Medical Pharmacology Commons^™

Chronic Acetaminophen Treatment Influences Indices Of Reactive Oxygen Species Accumulation In The Aging Fisher 344 X Brown Norway Rat Aorta, Sarath Meduru

Theses, Dissertations and Capstones

We have previously reported that aging in the Fisher 344 X Brown Norway (FBN) rat aorta is characterized by increased levels of ROS and alterations in cell signaling. Acetaminophen was found to scavenge free radicals in recent ischemia-reperfusion studies. Here we examined if chronic treatment with a therapeutic dose of acetaminophen attenuates age-associated increase in aortic ROS accumulation and signaling. FBN rats (27 month old; n=8) were subjected to 6 months of treatment with a therapeutic dose of acetaminophen (30mg/kg/day), with age-matched untreated FBN rats as controls. Protein oxidation levels were altered in control and treated aortae compared to aortae …

A Comparision Of Delta-9-Tetrahydrocannabinol Dependence In C57bl/6j Mice And Fatty Acid Amide Hydrolase Knock Out Mice, Brittany Leigh Alice Carlson

Theses and Dissertations

The idea that humans and laboratory animals can become physically dependent on marijuana or its primary psychoactive constituent, delta-9-tetrahydrocannabinol (THC), is gaining acceptance. However, there are no currently approved pharmacotherapies to treat cannabinoid withdrawal. The objective of this thesis was to evaluate whether elevating endogenous anandamide levels using mice lacking fatty acid amide hydrolase (FAAH), the enzyme responsible for anandamide metabolism, would ameliorate THC dependence. Mice were treated subchronically with a low or high THC dosing regimen and challenged with the CB1 receptor antagonist, rimonabant, to precipitate withdrawal. Following subchronic THC treatment, rimonabant precipitated a significant increase in paw flutters …

The Substituted Pyrrole Jb-03-14 Induces Autophagic Cell Death And Growth Arrest In Breast Tumor Cells, Christopher Ryan Arthur

Theses and Dissertations

The use of chemotherapy in the treatment of cancer has stimulated the demand for better chemotherapeutic agents that are more potent at destroying tumor cell populations and more selective for the specific tumor versus normal host tissues. This project is directed at discovering new anti-tumor agents that are effective against breast cancer based on structures derived from marine organisms, specifically brominated pyrroles. We utilized an in vitro breast cancer model to study the effects of pyrroles on tumor proliferation and survival, as well as growth arrest and cell death. Our findings indicate that the substituted pyrrole JG-03-14 induces time dependent …

Effects Of Advancing Age On Er Calcium Regulation In Rat Superior Cervical Ganglia, Conwin Kodel Vanterpool

Loma Linda University Electronic Theses, Dissertations & Projects

Intracellular calcium ([Ca²⁺]i) release from endoplasmic reticulum (ER) stores plays an important role in cell signaling. These stores are rapidly refilled via voltage-gated calcium channels or spontaneously via store-operated calcium channels and subsequent pumping by ER Ca²⁺-ATPases. Calcium release is triggered by the activation of the ryanodine receptor (RyR) channels and their function is in part dependent on their expression. We analyzed the [Ca²⁺]i transients in fura 2-loaded superior cervical ganglion (SCG) cells from 6, 12, 20, and 24-month-old Fischer 344 rats for their ability to rapidly and spontaneously refill. For rapid refilling, the …

Desulfovibrio Desulfuricans G20 Tetraheme Cytochrome Structure At 1.5 A˚ And Cytochrome Interaction With Metal Complexes, Mrunalini Pattarkine, J J. Tanner, C A. Bottoms, Y H. Lee, Judy D. Wall

Faculty Works

The structure of the type I tetraheme cytochrome c3 from Desulfovibrio desulfuricans G20 was determined to 1.5 A˚ by X-ray crystallography. In addition to the oxidized form, the structure of the molybdate-bound form of the protein was determined from oxidized crystals soaked in sodium molybdate. Only small structural shifts were obtained with metal binding, consistent with the remarkable structural stability of this protein. In vitro experiments with pure cytochrome showed that molybdate could oxidize the reduced cytochrome, although not as rapidly as U(VI) present as uranyl acetate. Alterations in the overall conformation and thermostability of the metal-oxidized protein were investigated …

Evaluación De Anticuerpos Contra El Virus De La Diarrea Viral Bovina De Un Hato En Proceso De Erradicación De La Enfermedad., Zuniga Alfonso H., Hermelinda G. Rivera, Mariluz Araínga, Alberto Manchego S.

Journal Articles: Pharmacology & Experimental Neuroscience

Antibodies against viral bovine diarrhea virus (BVDV) and of BVDV antigen in serum samples Were evaluated from cattle aged 10 to 23 months (n = 148) from a dairy herd disease eradication where the has-been carrying out since 2002. The herd is located in Santa Rita, Arequipa, Peru, and samples were collected twice on a 30-day interval. Antibodies against BVDV and BVDV antigen were analyzed by viral neutralization and capture ELISA tests respectively. Neutralising antibodies against BVDV were detected in 6.8% (10/148) of animals, and most reactors were 19 to 23 months of age. The antibody titer ranged from 8 …

Single Nucleotide Polymorphisms In The Folypoly-Gamma-Glutamate Synthetase Gene, Nadine Thompson

Theses and Dissertations

Folic acid is an essential vitamin utilized in the one-carbon metabolism pathway for the synthesis of purine and thymidine nucleotides, which are necessary for cell growth and proliferation. As a result, the enzymes that participate in the metabolism of folic acid have been good targets for cancer chemotherapy. Folylpoly-γ-glutamate synthetase (FPGS) is an enzyme in the folate metabolism pathway that catalyzes the addition of glutamic acid to the naturally occurring folates, thereby allowing the retention of folate cofactors in cells. Similarly, in the case of cancer chemotherapy, antifolates, such as Lometrexol and Tomudex are retained in cells through the activity …

The Influence Of Sustained Cb1 Blockade During Adolescence On Breakpoints In A Progressive-Ratio Paradigm, Mayo Jerry Wright Jr.

Theses and Dissertations

The developmental psychopharmacology of cannabinoids is poorly understood and little is known about the developmental consequences of repeated exposure to cannabinoid antagonists. In these experiments, male Long-Evans rats were treated with SR141716A, a cannabinoid antagonist, throughout adolescence and allowed unrestricted access to food. Control groups were treated with vehicle during the same developmental period and allowed either unrestricted access to food or were pair-fed with a member of the SR-treated group. Motivation to work for food was measured in progressive-ratio sessions at varying levels of food deprivation. For rats that consumed fewer calories throughout adolescence, whether because of pharmacological intervention …

Action Of Tyrosyl Dna Phosphodiesterase On 3'-Phosphoglycolate Terminated Dna Strand Breaks, Haritha Tatavarthi

Theses and Dissertations

Free radical-mediated DNA double strand breaks (DSBs) are induced either directly by ionizing radiation or by certain chemicals like bleomycin. These breaks are terminated by 3'-PG (PO4CH2COOˉ) or 3'-phosphate groups formed as a result of fragmentation of deoxyribose. To study the nature of repair of these 3'-blocked breaks, we constructed substrates mimicking free-radical induced DSBs. Human and yeast tyrosyl DNA-phosphodiesterase (Tdpl) efficiently processed substrates with 3'-PGs, in either the presence or absence of magnesium, to give a 3'-phosphate. Gel filtration chromatography and western blotting codmed that the putative enzyme in human extracts that efficiently processed PG was indeed tyrosyl DNA-phosphodiesterase. …

Relationship Between Cb1 And S1p Receptors In The Central Nervous System, Lauren Michele Collier

Theses and Dissertations

There is significant sequence homology and anatomical co-distribution between cannabinoid (CB1) and sphingosine-1-phosphate (S1P) receptors in the CNS, but potential functional relationships between these lysolipid receptors have not been examined. Therefore, to investigate possible relationships between these two systems at the level of G-protein activation, agonist-stimulated [35S]GTPγS binding and autoradiography were conducted. Autoradiographic studies were first performed to localize receptor-mediated G-protein activation in mouse brain. Coronal brain slices were processed for stimulation of [35S]GTPγS binding using the synthetic cannabinoid agonist WIN 55,212-2 (WIN) or SIP. High levels of WIN- and S1P-stimulated [35S]GTPγS binding were observed in the caudate putamen, hippocampus, …

Immunotoxicological Evaluation Of Critical Windows Of Development Following Exposure To 1,2:5,6 Dibenzanthracene In B6c3f1 Mice, Denise Marie Hernandez

Theses and Dissertations

Numerous findings have suggested that the increased prevalence of childhood illnesses such as cancer, infection, and allergy may be due to environmental exposures. One such cause may be maternal smoking or passive smoke exposure. Known immunotoxicants in cigarette smoke and environmental pollution include polycyclic aromatic hydrocarbons such as 1,2:5,6 Dibenzanthracene (DBA). The objective of these studies was to evaluate the immunosuppressive effects of DBA on various stages of immune system development. Adult mice were administered DBA daily in corn oil at dose levels of 158, 500, 1580, and 5000 µglkg S.C. for 28 days. Immunosuppression was not observed at levels …

Glutamate Excitotoxicty Activates A Novel Calcium Permeable Ion Channel In Cultured Hippocampal Neurons, Laxmikant Sudhir Deshpande

Theses and Dissertations

Glutamate excitotoxicity is the predominant mechanism implicated in neuronal cell death associated with neurological disorders such as stroke, epilepsy, traumatic brain injury and ALS. Excessive stimulation of NMDA subtypes of glutamate receptors leads to protracted intracellular calcium elevations triggering calcium mediated neurotoxic mechanisms culminating in delayed neuronal cell death. In addition, glutamate excitotoxicity induces a NMDA dependent extended neuronal depolarization mediated by continuous calcium influx that correlates with delayed neuronal death. Attempts to prevent neuronal death by blocking calcium entry into the neurons using calcium channel blockers or NMDA receptor antagonists have failed to provide any beneficial effects in clinical …

Influence Of The Vitamin D3 Analog Eb 1089 On Senescence And Cell Death Pathways In The Response Of Breast Tumor Cells To Ionizing Radiation, Gerald Alan Demasters

Theses and Dissertations

A senescence-like growth arrest succeeded by rapid recovery of proliferative capacity is observed in MCF-7 breast tumor cells exposed to fractionated radiation (5 x 2Gy) alone. Exposure to the vitamin D3 analog EB 1089 (100nM) prior to irradiation converts the initial growth arrest response to cell death in part through the inhibition of radiation-induced senescence and promotion of both apoptotic and autophagic cell death. More importantly, EB 1089 was shown to profoundly reduce the rate of recovery following fractionated irradiation. The effect of EB 1089 on the temporal response to radiation is also observed in MCF-7 cells expressing caspase 3, …

Pathological Upregulation Of A Calcium-Stimulated Phosphatase, Calcineurin, In Two Models Of Neuronal Injury, Jonathan Elledge Kurz

Theses and Dissertations

Excitotoxic calcium influx and activation of calcium-regulated systems is a common event in several types of neuronal injury. This mechanism has been the focus of intense research, with the hope that a more complete understanding of how neuronal injury affects calcium-regulated systems will provide effective treatment options. This study examines one such calcium-stimulated enzyme, calcineurin, in the context of two common neurological pathologies, status epilepticus and traumatic brain injury.Status epilepticus was induced by pilocarpine injection. NMDA-dependent increases in calcineurin activity were observed in cortical and hippocampal homogenates. Upon closer examination, the most profound increases in activity were found to be …

The Role Of Gonadal Hormones On Opioid Receptor Protein Density In Arthritic Rats, Matthew Kren

Theses and Dissertations

The majority of research on the endogenous opioid system has focused on various pain assays and the efficacy of different opioid agonists. However, minimal attention has been focused on the effects of gonadal hormones and their impact on the opioid peptide system. The present study was designed to determine the effects of modulation of gonadal hormones on the opioid receptor protein levels in Complete Freund's Adjuvant (CFA)-treated arthritic and non-arthritic male and female Lewis rats. Midbrain and spinal cord tissues were collected for comparison of the μ, δ, and κ receptor protein levels in arthritic and non-arthritic animals. Male gonadectomy …

Methods And Compositions Useful In Enhancing Oxygen Delivery To Cells, Elaine L. Jacobson, Myron Jacobson, Jaber G. Qasem, Hyuntae Kim, Moonsun Kim

Graduate Center for Nutritional Sciences Faculty Patents

The invention discloses compositions and methods which are useful in improving delivery of oxygen to cells. The compositions require at least one derivative of a compound. The derivatives are chosen to have log P values below about 6.0.

Anticuerpos Contra El Virus De La Estomatitis Vesicularen Sajinos (Tayassu Tajacu) De Zoocriaderos De Iquitos Y Pucallpa, Aldo D. Wilson, Mariluz Araínga, Hugo Galvez C., Alberto Manchego S., Hermelinda G. Rivera

Journal Articles: Pharmacology & Experimental Neuroscience

The objetive of this study was to detect antibodies against vesicular stomatitis virus (VSV) collared peccaries in (Tayassu tajacu) from farms of Iquitos and Pucallpa, Peru. Blood samples were collected in animals olders than 6 months of age (pregnant females were not included) from a farm in Iquitos (n = 21) and from four farms in Pucallpa (n = 47), for detection of antibodies against Indiana 1 and New Jersey serotype of VSV by viral neutralization test. No specific antibodies against both serotypes of VSV were detected, indicating that the peccaries were not exposed to VSV, and suggesting absence of …

Genes Encoding Several Poly (Adp-Ribose) Glycohydrolase (Parg) Enzymes, The Proteins And Fragments Thereof, And Antibodies Immnoreactive Therewith, Myron Jacobson, Elaine L. Jacobson, Jean-Christoph Amé, Winston Lin

Graduate Center for Nutritional Sciences Faculty Patents

The isolation and characterization of cDNAs encoding poly(ADP-ribose) glycohydrolase (PARG) enzymes and the amino acid sequences of PARGs from several species are described. PARG is involved in the cellular response to DNA damage and its proper function is associated with the body's response to neoplastic disorder inducing agents and oxidative stress. Expression vectors containing the cDNAs and cells transformed with the vectors are described. Probes and primers that hybridize with the cDNAs are described. Expression of the cDNA in E. coli results in an enzymatically active protein of about 111 kDa and an active fragment of about 59 kDa. Methods …

Method For Treating Cytokine Mediated Hepatic Injury, Peter R. Oeltgen, Paul D. Bishop, Craig J. Mcclain, Shirish Barve

Graduate Center for Nutritional Sciences Faculty Patents

A method of modulating cytokine mediated hepatic injury by administering compound-D SEQ ID NO:1 to a mammal. A concentration of the compound in the range of about 0.5 mg/kg to about 20 mg/kg in a physiologically acceptable formulation blocks a cytokine cascade. A therapeutic method of modulating cytokine mediated acute inflammatory, trauma induced and toxin induced hepatic injury, particularly via tumor necrosis factor modulation, is thus disclosed.

Dinámica De Seroconversión En Hembras Bovinas Post Eliminación De Animales Portadores Del Virus De La Diarrea Viral Bovina., Jayashi Cesar F., Gavidia Cesar C., Mariluz Araínga, Alberto Manchego, Hermelinda G. Rivera

Journal Articles: Pharmacology & Experimental Neuroscience

A study was conducted to determine the effect of culling BVDV carrier animals on the seroconversion against BVDV in the new generation of heifers from a dairy herd located in Arequipa, Peru. Blood samples were collected from 6-12 month old females in four sampling periods: January (n = 73), June (n = 48), October 2003 (n = 48), and January 2004 (n = 35) to evaluate their serological against BVDV status and to screen for carrier animals using the virus neutralization and antigen-capture ELISA tests, respectively. The prevalence of BVDV was 80.8 ± 9.0, 56.3 ± 14.0, 50.0 ± 14.2 …

Effect Of Genetic Variation On The Formation Of Hepatocarcinogenic Metabolites Of Trichloroethylene Using Chloral Hydrate Studies (An Interdisciplinary Approach), Apryl Bronley-Delancey

MUSC Theses and Dissertations

Trichloroethylene (TCE) is listed with the EPA as a suspected human carcinogen and is ubiquitous in the environment (US EPA 1992). Chloral hydrate (CH) is a sedative drug and a cytochrome P450 (CYP 450)-derived metabolite of TCE (Klaassen 2001). Chloral hydrate is metabolized in the liver to the rodent hepatocarcinogen trichloroacetate (TCA) by aldehyde dehydrogenase (ALDH), and to the non-carcinogenic metabolite trichloroethanol (TCEOH) by alcohol dehydrogenase (ADH) (Klaassen 2001). Both ALDH and ADH are polymorphic in humans which can presumably predict the disposition of chloral hydrate into the carcinogenic vs. non-carcinogenic pathways. The likelihood is then raised that subpopulations of …

The Effects Of Footshock On The Reinforcing Efficacy Of Cocaine In Male Long-Evans Rats, Elizabeth S. Hendrick

Theses and Dissertations

Many links exist between cocaine abuse and stress. The literature and laboratory studies in rats suggest that this could be because stress increases the reinforcing efficacy of cocaine. Using male Long-Evans rats, experiments in this thesis tested effects of footshock on the reinforcing efficacy of cocaine using a progressive ratio schedule of reinforcement. They also examined effects of footshock on the reinforcing efficacy of a half-maximal dose of cocaine. Finally, they tested the effects of footshock on cocaine self-administration in rats initially resistant to acquisition of cocaine self-administration. Footshock did not increase reinforcing efficacy of cocaine on a PR schedule …

Post-Juvenile Brain Development Modulates Seizure Characteristics And Diazepam Efficacy In The Rat Pilocarpine-Se Model, William H. Holbert Ii

Theses and Dissertations

These studies were completed to examine how status epilpeticus seizure characteristics are modulated during post-juvenile brain development. This may determine if postnatal age in rats is a better identifier of stages of post-juvenile brain development. The first study fully detailed the acute discrete seizure phase of the rat pilocarpine-SE model. Results for this study showed that Racine behavioral severity score, spike frequency, and seizure severity during the acute discrete seizure phase change in relation to post-juvenile brain developmental stages. The second study fully detailed early and late patterns of status epilepticus. Results for this study displayed modulation of time in …

The Study Of The Effect Of Drugs Of Abuse On Protein Kinase A Activity In Mouse Brain And Spinal Cord, George D. Dalton

Theses and Dissertations

Morphine and Δ9-THC are drugs that produce analgesia and rewarding effects. However, chronic treatment with morphine and Δ9-THC produces problematic side-effects including tolerance and physical dependence. The cellular mechanisms underlying opioid and cannabinoid antinociceptive tolerance have been studied for years. Research has demonstrated that the expression of morphine and Δ9-THC antinociceptive tolerance may be mediated through intracellular signaling pathways, such as the adenylyl cyclase /Protein Kinase A (PKA) cascade. The present study investigated the role of PKA in the expression of morphine and Δ9-THC antinociceptive tolerance. Male Swiss Webster mice were treated chronically with morphine or Δ9-THC and the warm-water …

Methods For Increasing Leptin Levels Using Nicotinic Acid Compounds, Elaine L. Jacobson, Myron Jacobson, Hyuntae Kim

Graduate Center for Nutritional Sciences Faculty Patents

The invention relates to the use of nicotinic acid and nicotinic acid esters, such as nicotinic acid alkyl esters, to increase the amount of leptin in a subject. As a result, one can treat conditions, such as conditions characterized by wounds, by administering sufficient amounts of nicotinic acid or nicotinic acid ester to increase leptin levels to alleviating amounts. Various conditions and modes of treatment are disclosed.

Method For Identifying Regulators Of Protein-Advanced Glycation End Product (Protein-Age) Formation, Elaine L. Jacobson, Myron Jacobson, Georg T. Wondrak

Graduate Center for Nutritional Sciences Faculty Patents

The invention relates to methods for identifying compounds which affect cellular stress. In particular, the method relates to identifying compounds which inhibit protein advanced glycation end product formation, where the compounds are carbonyl scavengers which inhibit the formation. The assay involves combing the substance of interest with histone H1 and ADP-ribose, and then measuring fluorescence and protein cross linking. Various inhibitors of protein AGE glycation have been identified, using this assay.

Indinavir And Rifabutin Drug Interactions In Healthy Volunteers., Walter K. Kraft, Jacqueline B. Mccrea, Gregory A. Winchell, Alexandra Carides, Richard C. Lowry, Eric J. Woolf, Sandra E. Kusma, Paul J. Deutsch, Howard E Greenberg, Scott A. Waldman

Department of Medicine Faculty Papers

Two studies examined the pharmacokinetics of indinavir and rifabutin when coadministered in healthy subjects. Rifabutin, which induces the expression of cytochrome P450 (CYP) 3A, and indinavir, which inhibits that enzyme system, are frequently coadministered in patients infected with HIV. The second study was undertaken to determine if altering the dose of rifabutin coadministered with indinavir would minimize the drug interaction observed in the first study. Two studies, each with a three-period crossover design, were performed. In study 1, standard doses of rifabutin and indinavir (300 mg of rifabutin qd and 800 mg indinavir q8h) were administered as monotherapy (with placebo …

Topical Formulations For The Transdermal Delivery Of Niacin And Methods Of Treating Hyperlipidemia, Elaine L. Jacobson, Myron Jacobson, Hyuntae Kim, Moonsun Kim, Jaber G. Qasem

Graduate Center for Nutritional Sciences Faculty Patents

Niacin and niacin prodrugs are topically administered as suitable formulations to device for impoving the lipid profiles of subjects, preferably humans.

Calcium And Glycolysis Mediate Multiple Bursting Modes In Pancreatic Islets, Richard Bertram, Leslie S. Satin, Min Zhang, Paul Smolen, Arthur Sherman

Pharmacology and Toxicology Publications

Abstract

Pancreatic islets of Langerhans produce bursts of electrical activity when exposed to stimulatory glucose levels. These bursts often have a regular repeating pattern, with a period of 10–60 s. In some cases, however, the bursts are episodic, clustered into bursts of bursts, which we call compound bursting. Consistent with this are recordings of free Ca²⁺ concentration, oxygen consumption, mitochondrial membrane potential, and intraislet glucose levels that exhibit very slow oscillations, with faster oscillations superimposed. We describe a new mathematical model of the pancreatic β-cell that can account for these multimodal patterns. The model includes the feedback of …

Nuovi Approcci Terapeutici Contro Il Cancro Del Colon, Giovanni Mario Pitari

Department of Pharmacology and Experimental Therapeutics Faculty Papers

This presentation was given in Augusta (Siracusa, Italy) for the 2004 Paul Harris Fellow Award, Rotary Foundation of Rotary International. The lecture discusses the clinical significance of the GC-C pathway and its potential as a therapeutic target for colon cancer and metastatic tumors. It underscores the importance of the dysregulation of the GC-C pathway in promoting colorectal tumorigenesis and of dietary calcium in the GC-C-mediated chemoprevention.

Questa e’ la presentazione per il Premio 2004 Paul Harris Fellow del Rotary International (Augusta, Siracusa, Italia). La dissertazione illustra l’importante significato clinico della via moleculare regulata da GC-C e dai suoi ligandi (guanilina, …