Medical Pharmacology Commons^™

Pediatric Pharmacogenomics: A Systematic Assessment Of Ontogeny And Genetic Variation To Guide The Design Of Statin Studies In Children., Jonathan B. Wagner, J Steven Leeder

Manuscripts, Articles, Book Chapters and Other Papers

The dose-exposure-response relationship for drugs may differ in pediatric patients compared with adults. Many clinical studies have established drug dose-exposure relationships across the pediatric age spectrum; however, genetic variation was seldom included. This article applies a systematic approach to determine the relative contribution of development and genetic variation on drug disposition and response using HMG-CoA reductase inhibitors as a model. Application of the approach drives the collection of information relevant to understanding the potential contribution of ontogeny and genetic variation to statin dose-exposure-response in children, and identifies important knowledge deficits to be addressed through the design of future studies.

Role Of Autophagy In The Response Of Hs578t Breast Tumor Cells To Radiation, Shweta Chakradeo

Theses and Dissertations

Breast cancer is the most commonly observed cancer type in women and is the second leading cause of cancer death in women. Radiation can be used to debulk tumors prior to surgery as well as to treat patients after surgery and/or chemotherapy. Previous studies from our laboratory have shown that the anti –malarial drug chloroquine sensitizes breast cancer cell lines to radiation by suppression of autophagy which is a conservative catabolic process that can be cytoprotective. The scientific literature has demonstrated that many tumor cell systems undergo cytoprotective autophagy and that pharmacological or genetic inhibition of autophagy leads to other …

Effect Of Concomitant Medications Affecting Gastric Ph And Motility On Posaconazole Tablet Pharmacokinetics, Walter K. Kraft, P. Chang, Mlps Van Iersel, H. Waskin, G. Krishna, W. Kersemaekers

Department of Pharmacology and Experimental Therapeutics Faculty Papers

Poster presented at: Interscience Conference on Antimicrobial Agents and Chemotherapy (52^nd ICAAC) held in San Francisco 9/9-9/12

Background: Posaconazole (POS) oral suspension is an extended-spectrum triazole that should be taken with food to maximize absorption. A new POS tablet formulation has demonstrated improved bioavailability over oral suspension in healthy adults in the fasting state. This study evaluated the effect of concomitant medications altering gastric pH (antacid, ranitidine, and esomeprazole) and motility (metoclopramide) on the pharmacokinetics of POS tablet.

Methods: This was a prospective, open-label, 5-way crossover study in 20 healthy volunteers. In each treatment period, a single 400-mg (100 …

Phthalate Exposure Changes The Metabolic Profile Of Cardiac Muscle Cells, Nikki G. Posnack, Luther M. Swift, Matthew W. Kay, Norman H. Lee, Narine Sarvazyan

Pharmacology and Physiology Faculty Publications

Background: Phthalates are common plasticizers present in medical-grade plastics and other everyday products. They can also act as endocrine-disrupting chemicals and have been linked to the rise in metabolic disorders. However, the effect of phthalates on cardiac metabolism remains largely unknown.

Objectives: We examined the effect of di(2-ethylhexyl)phthalate (DEHP) on the metabolic profile of cardiomyocytes because alterations in metabolic processes can lead to cell dysfunction.

Methods: Neonatal rat cardiomyocytes were treated with DEHP at a concentration and duration comparable to clinical exposure (50–100 μg/mL, 72 hr). We assessed the effect of DEHP on gene expression using microarray analysis. Physiological responses …

Exosome-Mediated Shuttling Of Microrna-29 Regulates Hiv Tat And Morphine-Mediated Neuronal Dysfunction., Guoku Hu, H Yao, A D. Chaudhuri, Sowmya V. Yelamanchili, H Wen, P D. Cheney, Howard S. Fox, Shilpa J. Buch

Journal Articles: Pharmacology & Experimental Neuroscience

Neuronal damage is a hallmark feature of HIV-associated neurological disorders (HANDs). Opiate drug abuse accelerates the incidence and progression of HAND; however, the mechanisms underlying the potentiation of neuropathogenesis by these drugs remain elusive. Opiates such as morphine have been shown to enhance HIV transactivation protein Tat-mediated toxicity in both human neurons and neuroblastoma cells. In the present study, we demonstrate reduced expression of the tropic factor platelet-derived growth factor (PDGF)-B with a concomitant increase in miR-29b in the basal ganglia region of the brains of morphine-dependent simian immunodeficiency virus (SIV)-infected macaques compared with the SIV-infected controls. In vitro relevance …

Role Of Nicotinic Acetylcholine Receptors In Experimental Colitis, Shakir Alsharari

Theses and Dissertations

Substantial evidence in the literature shows that tobacco smoking has complex and divergent effects on inflammatory bowel diseases (IBD). It ameliorates ulcerative colitis (UC); whereas it aggravates the risk of Crohn’s disease (CD) and affects the disease course and severity. Studies have shown that nicotine has a positive influence on symptoms of UC. Also, it is demonstrated that nicotinic acetylcholine receptor, especially α7 subunit plays an essential component in the vagus nerve-based cholinergic anti-inflammatory effects. In the present study, we explored the effect of nicotine and α7 nicotinic agonists treatment in the DSS colitis mouse model. We also investigated the …

Reversal By Rarα Agonist Am580 Of C-Myc-Induced Imbalance In Rarα/Rarγ Expression During Mmtv-Myc Tumorigenesis, Almudena Bosch, Silvina P. Bertran, Yongke Lu, Avalon Garcia, Alexis M. Jones, Marcia I. Dawson, Eduardo F. Farias

Pharmacology, Physiology and Toxicology

Introduction

Retinoic acid signaling plays key roles in embryonic development and in maintaining the differentiated status of adult tissues. Recently, the nuclear retinoic acid receptor (RAR) isotypes α, β and γ were found to play specific functions in the expansion and differentiation of the stem compartments of various tissues. For instance, RARγ appears to be involved in stem cell compartment expansion, while RARα and RARβ are implicated in the subsequent cell differentiation. We found that over-expressing c-Myc in normal mouse mammary epithelium and in a c-Myc-driven transgenic model of mammary cancer, disrupts the balance between RARγ and RARα/β in …

Development Of Dna Vaccination Approach For Tumor Immunotargeting, Nathaniel Sangster

Summer Training Program in Cancer Immunotherapy

The emergence of immunotherapy as a prominent modality to treat cancer is a crucial advancement in the fight against this devastating disease. Although DNA vaccines against cancer have not been effective in treating pre-existing tumors, this approach holds much promise particularly for the activation of immune responses to specific mutant antigens responsible for tumorigenesis. Recent studies demonstrated that Q209L point mutation in the GNAQ (and GNA11) is responsible for the development of more than 70% of uveal melanomas and pre-malignant cutaneous blue nevus in humans. Based on the epitope prediction, we hypothesized that DNA vaccination with mutant GNAQ may result …

Mini-Review: Decorin, A Guardian From The Matrix, Thomas Neill, Liliana Schaefer, Renato V. Iozzo

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Decorin, an archetypal member of the small leucine-rich proteoglycan gene family, has a broad binding repertoire that encompasses matrix structural components, such as collagens, and growth factors, particularly those that belong to the transforming growth factor-β ligand superfamily. Within the tumor microenvironment, stromal decorin has an inherent proclivity to directly bind and down-regulate several receptor tyrosine kinases, which are often overexpressed in cancer cells. The decorin interactome commands a powerful antitumorigenic signal by potently repressing and attenuating tumor cell proliferation, survival, migration, and angiogenesis. This collection of interacting molecules also regulates key downstream signaling processes indirectly via the sequestration of …

Development Of Natural Cyclic Peptide Inhibitors Of Xrcc4/Xlf Interaction For Radio-Sensitization Of Breast Tumor Cells, Mohaini Mohammed Al

Theses and Dissertations

Breast cancer is the second leading cause of cancer death in women according to the American Cancer Society. The standard treatment regimen for breast cancer involves ionizing radiation combined with surgery and chemotherapy. Ionizing radiation induces a complex signaling response in cells resulting in either growth arrest, senescence or cell death, and the cell killing after exposure to radiation results largely from DNA double-strand breaks (DSBs). There are two main mechanisms in mammalian cells responsible for repairing the DSBs; the primary mechanism is non-homologous end joining (NHEJ) and the secondary mechanism is homologous recombination (HRR). Previous studies showed that breast …

Cell Death And Growth Arrest Pathways Mediating The Actions Of Stilbene 5c In Hct-116 Colon Cancer Cells, Moureq Alotaibi

Theses and Dissertations

Abstract The stilbene derivative, cis-3, 4’, 5-trimethoxy-3’-aminostilbene (stilbene 5c), is a potentially potent antitumor agent that acts via binding to the colchicine-binding pocket in microtubules. Earlier studies have shown that stilbene 5c induces cell death in ovarian cancer cells and leukemic cells. The present study was designed to investigate the effectiveness of this microtubule poison against the HCT-116 human colon cancer cell line and its mechanisms of action. Time course studies demonstrated that stilbene 5c produces a biphasic decrease in cell viability. The capacity of the cells to proliferate was not restored upon removal of the drug after 6 days …

Treatment Options For Vasomotor Symptoms In Menopause: Focus On Desvenlafaxine., Elena M Umland, Laura Falconieri

College of Pharmacy Faculty Papers

Vasomotor symptoms (VMS), including hot flashes and night sweats, occur in as many as 68.5% of women as a result of menopause. While the median duration of these symptoms is 4 years, approximately 10% of women continue to experience VMS as many as 12 years after their final menstrual period. As such, VMS have a significant impact on the quality of life and overall physical health of women experiencing VMS, leading to their pursuance of treatment to alleviate these symptoms. Management of VMS includes lifestyle modifications, some herbal and vitamin supplements, hormonal therapies including estrogen and tibolone, and nonhormonal therapies …

Visualizing Spatiotemporal Dynamics Of Apoptosis After G1 Arrest By Human T Cell Leukemia Virus Type 1 Tax And Insights Into Gene Expression Changes Using Microarray-Based Gene Expression Analysis., Mariluz Araínga, Hironobu Murakami, Yoko Aida

Journal Articles: Pharmacology & Experimental Neuroscience

BACKGROUND: Human T cell leukemia virus type 1 (HTLV-1) Tax is a potent activator of viral and cellular gene expression that interacts with a number of cellular proteins. Many reports show that Tax is capable of regulating cell cycle progression and apoptosis both positively and negatively. However, it still remains to understand why the Tax oncoprotein induces cell cycle arrest and apoptosis, or whether Tax-induced apoptosis is dependent upon its ability to induce G1 arrest. The present study used time-lapse imaging to explore the spatiotemporal patterns of cell cycle dynamics in Tax-expressing HeLa cells containing the fluorescent ubiquitination-based cell cycle …

Frecuencia De Leptospira Spp En Porcinos De Crianza Tecnificada Y De Traspatio Beneficiados En Dos Mataderos De Lima, Luis Anampa V., Hermelinda Rivera G., Nestor Falcon P., Mariluz Araínga, Mercy Ramirez V.

Journal Articles: Pharmacology & Experimental Neuroscience

The objective of this study was to determine the frequency of antibodies against Leptospira spp in pigs reared in five well-managed farms (n = 163) and from 11 backyard breeding (n = 133) owners in the valley Lima, Peru. Blood samples (n=296) were collected in two slaughterhouses for antibody detection against eight serovars of Leptospira by microaglutination test. The 85.8 ± 3.9% (254/296) of samples had antibodies against one or more serovars of Leptospira. . The 89.6 ± 4.7% (146/163) and 82.1 ± 6.5% (108/133) of samples from well-managed farms and from backyard breeding pigs showed antibodies against Leptospira spp. …

Healthy Volunteer Registries And Ethical Research Principles, Erine A. Kupetsky-Rincon, Walter K. Kraft

Department of Pharmacology and Experimental Therapeutics Faculty Papers

The dual enrolling of phase I volunteers is a potential risk to subjects. It can also distort study results, threaten study validity, and possibly cause harm to future patients. Existing subject registries differ in structure, funding, and governance. Although the choice of the ideal system is driven by the scope of the risk and the funding mechanism, and is ultimately a value judgment of freedom versus paternalism, none of the registries significantly impinges on the tenets of ethically based research.

Phosphorylation Of Vasodilator-Stimulated Phosphoprotein Ser239 Suppresses Filopodia And Invadopodia In Colon Cancer., David S Zuzga, Joshua Pelta-Heller, Peng Li, Alessandro Bombonati, Scott A Waldman, Giovanni Mario Pitari

Department of Pharmacology and Experimental Therapeutics Faculty Papers

In colorectal cancer, the antitumorigenic guanylyl cyclase C (GCC) signalome is defective reflecting ligand deprivation from downregulation of endogenous hormone expression. Although the proximal intracellular mediators of that signal transduction system, including cyclic guanosine monophosphate (cGMP) and cGMP-dependent protein kinase (PKG), are well characterized, the functional significance of its distal effectors remain vague. Dysregulation of ligand-dependent GCC signaling through vasodilator-stimulated phosphoprotein (VASP), an actin-binding protein implicated in membrane protrusion dynamics, drastically reduced cGMP-dependent VASP phosphorylation levels in colorectal tumors from patients. Restoration of cGMP-dependent VASP phosphorylation by GCC agonists suppressed the number and length of locomotory (filopodia) and invasive (invadopodia) …

Inhibition Of Soluble Tumor Necrosis Factor Ameliorates Synaptic Alterations And Ca2+ Dysregulation In Aged Rats, Diana M. Sama, Hafiz Mohmmad Abdul, Jennifer L. Furman, Irina A. Artiushin, David E. Szymkowski, Stephen W. Scheff, Christopher M. Norris

Graduate Center for Gerontology Faculty Publications

The role of tumor necrosis factor α (TNF) in neural function has been investigated extensively in several neurodegenerative conditions, but rarely in brain aging, where cognitive and physiologic changes are milder and more variable. Here, we show that protein levels for TNF receptor 1 (TNFR1) are significantly elevated in the hippocampus relative to TNF receptor 2 (TNFR2) in aged (22 months) but not young adult (6 months) Fischer 344 rats. To determine if altered TNF/TNFR1 interactions contribute to key brain aging biomarkers, aged rats received chronic (4-6 week) intracranial infusions of XPro1595: a soluble dominant negative TNF that preferentially inhibits …

The Antinociceptive Effects Of Alpha 7 Nicotinic Acetylcholine Receptor Positive Allosteric Modulators In Different Animal Pain Models, Kelen Freitas

Theses and Dissertations

The α7 nicotinic acetylcholine receptor (nAChR) subtype is abundantly expressed in the central nervous system (CNS) and in the periphery. Positive allosteric modulators (PAMs) of the α7 increase the response to an agonist and are divided into two types depending on whether they also decrease desensitization of the receptor (type II) or not (type I). Therefore, this study aims to investigate whether the enhancement of endogenous α7 nAChR function will result in a beneficial effect in nociceptive, inflammatory and chronic neuropathic pain models. While NS1738 and PNU-120596 were not active to reduce acute thermal pain, measured by hot-plate and tail-flick …

Synaptic And Intrinsic Activation Of Gabaergic Neurons In The Cardiorespiratory Brainstem Network, Julie G. Frank, David Mendelowitz

Pharmacology and Physiology Faculty Publications

GABAergic pathways in the brainstem play an essential role in respiratory rhythmogenesis and interactions between the respiratory and cardiovascular neuronal control networks. However, little is known about the identity and function of these GABAergic inhibitory neurons and what determines their activity. In this study we have identified a population of GABAergic neurons in the ventrolateral medulla that receive increased excitatory post-synaptic potentials during inspiration, but also have spontaneous firing in the absence of synaptic input. Using transgenic mice that express GFP under the control of the Gad1 (GAD67) gene promoter, we determined that this population of GABAergic neurons is in …

Radiation Sensitization Of Breast Cancer Cells By Vitamin D Through The Promotion Of Autophagic Cell Death, Eden Wilson

Theses and Dissertations

Radiation therapy is a widely used tool in cancer therapy and is frequently offered as the first line of treatment for cancers of the breast. While radiotherapy is often initially effective in killing tumor cells or suppressing their growth, there are factors that confer tumor cell resistance to irradiation. Development of resistance may lead to disease recurrence despite the use of surgery, chemotherapy and radiation therapy. A primary goal of the studies in Dr. Gewirtz’s laboratory is to develop strategies to overcome resistance to radiation (and chemotherapy) in breast cancer, with the ultimate goal of preventing or attenuating disease recurrence. …

Chemosensitization Of Hepatocellular Carcinoma To Gemcitabine By Non-Invasive Radiofrequency Field-Induced Hyperthermia, Mustafa Raoof

Dissertations and Theses (Open Access)

Gemcitabine is a potent nucleoside analogue against solid tumors however drug resistance rapidly emerges. Removal of gemcitabine incorporated in the DNA by repair mechanisms could potentially contribute to resistance in chemo-refractory solid tumors. In this study, we evaluated homologous recombination repair of gemcitabine-stalled replication forks as a potential mechanism contributing to resistance. We also studied the effect of hyperthermia on homologous recombination pathway to explain the previously reported synergy between gemcitabine and hyperthermia. We found that hyperthermia degrades and inhibits localization of Mre11 to gemcitabine-stalled replication forks. Furthermore, gemcitabine-treated cells that were also treated with hyperthermia demonstrate a prolonged passage …

Is Less Really More?: Determining The Efficacy And Advantages Of Low Dose Chemotherapy, Natalie Toews

Senior Honors Theses

Chemotherapy is the preferred treatment for patients with breast cancer nationwide; however, the dosage and duration of this treatment have come under recent scrutiny. The efficacy of high dose chemotherapy is many times inadequate, and the adverse physical effects resulting from this regimen have a negative holistic impact on the patients. Studies suggest that low dose chemotherapy, through antiangiogenesis, affects the spread of breast cancer carcinomas and may produce less harmful side effects in relation to the heart, brain, and eyes. Thus, oncological research proposes that a low dose regimen improves the patient’s quality of life and may be an …

Mitogen Activated Protein Kinase Phosphatase-1 Prevents The Development Of Tactile Sensitivity In A Rodent Model Of Neuropathic Pain, Christian Ndong, Russell P. Landry, Joyce A. Deleo, Edgar A. Romero-Sandoval

Dartmouth Scholarship

Neuropathic pain due to nerve injury is one of the most difficult types of pain to treat. Following peripheral nerve injury, neuronal and glial plastic changes contribute to central sensitization and perpetuation of mechanical hypersensitivity in rodents. The mitogen activated protein kinase (MAPK) family is pivotal in this spinal cord plasticity. MAPK phosphatases (MKPs) limit inflammatory processes by dephosphorylating MAPKs. For example, MKP-1 preferentially dephosphorylates p-p38. Since spinal p-p38 is pivotal for the development of chronic hypersensitivity in rodent models of pain, and p-p38 inhibitors have shown clinical potential in acute and chronic pain patients, we hypothesize that induction of …

Hydrogen Sulfide As An Allosteric Modulator Of Atp Sensitive Potassium Channels In Colonic Inflammation., Aravind Gade

Theses and Dissertations

The ATP sensitive potassium channel (KATP) in mouse colonic smooth muscle cell is a complex containing a pore forming subunit (Kir6.1) and a sulfonyl urea receptor subunit (SUR2B). These channels are responsible for maintaining the cellular excitability of the smooth muscle cell which in turn regulates the motility patterns in the colon. We used whole-cell voltage-clamp techniques to study the alterations in these channels in smooth muscle cells in experimental model of colitis (colonic inflammation). Colitis was induced in BALB/C mice following an intracolonic administration of trinitrobenzene sulfonic acid (TNBS). KATP currents were measured at Vh -60 mV in high …

Cosmetic Neurology: Enhancement Of The Mind And Attention Deficit Hyperactive Disorder Medication Abuse Among College Students, Mary M. Huff

Senior Honors Theses

Cosmetic neurology is becoming increasingly popular, and it is not just sleep deprived, over worked college students who are interested. People are beginning to seek off-label prescriptions for medications that are typically used to treat disorders such as attention deficit hyperactive disorder (ADHD) or narcolepsy, while researchers are trying to create drugs used solely for mind enhancement purposes. Along with these drugs come many legal and ethical quandaries relating to the regulation of current use as well as the what ifs of future possibilities. A survey was conducted among college students regarding the diagnosis of ADHD, the abuse of ADHD …

Molecular Staging Individualizing Cancer Management, Alex Mejia, Stephanie Schulz, Terry Hyslop, David S. Weinberg, Scott A. Waldman

Department of Pharmacology and Experimental Therapeutics Faculty Papers

Although the most important prognostic and predictive marker in colorectal cancer is tumor cells in lymph nodes, ∼30% of patients who are node-negative die from occult metastases. Molecular staging employing specific markers and sensitive detection technologies has emerged as a powerful platform to assess prognosis in node-negative colon cancer. Integrating molecular staging into algorithms that individualize patient management will require validation and the definition of relationships between occult tumor cells, prognosis, and responses to chemotherapy. J. Surg. Oncol. 2012; 105:468-474. © 2012 Wiley Periodicals, Inc.

Copyright © 2012 Wiley Periodicals, Inc.

Myelin Gene Expression: Implications For Alcohol Abuse And Dependence, Sean Farris

Theses and Dissertations

Acute behavioral responses to ethanol have predictive value for determining an individual's risk of long-term drinking behavior. Although the neurobiology of alcohol abuse is complex, prior studies from our laboratory demonstrated differential myelin-associated gene expression (MAGE) in medial prefrontal cortex (PFC) as one potential mechanism influencing acute ethanol behaviors between C57BL/6J (B6) and DBA/2J (D2) mice. Our laboratory and others have also shown MAGE is reduced in PFC of alcoholics. Herein, I have extended these findings through expression profiling of PFC into chronic models of ethanol self-administration from non-human primates and mice. Together, these results suggest that regulation of MAGE …

Antinociceptive Effects Of Monoamine Reuptake Inhibitors In Assays Of Pain-Stimulated And Pain-Depressed Behaviors, Marisa Rosenberg

Theses and Dissertations

ANTINOCICEPTIVE EFFECTS OF MONOAMINE REUPTAKE INHIBITORS IN ASSAYS OF PAIN-STIMULATED AND PAIN-DEPRESSED BEHAVIOR By Marisa B. Rosenberg A thesis submitted in partial fulfillment of the requirements for the degree of Master of Science at Virginia Commonwealth University. Virginia Commonwealth University, 2012 Advisor: Sidney Stevens Negus, Ph.D. Professor, Department of Pharmacology/Toxicology Noxious stimuli can produce pain-related stimulation of some behaviors (e.g. withdrawal responses) and depression of other behaviors (e.g. feeding, locomotion, responding maintained by many types of positive reinforcement). Monoamine reuptake inhibitors are used clinically to treat depression and to manage some types of pain. This study examined the antinociceptive properties …

Identification Of Bovine Leukemia Virus Tax Function Associated With Host Cell Transcription, Signaling, Stress Response And Immune Response Pathway By Microarray-Based Gene Expression Analysis., Mariluz Araínga, Eri Takeda, Yoko Aida

Journal Articles: Pharmacology & Experimental Neuroscience

BACKGROUND: Bovine leukemia virus (BLV) is associated with enzootic bovine leukosis and is closely related to human T-cell leukemia virus type I. The Tax protein of BLV is a transcriptional activator of viral replication and a key contributor to oncogenic potential. We previously identified interesting mutant forms of Tax with elevated (TaxD247G) or reduced (TaxS240P) transactivation effects on BLV replication and propagation. However, the effects of these mutations on functions other than transcriptional activation are unknown. In this study, to identify genes that play a role in the cascade of signal events regulated by wild-type and mutant Tax proteins, we …

Effect Of Maternal Hypoxia On The Cerebral And Cardiac Tissue Remodeling, Wenni Tong

Loma Linda University Electronic Theses, Dissertations & Projects

Large epidemiological studies and animal studies have indicated a clear association of adverse intrauterine environment with an increased incidence of low birth weight, perinatal mortality, and cardiovascular disease in later adult life. In humans, one of the most common stresses in utero is hypoxia. The goal of this project is to test the hypothesis that fetal hypoxia causes reprogramming of MMPs and TIMPs expression patterns and activities leading to aberrant brain and heart development in the fetuses and neonates. In the first part of project, we tested the hypothesis that maternal hypoxia increases the activity of MMPs and decreases the …