Medicinal and Pharmaceutical Chemistry Commons^™

Inhibition Of Breast Cancer Angiogenesis And Metastasis Ay Targeting Hypoxia-Inducible Factor-1Α, Chikezie O. Madu

Theses and Dissertations (ETD)

The current clinical chemotherapy agents are not ideal for breast cancer as they are not curative, but only provide a modest extension of survival with sometimes a severely adverse effect on the patient’s quality of life. There is, therefore, an urgent need to search for new and more effective anti-breast cancer drugs. However, the existing screening system is inefficient and time-consuming despite the extremely large amount of small molecule compounds in database currently available, and thereby hindering the effort for selecting new and effective anti-cancer drugs.

The majority of locally advanced solid tumors contain regions of reduced oxygen availability. Hypoxia …

Investigation Of Enhancement Of Furosemide Solubilization With Cyclodextrins And A Novel Octenyl Succinate Anhydride Starch, Rui Zhu

Theses and Dissertations (ETD)

Solubility behavior is one of the most challenging aspects for drug commercialization and often the main reason of drug that do not reach to its full potential. Now nearly 60% new chemical entities possess solubility problems, whereas practically no drug products with less than 10 µg/ml solubility in 70’s or 80’s. There is an ever increasing need to develop new formulation techniques and exicipients with novel mechanisms of action. Various techniques have been applied to enhance the drug solubility such as co-solvents, particle size reduction, lipid based drug delivery systems, nanosuspension, use of surfactants, salt formation, cyclodextrin complexes and solid …

Plant Lectin Can Target Receptors Containing Sialic Acid, Exemplified By Podoplanin, To Inhibit Transformed Cell Growth And Migration, Jhon Ochoa-Alvarez, Harini Krishnan, Yongquan Shen, Nimish Acharya, Min Han, Dean Mcnulty, Hitoki Hasegawa

Rowan-Virtua School of Osteopathic Medicine Departmental Research

Cancer is a leading cause of death of men and women worldwide. Tumor cell motility contributes to metastatic invasion that causes the vast majority of cancer deaths. Extracellular receptors modified by α2,3-sialic acids that promote this motility can serve as ideal chemotherapeutic targets. For example, the extracellular domain of the mucin receptor podoplanin (PDPN) is highly O-glycosylated with α2,3-sialic acid linked to galactose. PDPN is activated by endogenous ligands to induce tumor cell motility and metastasis. Dietary lectins that target proteins containing α2,3-sialic acid inhibit tumor cell growth. However, anti-cancer lectins that have been examined thus far target receptors …

Anti-Neoplastic Activity Of Two Flavone Isomers Derived From Gnaphalium Elegans And Achyrocline Bogotensis, Christan M. Thomas, Robert C. Wood Iii, Jarrett E. Wyatt, Morgan H. Pendleton, Ruben B. Torrenegra, Oscar E. Rodriguez, Sam Harirforoosh, Maria Ballester, Janet Lightner, Koyamangalath Krishnan, Victoria P. Ramsauer

Pharmacy Faculty Articles and Research

Over 4000 flavonoids have been identified so far and among these, many are known to have antitumor activities. The basis of the relationships between chemical structures, type and position of substituent groups and the effects these compounds exert specifically on cancer cells are not completely elucidated. Here we report the differential cytotoxic effects of two flavone isomers on human cancer cells from breast (MCF7, SK-BR-3), colon (Caco-2, HCT116), pancreas (MIA PaCa, Panc 28), and prostate (PC3, LNCaP) that vary in differentiation status and tumorigenic potential. These flavones are derived from plants of the family Asteraceae, genera Gnaphalium and Achyrocline reputed …

Electronic Properties Of Memantine (Alzheimer's Disease) And Amantadine (Anti-Flu) Drugs, Kirsten Middleton, Guo-Ping Zhang, Thomas F. George

Symposium 2012

Alzheimer’s Disease is the 5th leading cause of death for Americans 65 and older Treatment The U.S. Food and Drug Administration Only five drugs approved that “temporarily slow worsening of symptoms for about six to 12 months.” Effective for only about half of all patients.

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 …

Development Of Co-Processed Plasticized Cellulose Acetate For Sustained Release Matrix Tablets, Yinqi Zhou

Theses and Dissertations (ETD)

Cellulose Acetate (CA) is a polymer extensively used in pharmaceutical applications. Because of the hydrophobic nature and good film properties of CA, it is a good polymer candidate for sustained release matrix tablets. Sustained release matrix tablets of cellulose acetate can be prepared by direct compression or wet granulation methods. However, previous studies showed that a large amount of CA was required to achieve the desired sustained release profile for a sparingly soluble drug and it was difficult to formulate a highly water soluble drug by using CA as the retarding agent. Some studies concluded that CA is very sensitive …

Preclinical Study Of Potential Antiglioma Novel Tetrahydroisoquinoline Analogs: Pharmacokinetics And Mechanism Of Action, Fei Ma

Theses and Dissertations (ETD)

Gliomas, the tumors of glial cells, account for 80% of primary malignant brain tumors. In 2011, there were about 18,300 new cases of maligant gliomas in the United States alone. Patients with glioblastoma multiforme or anaplastic astrocytoma, the two major types of malignant gliomas, have a median survival of 14 months or 2 to 3 years, respectively. Therefore novel treatments for malignant glioma are urgently needed.

A novel series of tetrahydroisoquinoline derivatives with antiglioma activity has been undergoing drug metabolism/pharmacokinetics (DMPK)-guided lead optimization. EDL-291 was result from structure modification of last generation compound EDL-155. Its preclinical pharmacokinetics were characterized in …

Pharmacokinetic/Pharmacodynamic (Pk/Pd) Modeling Of Anti-Neoplastic Agents, Daniel Lexcen, Ahmed H. Salem, Walid F. Elkhatib, Virginia Haynes, Ayman Noreddin

Pharmacy Faculty Books and Book Chapters

"Development of tumor resistance to chemotherapeutics is related to inherent tumor variations regarding sensitivity to chemotherapeutics and to sub-optimal dosing regimens, including variation in patient pharmacokinetics that result in suboptimal exposure of tumor cells to anti-neoplastic drugs [1, 2]. The rate and extent of drug efficacy depends on the extent of drug exposure at the tumor site and the time above the effective concentration [3]. In vitro models that incorporate these pharmacokinetic and pharmacodynamic (PK/PD) principles to optimize therapeutic response may be considered the method of choice for optimizing dosing schedules before translating data from static assays to animals and …

Pharmacists And Pharmacogenomics: An Evaluation Of Knowledge, Beliefs, Attitudes And Practices, Laressa Bethishou, Angela Chen, Chrissie Chew, Richard Dang, Courtney Greenber, Rebecca Ashlee Klevens, Vlada Treynker, Andrew Warnock, Melissa Durham, Jeffery A. Goad, Edith Mirzaian

Pharmacy Faculty Articles and Research

"Pharmacogenomics is the term used to describe the rapidly advancing study on how genetic makeup can impact drug therapy. In specialized clinical situations, such as the use of irinotecan in colon cancer or abacavir in HIV infections, it is now possible to identify specific genotypes that correlate strongly with a patient's therapeutic outcome, with implications on both efficacy and side effects. On a broader scale, a systematic review published by the Journal of the American Medical Association on the top 27 adverse reaction-causing drugs found that a majority of the adverse effects have a genetic component, suggesting that an analysis …

Anti-Malarial Activity Of Geldanamycin Derivatives In Mice Infected With Plasmodium Yoelii, Rubul Mout, Zhi-Dong Xu, Angela Kh Wolf, Vincent J. Davisson, Gotam K. Jarori

Borch Department of Medicinal Chemistry and Molecular Pharmacology Faculty Publications

Background

Geldanamycin (GA), a benzoquinone ansamycin antibiotic has been shown in vitro to possess anti-plasmodial activity. Pharmacological activity of this drug is attributed to its ability to inhibit PfHSP90. The parasite growth arrest has been shown to be due to drug-induced blockage of the transition from ring to trophozoite stage. To further evaluate the consequences of this pharmacodyamic feature, the anti-malarial activity of GA analogs with enhanced drug properties in a Plasmodium-infected animal model have been evaluated for their capacity to induce clearance of the parasite. In the process, a hypothesis was subsequently tested regarding the susceptibility of the …

Synthetic Peptides Derived From The Sequence Of A Lasso Peptide Microcin J25 Show Antibacterial Activity, Rania Soudy, Liru Wang, Kamaljit Kaur

Pharmacy Faculty Articles and Research

Microcin J25 (MccJ25) is a plasmid-encoded, ribosomally synthesized antibacterial peptide with a unique lasso structure. The lasso structure, produced with the aid of two processing enzymes, provides exceptional stability to MccJ25. We report the synthesis of six peptides (1–6), derived from the MccJ25 sequence, that are designed to form folded conformation by disulfide bond formation and electrostatic or hydrophobic interactions. Two peptides (1 and 6) display good activity against Salmonella newport, and are the first synthetic derivatives of MccJ25 that are bactericidal. Peptide 1 displays potent activity against several Salmonella strains including two …

Chemotherapy: The Physiological Cost Of A Cure, Megan Ellis

A with Honors Projects

This project focuses on the common long term side effects of cancer treatments, apart from cure. In addition to physiological function changes, it focuses on the chemical composition of chemotherapy drugs.

Structural Properties Of Thermoresponsive Poly(N-Isopropylacrylamide)-Poly(Ethyleneglycol) Microgels, J. Clara-Rahola, A. Fernandez-Nieves, B. Sierra-Martin, A. B. South, L. Andrew Lyon, J. Kohlbrecher, A. F. Barbero

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

The application of RNA interference to treat disease is an important yet challenging concept in modern medicine. In particular, small interfering RNA (siRNA) have shown tremendous promise in the treatment of cancer. However, siRNA show poor pharmacological properties, which presents a major hurdle for effective disease treatment especially through intravenous delivery routes. In response to these shortcomings, a variety of nanoparticle carriers have emerged, which are designed to encapsulate, protect, and transport siRNA into diseased cells. To be effective as carrier vehicles, nanoparticles must overcome a series of biological hurdles throughout the course of delivery. As a result, one promising …

Differential Effects Of Pravastatin And Simvastatin On The Growth Of Tumor Cells From Different Organ Sites, David G. Menter, Victoria P. Ramsauer, Sam Harirforoosh, Kanishka Chakraborty, Peiying Yang, Linda His, Robert A. Newman, Koyamangalath Krishnan

Pharmacy Faculty Articles and Research

3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) inhibitors, commonly known as statins, may possess cancer preventive and therapeutic properties. Statins are effective suppressors of cholesterol synthesis with a well-established risk-benefit ratio in cardiovascular disease prevention. Mechanistically, targeting HMGCR activity primarily influences cholesterol biosynthesis and prenylation of signaling proteins. Pravastatin is a hydrophilic statin that is selectively taken up by a sodium-independent organic anion transporter protein-1B1 (OATP1B1) exclusively expressed in liver. Simvastatin is a hydrophobic statin that enters cells by other mechanisms. Poorly-differentiated and well-differentiated cancer cell lines were selected from various tissues and examined for their response to these two statins. Simvastatin …

Novel Amino Acid Transporter-Targeted Radiotracers For Breast Cancer Imaging, Fanlin Kong

Dissertations and Theses (Open Access)

Breast cancer is the most common malignancy among women in the world. Its 5-year survival rate ranges from 23.4% in patients with stage IV to 98% in stage I disease, highlighting the importance of early detection and diagnosis. ¹⁸F-2-Fluoro-2-deoxy-glucose (¹⁸F-FDG), using positron emission tomography (PET), is the most common functional imaging tool for breast cancer diagnosis currently. Unfortunately, ¹⁸F-FDG-PET has several limitations such as poorly differentiating tumor tissues from inflammatory and normal brain tissues. Therefore, ¹⁸F-labeled amino acid-based radiotracers have been reported as an alternative, which is based on the fact that tumor cells uptake …

Compound 49b: A Novel Beta-Adrenergic Receptor Agonist In The Treatment Of Diabetic Retinopathy, Kimberly Williams-Guy

Theses and Dissertations (ETD)

Diabetic retinopathy is the leading cause of blindness in working Americans. While there are therapeutic regimens for the disease, more effective methods are needed. We have previously shown that a non-specific beta-adrenergic receptor agonist, isoproterenol, was effective in preventing functional and morphological changes associated with diabetic retinopathy in the rat. Isoproterenol also produced left ventricle remodeling suggesting it entered the systemic circulation. We therefore synthesized various novel beta-adrenergic receptor compounds and screened these compounds in vitro for their ability to reduce markers of inflammation and apoptosis. Of the various compounds tested, Compound 49b was able to reduce both inflammation and …

Preclinical Pharmacology Of The Mdm2 Antagonist Nutlin-3a, Fan Zhang

Theses and Dissertations (ETD)

Nutlin-3a is an MDM2-p53 interaction antagonist that is under investigation in preclinical models for a variety of pediatric malignancies, including neuroblastoma, retinoblastoma, leukemia, and rhabdomyosarcoma. In the current research, we conducted preclinical pharmacology studies of nutlin-3a to evaluate the synergistic effect of the nutlin-3a and topotecan combination on neuroblastoma cell growth, to assess the effect of nutlin-3a on breast cancer resistance protein (BCRP), and to characterize the disposition of nutlin-3a in the mouse plasma and multiple tissues.

Activating the p53 pathway might offer a new therapy for neuroblastoma. In the first part of the study, we assessed the effect of …

Reactive Oxygen Species Modulation Of Na/K-Atpase Regulates Fibrosis And Renal Proximal Tubular Sodium Handling, Jiang Liu, David J. Kennedy, Yanling Yan, Joseph I. Shapiro Md

Pharmaceutical Science and Research

The Na/K-ATPase is the primary force regulating renal sodium handling and plays a key role in both ion homeostasis and blood pressure regulation. Recently, cardiotonic steroids (CTS)-mediated Na/K-ATPase signaling has been shown to regulate fibrosis, renal proximal tubule (RPT) sodium reabsorption, and experimental Dahl salt-sensitive hypertension in response to a high-salt diet. Reactive oxygen species (ROS) are an important modulator of nephron ion transport. As there is limited knowledge regarding the role of ROS-mediated fibrosis and RPT sodium reabsorption through the Na/K-ATPase, the focus of this review is to examine the possible role of ROS in the regulation of Na/K-ATPase …