Medical Pharmacology Commons^™

The Development Of Novel Apurinic/Aprymidinic Endonuclease/Redox-Factor 1 Inhibitors For The Treatment Of Human Melanoma, Bella Sharifi

Pharmaceutical Sciences (MS) Theses

Apurinic/apyrimidinic DNA repair endonuclease-1 (APE1), first recognized as an important DNA excision repair enzyme, is also known as Redox Factor-1 (Ref-1) involved in the activation of many nuclear transcription factors in both redox-dependent and independent manner. It has been well-documented that the overexpression of APE/Ref-1 contributes to the development of chemo-resistance and is associated with tumor progression in many human malignancies [1].

Our previous study in melanoma demonstrated that the development of novel inhibitors targeting the redox regulation domain of APE/Ref-1 is a promising strategy for melanoma treatment. To date, limited successes have been reported in developing novel …

Genetic Variations In A Cytochrome P450 Enzyme And The Effects On Clopidogrel Bioactivation And Metabolism, Maryanne Ventura, Lauren Desko, Kimberly Gathers, Ashley Overy, David Kisor

Pharmacy and Wellness Review

Clopidogrel, the top prescribed antiplatelet medication for individuals who have experienced a myocardial infarction or cerebral vascular accident or who have peripheral arterial disease, is administered orally as a prodrug. It relies on hepatic metabolism through cytochrome P450 enzymes for conversion to its active form. Current research shows that allelic variation m the gene coding for CYP2C19 is the main factor contributing to the variability of response associated with clopidogrel treatment. Through the promotion of genetic testing for variability in the CYP2C19 gene and competently interpreting test results, pharmacists have the opportunity to use these findings to significantly impact clopidogrel …

Pharmacogenomics: Your Medical Identity, Hilary Stewart, Lisa Berni, Tyler Bulcher, Joel Rittenhouse, Ryan W. Naseman, Jon E. Sprague

Pharmacy and Wellness Review

Pharmacogenomics, the fusion of pharmacology and genomics, shows strong potential to solve many of today's dosing problems. lnter-patient dosing requirements, mainly due to genetic variability between patients, represent significant challenges for prescribers. Certain receptors, drug-targeted proteins, drug-transport mechanisms and drug-metabolizing enzymes are genetically established. Hence, any defect, absence or abnormality in the gene could alter how an affected individual will respond to a given drug. Due to advancements in technology, health care professionals who utilize pharmacogenomics may assess a patient's genetic profile and determine a predicted response to specific medications. This may result in potentially optimal dosing at the onset …

Cannabidiol, Behavior, And Immune Biomarkers In Idiopathic Autism Spectrum Disorder., Sarah Huang Shrader

Electronic Theses and Dissertations

Autism Spectrum Disorder (ASD) is a highly heterogenous neurodevelopmental disorder currently estimated by the CDC to affect 1 in 36 children in the U.S.. This uniquely human condition is characterized by a spectrum of symptoms that feature social communication deficits and repetitive behaviors with restricted interest. Autistic individuals commonly exhibit multiple comorbidities, including attention deficit hyperactivity disorder, anxiety, and seizures, which can complicate an already multi-faceted presentation. The majority of ASD cases are idiopathic in nature. Developing a well-validated animal model of ASD for translational research comes with many challenges, but is crucial for advancing our understanding of autism and …

Identification Of Novel Adenylyl Cyclase 5 (Ac5) Signaling Networks In D1 And D2 Medium Spiny Neurons Using Bimolecular Fluorescence Complementation Screening, Trevor B. Doyle, Brian S. Muntean, Karin F. Ejendal, Michael P. Hayes, Monica Soto-Velasquez, Kirill A. Martemyanov, Carmen W. Dessauer, Chang-Deng Hu, Val J. Watts

Purdue University Libraries Open Access Publishing Fund

Adenylyl cyclase type 5 (AC5), as the principal isoform expressed in striatal medium spiny neurons (MSNs), is essential for the integration of both stimulatory and inhibitory midbrain signals that initiate from dopaminergic G protein-coupled receptor (GPCR) activation. The spatial and temporal control of cAMP signaling is dependent upon the composition of local regulatory protein networks. However, there is little understanding of how adenylyl cyclase protein interaction networks adapt to the multifarious pressures of integrating acute versus chronic and inhibitory vs. stimulatory receptor signaling in striatal MSNs. Here, we presented the development of a novel bimolecular fluorescence complementation (BiFC)-based protein-protein interaction …

Metformin And Cancer: Pharmacoepidemiology Considerations, Sarah Kradel, Christina Spinaris, Victoria Pennington, Adam Trimble, Lara Long, Natalie Dipietro

Pharmacy and Wellness Review

No abstract provided.

Antidepressant Dosing In Major Depression: A Pharmacogenomic Approach, Morgan Homan, Haval Norman, Victoria Cho, Yousif Rojeab

Pharmacy and Wellness Review

Major depressive disorder (MDD) is the most predominant mental disorder in the United States, with serious and costly health risks if not successfully managed. Pharmacotherapy is a standard option for MDD treatment, but patients often require extensive therapy adjustments to find a suitable regimen. Pharmacogenomics may enable greater precision in antidepressant therapy. Genotypic variations in CYP2D6 and CYP2C19 metabolic enzymes are reliable predictors of serum drug concentration, but the complex dose-response relationship of antidepressants prevents such variations from predicting therapy success. Additionally, ABCBl has been examined for its role in P-glycoprotein efflux of antidepressants in the brain, yet it is …

Comparison Of Long-Term Oral Anticoagulation Therapies Including Newly Approved Reversal Agent For Dabigatran, Mackenzie Devine, Natalie Lennartz, Michaela Wolford, Rebecca Worden, Joelle Farano, Erin Petersen

Pharmacy and Wellness Review

Anticoagulants are a well-known class of agents essential for the prevention of blood clots, which may further develop into deep vein thrombosis, pulmonary embolism or stroke. Individuals at a high risk of clotting, such as those with atrial fibrillation, multiple risk factors or recent hip/knee surgery, are in need of long-term anticoagulation therapy. The purpose of this review is to highlight the pros and cons for each available anticoagulant as well as discuss pivotal clinical trials that evaluated the safety and efficacy of these agents. Warfarin, the oldest anticoagulant, requires the patient to attend frequent appointments with a health care …

Prevention And Treatment Of Glucocorticoid-Induced Osteoporosis, Mackenzie Devine, Anh Dao Le, Julie Puvogel, Victoria Cho, Michelle Musser

Pharmacy and Wellness Review

Osteoporosis is a disease state resulting in decreased bone mineral density (BMD) and increased risk of fracture, specifically of the vertebrae, spine and hip. Risk factors and high risk populations for developing osteoporosis include low BMD, long-term glucocorticoid therapy, genetics, diet, postmenopausal women and patients with inflammatory or chronic disease states. A variety of signaling pathways involving hormones, cytokines and other signaling molecules are involved in bone formation and are affected by long-term glucocorticoid therapy, leading to the development of glucocorticoid-induced osteoporosis (GIO).

There are a variety of drugs that work efficaciously to prevent and treat GIO. Alendronate is a …

Neonatal Abstinence Syndrome From Selective Serotonin Reuptake Inhibitor Use During Pregnancy, Elizabeth Kramer, Maria Patnella, Rachel Bulko, Allie Harrison, Hannah Lamb, Manoranjan D'Souza

Pharmacy and Wellness Review

Neonatal abstinence syndrome (NAS) is a concern for infants born to mothers receiving treatment with a selective serotonin reuptake inhibitor (SSRI) throughout the pregnancy. The risk of NAS associated with SSRI use during pregnancy varies with the specific SSRI that is used by the patient during pregnancy. Common symptoms of NAS include premature delivery, gastrointestinal disturbances, irritability, low birth weight, short length and lack of response to various stimuli. Neonates that present with these symptoms can be scored using either the Finnegan or Lipsitz scoring tools. Neonates experiencing NAS can be calmed or treated using nonpharmacologic methods such as swaddling, …

Treatment Of Basal Cell Carcinoma With Vismodegib, Sunitha Johns, Katlyn Brown, Emily Loudermilk, Crystal Zheng, Anh Dao Le, Sophocles Chrissobolis

Pharmacy and Wellness Review

The most prevalent nonmelanoma skin cancers are basal cell carcinoma (BCC) and locally advanced basal cell carcinoma (aBCC). Current, effective first-line treatments for BCC aim to remove and destroy cancerous skin cells through excision surgery, Mohs surgery, radiation therapy and cryotherapy, while treatment of aBCC remains limited. An emerging treatment option for aBCC that promotes tumor size reduction is vismodegib, a pharmaceutical product approved in 2012 by the U.S. Food and Drug Administration (FDA). Vismodegib was approved for the treatment of aBCC, metastasized HCC (mBCC) or recurrent BCC after surgery as well as for use in adults who are not …

Triple Therapy Or Triple Threat: An Analysis Of Triple Antiplatelet Therapy Compared To Dual Antiplatelet Therapy, Isabel E. Cwikla, Kara C. Horvath, Elaina Gollmar, Austin Hilverding, Erin Petersen

Pharmacy and Wellness Review

Triple antiplatelet therapy (TAPT, or triple therapy), is an oral medication regimen designed to reduce the risk of major cardiovascular events. It consists of aspirin, clopidogrel or an alternative, and an oral anticoagulant (OAC). It differs from dual antiplatelet therapy (DAPT) due to inclusion of an OAC. Multiple clinical studies have indicated that triple therapy is more effective at clot prevention, when compared to aspirin monotherapy and DAPT, but is associated with a higher risk of major bleeding. Pharmacists have a key role in determining candidates for DAPT and TAPT regimens. Other opportunities for pharmacists include patient monitoring, counseling and …

Programmed Death Pathway Inhibition: Emerging Therapeutic Options For Treatment Of Advanced Or Refractory Cancers, Katherine Elsass, Morgan Homan, Jana Randolph, Brendan Rasor, David Kinder

Pharmacy and Wellness Review

The programmed death-1 (PD-1) pathway has a significant role in the promotion of immune tolerance. The PD-1 receptor ligands are normally expressed on various inactive immune cells. When cancer cells express these ligands, they are able to interact with active T and B lymphocytes to induce this tolerance. Nivolumab and pembrolizumab are two recently approved agents that act to disrupt this binding and facilitate an immune response against cancer cells. Numerous trials, including KEYNOTE-002 and CheckMate 063, have demonstrated the superior safety and efficacy of these drugs in patients with advanced or refractory cancers. Initially approved for the treatment of …

Pcsk9 Inhibitors: A Novel Class Of Pharmacotherapy For Hypercholesterolemia, Angela Chu, Austin Hilverding, Elizabeth Kramer, Brendan Rasor, Boyd Rorabaugh

Pharmacy and Wellness Review

The recent U.S. Food and Drug Administration (FDA) approval of two new drugs, alirocumab (Praluent®) and evolocumab (Repatha®) is a breakthrough in the treatment of familial hypercholesterolemia. These drugs are a part of a new class called the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors that act by increasing the number of low density lipoprotein receptors (LDL-R) recycled to hepatocyte membranes. The increased density of LDL-R facilitates greater clearance of low density lipoproteins from the blood. Numerous clinical trials have demonstrated the efficacy of these agents, particularly for patients in whom standard cholesterol-lowering therapy is insufficient. However, data on long-term …

Belsomra®: A Novel Dual Orexin Receptor Antagonist For The Treatment Of Insomnia, Shane Bogusz, Steven Blake, Michaela Wolford, Victoria Cho, Manoranjan D'Souza

Pharmacy and Wellness Review

Insomnia is a disease state characterized by a persistent difficulty in falling asleep, and results in enormous health-related and economic costs to both the individual and society. Several medications are currently available for the treatment of insomnia; however, these medications are associated with several limitations including anterograde amnesia, dependence, withdrawal symptoms upon stopping the medication and rebound insomnia. The U.S. Food and Drug Administration recently approved suvorexant (Belsomra®) as a treatment for insomnia. Suvorexant is a first-in-class dual orexin receptor antagonist for the treatment of insomnia. This review will first describe the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) …

Pain Management In Dementia Patients In Nursing Homes, Tiffany Kneuss, Kelsey Weisenburger, Hannah Stewart, Kelly Reilly Kroustos

Pharmacy and Wellness Review

Pain in the elderly, especially those with dementia, is often undertreated and misdiagnosed by health care professionals in the long-term care setting. Communication barriers in patients with cognitive impairment force pain assessment to rely heavily on subjective interpretation of behavioral factors due to the inability of patients to self-report pain symptoms. It is important for clinicians to develop a standard method of identifying and assessing signs of pain in patients with dementia in order to appropriately treat those experiencing discomfort. Patients with dementia who present with a sudden onset of behavioral changes should receive a comprehensive evaluation that includes a …

The Effects Of Long-Term Benzodiazepine Use And Withdrawal In The Elderly, Lydia Suchecki, Hannah Granger, Jamie Kellner, Mary Ellen Hethcox

Pharmacy and Wellness Review

Benzodiazepines remain a commonly prescribed medication in the United States, and the high usage of this drug class is especially a concern in the elderly population for several reasons. First, elderly patients metabolize drugs differently, leading to varying responses. Age-related changes also have a significant impact on the effects of benzodiazepines. Second, elderly patients are more likely to be taking multiple centrally-acting drugs, which can further exacerbate negative effects. In regard to long-term benzodiazepine use, elderly patients experience an increased risk of cognitive impairment, motor vehicle accidents, decline in physical performance, falls and subsequent fractures, and sleep disturbances. Withdrawal is …

Current Trials And Therapies For The Treatment Of Amyotrophic Lateral Sclerosis And Frontotemporal Dementia, Adam Smith, Angela Chu, Lucy Wagala, Hannah Stewart, Lindsey Peters

Pharmacy and Wellness Review

An area of health care that provides many more questions than answers includes neurodegenerative disorders. Amyotrophic lateral sclerosis (ALS), commonly known as Lou Gehrig's disease, and frontotemporal dementia (FTD) are both diseases about which we know very little. However, ALS and FTD affect nearly 30,000 and 60,000 Americans respectively. Currently, there is not a cure for ALS or FTD and treatment options are aimed toward symptom management. Much of the pathophysiology of these diseases is unknown, but we do know there are genetic implications, specifically in SOD1, TARDBP and c90RF72. These mutations lead to cognitive deficits, muscle weakness and, eventually, …

Testosterone Replacement Therapy In Aging Males, Alexandra Dimit, Joelle Farano, Haley Armstrong, Michelle Musser

Pharmacy and Wellness Review

The U.S. Food and Drug Administration (FDA) cautions health care providers and patients regarding the use of testosterone replacement therapy products for the aging process, including a decrease in muscle strength, muscle mass, and lack of energy or sexual desire, due to an increased risk of heart attacks and strokes. Testosterone replacement therapy products are indicated for genetic defects, chemotherapy damage, or damage to the hypothalamus or pituitary gland, where testosterone is produced. A patient and his team of health care professionals must seriously consider the risks and benefits when using these products for other indications. Use of testosterone replacement …

Combined Neprilysin And Angiotensin Inhibitor For The Treatment Of Heart Failure, Albert Bui, Victoria Cho, Rebecca Worden, Haley Armstrong, Rachel Pucel, Lindsey Peters

Pharmacy and Wellness Review

Heart failure (HF) is a highly prevalent disease state worldwide that can progress into a disabling condition. It is pertinent to have a treatment regimen that is effective in lowering the number of HF exacerbations and, therefore, hospital readmission rates. A novel medication currently in clinical trials, LCZ696, blocks both neprilysin and angiotensin type I receptors. The overall effects are an inhibition of the breakdown of natriuretic peptides which leads to a decrease in renin and aldosterone release. This, combined with the antagonization of angiotensin type I receptors, leads to a decrease in blood pressure, blood volume and systemic vascular …

Potential Use Of Dopamine And Dopamine Agonists As Angiogenesis Inhibitors In The Treatment Of Cancer, Benjamin Finley, Katherine Liu, Daniel Powell, Jamie Kellner, David H. Kinder

Pharmacy and Wellness Review

In recent years, there have been numerous developments in monoclonal antibodies used as anticancer drugs with a focus on reducing the ability of cancers to metastasize and produce new vasculature. These agents are called angiogenesis inhibitors and although these agents have been proven effective in treating certain types of cancers, production and administration of monoclonal antibodies comes at a steep cost with a severe side effect profile. Under normal physiologic conditions, angiogenesis is an important mechanism to create new blood vessels from preexisting vessels, usually occurring in adults. Tumor cells can hijack the angiogenesis pathway to produce new distant tumors …

Pharmacogenetics: Cyps, Nat2 And 5-Htt Related To Antidepressants, Molly Kulp, Armond Cosiano, Kevin Krivanek, Amanda Lanker, Taylor Roberson, David F. Kisor

Pharmacy and Wellness Review

Pharmacogenetics (PGt), the study of a gene's influence on patient response to a drug, shows strong potential for explaining issues with efficacy related to antidepressant medications. Each year, antidepressants are one of the most commonly prescribed medications due to the millions of Americans affected by depression. Importantly, it is recognized that there is wide interpatient variability in drug response to antidepressants caused by genetic mutations, which can alter the pharmacodynamic (PD) and pharmacokinetic (PK) properties of various drugs used to treat depression. Proteins that are mainly involved in how patients respond to medications include receptors, drug-targeted proteins, drug transport proteins …

New Cholesterol Guidelines: An Update For Pharmacists, Emily Limberg, Benjamin Finley, Stacy Henthorne, Sarah Kradel, David Bright

Pharmacy and Wellness Review

The American College of Cardiology and American Heart Association published new blood cholesterol guidelines in November 2013. The new guidelines place an emphasis on evidence-based treatment of dyslipidemias and primarily use randomized controlled trials to create recommendations for health care providers. Major changes from the previous guidelines include eliminating low-density lipoprotein goals, the classification of statins by lipid-lowering potential and the creation of four major statin benefit groups. The new guidelines also establish the role of non-statins in dyslipidemias and use the Pooled Cohort Risk Assessment Equations to calculate patients' risk for cardiovascular events and the need for cholesterol-lowering medications. …

Crohn's Disease: Management, Emerging Therapies And The Role Of The Pharmacist, Sarah Turley, Tiffany Kneuss, Lydia Suchecki, Alison Steinbrunner, Kristen Timperman

Pharmacy and Wellness Review

Crohn's disease is a relapsing-remitting disorder of the gastrointestinal tract caused by a mixture of genetic and environmental factors. Pharmacologic treatment of Crohn's disease is patient-specific, and regimens vary widely between individuals. Drug regimens are typically based on 5-aminosalicylate therapy and may include a combination of steroids, histamine 2 receptor antagonists, proton pump inhibitors, immunomodulators, antibiotics, biologic agents and other medications aimed at symptom relief. A new medication, vedolizumab, is currently in phase III clinical trials awaiting U.S. Food and Drug Administration (FDA) approval for use in Crohn's disease. Vedolizumab is an alpha-integrin inhibitor, which is anticipated to have a …

Advances In Treatment Of Chronic Hepatitis C Virus (Hcv) Infection, Halle Orlinski, Kimberly Loughlin, Haley Armstrong, Emily Blum, Andrew M. Roecker

Pharmacy and Wellness Review

Hepatitis C virus (HCV) infection is a prominent cause of chronic liver disease and may lead to serious complications such as liver failure and need for a transplant. The virus is transmitted via exposure to blood and is classified into various genotypes based on genetic mutations in the virus. Current treatment options for HCV infection are not effective in all patients, and there are limited options for patients infected with a genotype other than genotype 1. Two new medications have been approved recently for treatment of HCV infection. Simeprevir (Olysio®) gained U.S. Food and Drug Administration (FDA) approval in November …

Lbrutinib (Lmbruvica™) For Treatment Of Mantle Cell Lymphoma, Brittany Crowe, Joy Hoffman, Hannah Stewart, Alison Steinbrunner, Mark E. Olah

Pharmacy and Wellness Review

Mantle cell lymphoma (MCL) is a rare and moderately aggressive form of non-Hodgkin's lymphoma (NHL) that predominantly presents at an advanced stage in older males. Patients often present with multiple involvement in the lymph nodes, blood, spleen, bone marrow and gastrointestinal tract (GIT). Some patients may be asymptomatic in early stages or present with an incurable, indolent (slow progressing) form, while other patients display rapid growth of more aggressive lymphomas. Overall survival for patients diagnosed with MCL is four to five years and treatment should be initiated in those who are symptomatic. Mantle cell lymphoma responds well to first-line treatment, …

Dapagliflozin: A Newly Approved Sglt2 Inhibitor For The Treatment Of Type 2 Diabetes Mellitus, Ann Marie Ruhe, Rachel Muhlenkamp, Austin Brown, Emily Blum, Sandra L. Hrometz

Pharmacy and Wellness Review

Type 2 diabetes mellitus (T2DM) is a chronic disease in which a hyperglycemic state is induced by insulin resistance. While there are numerous treatment options available to manage T2DM, many patients require changes in therapy throughout treatment, as well as multiple medications. The sodium/glucose cotransporter 2 (SGLT2) inhibitors, canagliflozin and dapagliflozin, offer a therapeutic alternative in T2DM management through the utilization of a unique mechanism of action to provide intensified glycemic control. This article will evaluate the safety and efficacy of dapagliflozin in the management ofT2DM.

Trametinib And Dabrafenib: New Agents For Advanced Stage Melanoma, Kelsey Weisenburger, Kevin Krivanek, Armond Cosiano, Kasie Bellmann, Mark E. Olah

Pharmacy and Wellness Review

Melanoma, the deadliest form of skin cancer, is caused primarily by exposure to ultraviolet radiation. Tumor formation occurs early in disease progression and can easily metastasize. The development of the disease can be described by one of four stages, characterized by tumor size and risk of spreading. The B-rafprotein plays an important role in cell proliferation and has the ability to develop a mutation for continuous activation, resulting in uncontrolled cell growth. Sixty percent of melanomas possess a V600E mutation in the BRAF gene. Recently, drug developers have turned the focus of melanoma treatments toward preventing the activation of the …

Phenoconversion: Drug-Drug-Gene Interactions, Molly Kulp, Emily Limberg, Brooke Marlowe, Taylor Roberson, David F. Kisor

Pharmacy and Wellness Review

Based on the extensive, poor, intermediate and ultrarapid phenotypes of patients, inferences may be made relative to drug metabolism, ultimately leading to changes in therapeutic drug choice or dosing. Phenoconversion is a phenomenon that occurs when an individual's drug metabolizing capacity is altered due to the combination of a drug-drug interaction and a drug-gene interaction. Phenoconversion can affect pharmacokinetics as well as pharmacodynamics. Some examples of phenoconversions include amiodarone-warfarin, duloxetine-codeine, rifampin-clopidogrel, and rifampinwarfarin. Pharmacists must consider phenoconversion in cases of multi-drug therapy.

A Review Of The Guidelines And Treatment Options For Major Depressive Disorder In Adolescents, Stacy Henthorne, Joy Hoffman, Albert Bui, Sarah Kradel, Suzanne M. Lifer, Mary Ellen Hethcox

Pharmacy and Wellness Review

Major depressive disorder (MOD) is a disease often underdiagnosed in adolescents. For adolescents in particular, MOD can have far-reaching implications on developmental, social and emotional functioning. Unfortunately, few guidelines detail consistent means by which to evaluate and treat these patients; significantly more information exists that solely pertains to the adult population. Governing bodies such as the American Academy of Child and Adolescent Psychiatry (AACAP) and Resource for Advancing Children's Health (REACH) recommend that primary care physicians be diligent in their psychiatric analyses and follow-ups with young patients who may be experiencing MOD. Both psychotherapy and medications, either as monotherapy or …