ertapenem-Induced Encephalopathy In A Patient With Normal Renal Function, S. Scott Sutton, Mark Jumper, Michael D. Wyatt

Faculty Publications

Drug-induced neurotoxicity is a rare adverse reaction associated with ertapenem. Encephalopathy is a type of neurotoxicity that is defined as a diffuse disease of the brain that alters brain function or structure. We report a patient with normal renal function who developed ertapenem-induced encephalopathy manifesting as altered mental status, hallucinations, and dystonic symptoms. The patient’s symptoms improved dramatically following ertapenem discontinuation, consistent with case reports describing ertapenem neurotoxicity in renal dysfunction. Since clinical evidence strongly suggested ertapenem causality, we utilized the Naranjo Scale to estimate the probability of an adverse drug reaction to ertapenem. Our patient received a Naranjo Scale …

Impact Of Prenatal Exposure To Antidepressants On Adverse Birth Outcomes, Sudeepti Pahuja

Theses and Dissertations

BACKGROUND: There has been an increase in the diagnosis of depression and the use of antidepressants, especially in women of childbearing age, in the past decade. This has drawn attention to the potential impact of depression and antidepressants on pregnancy and fetal development.

OBJECTIVE: (i) To determine the impact of prenatal exposure to antidepressant on the risk of adverse birth outcomes. (ii) To assess the effect of type of antidepressants on the risk of adverse birth outcomes using selective serotonin reuptake inhibitors as the referent group. (iii) To assess the effect of duration and time of prenatal exposure …

Management Of Viral Central Nervous System Infections: A Primer For Clinicians, P Brandon Bookstaver, Phillip L. Mohorn, Ansal Shah, Lauren D. Tesh, April M. Quidley, Ravish Kothari, Christopher M. Bland, Sharon Weissman

Faculty Publications

Viruses are a common cause of central nervous system (CNS) infections with many host, agent, and environmental factors influencing the expression of viral diseases. Viruses can be responsible for CNS disease through a variety of mechanisms including direct infection and replication within the CNS resulting in encephalitis, infection limited to the meninges, or immune-related processes such as acute disseminated encephalomyelitis. Common pathogens including herpes simplex virus, varicella zoster, and enterovirus are responsible for the greatest number of cases in immunocompetent hosts. Other herpes viruses (eg, cytomegalovirus, John Cunningham virus) are more common in immunocompromised hosts. Arboviruses such as Japanese encephalitis …