21 |
The effect acetylsalicylic acid and acetaminophen on edema, adrenocorticotropin, and beta-endorphin during orofacial inflammationMidroni, Ran, January 1996 (has links)
Thesis (M. Sc.)--University of Toronto, 1996. / Includes bibliographical references.
|
22 |
Effects of pharmaceutical pollutants and their mixtures on aquatic organisms, with particular focus on reproduction and endocrine function in a fish model speciesThrupp, Tara Joanne January 2016 (has links)
A number of pharmaceuticals have been shown to have adverse effects on key biological processes of aquatic organisms at low concentrations (ng/l range). Key questions for chemical risk assessment are whether such pharmaceuticals can produce adverse effects on organisms when present in the environment in combination and at low concentrations, whether these can be classified as additive, and under what circumstances can they be predicted. The main purpose of this study was to assess the potential for combination effects of a multicomponent steroid pharmaceutical mixture of dissimilarly acting compounds on an ecologically relevant end point – reproduction, using the existing predictive toxicity models Concentration Addition (CA) and Independent Action (IA). Concentrations of steroids close to those reported in the environment were shown to produce adverse effects on reproduction when present in combination with other steroids. Clear combination effects significantly larger than the effects of the individual compounds were observed when each compound was present at a concentration below the detection limit of the assay, demonstrating a ‘something from nothing’ mixture effect. Furthermore, IA predicted more pronounced effects on egg production that CA, an observation previously unreported from the literature. Actual observed effects were closer to the IA prediction. Additional biomarker and molecular endpoints were examined in subsequent studies to establish the mechanisms of disrupted reproduction in pair-breeding FHMs exposed to the steroid mixture. Results from this study indicate that reproductive impairment of fish exposed to the steroid mixture is likely due to the masculinisation of female fish due to the androgenic activity of the mixture. These results have implications for chemical risk assessment, and in particular, highlight the need for caution when using CA as a worst-case approximation of mixture effects.
|
23 |
Glucocorticoid receptor function : new insights from genetic and chemical biology approachesTrebble, Peter January 2013 (has links)
Glucocorticoids (Gc) are vital for development, maintenance of glucose homeostasis and the resolution of inflammation. As potent modulators of the immune response Gc are routinely prescribed in the management of a variety of inflammatory diseases including asthma and rheumatoid arthritis. However clinical use of Gc is limited by variation in patient sensitivity to Gc treatment and development of a wide range of side effects. In this thesis I present two studies that have advanced our understanding of Gc action in vivo. The first defines and characterises the cause of familial glucocorticoid resistance, and the second describes the action of two potent non-steroidal Gc in a cell line model. Familial Gc Resistance: Cases of primary generalised Gc resistance are very rare and typically present as mineralocorticoid and androgen excess leading to hypertension, hypokalemia and hirsutism. Gc resistance is attributed to loss of function mutations within the glucocorticoid receptor (GR). Here I identify a family with a novel mutation in GR exon 6 that gives rise to a very mild phenotype. Analysis of transformed patient peripheral blood lymphocytes revealed a 50% reduction in full length GR but no expression of a mutant form. As this did not rule out expression in vivo, the mutant receptor (Δ612GR) was characterised in a cell line. Investigation using reporter genes revealed that Δ612GR lacked any activity, but had dominant negative action when co expressed with full length GR. In response to Gc Δ612GR was not phosphorylated or targeted for degradation. Fluorophore tagged Δ612GR was unable to translocate to the nucleus in response to Gc, but delayed the translocation of full length GR when co-expressed. Together this indicates that Δ612GR is unable to bind ligand but has dominant negative action upon full length GR most likely due to heterodimerisation. Therefore I describe a novel GR mutation that results in Gc resistance but presents with a mild very phenotype. Novel Non-steroidal Gc: Non-steroidal Gc can be used as tools to determine how ligand structure directs GR function. Here I describe two highly potent non steroidal Gc ligands, GSK47867A and GSK47869A which alter the kinetics of receptor activity. Treatment with either ligand induces slow GR nuclear translocation, promotes GR nuclear retention and prolongs transcriptional activity following ligand withdrawal. Crystal structure analysis revealed that GSK47867A and GSK47869A specifically alter the surface charge of the GR at a site important for Hsp90 binding. GR bound to GSK47867A and GSK47869A shows prolonged activity in the presence of Hsp90 inhibitor geldanamycin. Therefore this work identifies a new chemical series that could prolong GR activity due to altered pharmacodynamics rather than altered pharmacokinetics.In summary this work uses a combination of genetic and chemical biology approaches to broaden our understanding of GR function. Characterisation of naturally occurring GR mutations gives insight into the complex function of the GR, and non-steroidal Gc act as useful tools that will aid in the design of improved therapeutics.
|
24 |
Comparison of the Effects of Deracoxib, Buffered Aspirin, and Placebo on the Gastric Mucosa of Healthy DogsSennello, Kathleen Ann 04 May 2005 (has links)
This study tested the hypothesis that administration of deracoxib, a cyclooxygenase-2 specific (COX-2) inhibitor, would result in lower gastric lesion scores than administration of buffered aspirin and gastric lesion scores similar to placebo when administered to healthy dogs for 28 days. Twenty-four, healthy, random source dogs were divided into three groups. Group I received buffered aspirin, 23.6 mg/kg PO q 8h, group II received deracoxib, 1.6 mg/kg PO q 24h and placebo twice daily PO q 8h after deracoxib administration, and group III received placebo PO q 8h. Gastroscopy was performed on days -7, 6, 14, and 28 of treatment. Four regions of the stomach (pylorus, incisura, cardia, and body) were evaluated separately and lesions scored on a scale of 1 (mucosal hemorrhage) to 12 (perforating ulcer) by an observer unaware of which treatments the dogs received. Dogs were observed every 8 hours for vomiting, diarrhea and anorexia. Feces were scored from 1-5 (scores <4 were considered diarrhea).
Lesion scores for each group, at each location, and total scores, at each time period, were evaluated for the effects of time and treatment using a Kruskal-Wallis test. Total dog days of vomiting and dog days of diarrhea in each group were compared using a Wilcoxon rank sums test. Significance was determined at p<0.05.
Significantly higher median total gastric lesion scores were found in the aspirin group compared to the deracoxib or placebo groups on days 6, 14, and 28. There were no significant differences in median total gastric lesion scores between the deracoxib or placebo groups at any time during the study. There was no location effect on gastric lesion scores and there was no significant change in gastric lesion scores over time in any of the groups during treatment. Significantly more dog-days of vomiting occurred in the aspirin group as compared to the deracoxib group. No significant differences were found between groups for dog-days of diarrhea.
In this study, the administration of deracoxib to healthy dogs resulted in significantly lower gastric lesion scores compared to dogs receiving aspirin and lesion scores similar to those receiving placebo. / Master of Science
|
25 |
Biotechnological Modification Of Steroidal StructuresErkilic, Umut 01 February 2008 (has links) (PDF)
Steroids are important biological regulators existing in hormones which are used to
control metabolism of the body. There are widespread applications in the
pharmaceutical industry. Drugs of steroid nature - anti-inflammatory and antiallergic
corticosteroids, diuretics, anabolics, androgens, gestagens, contraceptives,
antitumor medications, etc. - are now widely used in human and veterinary medicine.
Nowadays, biotechnological modifications of steroids are preferred over chemical
modifications as a green chemistry since they are more likely to be natural.
In this work four different Fusarium species were screened for bioconversion of
steroids into pharmaceutically important derivatives of steroids by reduction,
dehydrogenation, side-chain degradation etc. on A and D-rings containing many
active sites.
Fusarium spp. used in this work, namely Fusarium roseum OUT 4019, Fusarium
anguioides OUT 4017, Fusarium bulbigenum OUT 4115 and Fusarium solani OUT
4021 are filamentous fungi, which belong to the class of Deuteromyces. They can
grow using simple carbohydrates and nitrogen sources.
4-androstene-3,17-dione conversion is used as a model system. Under same
environmental conditions it is found that whole cells of Fusarium roseum OUT 4019
can dehydrogenate at C-1 and C-2 producing androsta-1,4-diene-3,17-dione and also
reduce at C-17 in addition to dehydrogenate at C-1 and C-2 producing 17-hydroxyandrosta-
1,4-dien-3-one, Fusarium anguioides OUT 4017 can reduce at C-17
producing 17-hydroxy-androst-4-en-3-one, Fusarium solani OUT 4021 can reduce at
C-3 and C-17 producing androst-4-ene-3,17-diol at 25 C° / and 160 rpm with
uncontrolled pH.
In these conversions, androsta-1,4-diene-3,17-dione, 17-hydroxy-androsta-1,4-dien-
3-one, 17-hydroxy-androst-4-en-3-one, androst-4-ene-3,17-diol were isolated with 54
%, 22 %, 26 %, 90 % yields, respectively.
In another study, bioconversion reactions of aromatic methyl ethers by Fusarium
roseum OUT 4019 were investigated and for some compounds, cleavage of methyl
ether was observed.
|
26 |
Exploring metabolic and genetic diversity in tomato secondary metabolitesDzakovich, Michael Paul January 2020 (has links)
No description available.
|
27 |
Opioid reducing strategies in post-operative pain management /Legeby, Mariann, January 2006 (has links)
Diss. (sammanfattning) Stockholm : Karolinska institutet, 2006. / Härtill 4 uppsatser.
|
28 |
Methods of programming increased milk production and its relationship with sustainability of the dairy industryCarpenter, Abigail Joy January 1900 (has links)
Doctor of Philosophy / Department of Animal Sciences and Industry / Barry Bradford / High levels of milk production has been and will continue to be a priority for the global dairy industry. Non-steroidal antiinflammatory drugs administered to dairy cattle following calving can be an effective way of programming higher milk production for the entirety of lactation. When dairy cattle on a commercial dairy received either sodium salicylate or meloxicam following calving, they responded with increased whole-lactation milk production, which was driven by higher daily milk yields following the seventh week of lactation. When dairy cattle at a research dairy received sodium salicylate following calving, they did not show the same increase in milk production but feed intake, feeding behavior, and blood parameters were altered for an extended period of time. The response to treatment was largely dependent on the parity of the animal. In an effort to determine whether re-programming of the rumen environment could explain these findings, sodium salicylate was administered to batch cultures of rumen fluid, and as a result, fermentation was inhibited. When substrate was fermented in rumen fluid from heifers who had been dosed with sodium salicylate, fermentation was inhibited for an extended period of time following sodium salicylate administration. Beyond the use of compounds such as these, other factors can program lactation for higher milk production, including the gender of the calf. Analysis of lactation records from the US has indicated that cows produce more milk following the birth of a heifer calf compared to a bull. With further research, findings such as these can provide farmers with more tools for improving productivity and lead to the sustainability of the dairy industry as a whole.
|
29 |
Biological Activity of Steroid Analogues:Synthesis and Receptor/Enzyme InteractionsMcCarthy, Anna Rose January 2006 (has links)
This thesis investigates the biological activity of selected non-steroidal analogues of sex steroid hormones by examining two different effects of analogues on endogenous sex hormone activity. Non-steroidal analogues of sex hormones were synthesised to study their biological interactions with a sex steroid receptor and a sex steroid metabolising enzyme. Chapter One introduces the steroid hormones and their physiology, which leads to a review of the mechanisms by which steroids exert their effects. Their implication in disease is discussed, with particular emphasis on the sex steroids. As the biological activity of steroids is related to their chemical structure, the important features of steroid structure are identified, including the cyclopentanoperhydrophenanthrene nucleus, arrangement of ring substituents and ring junction conformation. The concept of non-steroidal analogues of steroids is introduced, and the harmful or beneficial effects analogues have on endogenous steroid activity are considered. Alteration of steroid activity and its consequences are focussed on two main areas; the potential adverse effects of environmental chemicals which mimic sex steroid activity, and the use of non-steroidal analogues in medicinal chemistry for treating sex steroid related disease. Chapter Two describes an investigation into the 17β-estradiol mimicking activity of non-steroidal analogues. Exogenous chemicals that mimic estradiol are of concern as they may alter endogenous estradiol activity and disrupt endocrine systems. Firstly, an introduction to the field of research concerned with environmental chemicals that mimic steroid hormones is given. The interaction of xenoestrogens with the estrogen receptor is described, as are the methods available for assessing the estrogen mimicking activity of xenoestrogens. The concern for insecticides mimicking estrogen activity is described by reviewing reported activities of insecticides, which leads into a discussion of work carried out as part of this thesis. Metabolites of the pyrethroid insecticides permethrin and cypermethrin, 2.14, 2.15, and 2.16 were synthesised while others were commercially obtained. The interaction of pyrethroid insecticide metabolites with the human estrogen receptor expressed in recombinant yeast (Saccharomyces cerevisiae) was studied, following the establishment and validation of the assay. Metabolites 2.11, 2.12, and 2.14 were found to weakly stimulate estrogen receptor-mediated estradiol responsive gene expression in the yeast assay (105 less active than 17β-estradiol). Since the activity of the metabolites using the yeast assay was greater than for the parent compounds, metabolic pathways need to be considered when assessing the impact of exposure to environmental estrogens. The low estrogenic activity suggests these compounds are not individually contributing significantly to the xenoestrogenic impact on humans, but will add to total xenoestrogen exposure. Chapter Three describes the inhibition of a sex steroid metabolising enzyme, steroid 5a-reductase, by novel non-steroidal compounds. Inhibitors of this enzyme are potentially useful therapeutic agents for regulating the activity of an androgen in prostate disorders. A review of the literature on non-steroidal inhibition of 5a-reductase identified three key structural features known to enhance inhibitor potency; ring substitution, position and nature of ring unsaturation and angular methyl group presence. These features were taken into account in the design of inhibitors synthesised in this thesis (3.55-3.57, 3.59, 3.61, 3.62, 3.110 and 3.111). Inhibitors consisting of non-steroidal 5- or 1-aryl pyridone scaffolds were synthesised to investigate SAR for 4'-substituents. The 5-aryl 1-methyl-2-pyridone/piperidone scaffold of compounds 3.55-3.57 and 3.59 was constructed by Suzuki cross coupling methodology, while the 1-aryl 2-methyl 2,3-dihydro-4-pyridone scaffold of 3.61 and 3.62 was constructed by aza Diels-Alder methodology. Long carbon chain olefin containing tethers 3.107 and 3.108 were synthesised for conjugation to inhibitor 3.57 by cross metathesis to give conjugates 3.110 and 3.111. Compounds 3.55-3.57, 3.59, 3.61, 3.62, 3.110 and 3.111 inhibited the type 1 5a-reductase isozyme expressed by HEK-I cells, with activities comparable to those of related literature compounds. The 1-aryl 2,3-dihydro-4-pyridone 3.62 inhibited both the type 1 and 2 isozymes (expressed by HEK-II cells) of 5a-reductase. The presence of bulky hydrophobic groups (benzoyl, long chain tethers) at the 4' position enhanced the potency of type 1 inhibition by 5-aryl pyridone type compounds in comparison to N,N-diisopropyl- and N-allylacetamide groups. This information provides further understanding of SAR within and across different classes of non-steroidal inhibitors of steroid 5a-reductase towards improved drug design.
|
30 |
Effects of inflammation on the transition dairy cow / Effects of inflammation on transition dairy cowsFarney, Jaymelynn Kay January 1900 (has links)
Doctor of Philosophy / Department of Animal Sciences / Barry Bradford / The transition into lactation is a period of primary concern to dairy producers because of the tremendous incidence of health disorders observed during this time. Two common disorders that lead to decreases in production and retention within the herd include fatty liver disorder (FL) and ketosis. These two disorders have been commonly associated with negative energy balance, yet recently it has been hypothesized that inflammation is a contributor to the etiology of these disorders. Three individual projects were completed for this dissertation, all involving inflammation. The role of endogenous inflammation was determined by administration of sodium salicylate (SS) to cows for 7 d after parturition, and metabolites and production responses were evaluated. Overall it appears that SS induced hypoglycemic conditions and increased triglyceride accumulation in the liver (while administered), increased lipid mobilization and ketones (2 weeks after administration ended), and increased whole lactation milk production in older cows. A sensitive, specific sandwich ELISA for bovine tumor necrosis factor-[alpha] was developed, which provided the ability to measure “normal” circulating levels of this cytokine. The final study involved inducing inflammation by daily injections of the TNF[alpha] to the early lactation dairy cow. In this model, cows receiving TNF[alpha] had a reduction in dry matter intake, water intake, and decreases in milk production and milk components. Overall, it appears that inflammation is involved in the normal biology of the transition dairy cow and disrupting this can lead to interesting negative effects and some improvements of production; however, when inflammation is much greater it can lead to negative production effects.
|
Page generated in 0.0698 seconds