Pharmaceutics and Drug Design Commons^™

Sildenafil As An Appropriate Monotherapy Option In The Treatment Of Pulmonary Arterial Hypertension (Pah), Kaitlin Horton, Kent Wilin, Sarah Ginty, Lara Long, David Bright

Pharmacy and Wellness Review

Pulmonary arterial hypertension (PAH) is a debilitating disease characterized by constriction in the diameter of the pulmonary arterial lumen.1,2 This leads to increased pressure and stress on the right ventricle of the heart, which may lead to heart failure and death.2,3 Currently there are only a few treatment options for patients with PAH. Sildenafil, a phosphodiesterase type 5 (PDE-5) inhibitor, can be used to treat PAH. Sildenafil inhibits the degradation of cyclic guanosine monophosphate (cGMP). Increased cGMP concentration results in pulmonary vasculature relaxation. Current clinical trials have indicated that sildenafil can significantly improve many of the symptoms of PAH. The …

Overview Of Stevens-Johnson Syndrome And Toxic Epidermal Necrolysis, Christina Spinaris, Sarah Kradel, Tara Tokar, Zachary Crawford, Michael M. Milks

Pharmacy and Wellness Review

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are immunologic reactions that typically present due to drug hypersensitivity. These reactions present with serious mucocutaneous manifestations that can lead to significant morbidity and mortality. The pathogeneses of SJS and TEN have yet to be clearly elucidated, but three potential immunologic mechanisms have been defined in literature: granulysin, Fas-FasL, and perforin and granzyme B. Medications have been immunologically linked as the primary causative agents of SJS/TEN. Corticosteroids, intravenous immunoglobulin administration (IVIG) and cyclosporine have been employed as treatments; however, none have resulted in consistent positive outcomes. Pharmacists have a significant role in …

The Impact Of Pharmacogenomics On Chemotherapeutic Drug Development And Use, Lara Long, Amy Pasternak, Ellen Hazelet, David Kisor

Pharmacy and Wellness Review

Cancer therapy is largely dependent on general treatment guidelines, and patients undergoing chemotherapy often experience treatment failure with standard drugs. The development of individualized drug therapy through pharmacogenomics has the potential to enhance chemotherapy regimen selection and improve patient outcomes. Antineoplastic agents such as cetuximab and trastuzumab are effective in treating cancers possessing specific genetic biomarker characteristics. Patients need to undergo genetic testing before these agents are administered to ensure appropriate use. Cetuximab has been shown to improve outcomes in metastatic colorectal cancers and head and neck squamous cell carcinomas positive for EGFR. Trastuzumab has shown benefit in human epidermal …

Improving Maternal And Fetal Health: A Look At Thyroid Function During Pregnancy, Sarah Ginty, Jessica Beck, Taylor Gauthier, Amanda Meyer, Michelle R. Musser

Pharmacy and Wellness Review

Maintenance of thyroid function during pregnancy is critical for both maternal and fetal health and development; therefore, knowledge regarding the relationship between thyroid hormones and pregnancy is essential. The American Thyroid Association task force has developed clinical guidelines on the diagnosis and treatment of thyroid disease during pregnancy. Gestational thyroid diseases are divided into two classifications, hypothyroidism and hyperthyroidism, which are further divided into more specific classifications based on clinical presentation. Differentiation, diagnosis, and monitoring of thyroid diseases throughout pregnancy require assessing symptoms, as well as obtaining levels of thyroid-stimulating hormone (TSH) and free thyroxine (FT4) concentration by a simple …

Dronedarone: An Update To A Controversial Therapy For Atrial Fibrillation, Zachary Crawford, Sara Mcallister, Amanda Hoersten, Jennifer Bauer, Megan Keller, David Bright

Pharmacy and Wellness Review

As of 2004, it was estimated that 2.2 million Americans were diagnosed with paroxysmal or persistent atrial fibrillation (AF) resulting in one out of every six strokes in the United States. AF leads to a reduction in pumping efficiency of the heart increasing the risk of several serious sequelae such as thromboembolic stroke and congestive heart failure (CHF). It also results in a reduced quality of life for the patients suffering from the disease. Patients with AF require appropriate antiarrhythmic therapy to control symptoms and prevent adverse effects of the condition. Multaq® (dronedarone), an antiarrhythmic drug approved for AF in …

Lysteda® For Heavy Menstrual Bleeding, Erica B. Schoenberger, Todd A. Tucker Jr., Justin W. Steele, Amanda Meyer, Sandra L. Hrometz

Pharmacy and Wellness Review

Lysteda®, a novel formulation of tranexamic acid, is an antifibrinolytic medication recently approved by the Food and Drug Administration (FDA) for the treatment of heavy menstrual bleeding. Tranexamic acid has been shown to significantly reduce menstrual blood loss while simultaneously allowing a woman to safely become pregnant. The major advantage of Lysteda® (an oral modified-release formulation of tranexamic acid) compared to oral immediate-release tranexamic acid, is the decreased occurrence of gastrointestinal side effects. As there are no therapeutic equivalents to Lysteda® for heavy menstrual bleeding, it is important for pharmacists to be able to counsel patients appropriately on the specific …

Pharmacogenetic Implications Regarding Second Generation Antipsychotics Clozapine And Risperidone, Sarah E. Ginty, Amy Pasternak, Lauren Desko, Jamie Amero, David Kisor

Pharmacy and Wellness Review

Pharmacogenomics is a growing area of pharmacy that has the potential to improve individualization of medication choices, dosing and predictability of side effects. Clozapine and risperidone are atypical antipsychotics whose metabolism, efficacy and side effects are influenced by single nucleotide polymorphisms (SNPs) in a patient's genetic makeup. It has been shown that a polymorphism in the D3 dopamine receptor is associated with an increased risk in developing tardive dyskinesia as an adverse event while taking risperidone. Also, there is evidence that a patient with a homogenous C genotype in the gene coding for the 5-HTzc receptor has a higher risk …

Effects Of Hormone Therapy On Cognition In Post-Menopausal Women, Jessica Langhals, Megan Meyer, Erica Schoenberger, Amanda Meyer, Kristen Finley Sobota

Pharmacy and Wellness Review

Menopause occurs as a result of decreased natural estrogen production by the body. A variety of short-term and long-term symptoms can occur during menopause, which may significantly impact a woman's daily life. Hormone therapy (HT) is commonly employed to alleviate these unwanted symptoms and to regain balance of hormone levels. Options include estrogen-only or estrogen-progestin combination therapy. While HT may help relieve symptoms such as cognitive decline caused by menopause, it also carries potential side effects. Although HT has shown a potential benefit in women with Alzheimer's disease (AD), overall outcomes measuring cognitive function improvement are inconclusive. Therefore, HT should …

The Use Of Crizotinib In Late Stage Lung Cancer Patients With An Abnormal Alk Gene, Lara Long, Kelly Dye, Courtney Porter, Ellen Hazelet, Karen L. Kier

Pharmacy and Wellness Review

The relatively new anti-cancer drug, crizotinib (Xalkori®, Pfizer), has created excitement in the research community. This drug has exhibited dramatic clinical benefits for select non-small cell lung cancer patients showing evidence of a mutation in the EML4-ALK gene. This gene mutation is present in 4 to 5 percent of non-small cell lung cancer patients. Crizotinib acts through a tyrosine kinase inhibition pathway, targeting the ALK and MET tyrosine kinases, to inhibit phosphorylation of activated ALK, which halts the ALK gene mutation and impedes metastasis. In phase I clinical trials, a 57 percent overall response rate was shown, and researchers calculated …

Lithium Therapy In Alzheimer's Disease, Ross Robison, Sara Swick, Lauren Bajbus, Jennifer Bauer, B. Shane Martin

Pharmacy and Wellness Review

Alzheimer's disease (AD) is a neurodegenerative disorder with no known cure which has a strong impact on patients and their caregivers. Current treatments for AD can slow the disease progression, but cannot reverse the damage that has already been done, resulting in some level of lifelong disability for affected patients. The use of lithium has shown promising results in mice models of AD. While animal models have produced positive results, additional human trials need to be conducted in order to determine a place for lithium in Alzheimer's disease therapy. Pharmacists should be aware of this potential new use of lithium …

Fidaxomicin (Dificid®): New Antibiotic Approved For The Treatment Of Clostridium Difficile Infections, Sara M. Mcallister, Zachary Crawford, Joshua Ilenin, Ellen Hazelet, Andrew M. Roecker

Pharmacy and Wellness Review

Clostridium difficile is a gram-positive, spore forming bacteria normally transmitted by the fecal-oral route. Infection develops in patients with decreased normal gut flora and is typically associated with recent antibiotic use. Other risk factors include bowel surgery, compromised immune system function, extended hospital stays, and other underlying diseases. C. difficile bacteria produce two toxins, which cause increased intestinal fluid secretion and inflammation. Patients commonly present with diarrhea, abdominal discomfort, loss of appetite, and nausea. Current treatment guidelines are to discontinue antimicrobial agents and increase hydration. Less severe C. difficile associated diarrhea (CDAD) cases are treated with metronidazole 500 mg three …

The Emerging Role Of Ticagrelor In Acute Coronary Syndromes, Jennifer Bauer, Brittany Dye, Kimberly Baucher, Megan Keller, David Bright, Karen L. Kier

Pharmacy and Wellness Review

Antiplatelet therapy has become a mainstay in the treatment of acute coronary syndromes (ACS). Until recently, options were somewhat limited when it came to individualizing drug selection. Plavix® (clopidogrel) has been successfully used for many years but requires activation by CYP enzymes. Depending on an individual patient's genetic makeup, function of these CYP enzymes may be altered, which may increase the risk for clots. The recent approval of Effient® (prasugrel) and Brilinta® (ticagrelor) has provided physicians and pharmacists with more options and may hopefully lead to improved clinical outcomes. Ticagrelor specifically exhibits clinically different pharmacologic characteristics that require twice daily …

Sipuleucel-T (Provenge®): Therapeutic Use And Financial Implications, Courtney Porter, Joshua Ilenin, Lisa Berni, Ashley Overy, Karen L. Kier

Pharmacy and Wellness Review

Although mortality rates have been declining, prostate cancer accounts for a large percentage of cancer diagnoses around the world. Sipuleucel-T (Provenge®), an autologous cellular immunotherapy targeted against the antigen expressed in most prostate cancers, has been shown to increase the median survival rate of castration-resistant prostate cancer. Even so, the therapeutic risks and benefits, as well as financial implications, all currently play a role in the governmental decision to reimburse for this new therapy.

Investigating Trail Sensitivity In Platinum-Resistant Ovarian Cancer, Nicholas Pathoulas

All College Thesis Program, 2016-2019

Ovarian cancer is the deadliest gynecologic malignancy in the United States. While these tumors may have a promising initial response to platinum-based chemotherapies, the patient’s prognosis is commonly hindered by the development of platinum resistant cancer. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been implicated as a potential treatment for many cancers based on its tumor selective nature. Combination therapies with TRAIL and platinum drugs have been shown to increase apoptosis and have been used in a variety of clinical trials, which have thus far failed to pass phase II.1 Researchers have not yet elucidated the complex mechanism(s) of TRAIL …

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 …

Inhibition Of Cancer Stem Cells By Glycosaminoglycan Mimetics, Connor P. O'Hara

Theses and Dissertations

Connor O’Hara July 29, 2019

Inhibition of Cancer Stem Cells by Glycosaminoglycan Mimetics

In the United States cancer is the second leading cause of death, with colorectal cancer (CRC) being the third deadliest cancer and expected to cause over 51,000 fatalities in 2019 alone.¹ The current standard of care for CRC depends largely on the staging, location, and presence of metastasis.² As the tumor grows and invades nearby lymph tissue and blood vessels, CRC has the opportunity to invade not only nearby tissue but also metastasize into the liver and lung (most commonly).³ The 5-year survival rate …

Non-Genomic Effects Of Glucocorticoids: An Updated View, Reynod A. Panettieri, Dedmer Schaafsma, Yassine Amrani, Cynthia Koziol-White, Rennolds S. Ostrom, Omar Tliba

Pharmacy Faculty Articles and Research

Glucocorticoid (GC) anti-inflammatory effects generally require a prolonged onset of action and involve genomic processes. Because of the rapidity of some of the GC effects, however, the concept that non-genomic actions may contribute to GC mechanisms of action has arisen. While the mechanisms have not been completely elucidated, the non-genomic effects may play a role in the management of inflammatory diseases. For instance, we recently reported that GCs ‘rapidly’ enhanced the effects of bronchodilators, agents used in the treatment of allergic asthma. In this review article, we discuss (i) the non-genomic effects of GCs on pathways relevant to the pathogenesis …

Synthesis And Antiproliferative Activities Of Doxorubicin Thiol Conjugates And Doxorubicin-Ss-Cyclic Peptide, Shaban Darwish, Neda Sadeghiani, Shirley Fong, Saghar Mozaffari, Parinaz Hamidi, Thimanthi Withana, Sun Yang, Rakesh Kumar Tiwari, Keykavous Parang

Pharmacy Faculty Articles and Research

Myocardial toxicity and drug resistance caused by drug efflux are major limitations of doxorubicin (Dox)-based chemotherapy. Dox structure modification could be used to develop conjugates with an improved biological profile, such as antiproliferative activity and higher cellular retention. Thus, Dox thiol conjugates, Dox thiol (Dox-SH), thiol-reactive Dox-SS-pyridine (SS = disulfide), and a Dox-SS-cell-penetrating cyclic peptide, Dox-SS-[C(WR)4K], were synthesized. Dox was reacted with Traut's reagent to generate Dox-SH. The thiol group was activated by the reaction with dithiodipyridine to afford the corresponding Dox-SS-Pyridine (Dox-SS-Pyr). A cyclic cell-penetrating peptide containing a cysteine residue [C(WR)4K] was prepared using Fmoc solid-phase strategy. Dox-SS-Py was …

Development And Preclinical Evaluation Of Long-Lasting Cocaine Hydrolases For Cocaine Overdose And Cocaine Use Disorder Treatment, Ting Zhang

Theses and Dissertations--Pharmacy

Cocaine is a plant-based illicit drug commonly involved in substance use disorder. Although cocaine overdose and cocaine use disorders cause adverse health consequences to individuals and the economic burden on their family and society, there are no FDA (Food and Drug Administration) approved medications for treatment. Recently, it has been recognized that delivery of cocaine hydrolase (CocH) is a promising therapeutic strategy. Human butyrylcholinesterase (hBChE), the primary enzyme involved in cocaine metabolism in human, have advantages over other candidates for the development of CocH. Previous studies in our laboratory have designed and characterized hBChE mutants that have ~4,000-fold improved catalytic …

Development And Validation Of A Semi-Physiological Pharmacokinetic (Pbpk) Model To Predict Systemic And Pulmonary Exposures After Intravenous, Oral Administration And Pulmonary Inhalation Of Selected Drugs, Budesonide, Tobramycin And Ciprofloxacin, In Humans, Bishoy Hanna

Theses and Dissertations

Using a semi-PBPK modeling/quantitative meta-analysis approach, this project investigated what factors affect pulmonary and systemic exposures of Budesonide (BUD), Tobramycin (TOB), and Ciprofloxacin (CIP) after inhalation:

Three structurally different pulmonary disposition models were developed for each drug, including pulmonary absorption (all three), excretion (TOB and CIP) and sequestration (TOB) in a peripheral and central lung compartment. Systemic disposition parameters were estimated using available human mean plasma (c_p(t)) and sputum (c_s(t)) concentration profiles after IV administration, and GI absorption parameters were estimated from these profiles after oral administration. Pulmonary disposition parameters were estimated from c_p(t) …

Synthesis Of Oxadeazoles With Electron Withdrawing Groups And The Analysis Of Product Yield With Bond Length, Elizabeth Ann Hall Peters

Undergraduate Honors Thesis Projects

2,5-disubstituted 1,3,4-oxadiazoles are a class of organic compound that are widely used and successful in pharmaceutical chemistry because they demonstrate strong biological activity. They are part of a larger class of compound called heterocycles, which make up most pharmaceutical drugs today. When synthesizing the compounds, higher yield means higher reactivity of the compound, and this is important for pharmaceuticals that need to have a strong biological activity. Per past studies, electron withdrawing groups on the compound allow higher, product yields. Along with electron withdrawing group addition, the bond length from electron withdrawing group and its corresponding carbon is analyzed to …

Stabilization Of Gp120 Outer Domain For Hiv-1-1 Vaccine Immunogen Design, Duoyi Hu

School of Veterinary and Biomedical Sciences: Dissertations, Theses, and Student Research

The sole envelope glycoprotein spike on the surface of Human Immunodeficiency Virus (HIV-1) is composed of two subunits: gp120 and gp41. The gp120 consists of three domains: the inner domain, outer domain and bridging sheet, to which the viral primary receptor CD4 binds and induces a conformational change in gp120 to expose the co-receptor binding site. Previous studies have found that the outer domain of gp120 is relatively more stable than the inner domain and bridging sheet. When superimposed, the co-crystal structures of CD4-gp120 complex and VRC01-gp120 complex revealed that the CD4-binding site (CD4-BS) antibody VRC01 actually mainly bound to …

Development And Evaluation Of Amphotericin B Loaded Iron Oxide Nanoparticles For Targeted Drug Delivery To Systemic Fungal Infections, Pavan Balabathula

Theses and Dissertations (ETD)

A targeted nanotheronostic drug delivery system to diagnose and treat life threatening invasive fungal infections (IFIs) such as cryptococcal meningitis was designed, developed, characterized, and evaluated. To address the development processes, first, iron oxide nanoparticles (IONP) (34-40 nm) coated with bovine serum albumin (BSA), loaded and targeted with amphotericin B (AMB) (AMB-IONP) was formulated by applying a layer by layer approach. Several designs (A, B, C, D, & E) of AMB-IONP were developed and their physicochemical properties such as drug loading with HPLC method, particle size, poly dispersity index (PDI), and ζ-potential using dynamic light scattering (DLS) technique, morphology with …

2014 Brings New Drugs, Rodney Richmond

Faculty Research ​and Publications

No abstract provided.

Feasibility Of Integrating Tripterygium Wilfordii Into Modern Cancer Therapy For Increased Efficacy And Minimal Toxicity, Ngoc T. Vo

Undergraduate Research Posters

Cancer is the second leading cause of death in the U.S. and millions of novel cancer cases are being diagnosed each year. While chemotherapy and ionizing radiation are effective treatments against these malignant tumors, the adverse effects that accompany such treatments are devastating. In order to find alternative treatment methods with less side effects, we turn to Eastern herbal medicine. Recent scientific research has found that Tripterygium wilfordii, an herbal medicine traditionally used to treat inflammation in China, contains compounds (triptolide and celastrol) that prevent the growth of solid tumors, induce apoptosis, and prevent metastasis of developed tumors. Investigations …

Facile, Regio-And Diastereoselective Synthesis Of Spiro-Pyrrolidine And Pyrrolizine Derivatives And Evaluation Of Their Antiproliferative Activities, Abdulrahman I. Almansour, Raju Suresh Kumar, Farzana Beevi, Amir Nasrolahi Shirazi, Hasnah Osman, Rusli Ismail, Tan Soo Chen, Brian Sullivan, Kellen Mccaffrey, Alaa Nahhas, Keykavous Parang, Mohamed Ashraf Ali

Pharmacy Faculty Articles and Research

A number of novel spiro-pyrrolidines/pyrrolizines derivatives were synthesized through [3+2]-cycloaddition of azomethine ylides with 3,5-bis[(E)-arylmethylidene] tetrahydro-4(1H)-pyridinones 2a-n. Azomethine ylides were generated in situ from the reaction of 1H-indole-2,3-dione (isatin, 3) with N-methylglycine (sarcosine), phenylglycine, or proline. All compounds (50 M) were evaluated for their antiproliferative activity against human breast carcinoma (MDA-MB-231), leukemia lymphoblastic (CCRF-CEM), and ovarian carcinoma (SK-OV-3) cells. N-alpha-Phenyl substituted spiro-pyrrolidine derivatives (5a-n) showed higher antiproliferative activity in MDA-MB-231 than other cancer cell lines. Among spiro-pyrrolizines 6a-n, a number of derivatives including 6a-c and 6i-m showed a comparable activity with doxorubicin in all three cell lines. Among all compounds …

Phosphatidylinositol 3-Kinase (Pi3k) As A Therapeutic Target In Nsclc, Christopher W. Stamatkin

Theses and Dissertations--Pharmacy

Deregulated activation of phosphatidylinositol 3-kinase (PI3K) pathway is central to many human malignancies. The functions of this pathway are critical for normal cell metabolism, proliferation, and survival. In lung cancers, the PI3K pathway activity is often aberrantly driven by multiple mutations, including EGFR, KRAS, and PIK3CA. Molecules targeting the PI3K pathway are intensely investigated as potential anti-cancer agents. Although inhibitors of the pathway are currently in clinical trials, rational and targeted use of these compounds, alone or in combination, requires an understanding of isoform-specific activity in context. We sought to identify class IA PI3K enzyme (p110a/PIK3CA, p110b/PIK3CB, p110d/PIK3CD) activities using …

The Fit-Hansa Demonstrates Reliability And Convergent Validity Of Functional Performance In Patients With Shoulder Disorders, Prajyot Kumta, Joy C. Macdermid, Saurabh Mehta, Paul W. Stratford

Physical Therapy Faculty Research

Study

DesignPsychometric study design.

Objectives

To assess the test-retest reliability and convergent validity of the Functional Impairment Test-Hand and Neck/Shoulder/Arm (FIT-HaNSA) in patients with shoulder disorders.

Background

Performance tests that assess functional ability of patients with shoulder disorders can provide useful information for making clinical or return-to-activity decisions. No performance-based shoulder test has yet demonstrated sufficient relevance or clinical measurement properties. The FIT-HaNSA examines upper extremity performance during repetitive tasks that emphasize shoulder reaching and static postures and, therefore, has greater relevance for assessing performance.

Methods

Thirty-six patients with shoulder disorders and 65 healthy controls were recruited for the study. …

A Glycosylated Recombinant Human Granulocyte Colony Stimulating Factor Produced In A Novel Protein Production System (Avi-014) In Healthy Subjects: A First-In Human, Single Dose, Controlled Study., Roslyn Varki, Ed Pequignot, Mark C Leavitt, Andres Ferber, Walter K Kraft

Department of Pharmacology and Experimental Therapeutics Faculty Papers

BACKGROUND: AVI-014 is an egg white-derived, recombinant, human granulocyte colony-stimulating factor (G-CSF). This healthy volunteer study is the first human investigation of AVI-014. METHODS: 24 male and female subjects received a single subcutaneous injection of AVI-014 at 4 or 8 mcg/kg. 16 control subjects received 4 or 8 mcg/kg of filgrastim (Neupogen, Amgen) in a partially blinded, parallel fashion. RESULTS: The Geometric Mean Ratio (GMR) (90% CI) of 4 mcg/kg AVI-014/filgrastim AUC(0-72 hr) was 1.00 (0.76, 1.31) and Cmax was 0.86 (0.66, 1.13). At the 8 mcg/kg dose, the AUC(0-72) GMR was 0.89 (0.69, 1.14) and Cmax was 0.76 (0.58, …