Pharmacology Commons^™

The Proton-Coupled Folate Transporter: Biology And Therapeutic Applications To Cancer, Sita Desmoulin

Wayne State University Dissertations

Folates are essential cofactors of tumor cell proliferation and survival required for nucleotide biosynthesis and amino acid metabolism. In cancer therapy, inhibition of folate-dependent metabolic pathways has been achieved through the use of antifolates. Unfortunately, the efficacy of many clinically approved antifolates is limited by a lack of tumor selectivity. Facilitative transport of folates into mammalian cells is achieved by the reduced folate carrier (RFC) and proton-coupled folate transporter (PCFT). As PCFT is a folate-proton symporter with an acidic pH optimum, PCFT may provide a mechanism for targeting cytotoxic antifolates to tumors, based on their acidic microenvironments. To establish the …

Maternal Immune Dysregulation In The Pathogenesis Of Neurodevelopmental Disorders: Interleukin-6 As A Central Mechanism And Therapeutic Target Of Flavonoids, Ellisa Carla Parker-Athill

USF Tampa Graduate Theses and Dissertations

Activation of the maternal immune system and resultant maternal cytokine expression due to prenatal infection has been implicated as a significant contributor to the pathology of neuropsychiatric and neurodevelopmental disorders such as schizophrenia and Autism Spectrum Disorder (ASD). Increased maternal interleukin-6 (IL-6) expression, observed clinically and in animal models of prenatal infection, and resultant activation of key signaling pathways, has been shown to be a biological indicator of pathology, and a central component of the pathological mechanism. In animal models of prenatal infection and clinically in pregnancy disorders hallmarked by immunological irregularities and increased IL-6 expression, inhibition of IL-6 has …

Modulating The Pharmacokinetics Of Bioflavonoids, Adam John Smith

USF Tampa Graduate Theses and Dissertations

One of the largest obstacles in drug development is to overcome solubility and bioavailability problems. Preformulation strategies such as nanoparticle formation are often employed but sometimes create new issues and are limited in their effectiveness and applications. Since the majority of drugs are marketed and sold as solid forms, drug delivery systems are not always desirable. This is where solid-state chemistry becomes important. Traditional solid-state chemistry approaches are often successful but are sometimes too restrictive and cannot be applied to certain compounds. Cocrystals have emerged as an alternative solid-state technique that can be applied to a broad range of compounds. …

Targeting Α4 Integrin Containing Complexes In Multiple Myeloma Using Peptidomimetics, Michael Foster Emmons

USF Tampa Graduate Theses and Dissertations

In our previous work we demonstrated that the integrin antagonist, HYD1, induced necrotic cell death in myeloma cell lines in vitro and in vivo as a single agent. In order to further delineate biomarkers of response to HYD1 we developed an isogenic drug resistant variant named H929-60. We show that the acquisition of resistance towards HYD1 correlates with reduced expression of the cleaved α4 integrin subunit and beta 1 integrin. Moreover, we demonstrate that HYD1 interacts with α4 integrin in myeloma cells. Consistent with reduced VLA-4 expression, the resistant variant showed ablated functional binding to fibronectin, VCAM-1 and the bone …

Use And Development Of Computational Tools In Drug Discovery: From Small Molecules To Cyclic Peptides, Daniel Navarrete Santiago

USF Tampa Graduate Theses and Dissertations

The scope of this work focuses on computationally modeling compounds with protein structures. While the impetus of drug discovery is the innovation of new therapeutic molecules, it also involves distinguishing molecules that would not be an effective drug. This can be achieved by inventing new tools or by refining old tools. Virtual screening (VS, also called docking), the computational modeling of a molecule in a receptor structure, is a staple in predicting a molecule's affinity for an intended target. In our Virtual Target Screening system (also called inverse-docking), VS is used to find high-affinity targets, which can potentially explain absorption, …

Classification Of Plants According To Their Heavy Metal Content Around North Mara Gold Mine, Tanzania: Implication For Phytoremediation, N. Mganga, Mlk Manoko, Z. K. Rulangaranga

Tanzania Journal of Science

Plants like other living organisms respond differently under different environmental conditions. An elevated level of heavy metals is one of the stresses which results into three classes of plants depending on their heavy metal content. The classes of plant species according to their accumulated heavy metals around North Mara Gold Mine were not known. To study such classes, a line transect of 700m long was established opposite the gold mine wastes. A total of eight sampling points were systematically established each after every 100m in that transect. Fifteen plant species were sampled; at least one species per sampling point. Approximately …

Modelling Β2ar Regulation, Sharat J. Vayttaden

Dissertations and Theses (Open Access)

The β2 adrenergic receptor (β2AR) regulates smooth muscle relaxation in the vasculature and airways. Long- and Short-acting β-agonists (LABAs/SABAs) are widely used in treatment of chronic obstructive pulmonary disorder (COPD) and asthma. Despite their widespread clinical use we do not understand well the dominant β2AR regulatory pathways that are stimulated during therapy and bring about tachyphylaxis, which is the loss of drug effects. Thus, an understanding of how the β2AR responds to various β-agonists is crucial to their rational use. Towards that end we have developed deterministic models that explore the mechanism of drug- induced β2AR regulation. These mathematical models …

Store-Operated Calcium Channels In The Function Of Intracardiac Neurons, Timetria Bonds

USF Tampa Graduate Theses and Dissertations

Proper autonomic regulation of mammalian cardiac function is dependent upon very complex and precise communication among the intracardiac ganglia and individual neurons within the ganglia. An array of neuromodulators is found within the ganglia that direct neuronal activity by modulating the movement of calcium. The current study determines that opioidergic agonists, which have been found to contribute to severe cardiac disease states and intracellular calcium mobilization, are also responsible for changes in the function of the intracardiac neuron via their effects on store-operated calcium channels (SOCs).

Previous studies suggest that phosphorylation plays a role in SOC regulation. Using Fura-2 calcium …

Minimal Structural Requirements Of Alkyl Γ-Lactones Capable Of Antagonizing The Cocaine-Induced Motility Decrease In Planarians, Debra Baker, Sean Deats, Peter Boor, James Pruitt, Oné R. Pagán

Biology Faculty Publications

We recently reported that the natural cyclic lactone, parthenolide, and related analogs prevent the expression of behavioral effects induced by cocaine in planarians and that parthenolide’s γ-lactone ring is required for this effect. In the present work, we tested a series of alkyl γ-lactones with varying chain length (1–8 carbons) to determine their ability to antagonize the planarian motility decrease induced by 200 μM cocaine. Alkyl lactones with up to a 4-carbon alkyl chain did not affect planarian motility or antagonized the cocaine-induced motility decrease; only the compound γ-nonalactone (a γ-lactone with a 5-carbon chain) was able to prevent the …

Physiologically-Based Pharmacokinetic Modeling For Predicting Drug-Drug Interactions, David M. Ng, Ali Navid

STAR Program Research Presentations

Dynamics of interactions between the drugs caffeine and ciprofloxacin are predicted using physiologically-based pharmacokinetic (PBPK) modeling. Pharmacokinetic means the model determines where the drugs are distributed in the body over time. Physiologically-based means the anatomy and physiology of the human body is reflected in the structure and functioning of the model. Multiple drugs can interact to increase or decrease their beneficial and/or undesired effects. This is important because some common substances, such as caffeine in coffee and soft drinks, are actually drugs that affect the body. By implementing the model as a computer program, it is relatively straightforward to perform …

Role Of Dopamine In Impulse Control, Paul Rafael Sabandal ^, Young-Cho Kim, Kyung-An Han *

COURI Symposium Abstracts, Summer 2011

No abstract provided.

Formulation And Characterization Of Lipid-Based Drug Delivery System Of Raloxifene-Microemulsion And Self-Microemulsifying Drug Delivery System, Hetal Thakkar, Jitesh Nangesh, Mayur Parmar, Divyakant Patel

HPD Articles

BACKGROUND: Raloxifene, a second-generation selective estrogen receptor modulator (SERM) used to prevent osteoporosis in postmenopausal women is administered orally in the form of a tablet. The absolute bioavailability of the drug is only 2% because of extensive hepatic first-pass metabolism. Lipid-based formulations are reported to reduce the first-pass metabolism by promoting its lymphatic uptake. MATERIALS AND METHODS: In the present investigation, microemulsion and Self-Microemulsifying Drug Delivery System (SMEDDS) formulations of Raloxifene were prepared. The prepared formulations were characterized for drug loading, size, transparency, zeta potential, Transmission Electron Microscopy (TEM) and in vitro intestinal permeability. RESULTS: The results indicated that high …

Physician Perceptions Of Risk Regarding Mood Disorders And Pharmacological Management During Pregnancy: What Is Current Practice?, Laura G. Hendon

Dissertations and Theses (Open Access)

Mood disorders are the most common form of mental illness and one of the leading causes of morbidity worldwide.  Major depressive disorder and bipolar disorder have a lifetime prevalence of 16.2% and 4.4%, respectively.  Women comprise a substantial proportion of this population, and an estimated 500,000 pregnancies each year involve women with a psychiatric condition.  Management with psychotropic medications is considered standard of care for most patients with mood disorders.  However, many of these medications are known human teratogens.  Because pregnant women with mood disorders face a high risk of relapse if unmanaged, the obstetrician faces a unique challenge in …

Parthenolide Blocks Cocaine’S Effect On Spontaneous Firing Activity Of Dopaminergic Neurons In The Ventral Tegmental Area, David Schwarz, Damaris Bloom, Rocío Castro, Oné R. Pagán, C. A. Jiménez-Rivera

Biology Faculty Publications

Chronic cocaine administration leads to catecholamine reuptake inhibition which enhances reward and motivational behaviors. Ventral Tegmental Area dopaminergic (VTA DA) neuronal firing is associated with changes in reward predictive signals. Acute cocaine injections inhibit putative VTA DA cell firing in vertebrates. Parthenolide, a compound isolated from the feverfew plant (Tanacetum parthenium), has been shown to substantially inhibit cocaine’s locomotion effects in a planarian animal model (Pagán et al., 2008). Here we investigated the effects of parthenolide on the spontaneous firing activity of putative VTA DA neurons in anesthetized male rats (250-300g). Single-unit recordings were analyzed after intravenous (i.v.) parthenolide administration …

Hedgehog Signaling: A Potential Therapeutic Target For Non-Small Cell Lung Cancer, Ma'in Yehya Maitah

Wayne State University Dissertations

The American Cancer Society estimated that 222,520 Americans were diagnosed with lung cancer and 157,300 died of lung cancer in 2010 (Jemal et al. 2009, 225-249;Jemal et al. 2011, 69-90). The clinical outcome of patients diagnosed with non-small cell lung cancer (NSCLC), the major lung cancer sub-types, is very poor, which calls for innovative research for finding novel therapeutic targets and agents for better treatment outcome.

Emerging evidences have suggested that a phenomenon called Epithelial-to-Mesenchymal Transition (EMT), which shares similar molecular characteristics with cancer stem-like cells, contributes to lung cancer treatment failure. In view of the fact that EMT process …

Compensatory Renal Hypertrophy, Mitochondria And Redox Status, Bavneet Benipal

Wayne State University Dissertations

A reduction in functional renal mass occurs in humans during aging and severe kidney damage from diseases, injuries, infections and congenital conditions and after nephrectomy. Nephrectomy, or surgical removal of a kidney or a section of a kidney, is performed for treatment of unilateral secondary renal cancer, infections and for kidney transplantation. As a result, the remaining renal tissue undergoes compensatory growth due primarily to hypertrophy, in which both the size and functional capacity of the remaining kidney are increased. Renal compensatory hypertrophy is associated with a series of physiological, morphological and biochemical changes that also have toxicological implications.

Previous …

An Overview Of New Psychoactive Substances And The Outlets Supplying Them, Cathy Kelleher, Rachel Christie, Kevin Lalor, John Fox, Matt Bowden, Cora O'Donnell

Reports

This report represents the outcome of a review of new psychoactive substances2 within the Irish context, including a review of the outlets that supply these substances. The review was commissioned by the National Advisory Committee on Drugs (NACD) in accordance with Action 14 of the National Drugs Strategy (interim) 2009–2016. Action 14 provides for the monitoring of ‘head shops’3 and other outlets for the sale of psychoactive substances, under the Misuse of Drugs Act 1977 and the Misuse of Drugs (Amendment) Regulations 2007. Researchers at the Centre for Social and Educational Research (CSER) within the School of Social Sciences and …

The Role Of Androstane Neurosteroids In Alcohol-Mediated Social Behavior, Jason J. Paris

Legacy Theses & Dissertations (2009 - 2024)

Androgenic steroids, such as testosterone, may influence the propensity for aggression in both people and animals. Some of testosterone's effects on aggression may be due, in part, to its metabolic products that are 5á-reduced and 3á-hydroxylated to form, 3á-androstanediol (3á-diol), which can also enhance aggression in mice. Notably, alcohol (EtOH) consumption facilitates aggression in people and animals, particularly among those predisposed to act aggressively. In rats, EtOH can increase 3á-diol in prefrontal cortex, which may facilitate aggression. The present work aimed to elucidate the role of 3á-diol for EtOH-enhanced aggression. We hypothesized that EtOH would enhance inter-male aggression, social dominance, …

In Vitro And In Vivo Pharmacodynamic Characterization Of The Novel Plasma Kallikrein Inhibitor Pf-04886847, Dhaval Sanjeev Kolte

Electronic Theses and Dissertations

Plasma kallikrein plays an important role in the pathogenesis of inflammation and thrombosis. Kallikrein cleaves high molecular weight kininogen (HK) to liberate the potent pro-inflammatory peptide bradykinin (BK). BK upon activation of its constitutive B2 receptors on endothelial cells leads to an increase in intracellular Ca2+ level and subsequent production of nitric oxide (NO) and prostacyclin (PGI2), ultimately leading to vasodilation, hypotension, increased vascular permeability and vascular leakage. Further, kallikrein activates the complement system and stimulates neutrophil chemotaxis, aggregation and elastase release. Furthermore, kallikrein mediates the conversion of factor XII (FXII) to activated factor XII (FXIIa) thereby potentiating the intrinsic …

Electro-Gene Transfer To Skin Using A Noninvasive Multielectrode Array, Siqi Guo, Amy Donate, Gaurav Basu, Cathryn Lundberg, Loree Heller, Richard Heller

Bioelectrics Publications

Because of its large surface area and easy access for both delivery and monitoring, the skin is an attractive target for gene therapy for cutaneous diseases, vaccinations and several metabolic disorders. The critical factors for DNA delivery to the skin by electroporation (EP) are effective expression levels and minimal or no tissue damage. Here, we evaluated the non-invasive multielectrode array (MEA) for gene electrotransfer. For these studies we utilized a guinea pig model, which has been shown to have a similar thickness and structure to human skin. Our results demonstrate significantly increased gene expression 2 to 3 logs above injection …