Pharmacology, Toxicology and Environmental Health Commons^™

Synthesis And Evaluation Of Azetidinone Analogues Of Combretastatin A-4 As Tubulin Targeting Agents, Niamh O'Boyle, Miriam Carr, Lisa M. Greene, Orla Bergin, Seema M. Nathwani, Thomas Mccabe, David G. Lloyd, Daniela M. Zisterer, Mary J. Meegan

Articles

The synthesis and antiproliferative activity of a new series of rigid analogues of combretastatin A-4 are described which contain the 1,4-diaryl-2-azetidinone (β-lactam) ring system in place of the usual ethylene bridge present in the natural combretastatin stilbene products. These novel compounds are also substituted at position 3 of the β-lactam ring with an aryl ring. A number of analogues showed potent nanomolar activity in human MCF-7 and MDA-MB-231 breast cancer cell lines, displayed in vitro inhibition of tubulin polymerization and did not cause significant cytotoxicity in normal murine breast epithelial cells. 4-(4-Methoxyaryl)-substituted compound 32, 4-(3-hydroxy-4-methoxyaryl)-substituted compounds 35 and 41 and …

Antidepressant Stimulation Of Cdp-Diacylglycerol Synthesis Does Not Require Monoamine Reuptake Inhibition, Ashiwel S. Undieh, Marwa A. Aboukhatwa

Publications and Research

Background: Recent studies demonstrate that diverse antidepressant agents increase the cellular production of the nucleolipid CDP-diacylglycerol and its synthetic derivative, phosphatidylinositol, in depression-relevant brain regions. Pharmacological blockade of downstream phosphatidylinositide signaling disrupted the behavioral antidepressant effects in rats. However, the nucleolipid responses were resistant to inhibition by serotonin receptor antagonists, even though antidepressant-facilitated inositol phosphate accumulation was blocked. Could the neurochemical effects be additional to the known effects of the drugs on monoamine transmitter transporters? To examine this question, we tested selected agents in serotonin-depleted brain tissues, in PC12 cells devoid of serotonin transporters, and on the enzymatic activity of …

Special 301 And Access To Medicine In The Obama Administration, Sean Flynn

Scholarly Articles in Law Reviews & Journals

I. Introduction

This article examines the history and current use of the Special 301 program to restrict access to generic medicines in developing countries, specifically the 2009 and 2010 reports released under the Obama Administration. The news for access to medicines advocates is not good overall. Both reports continue the previous Administration’s policies of using Special 301 to promote Trade-Related Aspects of Intellectual Property Rights (“TRIPS”) policies (“TRIPS-plus”) endangering access to medicines for millions of people worldwide. These policies violate not only the Obama Administration’s pledges to promote access to affordable medications in developing countries, but also U.S. commitments under …

Copper(Ii) Complexes Of Coumarin-Derived Schiff Bases And Their Anti-Candida Activity, Bernadette S. Creaven, Michael Devereux, Dariusz Karcz, Andrew Kellett, Malachy Mccann, Andy Noble, Maureen Walsh

Articles

The condensation of 7-amino-4-methyl-coumarin (1) with a number of substituted salicylaldehydes yielded a series of Schiff bases (2a–2k) in good yields. Subsequent reaction of these ligands with copper( II) acetate yielded Cu(II) complexes (3a–3k) and some were characterised using X-ray crystallography. All of the free ligands and their metal complexes were tested for their anti-Candida activity.

Apoptotic And Chemotherapeutic Properties Of Iron (Iii)-Salophene In An Ovarian Cancer Animal Model, Thilo S. Lange, Carolyn Mccourt, Rakesh K. Singh, Kyu Kwang Kim, Ajay P. Singh, Brian S. Luisi, Onur Alptürk, Robert M. Strongin, Laurent Brard

Chemistry Faculty Publications and Presentations

The cytotoxicity of organometallic compounds iron(III)-, cobalt(III)-, manganese(II)-, and copper(II)-salophene (-SP) on platinum-resistant ovarian cancer cell lines was compared. Fe-SP displayed selective cytotoxicity (IC(50) at ~1 muM) against SKOV-3 and OVCAR-3 cell lines while Co-SP caused cytotoxic effects only at higher concentrations (IC(50) at 60 muM) and Cu-SP effects were negligible. High cytotoxicity of Mn-SP (30-60 muM) appeared to be nonspecific because the Mn-chloride salt reduced cell viability similarly. The effect of Fe-SP at 1 muM proved to be ovarian cancer cell selective when compared to a panel of cell lines derived from different tumors. The first irreversible step in …

Accumulation Of Artemisinin Trioxane Derivatives Within Neutral Lipids Of Plasmodium Falciparum Malaria Parasites Is Endoperoxide-Dependent, Carmony L. Hartwig, Andrew S. Rosenthal, John D'Angelo, Carol E. Griffin, Gary H. Posner, Roland A. Cooper

Collected Faculty Scholarship

The antimalarial trioxanes, exemplified by the naturally occurring sesquiterpene lactone artemisinin and its semi-synthetic derivatives, contain an endoperoxide pharmacophore that lends tremendous potency against Plasmodium parasites. Despite decades of research, their mechanism of action remains unresolved. A leading model of anti-plasmodial activity hypothesizes that iron-mediated cleavage of the endoperoxide bridge generates cytotoxic drug metabolites capable of damaging cellular macromolecules. To probe the malarial targets of the endoperoxide drugs, we studied the distribution of fluorescent dansyl trioxane derivatives in living, intraerythrocytic-stage Plasmodium falciparum parasites using microscopic imaging. The fluorescent trioxanes rapidly accumulated in parasitized erythrocytes, localizing within digestive vacuole-associated neutral lipid …

Genome-Wide Compensatory Changes Accompany Drug Selected Mutations In The Plasmodium Falciparum Crt Gene, Hongying Jiang, Jigar J. Patel, Ming Yi, Jianbing Mu, Jinhui Ding, Robert Stephens, Roland Cooper, Michael T. Ferdig, Xin-Zhuan Su

Collected Faculty Scholarship

Mutations in PfCRT (Plasmodium falciparum chloroquine-resistant transporter), particularly the substitution at amino acid position 76, confer chloroquine (CQ) resistance in P. falciparum. Point mutations in the homolog of the mammalian multidrug resistance gene (pfmdr1) can also modulate the levels of CQ response. Moreover, parasites with the same pfcrt and pfmdr1 alleles exhibit a wide range of drug sensitivity, suggesting that additional genes contribute to levels of CQ resistance (CQR). Reemergence of CQ sensitive parasites after cessation of CQ use indicates that changes in PfCRT are deleterious to the parasite. Some CQR parasites, however, persist in the field and grow well …

Iron(Iii)-Salophene: An Organometallic Compound With Selective Cytotoxic And Anti-Proliferative Properties In Platinum-Resistant Ovarian Cancer Cells, Thilo S. Lange, Kyu Kwang Kim, Rakesh K. Singh, Robert M. Strongin, Carolyn Mccourt, Laurent Brard

Chemistry Faculty Publications and Presentations

Background: In this pioneer study to the biological activity of organometallic compound Iron(III)-salophene (Fe-SP) the specific effects of Fe-SP on viability, morphology, proliferation, and cell-cycle progression on platinum-resistant ovariancancer cell lines were investigated.

Methodology/Principal Findings: Fe-SP displayed selective cytotoxicity against SKOV-3 and OVCAR-3 (ovarian epithelial adenocarcinoma) cell lines at concentrations between 100 nM and 1 μM, while the viability of HeLa cells (epithelial cervix adenocarcinoma) or primary lung or skin fibroblasts was not affected. SKOV-3 cells in contrast to fibroblasts after treatment with Fe-SP revealed apparent hallmarks of apoptosis including densely stained nuclear granular bodies within fragmented nuclei, highly condensed …

Respiratory Effects Of 1-Propylxanthine On Neonatal Rats, Amanda Hance

Student Honors Theses

Neonatal apnea is commonly treated by methylxanthines like caffeine or theophylline, but these drugs have the potential to create serious side effects. As an alternative, a new xanthine analog, 1-propylxanthine (1-PX), was recently synthesized at Eastern Illinois University. The respiratory effects of 1-PX were investigated in 4- to 7-day-old rats to determine if 1-PX could be a respiratory stimulant. Each rat was placed in a heated body plethysmograph, and its respiratory rate and volume were measured using a flow transducer, pneumotachograph, and Power Lab data acquisition system. After a 10-min control period, the rat was given a s.c. dose of …

The Evaluation Of Midazolam On Head Injured Patients In The Prehospital Setting, Dragana Klinac

Theses: Doctorates and Masters

Midazolam (Hypnovel ®) is the only sedating agent used by paramedics at St John Ambulance Service W.A. in the management of many conditions including seizure activities, antisocial or uncontrollable behaviours, back pain incidents and head injuries. Midazolam, with a rapid absorption, fast onset of action and short duration on neurological activity, has been accepted as a safe and effective agent in prehospital treatment since the late-1990s. Often, if a patient is not complying with treatment or is uncontrollable or aggressive, paramedics are required to sedate the individual. This study primarily examines the use of midazolam for the sedation of unmanageable …

La Flore Qui A Faim : Une Enquête Chimique, Biologique Et Culturelle De La Dimorphisme Rouge/Verte Et Les Applications Médicinales De Nepenthes Madagascariensis, Keirnan Willett

Independent Study Project (ISP) Collection

Le Nepenthes madagascariensis est une plante carnivore endémique du côté sud-est de Madagascar qui attirent la proie arthropode (insectes, araignées etc.) en employant les bouts de feuilles convertis en forme des pichets ou urnes. Après d’être attiré par le suc au bord de l’urne, les insectes devint désorientés, perdent la traction et se coulent dans le liquide riche en enzymes digestifs au dessous (14). Les substances nutritives des cadavres sont absorbées par la plante en compensant pour la lacune d’azote dans le sol. Les couvercles des urnes expriment une couleur rouge ou verte. Notre étude examine les différences chimiques et …

Bioprospecting, Philip A. Reed

STEMPS Faculty Publications

The article discusses that the product applications of bioprospecting are almost limitless. This area of biotechnology has been labeled bioprospecting, and it is a practice that is creating worldwide controversy. Defined simply, bioprospecting is "scientific research that looks for a useful application, process, or product in nature." However, as with most biotechnologies, the definition does not address the complexities of bioprospecting. Archeologists are finding that some biotechnologies, such as the use of herbs for medicine and the use of fermentation and yeast in food products, date back 5,000 to 10,000 years (De Miranda, 2004). The four main categories of biotechnologies …

Inhibition Of Amyloid-Β Aggregation And Caspase-3 Activation By The Ginkgo Biloba Extract Egb761, Yuan Luo, Julie V. Smith, Vijaykumar Paramasivam, Adam Burdick, Kenneth J. Curry, Justin P. Buford, Ikhlas Khan, William J. Netzer, Huaxi Xu, Peter Butko

Faculty Publications

Standardized extract from the leaves of the Ginkgo biloba tree, labeled EGb761, has been used in clinical trials for its beneficial effects on brain functions, particularly in connection with age-related dementias and Alzheimer's disease (AD). Substantial experimental evidence indicates that EGb761 protects against neuronal damage from a variety of insults, but its cellular and molecular mechanisms remain unknown. Using a neuroblastoma cell line stably expressing an AD-associated double mutation, we report that EGb761 inhibits formation of amyloid-β (Aβ) fibrils, which are the diagnostic, and possibly causative, feature of AD. The decreased Aβ fibrillogenesis in the presence of EGb761 was observed …

Oxidation-Reduction Characteristics Of Chlorophenols In An Aprotic Medium, Cecil A. Sorrells, Ali U. Shaikh, Victor M. Samokyszyn

Journal of the Arkansas Academy of Science

Eighteen chlorophenols, containing from one to five chlorine atoms on the benzene ring at various positions, have been studied by cyclic voltammetric methods to evaluate their oxidation-reduction characteristics in an aprotic medium. The compounds were dissolved in dimethylsulfoxide containing 0.10 M tetrabutylammonium perchlorate as the supporting electrolyte and were then both oxidized and reduced on a glassy carbon electrode. The results indicate that phenols oxidize in a one-step process to phenoxium ion which dimerizes to quinone ether. The ether can be reduced back to phenol in a two-step reduction process. The oxidation potential of the chlorophenols varies with the number …

Growing Lavender In Western Australia, Aileen Reid

Bulletins 4000 -

Lavender oil is an essential oil, derived from plants (genus Lavendulai primarily by steam distillation of the flowers. There are several types of lavender oil. The 'true' lavender oil, and the most highly prized, comes from Lavendula augustifolia; it is primarily used in the fragrance and perfume industry. World production is about 200 tonnes per year. Spike lavender oil, derived from Lavendula latifolia, has a world production of about 150-200 tonnes per year. Lavandin oil is derived from hybrids of L. augustifolia x L. latifolia that yield much higher than L. augustifolia but the oil is lower quality, hence it …

Trans-Resveratrol Inhibits Calcium Influx In Thrombin-Stimulated Human Platelets, Yuliya Dobrydneva, Roy L. Williams, Peter F. Blackmore

Chemistry & Biochemistry Faculty Publications

1 The phytoestrogenic compound trans-resveratrol (trans-3,5,4'-trihydroxystilbene) is found in appreciable quantities in grape skins and wine. It has been shown that both products rich in trans-resveratrol and pure trans-resveratrol inhibit platelet aggregation both in vivo and in vitro. However the mechanism of this action still remains unknown.

2 An essential component of the aggregation process in platelets is an increase in intracellular free Ca²⁺ ([Ca²⁺]_i). Ca²⁺ must enter the cell from the external media through specific and tightly regulated Ca²⁺ channels in the plasma membrane. The objective …

The Effect Of 48 Hr Glucose Administration On The Hepatic P-450 System, John N. Buchholz

Loma Linda University Electronic Theses, Dissertations & Projects

The administration of glucose for 48 hrs to mice resulted in a shift of the dose response curve of phenobarbital, an indication that glucose administration significantly sensitized the animals to the effects of the drug. Glucose administration produced a reduction in the catalytic activity of hepatic microscopical P-450 as measured by the in vitro conversion of p-Nitrocellulose to p-Nitrophenol.

The administration of glucose to rats for 48 hrs resulted in prolonged anesthesia after the administration of pentobarbital. The spectral binding of hexobarbital and methadone to hepatic microsomal P-450 was found to be significantly reduced following glucose administration. The changes in …

Cattle Fertility Not Harmed By Pour-On Insecticides, D J. Barker

Journal of the Department of Agriculture, Western Australia, Series 4

Pour-on insecticides have been a feature of lice and fly control on cattle for many years and in many countries, but it seems that only in Western Australia have they been suspected of lowering fertility.

Frequent reports of this effect have been received by the Department of Agriculture since the first pour-on insecticide was marketed in W.A. in the late 1960's, culminating in the research work reported below.

The work clears pour-ons as a cause of reduced fertility in herds.

Emergency Chlorination Of Farm Water Supplies, H C. Hughes

Journal of the Department of Agriculture, Western Australia, Series 4

TOWARDS the end of summer (and especially in a drought) the risk of water in dams, soaks, wells or tanks becoming polluted is increased.

Bore water is much less likely to be affected unless the bore is poorly sited near a farm building, such as a shearing or milking shed, a pig pen, or a septic tank system.

Marker Dyes In Antibiotics, K Needham, N. Ingleton

Journal of the Department of Agriculture, Western Australia, Series 4

'For some years the presence of penicillin in milk has been a serious problem for the dairy industry.

When cows are treated for mastitis with antibiotics some residue finds its way into the milk.

Unless the milk from treated cows is withheld for at least 72 hours after treatment this residue enters the bulk milk supply.

List Of Registered Stock Foods : 1963-64, H G. Cariss

Journal of the Department of Agriculture, Western Australia, Series 4

All foods for stock sold in Western Australia are required by the Feeding Stuffs Act, 1928-1951, to be registered annually with the Department of Agriculture.

A list of stock foods which have now been registered with the Department of Agriculture for the current registration year appears here.

Drugs For Worm Control. 1. Sheep Drenching Trials With Mk 360, M R. Gardiner, J. Craig

Journal of the Department of Agriculture, Western Australia, Series 4

DRENCHING sheep with drugs designed to eliminate parasites has become an established practice in the higher rainfall districts of Western Australia.

has been tested in many trials, and their is little doubt that drenching sheep clinically affected with worms—the so-called "tactical" drench—is valuable and necessary.

However, there is usually less general acceptance of the value of "strategic" drenching— the prevention of clinical parasitism by giving the drug at certain specific times, pre-determined by a knowledge of the numerical rise and fall of the various parasites within the animal body.

The Effect Of Drugs On Experimental Renal Hypertension In The Dog., J. J. Prusmack

Electronic Theses and Dissertations

No abstract provided.