Medical Pharmacology Commons^™

Polymeric Chloroquine: Modifying An Old Drug To Make It A Little Sweeter, Richard Sleightholm

Theses & Dissertations

Hydroxyethyl starch (HES) is a clinically used polysaccharide colloidal plasma volume expander. The goal of this study was to synthesize HES modified with hydroxychloroquine (HCQ) as a novel polymeric drug with the ability to inhibit the invasive character of pancreatic cancer (PC) cells. HES was conjugated with HCQ using a simple carbonyldiimidazole coupling to prepare Chloroquine-modified HES (CQ-HES). CQ-HES with various degrees of HCQ substitution were synthesized and characterized. In vitro studies showed CQ-HES to have a similar toxicity profile as HCQ. Confocal microscopy revealed the propensity of CQ-HES to localize to lysosomes, and mechanistic studies confirmed the ability of …

The Effect Of Antihypertensive Dosing On Hypertension In Children With Chronic Kidney Disease, Benjamin A. Matta, Uri S. Alon, Tarak Srivastava, Bradley A. Warady, Darcy Weidemann

Posters

This study's objective was to determine the effect of antihypertensive dose on hypertension status in children with chronic kidney disease. This was the first quantitative analysis of antihypertensive dose expressed as a newly developed measure, cDDI, and is relationship with hypertension status in children with CKD.

Silencing The Guca2a-Gucy2c Tumor Suppressor Axis In Cin, Serrated, And Msi Colorectal Neoplasia., Babar Bashir, Dante J. Merlino, Jeff A. Rappaport, Esteban Gnass, Juan P. Palazzo, Ying Feng, Eric R R. Fearon, Adam E. Snook, Scott A. Waldman

Department of Pharmacology and Experimental Therapeutics Faculty Papers

Colorectal cancers (CRCs) initiate through distinct mutations, including in APC pathway components leading to tubular adenomas (TAs); in BRAF, with epigenetic silencing of CDX2, leading to serrated adenomas (SAs); and in the DNA mismatch repair machinery driving microsatellite instability (MSI). Transformation through the APC pathway involves loss of the hormone GUCA2A that silences the tumor-suppressing receptor GUCY2C. Indeed, oral hormone replacement is an emerging strategy to reactivate GUCY2C and prevent CRC initiation and progression. Moreover, retained expression by tumors arising from TAs has established GUCY2C as a diagnostic and therapeutic target to prevent and treat metastatic CRC. Here, we defined …

Prospective Evaluation Of A Population Pharmacokinetic Model Of Pantoprazole For Obese Children, Alenka Chapron, Susan M. Abdel-Rahman, Valentina Shakhnovich

Posters

We previously developed a population pharmacokinetic (popPK) model of pantoprazole for obese children. Our objective was to evaluate the predictive performance of this model in an independent cohort of normal weight, overweight and obese children.

Predictive Performance Of Existing Population Pharmacokinetic Models Of Tacrolimus In Pediatric Kidney Transplant Recipients, Alenka Chapron, Susan M. Abdel-Rahman

Posters

With the goal of developing a clinician-driven tacrolimus (TAC) pharmacokinetic dosing tool, our initial objectives were 1) to examine whether published TAC population pharmacokinetic (popPK) models could serve as a foundation for the dosing tool, and 2) evaluate their performance predicting TAC concentrations in an independent cohort of Children's Mercy patients.

The Effect Of Antihypertensive Dosing On Hypertension In Children With Chronic Kidney Disease, Benjamin A. Matta, Uri S. Alon, Bradley Warady Md, Tarak Srivastava, Darcy Weidemann

Posters

Background

Hypertension (HTN) is a highly prevalent and major risk factor for poor cardiovascular and renal outcomes in chronic kidney disease (CKD). Previous research suggests that HTN is underdiagnosed and undertreated in children with CKD. To our knowledge no studies have investigated the effect of antihypertensive (antiHTN) dose on blood pressure (BP) control in this population.

Objective

To determine the effect of antiHTN dose on HTN status in children with CKD.

Methods

Study population: 255 participants studied in the Chronic Kidney Disease in Children (CKiD) study at their 3rd visit, taking at least 1 antiHTN drug.

Cumulative Drug Dose Index …

The Effect Of Glucosamine, Chondroitin And Harpagophytum Procumbens On Femoral Hyaline Cartilage Thickness In Patients With Knee Osteoarthritis– An Mri Versus Ultrasonography Study, Florentin Ananu Vreju, Paulina Lucia Ciurea, Anca Rosu, Beatrice Andreea Chisalau, Cristina Dorina Parvanescu, Sineta Cristina Firulescu, Adina Turcu Stiolica, Andreea Lili Barbulescu, Stefan Cristian Dinescu, Cristiana Iulia Dumitrescu, Roxana Mihaela Dumitrascu, Cristina Criveanu, Lucretiu Radu, Mihai Tusaliu, Daniela Dumitrescu

Journal of Mind and Medical Sciences

Background: the evaluation of cartilage thickness has become possible with new techniques such as musculoskeletal ultrasonography (US) and magnetic resonance imagining (MRI), making the evaluation of the treatment response and the progression of the disease more accurate. Objective: to evaluate the efficacy of a Symptomatic Slow Acting Drug for Osteoarthritis using both US and MRI for measuring cartilage thickness at baseline and after 1 year. Methods: The study included the clinical evaluation of 20 patients at baseline, at 6 and 12 months as well as imaging exams (US and MRI) at baseline and after 1 year. Measurements …

Split Tolerance Permits Safe Ad5-Gucy2c-Padre Vaccine-Induced T-Cell Responses In Colon Cancer Patients., Adam E. Snook, Trevor R. Baybutt, Bo Xiang, Tara S. Abraham, John C. Flickinger, Terry Hyslop, Tingting Zhan, Walter K. Kraft, Takami Sato, Scott A. Waldman

Department of Pharmacology and Experimental Therapeutics Faculty Papers

Background: The colorectal cancer antigen GUCY2C exhibits unique split tolerance, evoking antigen-specific CD8+, but not CD4+, T-cell responses that deliver anti-tumor immunity without autoimmunity in mice. Here, the cancer vaccine Ad5-GUCY2C-PADRE was evaluated in a first-in-man phase I clinical study of patients with early-stage colorectal cancer to assess its safety and immunological efficacy.

Methods: Ten patients with surgically-resected stage I or stage II (pN0) colon cancer received a single intramuscular injection of 1011 viral particles (vp) of Ad5-GUCY2C-PADRE. Safety assessment and immunomonitoring were carried out for 6 months following immunization. This trial employed continual monitoring of both efficacy and toxicity …

Dual Therapy Treatment Of Pediatric Acute Lymphoblastic Leukemia With Blinotumomab And A Standard Chemotherapy Regimen, Tori I. Scheffler

Selected Honors Theses

Leukemia is the number one cancer affecting children in the nation, with acute lymphoblastic leukemia being the most prevalent classification.1 While new and innovative treatment protocols have greatly increased the success rate of primary cancer patients, those who face relapse receive a much more dismal prognosis. Recent studies have shown that patients who relapse quite frequently have developed drug-resistant clones of the original cancer cells, leading to a need for various secondary treatment options. The drug-resistance is due to clonal mutations that take place within the cancer cell, most often because of an outside pressure or stress within the environment …

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 …

Pharmacokinetics Of Ketamine At Dissociative Doses In An Adult Patient With Refractory Status Asthmaticus Receiving Extracorporeal Membrane Oxygenation Therapy., Edwin Lam, Ankit K. Rochani, Gagan Kaushal, Brandi N. Thoma, Julian Tanjuakio, Frances Mae West, Hitoshi Hirose

Department of Pharmacology and Experimental Therapeutics Faculty Papers

PURPOSE: First-line management of severe asthma exacerbations include the use of inhaled short-acting β-agonists, anticholinergics, and systemic corticosteroids. Continuous intravenous ketamine given at dissociative doses may be a pharmacologic option in patients who are intubated with life-threatening severe bronchospasm unresponsive to standard therapy. We describe the case of a 44-year-old man admitted to the intensive care unit for status asthmaticus requiring intubation and mechanical ventilation.

METHODS: The patient developed severe refractory hypercapnic respiratory failure necessitating additional respiratory support with veno-venous extracorporeal membrane oxygenation (ECMO) therapy. Ketamine treatment was initiated at 0.5 mg/kg/h continuous infusion on the day of admission for …

Apixaban Discontinuation Prior To Major Surgery: Results From A Prospective Single Center Study, Edwin Lam, Luis Eraso, Taki Galanis, Walter K. Kraft, Geoffrey Ouma, Lynda Thomson, Eugene Viscusi, Douglas Stickle, Jerald Z. Gong, Suzanne Adams, Geno Merli

Department of Pharmacology and Experimental Therapeutics Posters

Primary Objective

• Estimate the proportion of patients who achieve a plasma apixaban concentration of/mL following at least 48 hours of discontinuation prior to surgery or invasive procedure

Secondary Objective

• Perioperative and follow up arterial or venous thromboembolic events, major bleeding, clinically significant non-major bleeding complications. Correlation of apixaban anti-Factor Xa (FXa) activity and plasma apixaban concentrations at pre-admission and prior to surgery

Mass Caffeination, Michael J. Leach

The Transdisciplinary STEAM+ Journal

This poem reflects on caffeine intake in modern society from the perspective of a pharmacologist. It is a free verse, concrete poem that communicates the science of caffeine through both words and visual images.

Considerations For Implementing Precision Therapeutics For Children., Matthew J. Mclaughlin, Jonathan B. Wagner, Valentina Shakhnovich, Bruce Carleton, J Steven Leeder

Manuscripts, Articles, Book Chapters and Other Papers

Improving the utilization of pharmacologic agents in the pediatric population yields significant, perhaps life-long, benefits. Genetic factors related to the disposition of a medication or an alteration at the target receptor site contributes to the observed variability of exposure and response between individuals. An additional source of this variability specific to the pediatric population is ontogeny, where age-specific changes during development may require dose adjustments to obtain the same levels of drug exposure and response. With significant improvements in characterizing both the ontogeny and genetic contributions of drug metabolizing enzymes, the time is right to begin placing more emphasis on …

Saturated Fatty Acid Activates T Cell Inflammation Through A Nicotinamide Nucleotide Transhydrogenase (Nnt)-Dependent Mechanism, Grace Mccambridge, Madhur Agrawal, Alanna Keady, Philip A. Kern, Hatice Hasturk, Barbara S. Nikolajczyk, Leena P. Bharath

Pharmacology and Nutritional Sciences Faculty Publications

Circulating fatty acids (FAs) increase with obesity and can drive mitochondrial damage and inflammation. Nicotinamide nucleotide transhydrogenase (NNT) is a mitochondrial protein that positively regulates nicotinamide adenine dinucleotide phosphate (NADPH), a key mediator of energy transduction and redox homeostasis. The role that NNT-regulated bioenergetics play in the inflammatory response of immune cells in obesity is untested. Our objective was to determine how free fatty acids (FFAs) regulate inflammation through impacts on mitochondria and redox homeostasis of peripheral blood mononuclear cells (PBMCs). PBMCs from lean subjects were activated with a T cell-specific stimulus in the presence or absence of generally pro-inflammatory …

Icatibant Is Not Helpful For The Treatment Of Ace Inhibitor-Induced Angioedema, Samantha R. Schwartz

Clinical Research in Practice: The Journal of Team Hippocrates

A critical appraisal and clinical application of Sinert R, Levy P, Bernstein JA, et al. Randomized trial of icatibant for angiotensin-converting enzyme inhibitor-induced upper airway angioedema. J Allergy Clin Immunol Pract. 2017; 5(5): 1402-1409. doi: 10.1016/j.jaip.2017.03.003.

Pharmacological And Non-Pharmacological Treatments For The Neonatal Abstinence Syndrome (Nas)., A. K. Mangat, G. M. Schmölzer, W. K. Kraft

Department of Pharmacology and Experimental Therapeutics Faculty Papers

Neonatal abstinence syndrome is defined by signs and symptoms of withdrawal that infants develop after intrauterine maternal drug exposure. All infants with documented in utero opioid exposure, or a high pre-test probability of exposure should have monitoring with a standard assessment instrument such as a Finnegan Score. A Finnegan score of >8 is suggestive of opioid exposure, even in the absence of declared use during pregnancy. At least half of infants in most locales can be treated without the use of pharmacologic means. For this reason, symptom scores will drive the decision for pharmacologic therapy. Nevertheless, all infants, regardless of …

Pharmacokinetics Of Midazolam And Ketamine In Critically Ill Adults On Extracorporeal Membrane Oxygenation (Ecmo) Therapy, Julian Tanjuakio, Edwin Lam, Walter K. Kraft, Hitoshi Hirose, Nicholas C. Cavarocchi

Phase 1

Introduction: Extracorporeal Membrane Oxygenation (ECMO) is a form of life support for temporary mechanical cardiopulmonary support. Critically ill adults receiving ECMO support are often sedated using ketamine and benzodiazepines. Previous studies have showed altered connects of benzodiazepines and ketamine in ECMO patients compared to non-ECMO patients. However, no studies have shown prospective data regarding the pharmacokinetics of these drugs in vivo.

Objective: The primary purpose of this study is to characterize the pharmacokinetic parameters of Ketamine and Midazolam in adult patients on ECMO. As a secondary objective, we will develop a pharmacokinetic model of these drugs using various clinical endpoints. …

Association Of Cyp2c19*17 Allele And Choice Of P2y12 Inhibitor On Cardiovascular Outcomes Following Percutaneous Coronary Intervention, Yash Varma, Bs, Craig R. Lee, Phd, Pharmd, Joseph S. Rossi, Md, George A. Stouffer, Md

Phase 1

Introduction: The CYP2C19*17 allele variant is a gain-of-function polymorphism which increases levels of the active metabolite of clopidogrel.

Objective: *17 is associated with increased bleeding risk during clopidogrel therapy, but it is unclear whether alternative P2Y12 inhibitors, prasugrel and ticagrelor, produce better clinical outcomes in patients undergoing percutaneous coronary intervention (PCI).

Methods: A single-center observational study was conducted in 928 PCI patients who received CYP2C19 testing and dual anti-platelet therapy (DAPT). Risk of major adverse cardiovascular or cerebrovascular events (MACCE) and clinically significant bleeding over 12 months were compared across genotype and DAPT groups by proportional hazards regression.

Results: 584 …

Coordinating An Oncology Precision Medicine Clinic Within An Integrated Health System: Lessons Learned In Year One, Michael A. Thompson, Jennifer J. Godden, Deborah Wham, Antony Ruggeri, Michael P. Mullane, Amanda Wilson, Shamsuddin Virani, Scott M. Weissman, Brenda Ramczyk, Pamela Vanderwall, James L. Weese

Journal of Patient-Centered Research and Reviews

Precision medicine is a term describing strategies to promote health and prevent and treat disease based on an individual’s genetic, molecular, and lifestyle characteristics. Oncology precision medicine (OPM) is a cancer treatment approach targeting cancer-specific genetic and molecular alterations. Implementation of an OPM clinical program optimally involves the support and collaboration of multiple departments, including administration, medical oncology, pathology, interventional radiology, genetics, research, and informatics. In this review, we briefly introduce the published evidence regarding OPM’s potential effect on patient outcomes and discuss what we have learned over the first year of operating an OPM program within an integrated health …