Medicinal and Pharmaceutical Chemistry Commons^™

Genomic Context And Tp53 Allele Frequency Define Clinical Outcomes In Tp53-Mutated Myelodysplastic Syndromes, Guillermo Montalban-Bravo, Rashmi Kanagal-Shamanna, Christopher B. Benton, Caleb A. Class, Kelly S. Chien, Koji Sasaki ,, Kiran Naqvi, Yesid Alvarado, Tapan M. Kadia, Farhad Ravandi, Naval Daver, Koichi Takahashi, Elias Jabbour, Gautham Borthakur, Naveen Pemmaraju, Marina Konopleva, Kelly A. Soltysiak, Sherry R. Pierce, Carlos E. Bueso-Ramos, Keyur P. Patel, Hagop Kantarjian, Guillermo Garcia-Manero

Scholarship and Professional Work – COPHS

TP53 mutations are associated with adverse outcomes and shorter response to hypomethylating agents (HMAs) in myelodysplastic syndrome (MDS). Limited data have evaluated the impact of the type, number, and patterns of TP53 mutations in response outcomes and prognosis of MDS. We evaluated the clinicopathologic characteristics, outcomes, and response to therapy of 261 patients with MDS and TP53 mutations. Median age was 68 years (range, 18-80 years). A total of 217 patients (83%) had a complex karyotype. TP53 mutations were detected at a median variant allele frequency (VAF) of 0.39 (range, 0.01-0.94). TP53 deletion was associated with lower overall response rate …

Nucleosome Distortion As A Possible Mechanism Of Transcription Activation Domain Function, Tamara Y. Erkina, Alexandre M. Erkine

Scholarship and Professional Work – COPHS

After more than three decades since the discovery of transcription activation domains (ADs) in gene-specific activators, the mechanism of their function remains enigmatic. The widely accepted model of direct recruitment by ADs of co-activators and basal transcriptional machinery components, however, is not always compatible with the short size yet very high degree of sequence randomness and intrinsic structural disorder of natural and synthetic ADs. In this review, we formulate the basis for an alternative and complementary model, whereby sequence randomness and intrinsic structural disorder of ADs are necessary for transient distorting interactions with promoter nucleosomes, triggering promoter nucleosome translocation and …

The Impact Of Peptide Nucleic Acid Fluorescence In Situ Hybridization (Pna Fish®) Rapid Diagnostic Testing On The Initiation Of Appropriate Antifungal Therapy In Patients With Candida Species Bloodstream Infections, Jenna Lee Ksiazkiewicz

Undergraduate Honors Thesis Collection

Background: Traditional methods for detecting positive blood cultures include the use of broth bottles with sensitive indicators for growth. These techniques can take 24-48 hours to signal a positive test. Another 24 hours are often required to determine the species of the organism. The use of rapid diagnostic testing for Candida species bloodstream infections provides accurate species identification in less than two hours.

Objective: Evaluate the time to appropriate antifungal therapy in patients in which rapid diagnostic testing was utilized.

Methods: This study was a retrospective, observational cohort of patients who had positive blood cultures for Candida species and had …

Evaluating The Non-Evidence Based Practice Of Rounding Serum Creatinine In The Elderly And The Impact On Medication Dosing, Kelly Lynn Roden

Undergraduate Honors Thesis Collection

Background: The Cockcroft and Gault equation is widely accepted in practice as the most appropriate way to calculate an estimated creatinine clearance. Geriatric patients often present with reduced muscle mass, and therefore lower creatinine production, due to normal changes in body composition associated with aging. Because serum creatinine and creatinine clearance are inversely proportional using the Cockcroft and Gault equation, a lower serum creatinine may falsely overestimate renal function in the elderly population. Rounding to a normal serum creatinine is believed by some practitioners to prevent over estimation of creatinine clearance and renal function.

Objective: The objective of this study …

Acid-Suppressing Agents And Risk For Clostridium Difficile Infection In Pediatric Patients, Katelyn E. Brown, Chad A. Knoderer, Kristen R. Nichols, Ashley S. Crumby

Scholarship and Professional Work – COPHS

Background. Acid-suppressing agents have been associated with increased Clostridium difficile infection (CDI) in adults. The objective of this study was to evaluate the association of acid-suppressing therapy with the development of CDI in the pediatric population.

Methods. This was a retrospective case-control study. Children aged 1 through 17 years with a positive C difficile polymerase chain reaction (PCR) result obtained between June 1, 2008, and June 1, 2012, were randomly matched to a control population selected from patients with negative PCR.

Results. A total of 458 children were included. No difference was observed in acid-suppressive therapy prior …

Implementing Extended-Infusion Cefepime As Standard Of Care In A Children’S Hospital: A Prospective Descriptive Study, Kristen R. Nichols, Lauren C. Karmire, Elaine G. Cox, Michael B. Kays, Chad A. Knoderer

Scholarship and Professional Work – COPHS

Background: Extended-infusion cefepime (EIC) has been associated with decreased mortality in adults, but to our knowledge, there are no studies in children.

Objective: The objective of this study was to determine the feasibility of implementing EIC as the standard dosing strategy in a pediatric population.

Methods: This was a descriptive study of children aged 1 month to 17 years, including patients in the intensive care unit, who received cefepime after admission to a freestanding, tertiary care children’s hospital. Patients were excluded if they were admitted to the neonatal intensive care unit or received cefepime in the outpatient, …

Self-Assembling Modified Β -Cyclodextrin Conjugated Sirna Nanoparticles And Liposomal Sirna Efficiently Knock Down The Mutant Huntingtin Gene In A Modified Pc-12 Cell Line, Rukmini Ladi, Sudip Das, Nandita Das

Scholarship and Professional Work – COPHS

Purpose: To formulate and characterize liposomal siRNA (LP-siRNA) and cationic β-cyclodextrin siRNA (CD-siRNA) nanoparticle complexes and evaluate their efficacy in knockdown of mutant Huntingtin protein (mHtt) in a modified PC-12 cell line.

Curcuminoid In Nanoemulsion Formulations Cause Enhanced Cell Death In The Hela Cancer Cell Culture Model, Nikita Kheradia, Nandita Das, Sudip Das

Scholarship and Professional Work – COPHS

Purpose: To formulate and characterize curcuminoid (insoluble chemoprevention agent) loaded nanoemulsions and evaluate their cytotoxicity in HeLa cells.

Beta-Blockers Act Through Clathrin-Dependent Internalization And Egfr Transactivation To Promote Erk Phosphorylation, Taiwo Ajumobi

Graduate Thesis Collection

For cardiovascular diseases such as high blood pressure, angina pectoris, and left ventricle hypertrophy; long-term activation of beta-adrenergic receptors is strongly linked to the progression of these diseases. A class of antagonistic drugs that target betaadrenergic receptors are collectively called beta-blockers. These drugs are commonly used to reduce the inotropic and chronotropic effects of beta-adrenergic receptor activation. This past decade has revealed that beta-blockers and other ligands are capable of functional selectivity at receptors. Functional selectivity describes the ability of ligands acting at 0 protein-coupled receptors (OPCRs) to preferentially activate or inhibit different signal transduction pathways. The studies on beta-adrenergic …

Simvastatin: A Risk Factor For Angioedema?, Sarah A. Nisly, Areeba Kara, Tamara B. Knight

Scholarship and Professional Work – COPHS

Objective. To report a case of simvastatin-induced angioedema in a patient with near nightly episodes of orofacial angioedema.

Case Summary. A 75-year-old African American female presented to the emergency department with recurrent face, lip, and tongue swelling. The patient described frequent episodes of orofacial edema, with 4 emergency department visits over the previous 6 months. Her home medications were reviewed and simvastatin was identified as a possible contributing medication. Simvastatin was discontinued with resolution of the symptoms during hospitalization and a significant reduction in episodes.

Discussion. Drug-induced angioedema has been documented with several agents, most commonly angiotensin-converting enzyme inhibitors. …

Canagliflozin, A New Sodium-Glucose Co-Transporter 2 Inhibitor, In The Treatment Of Diabetes, Sarah A. Nisly, Denise M. Kolanczyk, Alison M. Walton

Scholarship and Professional Work – COPHS

Purpose. The published evidence on the pharmacology, pharmacodynamics, pharmacokinetics, safety, and efficacy of a promising investigational agent for managing type 2 diabetes is evaluated.

Summary. Canagliflozin belongs to a class of agents—the sodium–glucose cotransporter 2 (SGLT2) inhibitors—whose novel mechanism of action offers potential advantages over other antihyperglycemic agents, including a relatively low hypoglycemia risk and weight loss-promoting effects. Canagliflozin has dose-dependent pharmacokinetics, and research in laboratory animals demonstrated high oral bioavailability (85%) and rapid effects in lowering glycosylated hemoglobin (HbA1c) values. In four early-stage clinical trials involving a total of over 500 patients, the use of canagliflozin for varying periods …

Vancomycin And Gentamicin Pharmacokinetic Alterations In An Adolescent Amputee, Kristen R. Nichols, Kari M. Edison, Michelle D. Rosenbaum, Chad A. Knoderer

Scholarship and Professional Work – COPHS

A 14-year-old male with bilateral above-the-knee amputations presented to our hospital for treatment of a skin and soft-tissue infection. We report the experience of vancomycin and gentamicin therapy in this patient. Because these medications require weight-based dosages and pharmacokinetic monitoring of serum levels, it was necessary to obtain peak and trough levels of the two drugs in order to determine the pharmacokinetic differences in this patient compared to those in an adolescent male without amputations. To our knowledge, this is the first report describing pharmacokinetic differences in an adolescent amputee.

Safety Of Saccharomyces Boulardii (Florastor) In Solid Organ Transplant Patients, Nicole Marie Dores

Undergraduate Honors Thesis Collection

Probiotics have been promoted for use in many gastrointestinal ailments. Most studies find probiotics safe for human use, reporting no severe adverse effects. However, probiotics are live microorganisms and thus have the potential to cause infection. Transplant recipients are considered at high risk for infectious complications from probiotics due to the immunosuppressive medications used to prevent organ rejection. Nonetheless, clinicians are currently utilizing probiotics in the transplant population, due to their benefit in gastrointestinal disorders, particularly recurrent Clostridium difficile. Limited knowledge and paucity of prospective trials in this patient population demands the need for completion of studies to identify the …

Over-The-Counter Non-Steroidal Anti-Anflammatory Drugs In Adolescent Athletes, Anna Christine Parada

Undergraduate Honors Thesis Collection

Non-steroidal anti-inflammatory drugs (NSAIDs) are common medications used by the general population due their anti-inflammatory and analgesic properties. These are especially popular in athletes since they are not prohibited in many rules of athletic competition. Over-the-counter (OTC) NSAIDs comprise several drugs that may be purchased without a prescription. These are often over-utilized by the general population due to their accessibility and relatively low cost. The unsuspecting victims are the children, especially adolescent athletes, who deem OTC NSAIDs safe without realizing the potential adverse effects of inappropriate consumption of these medications. This article reviews the approved indications and side effects of …

Hyperphosphatemia In Pediatric Oncology Patients Receiving Liposomal Amphotericin B, Chad A. Knoderer, Holly M. Knoderer

Scholarship and Professional Work – COPHS

OBJECTIVE: After transitioning our front-line amphotericin product to the liposomal formulation, we observed an increased incidence of hyperphosphatemia. We aimed to determine the incidence of hyperphosphatemia in children with oncologic disorders receiving an amphotericin B product and to establish whether the incidence varies depending on amphotericin formulation.

METHODS: This retrospective review of the medical record was conducted at a tertiary, free standing children’s hospital. Pharmacy data revealed 159 patients receiving an amphotericin product between November 2006 and December 2008. Doses of amphotericin, serum phosphorous, calcium and creatinine concentrations were recorded at daily time points during the 10 days following both …

Aspirin Dosing For The Prevention And Treatment Of Ischemic Stroke: An Indication-Specific Review Of The Literature, Alexander J. Ansara, Sarah A. Nisly, Sally A, Arif, Julia M. Koehler, Sarah T, Nordmeyer

Scholarship and Professional Work – COPHS

OBJECTIVE: To evaluate the efficacy of aspirin for the treatment and prevention of ischemic stroke and identify the minimum dose proven to be effective for each indication.

DATA SOURCES: PubMed and MEDLINE searches (January 2009–January 2010) were performed to identify primary literature, using search terms including aspirin, stroke prevention, acute ischemic stroke, acetylsalicylic acid, atrial fibrillation, myocardial infarction, and carotid endarterectomy. Additionally, reference citations from publications identified were reviewed.

STUDY SELECTION AND DATA EXTRACTION: Articles published in English were evaluated and relevant primary literature evaluating the efficacy of aspirin in the prevention of stroke was included in …

Continuous Infusion Of Nafcillin For Sternal Osteomyelitis In An Infant After Cardiac Surgery, Chad A. Knoderer, Jennifer L. Morris, Elaine G. Cox

Scholarship and Professional Work – COPHS

We report the use of the continuous infusion of nafcillin for the treatment of an infant who had methicillinsusceptible Staphylococcus aureus sternal osteomyelitis not responsive to traditional nafcillin dosing. The patient was successfully treated with surgical debridement and the continuous infusion of nafcillin. To our knowledge, this is the first report describing the successful use of the continuous infusion of nafcillin to treat an infant who had sternal osteomyelitis after cardiac surgery.

Functional Interplay Between Chromatin Remodeling Complexes Rsc, Swi/Snf And Iswi In Regulation Of Yeast Heat Shock Genes, Tamara Y. Erkina, Y. Zou, S. Freeling, V. I. Vorobyev, Alexander M. Erkine

Scholarship and Professional Work – COPHS

Chromatin remodeling is an essential part of transcription initiation. We show that at heat shock gene promoters functional interactions between individual ATP-dependent chromatin remodeling complexes play critical role in both nucleosome displacement and Pol II recruitment. Using HSP12, HSP82 and SSA4 gene promoters as reporters, we demonstrated that while inactivation of SNF2, a critical ATPase of the SWI/SNF complex, primarily affects the HSP12 promoter, depletion of STH1- a SNF2 homolog from the RSC complex reduces histone displacement and abolishes the Pol II recruitment at all three promoters. From these results, we conclude that redundancy between SWI/SNF and RSC complexes …

Different Requirements Of The Swi/Snf Complex For Robust Nucleosome Displacement At Promoters Of Heat Shock Factor And Msn2- And Msn4-Regulated Heat Shock Genes, Tamara Y. Erkina, P. A. Tschetter, Alexander M. Erkine

Scholarship and Professional Work – COPHS

The stress response in yeast cells is regulated by at least two classes of transcription activators—HSF and Msn2/4, which differentially affect promoter chromatin remodeling. We demonstrate that the deletion of SNF2, an ATPase activity-containing subunit of the chromatin remodeling SWI/SNF complex, eliminates histone displacement, RNA polymerase II recruitment, and heat shock factor (HSF) binding at the HSP12 promoter while delaying these processes at the HSP82 and SSA4 promoters. Out of the three promoters, the double deletion of MSN2 and MSN4 eliminates both chromatin remodeling and HSF binding only at the HSP12 promoter, suggesting that Msn2/4 activators are primary determinants of …

Tobramycin-Induced Hepatotoxicity, Sarah A. Nisly, Shaunta' M. Ray, Robert A. Moye

Scholarship and Professional Work – COPHS

OBJECTIVE. To report a case of tobramycin-induced hepatotoxicity. CASE

SUMMARY: A 20-year-old female was hospitalized for treatment of Pseudomonas aeruginosa bacteremia and osteomyelitis. Empiric intravenous antibiotic therapy with piperacillin/tazobactam, vancomycin, and ciprofloxacin was started, and based on the results of culture and sensitivity testing, was changed to intravenous ceftazidime and tobramycin 70 mg every 8 hours on hospital day 3. Liver enzyme levels then increased over days 3–6. Tests for hepatitis A, B, and C were all nonreactive, and HIV testing was negative. On day 8, therapy was changed from ceftazidime to piperacillin/tazobactam and the tobramycin dose was increased …