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1
Rawal, Sumit. "Mechanisms of the Extreme Sensitivity of Turkeys to Aflatoxin B1." DigitalCommons@USU, 2010. https://digitalcommons.usu.edu/etd/568.
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The pathogenesis of hepatotoxic and hepatocarcinogenic actions of the mycotoxin aflatoxin B1 (AFB1) involves initial bioactivation by microsomal cytochrome P450s (P450) to a reactive and electrophilic intermediate, exo-aflatoxin B1-8,9-epoxide (exo-AFBO). Poultry, especially turkeys, are extremely sensitive to AFB1, a condition associated with efficient epoxidation by P450s. The purpose of this research was to 1) discover and characterize the P450s in turkey liver responsible for AFB1 bioactivation, and 2) determine the relative importance of these P450s in turkey liver. Initial investigations led to the discovery of CYP1A5. We then identified CYP3A37, a human CYP3A4 homologue from turkey liver, which along with CYP1A5 plays an important role in the bioactivation of AFB1 to exo-AFBO. The E. coli-expressed CYP3A37 possessed striking similarities to human CYP3A4, in terms of its catalytic activities and the kinetics of AFB1 oxidation. After the discovery of CYP3A37, further research evaluated its relative importance to CYP1A5, with respect to the epoxidation of AFB1, to determine which of the homologues bioactivated relatively low "real world" AFB1 concentrations, reflective of the potential dietary exposure. Using antibodies directed to both the enzymes as tools in immuno-inhibition experiments, we determined that CYP1A5 contributes to about 98% of the exo-AFBO formation at the low AFB1 concentrations (0.1 µM), which led us to conclude that CYP1A5 is likely the dominant homologue involved in the extreme sensitivity of the turkeys to AFB1. CYP3A37 also efficiently epoxidated AFB1, but only at high concentrations of this mycotoxin, not likely to be achievable in turkey liver in vivo. Our research has helped shed light on the relative importance of CYP1A5 and CYP3A37 in the bioactivation of AFB1 to the toxic exo-AFBO, and thus on the mechanisms of the extreme sensitivity of turkeys to AFB1. Given that AFB1 is a ubiquitous component of corn-based poultry feed and contamination is practically unavoidable, we conducted further studies evaluating the chemopreventive action of probiotic bacteria, Lactobacillus, on AFB1 toxicity in turkeys. Probiotic bacteria are known to bind AFB1, thus reducing its bioavailability. A mix of probiotic bacteria provided protection against key endpoints of aflatoxicosis, like AFB1-induced reduction in body and liver weights. Our data demonstrate that Lactobacillus was protective against aflatoxicosis in turkeys, thus validating its use as a possible chemopreventive, thereby helping alleviate the significant annual losses to the poultry industry due to feed contamination by AFB1.
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Thomas, Sarah Elizabeth. "A Prevalence Study of Southeast Origin Sale Barn Beef Cattle, Comingled in Warren County, Kentucky, Persistently Infected with Bovine Viral Diarrhea Virus, including the Effects of Season and Body Weight." TopSCHOLAR®, 2011. http://digitalcommons.wku.edu/theses/1070.
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Bovine viral diarrhea (BVD) is an economically important disease of cattle. Calves persistently infected (PI) with the bovine viral diarrhea virus (BVDV) are a powerful agent for spread of the virus. A total of 24,423 southeast origin beef cattle comingled at three Warren County, Kentucky locations were tested from November 2007 to June 2010 for PI BVDV. A total of 97 head tested positive for PI BVDV, giving an average overall prevalence of 0.397%. Calves tested were subdivided into categories for additional calculations of dependence. A total of 8,910 were categorized by weight range upon testing (300-399 lbs, 400-499 lbs, 500-599 lbs, and 600-699 lbs). Prevalence does show a dependence on weight, with a higher prevalence found in lower weight classes, especially 300-399 lb calves (P<0.001). A total of 24,423 were categorized by season at time of testing (Fall, Winter, Spring, Summer). Prevalence does not show a dependence on season (P>0.05). Although eradication programs are not likely to be organized in the United States, several control programs have been developed. These findings can be used as additional support for PI testing of calves, especially those in lighter weight classes, as part of a BVD control program.
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Monteiro, Davolli Gabriel. "REVERSIBLE DOWNREGULATION OF HYPOTHALAMIC-PITUITARY-GONADAL AXIS IN THE STALLION WITH A THIRD-GENERATION GNRH ANTAGONIST." UKnowledge, 2015. http://uknowledge.uky.edu/gluck_etds/22.
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The objectives of this thesis were: (1) to evaluate the downregulation of the stallion hypothalamic-pituitary-gonadal (HPG) axis by a GnRH antagonist (acyline) based upon endocrine, seminal, testicular and behavioral effects, and (2) to assess recovery after treatment. Stallions were treated for 50 days (n=4; 330µg/kg acyline q 5d) and controls (n=4) received vehicle alone. Stallions were assessed pre-treatment and for 72 days after last treatment. Treatment induced declines (p<0.05) in FSH, LH, testosterone (to castrate levels) and estrone sulfate. Gonadotropins and testosterone returned to control values within nine days and estrone sulfate by 14 days after treatment discontinuation. Acyline-treated stallions failed to respond with FSH, LH and testosterone increase after exogenous GnRH stimulation (25µg gonadorelin, IV) compared to pre-treatment and control stimulation. Total sperm numbers and motility were reduced in acyline-treated stallions, as well as total seminal plasma protein and testicular volume (p<0.05). Time to ejaculation was increased in acyline group (p<0.5). Testicular, sexual behavior and most seminal parameters regained normal levels within 72 days after treatment ceased. Sperm output of acyline-treated stallions was regained within seven months after ending treatment. Acyline reversibly suppressed the stallion HPG axis, thus has potential for treating the androgen-dependent Equine-Arteritis-Virus carrier state and as behavior modulator.
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Zhu, Wenying. "GLUCOCORTICOID-INDUCED CHONDROCYTE CYTOTOXICITY AT DOSES RECOMMENDED FOR INTRA-ARTICULAR THERAPY IN HORSES." UKnowledge, 2015. http://uknowledge.uky.edu/gluck_etds/23.
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Intra-articular glucocorticoid injections are commonly used to treat synovitis and osteoarthritis in horses. These agents are highly effective at relieving pain, swelling, and other symptoms of joint inflammation. The drugs also have therapeutic benefits by down regulating the expression of cytokines and protease enzymes that participate in the degradation of articular cartilage. However, detrimental effects on chondrocyte function and cell viability that is independent of osteoarthritis pathogenesis have been described and linked to glucocorticoid use. These side effects are both drug- and dose-dependent. This study tested the hypothesis that manufacture recommended dosage levels of methylprednisolone, betamethasone, and triamcinolone that are widely used in equine clinical practice are cytotoxic to articular chondrocytes. Drug-induced chondrocyte cytotoxicity was evaluated in monolayer cultures, cartilage explants, and equine fetlock joints. Total RNA was isolated from control and IL-1β stimulated primary chondrocytes and synoviocytes in culture. Changes in steady state mRNA for targeted gene transcripts related to inflammation and normal cell function were measured using reverse transcription and quantitative PCR. Inducible nitric oxide synthase activity was evaluated using nitrite production. Drug-induced chondrocyte cytotoxicity occurred at drug dosage levels frequently used in equine clinical practice. Both drug- and dose-dependent effects on chondrocyte and synoviocyte gene expression were observed. Maximum anti-inflammatory activities for the glucocorticoids were observed at in vitro concentrations below manufacturer-recommended levels. Results from this study suggest that lower glucocorticoid dose ranges for intra-articular therapy in horses should be validated to maximize the ratio of their therapeutically beneficial anti-inflammatory efficacy against detrimental effects on cell function and viability.
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Taylor, Victoria A. "PHYSIOLOGICAL CHANGES ASSOCIATED WITH PREGNANT OR NONPREGNANT MARES GRAZING PASTURES OF ORCHARDGRASS-BLUEGRASS, KENTUCKY 31 TALL FESCUE INFECTED WITH EPICHLOË COENOPHIALA, OR KYFA9821 TALL FESCUE INFECTED WITH THE NOVEL ENDOPHYTE AR584." UKnowledge, 2017. https://uknowledge.uky.edu/gluck_etds/33.
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Kentucky 31 tall fescue (KY31) infected with the common toxic endophyte strains of Epichloё coenophiala produces toxic alkaloids that improve plant vigor, but cause numerous adverse effects in grazing animals. Researchers developed a variety of KY31 containing an alternative strain of E. coenophiala, termed novel endophyte (NE). Adverse health effects in mares have not been evaluated.
Experiments in this thesis tested the hypothesis that the NE pasture does not cause adverse effects typically associated with KY31. Specific aims were to: 1) compare forage ergovaline concentrations between KY31 vs NE pastures; 2) evaluate palmar artery diameters in mares grazing KY31, NE, or orchardgrass-bluegrass (OGBG) pastures; 3) determine mare serum prolactin, estradiol, and progesterone concentrations associated with ingesting each pasture type over time; and 4) measure foaling outcomes, including percentage of live foals, foal birth weights, and foal growth rates. In 2015, six nonpregnant mares grazed KY31, six pregnant mares grazed NE and six pregnant mares grazed OGBG pastures. In 2016, eighteen mares were used; six mares grazed each pasture type.
Study results showed that ergovaline did not appear to be produced by NE. Novel endophyte pasture did not have negative effects on palmar artery diameter, reproductive hormones, or foaling outcomes.
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Sargeant, Aaron Matthew. "Preclinical Efficacy and Safety Evaluation of Novel Small-Molecule Targeted Agents for the Prevention and Treatment of Prostate Cancer." The Ohio State University, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=osu1243948876.
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Al-Amer, Saleh Suliaman. "Nutritional and toxicological studies on New Zealand mutton bird meat (Puffinus griseus)." Lincoln University, 2009. http://hdl.handle.net/10182/1659.
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New Zealand mutton bird or tītī (Puffinus griseus and order procellariiformes) nest in New Zealand during the summer months, migrate to the northern hemisphere during May and return in September. Their eggs are laid during November and December and the chicks are hatched in the following January and February. Large numbers of them are harvested from April to May in New Zealand. They are wild seabirds annually harvested by Maori according to the customary rights agreement set by Treaty of Waitangi.NZ mutton birds also called Sooty Shearwaters are noted for their high proportion of body fat.These birds are interesting since its sole diet is based on krill and other small marine organisms that are potentially rich in n-3 fatty acids and other marine bioactive compounds. The proximate composition, fatty and amino acids and cholesterol content of mutton bird pectoral muscle were determined and compared with other common meat to explore the nutritional value of this New Zealand delicacy. The concentration of twenty two essential and toxic elements including silver (Ag), aluminium (Al), arsenic (As), cadmium (Cd), chromium (Cr), copper (Cu), mercury (Hg), manganese (Mn), lead (Pb), selenium (Se), potassium (K), calcium (Ca), magnesium (Mg), boron (B), iron (Fe), nickel (Ni), sulphur (S), sodium (Na) and cobalt (Co) and zinc (Zn) in mutton bird breast meat (Puffinus griseus) were measured over two years to evaluate its safety for human consumption. Persistent organochlorine, dichlorodiphenyltrichloroethane (DDT) and their metabolites, and aldrin and lindane were also measured.Twenty bird carcasses were purchased in both 2006 and 2007 from a local source. Meat samples from the pectoral muscle of two carcasses were pooled to generate 10 samples for each year. These were used for trace element analysis using inductively coupled plasma-mass spectrometry (ICP-MS). Trace elements were in the range of 0 to 1.09 mg/kg wet weight for Ag, 0 to 3.32 for Al, 0.17 to 0.79 for As, 0.01 to 0.07 for Cd, 0.03 to 0.15 for Cr, 3.56 to 4.88 for Cu, 0 to 0.15 for Hg, 0.22 to 0.50 for Mn, 0 to 0.09 for Pb, 0.66 to 1.18 for Se and 11.49 to 23.70 for Zn. In 2006, Ag, Al, Mn and Zn concentrations were significantly higher but Pb and Hg concentrations significantly lower compared to the 2007 samples (P < 0.05). Apart from one sample in 2006, all the samples were below the published maximum level for concern. However, our preliminary data indicated that the higher level of Cd and other metals in the skin of mutton bird may compromise the overall safety to humans consuming the skin of mutton birds. It is suggested that the evaluation of the metals in different parts and/or the whole mutton bird at different seasons is required to assure complete safety to the consumers.Furthermore, the nutritional value of mutton bird meat was studied over two harvesting seasons (2006 and 2007) to investigate the impact of seasonal variation. The moisture and carbohydrates contents ranged between 54.0 to 55.0 % and 2.8 to 3.0 %, respectively, and no seasonal effects were evident in these components. The values for fat and ash contents were higher and the protein content lower for birds harvested in 2007 compared with the 2006 values which ranged from 11.8 to 13.0, 10.3 to 11.7, and 20.3 to 18.5 % for fat, ash and protein content respectively. The major amino acids in mutton bird pectoral muscle were glutamate, aspartate, lysine, leucine, and arginine. Higher lysine concentrations and lower proline, cystein and methionine were found in mutton birds compared with the literature values for beef, lamb and pork. The essential amino acid content in mutton bird (43.8 and 44.9 % in 2006 and 2007, respectively) was slightly higher than those found in beef and lamb meats (42-43%).The major fatty acids detected were palmitic (C16:0), stearic (C18:0), oleic and isomers (C18:1), eicosenoic (C20:1), Docosahexaenoic acid (DHA) (C22:6), icosapentaenoic acid (EPA) (C 20:5) and these accounted for approximately 77% of the fatty acids. The 3/6 ratio of fats from pectoral muscle was 1.3. The cholesterol concentration varied slightly in the two years with 184.4±37.37and 134.4±25.55mg/100 g fresh weight for 2007 and 2008 respectively. Mutton bird was shown to contain significantly higher cholesterol content (134.4-184.4) than other common meat such as chicken (80.3-88.9), lamb (62.3), fish (52.79) and beef (51.97). Overall, the nutritional value of mutton bird muscle was similar to or superior to the traditionally protein sources such as seafood and red meat. Annual variations existed in the composition of Mutton bird pectoral muscle but this is not of nutritional consequence but might be a useful indicator for ecological events such as feed availability and other environmental issues. Mutton bird seems to be a good source of essential minerals, Zn and Fe compared with other traditional meats source. Mutton bird meat is nutritionally as good as the major sources of red or white meats. It may even have advantages over the other common meats (beef, lamb, fish and chicken) due to its high protein and monounsaturated fatty acids (omega n-3 and n-6) content. However, its high cholesterol content may represent a risk factor for some people.
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Winstanley, Peter Andrew. "The pharmacology and toxicology of amodiaquine." Thesis, University of Liverpool, 1988. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.237571.
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Lepera, Michael Anthony. "Response of Monovalent Cation Transporters to Pro-apoptotic Protein Kinase C Modulators in Human Lens Epithelial Cells." Wright State University / OhioLINK, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=wright1314376525.
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Wang, Jinju. "Differentiation of Megakaryocytes/Platelets and Neurons from Human Endometrial Stromal Progenitor Cells." Wright State University / OhioLINK, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=wright1314976408.
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Alghamri, Mahmoud. "Enhanced Angiotensin II-Induced Cardiac and Aortic Remodeling in ACE2 Knockout Mice." Wright State University / OhioLINK, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=wright1343838851.
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Martin, Richard John. "Veterinary pharmacology, ion-channels and anthelmintics." Thesis, University of Edinburgh, 1997. http://hdl.handle.net/1842/30450.
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In this collection of papers modes of action of anthelmintic and anaesthetic drugs used in Veterinary Practice are investigated using electrophysiological techniques. New preparations and analytical techniques for investigation are described along with properties of ion-channel target sites. The pharmacology of piperazine, levamisole, pyrantel, morantel, oxtantel, avermectins, cyclic depsipeptides, ketamine, metomidate, alphaxalone and xylazine are studied. This information is reviewed in formats suitable for graduate and undergraduate study. Two-micropipette current-clamp and voltage-clamp techniques for recording effects of GABA agonists and antagonists on nematode muscle are developed using Ascaris suum. Piperazine, an anthelmintic, is shown to act as a GABA agonist of low potency and, like GABA, to mediate an increase in Cl conductance by an action on extrasynaptic receptors. Diethylcarbamazine, a piperazine derivative, did not act as a GABA agonist but blocked a voltage-activated K current. The agonist profile of the Ascaris GABA receptor was similar to vertebrate GABAA receptors but the antagonist profile was very different, indicating the presence of a distinctive type of receptor (GABAN). Novel arylaminopyridazine derivatives were synthesised and tested as competitive antagonists on the GABAN receptor. The KB for NCS 281-93, was 4.7 μM. A preparation suitable for patch-clamp studies was developed and GABA receptors activated by GABA and piperazine. Both agonists activated channels with a mean single-channel conductance of 22 pS but GABA mean open-times were longer (32ms) than those of piperazine (14 ms). The effects of ivermectin on muscle GABA receptors in Ascaris and on 19 pS Cl channels were observed using cell-attached and isolated inside-out patches. Ivermectin locked open the small Cl channels when applied to the outside membrane. A novel fluorescent and active bodily ivermectin analogue was synthesised and the movement of the probe followed in vesicle membranes using the FRAP (fluorescence recovery after photobleaching) technique. Quenching experiments showed that the ivermectin probe did not move through the cell membrane in the time scale of the experiment (30 min). A novel two-microelectrode current-clamp preparation of the Ascaris pharynx was used to show that an ivermectin analogue potentiated a glutamate gated Cl channel at low concentrations and produced an increase in the Cl conductance at a higher concentration. The actions of potent and novel potential anthelmintic cyclic depsipeptides were investigated using conventional parasitological techniques and the mode of action investigated in Ascaris muscle using current-clamp. It was found that these compounds did not act directly as a GABA agonist or acetylcholine antagonist. The actions of the anthelmintic praziquantel are reviewed and a tegumental preparation of Schistosoma mansoni developed for single-channel recording.
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Brown, Larry Dale. "Subchronic bioavailability and disposition of bivalent lead in pregnant swine and fetuses." free to MU campus, to others for purchase, 1998. http://wwwlib.umi.com/cr/mo/fullcit?p9901221.
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Cooper, Rose. "Behavior of Gold Nanoparticles in Physiological Environment and the Role of Agglomeration and Fractal Dimension." Wright State University / OhioLINK, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=wright1440168780.
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Chmura, Douglas F. "Response of Neuroinflammatory and Neurodegenerative Markers Following Sub-lethal Sarin Exposure and Subsequent Treatment via an in-vivo Caspase Inhibitor." Wright State University / OhioLINK, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=wright1324414961.
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Vicente, Carrillo Alejandro. "Sperm Membrane Channels, Receptors and Kinematics : Using boar spermatozoa for drug toxicity screening." Doctoral thesis, Linköpings universitet, Avdelningen för kliniska vetenskaper, 2016. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-131862.
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Internal fertilization usually implies that a spermatozoon, with intact attributes for zygote formation, passes all hurdles during its transport through the female genitalia and reaches the oocyte. During this journey, millions to billions of other spermatozoa perish. Spermatozoa are highly differentiated motile cells without synthetic capabilities. They generate energy via glycolysis and oxidative phosphorylation to sustain motility and to maintain the stability and functionality of their plasma membrane. In vivo, they spend their short lifespan bathing in female genital tract fluids of different origins, or are in vitro exposed to defined media during diverse sperm handling i.e. extension, cryopreservation, in vitro fertilization, etc. Being excitable cells, spermatozoa respond in vivo to various stimuli during pre-fertilization (capacitation, hyperactivation, oocyte location) and fertilization (acrosome reaction, interaction with the oocyte) events, mediated via diverse membrane ion-conducting channels and ligand-gated receptors. The present Thesis has mapped the presence and reactivity (sperm intactness and kinematics) of selected receptors, water and ion channels in ejaculated boar spermatozoa. The final aim was to find a relevant alternative cell type for in vitro bioassays that could ease the early scrutiny of candidate drugs as well as decreasing our needs for experimental animals according to the 3R principles. Spermatozoa are often extended, cooled and thawed to warrant their availability as fertile gametes for breeding or in vitro testing. Such manipulations stress the cells via osmotic variations and hence spermatozoa need to maintain membrane intactness by controlling the exchange of water and the common cryoprotectant glycerol, via aquaporins (AQPs). Both AQPs-7 and -9 were studied for membrane domain changes in cauda- and ejaculated spermatozoa (un-processed, extended, chilled or frozen-thawed). While AQP-9 maintained location through source and handling, thawing of ejaculated spermatozoa clearly relocated the labelling of AQP-7, thus appearing as a relevant marker for non-empirical studies of sperm cryopreservation. Alongside water, spermatozoa interact with calcium (Ca2+) via the main Ca2+ sperm channel CatSper. Increments in intracellular Ca2+ initiate motility hyperactivation and the acrosome reaction. The four subunits of the CatSper channel were present in boar spermatozoa, mediating changes in sperm motility under in vitro capacitation-inducing conditions (increased extracellular Ca2+ availability and bicarbonate) or challenge by the CatSper antagonists mibefradil and NNC 55-0396. Uterine and oviduct fluids are richest in endogenous opioids as β-endorphins during mating and ovulation. Both μ- and δ- opioid receptors were present in boar spermatozoa modulating sperm motility, as in vitro challenge with known agonists (μ: morphine; δ: DPDPE and κ: U 50488) and antagonists (μ: naloxone; δ: naltrindole and κ: nor-binaltrorphimine) showed that the μ-opioid receptor maintained or increased motility while the δ-opioid receptor mediated decreased motility over time. Finally, boar spermatozoa depicted dose-response effects on sperm kinematics and mitochondrial potential following in vitro challenge with 130 pharmacological drugs and toxic compounds as well as with eight known mito-toxic compounds. In conclusion, boar spermatozoa expressing functional water (AQPs-7 and -9) and ion (CatSper 1-4) channels as well as μ- and δ-opioid receptors are able to adapt to stressful environmental variations, capacitation and pharmacological compounds and drug components. Ejaculated sperm suspensions are easily and painlessly obtained from breeding boars, and are suitable biosensors for in vitro drug-induced testing, complying with the 3R principles of reduction and replacement of experimental animals, during early toxicology screening.
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Coleman, M. D. "The biochemical pharmacology and toxicology of anti-parasitic agents." Thesis, Aston University, 2004. http://publications.aston.ac.uk/21356/.
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Schnapp, Alaina M. "The Effects of Benzyl Alcohol on Developing Zebrafish (Danio rerio)." University of Toledo Health Science Campus / OhioLINK, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=mco1365083632.
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Aal-Aaboda, Munaf Sabah. "Glutamate Transporter 1 and Cystine-Glutamate Antiporter as Potential Targets for Attenuating Alcohol Consumption in Male P Rats." University of Toledo Health Science Campus / OhioLINK, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=mco1403010118.
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Alasmari, Fawaz Fayez. "Effects of Beta-Lactam Antibiotics on Cystine /Glutamate Exchanger Transporter and Glutamate Transporter 1 Isoforms as well as Ethanol Drinking Behavior in Male P Rats." University of Toledo Health Science Campus / OhioLINK, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=mco1435826676.
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McIntosh, Kyle Douglas. "Pharmaceutical applications and toxicity of extracted alkenones from marine Isochrysis algae." University of Toledo Health Science Campus / OhioLINK, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=mco1564780576118206.
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Duffin, Roger. "Molecular toxicology studies on the quartz hazard." Thesis, Edinburgh Napier University, 2003. http://researchrepository.napier.ac.uk/Output/2777.
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Silicon makes up almost 28% of the Earth's crust and within that crust, quartz (crystalline silica) is one of the most abundant minerals. Exposure to quartz can occur in a number of occupations, including the mining and construction industries in which respirable quartz particles are generated and become airborne. Inhalation of quartz can lead to the fibrosing lung disease silicosis and cancer. Silicosis has been recognised for many decades as one of the most prevalent occupational lung diseases. In 1997, an IARC working Group classified quartz as a class 1 lung carcinogen, but only in some industries, suggesting that the quartz hazard is a variable entity. The reactivity of the quartz surface may underlie its ability to cause inflammation and treatments that ameliorate this reactivity would then reduce the quartz hazard. In the present study the effect of treating quartz with aluminium lactate, a procedure reported to decrease the quartz hazard, on the highly reactive quartz surface and on proinflammatory events in the rat lung were explored. Aluminium lactate-treated quartz showed a reduced surface reactivity as measured by electron spin resonance. Eighteen hours post-instillation of quartz into the rat lung, there was massive inflammation as indicated by the number of neutrophils in the bronchoalveolar lavage (BAL) and an increase in BAL macrophage inflammatory protein-2 (MIP-2). However, aluminium lactate-treated quartz had no significant effect when compared to control. Epithelial damage as indicated by BAL protein and gamma glutamyl transpeptidasea lso increased with quartz instillation but not with aluminium lactate-treated quartz and furthermore, quartz induced an increase in MIP-2 mRNA content of BAL cells while aluminium lactate-treated quartz had no effect compared to controls. There was an increase in nuclear binding of the transcription factor nuclear factor-kappa B (NF-xB) in the quartz exposed BAL cells and again, no effect on nuclear NF-xB binding in BAL cells from aluminium lactate-treated quartz instilled rats. In addition, the effect of aluminium lactate and PVNO quartz treatment on DNA damage, cell cytotoxicity and particle uptake by A549 cells was assessed. DNA strand breakage, as produced by quartz at non-toxic concentrations, could be completely prevented by both coating materials. Particle uptake by A549 cells appeared to be significantly inhibited by the PVNO coating, and to a lesser extent by the aluminium lactate coating, demonstrating that respirable quartz particles induce oxidative DNA damage in human lung epithelial cells and indicating that the surface properties of the quartz as well as particle uptake by these target cells are important in the cytotoxic and genotoxic effects of quartz in vitro. Finally, the role played by surface area and specific reactivity in the acute inflammatory response to particles was investigated. Acute inflammatory response following instillation of particles has been used to evaluate hazard but has been criticised because of the non-physiological delivery and the problems of local overload. Here, a number of low toxicity dusts of various particle sizes were instilled and the neutrophil influx into the lung 18-24 hours post-instillation assessed. The extent of inflammation was shown to be a function of the surface area instilled and ultrafine particles, which present a case of high surface area per unit mass, were inflammogenic pro rata with their surface area. There is no evidence that ultrafine particles of carbon black, titanium dioxide or polystyrene have any special reactivity in addition to their large surface area. We further tested whether this approach could be used to model the reactivity of highly toxic dusts. Rats were instilled with either quartz or aluminium lactate-treated quartz and, as anticipated, the high specific surface reactivity of quartz meant that it was much more inflammogenic than was predicted using the relationship described for `low toxicity' dusts. This approach represents the possibility of modelling potential toxicity for nuisance dusts based on the inflammatory response of a given instilled surface area dose.
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Israel, Davelene Davinah. "Differential Signaling and Gene Regulation Among Three Human EP3 Prostanoid Receptor Isoforms." Diss., The University of Arizona, 2008. http://hdl.handle.net/10150/196148.
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Prostaglandin E2 (PGE2) is a hormone derived from the metabolism of arachidonic acid whose functions include regulation of platelet aggregation, fever and smooth muscle contraction/relaxation. PGE2 mediates its physiological and pathophysiological effects through its binding to four G-protein coupled receptor subtypes, named EP1, EP2, EP3 and EP4. The EP3 prostanoid receptor is unique in that it has multiple isoforms generated by alternative mRNA splicing. These splice variants display differences in tissue expression, constitutive activity and regulation of signaling molecules. To date there are few reports identifying differential activities of EP3 receptor isoforms and their effects on gene regulation.We generated HEK 293 EBNA cell lines expressing the EP3-Ia, EP3-II, or EP3-III isoforms. After confirming the functional expression of each of these isoforms, we examined their activation of cellular signal transduction pathways.We found that each of these isoforms utilize distinct mechanisms to regulate ERK 1/2 phosphorylation and that these differences lead to unique regulation of the downstream effectors ELK-1 and AP-1. We also found MAPK dependent differences in regulation of cell proliferation. The EP3-III isoform increases cell proliferation in a MAPK dependent manner while the EP3-Ia dose dependently regulates cell proliferation via Gαi and not ERK 1/2. Activation of the EP3-II receptor had no effects on cell proliferation.To study differential gene regulation by these three EP3 receptor isoforms, we conducted microarray studies. Over 300 genes were differentially regulated by these isoforms. Quantitative real-time PCR analysis was used to validate 15 candidate genes. Five genes were chosen for further analysis of protein expression using immunoblotting, but only one of these, WT-1, was significantly increased following treatment with PGE2. WT-1, a transcription factor important for kidney and heart development, was strongly upregulated by PGE2 stimulation of the EP3-II receptor, but only weakly by the other isoforms.In conclusion, these studies show that the human EP3 prostanoid receptor isoforms are capable of distinct regulation of both signal transduction pathways and gene transcription. Elucidating the differential functions of EP3 receptor isoforms may allow for greater understanding of the diverse functions attributed to this receptor and their physiological functions.
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Wu, Tongde. "Post-Transcriptional Regulation of Nrf2: Novel Mechanisms beyond Keap1." Diss., The University of Arizona, 2013. http://hdl.handle.net/10150/301750.
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Nrf2 (NF-E2-related factor 2) is a transcription factor that regulates a battery of downstream genes that contain the antioxidant response element (ARE) in their promoter regions, including intracellular redox-balancing proteins, phase II detoxifying enzymes, and transporters. These Nrf2-dependent proteins work in collaboration to protect against many diseases where oxidative stress plays an essential role in disease onset and progression. Consequently, it is imperative to understand the basic molecular mechanisms of how Nrf2 is regulated so that this pathway can be targeted for disease prevention and treatment.Nrf2 is mainly regulated at the protein level by the ubiquitin proteasome system. Under basal conditions Nrf2 is constantly ubiquitinated by the Keap1-Cul3-E3 ubiquitin ligase complex and subsequently degraded by the 26S proteasome. Currently, regulation of the Nrf2-Keap1 pathway by ubiquitination is largely understood. However, other mechanism responsible for modulating Nrf2-ARE signal remains to be explored. This dissertation identifies three molecular mechanisms that are important in understanding how the Nrf2-Keap1 pathway is regulated: (i) In Chapter 2, KPNA6 was identified and characterized as a negative regulatory mechanism of the Nrf2 pathway, which mediates Keap1 nuclear import and represses the Nrf2-dependent antioxidant response at post-induction phase. (ii) In Chapter 3, I identified PARP-1 as a new transcription co-activator of Nrf2, which augments ARE-specific DNA binding of Nrf2 and enhances the transcription of Nrf2 target genes. This indicates a novel function of PARP-1 and reveals another layer of regulation of Nrf2. (iii) In Chapter 4, I demonstrated that XBP1 and SYVN1 are involved in regulating the Nrf2 pathway in a Keap1-independent mechanism. During ER stress, XBP1s upregulates transcription of SYVN1, which is an ubiquitin E3 ligase. SYVN1 accelerates the clearance of Nrf2 protein through promoting ubiquitination of Nrf2, and subsequent proteasomal degradation. Moreover, we observed an inverse correlation between XBP1s/SYVN1 and Nrf2 expression in the end stage alcoholic cirrhosis liver samples, implying a pathological role of ER stress-oxidative stress crosstalk. Taken together, these findings further our understanding of how the Nrf2-Keap1 pathway is regulated, providing novel targets of chemoprevention or chemotherapy.
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Qiao, Shuxi. "Pharmacological Modulation of Oxidative and Proteotoxic Stress for Antimelanoma Intervention." Diss., The University of Arizona, 2013. http://hdl.handle.net/10150/311348.
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Cumulative evidence suggests that constitutively elevated levels of proteotoxic stress represent a specific vulnerability of malignant cells that can be targeted by pharmacological modulation of the intracellular proteotoxic stress response. According to this emerging mechanism, small molecule stress modulators may induce deviations from protein homeostasis causing cytotoxicity confined to malignant cells already at a high set point of constitutive proteotoxic stress leading to functional impairment and even cell death. In contrast, normal cells with sufficient protein degradation capacity can tolerate the extra dysfunctional protein overload. My graduate research has focused on testing the feasibility of repurposing clinically used non-oncological drugs for experimental chemotherapy targeting metastatic melanoma cells. The following specific aims were pursued: (1) To identify clinically used non-oncological drugs that preferentially induce cytotoxicity in melanoma cells but not primary melanocytes through upregulation of proteotoxic and/or oxidative stress; (2) To explore the specific molecular mechanisms underlying induction of melanoma cell apoptosis by lead compounds focusing on oxidative and proteotoxic stress modulation; (3) To explore efficacy of selected lead compounds for antimelanoma intervention in a murine xenograft model. First, we demonstrate feasibility of using the FDA-approved redox-active D-cysteine-derivative D- penicillamine for chemotherapeutic intervention targeting human A375 melanoma cells in vitro and in vivo through induction of the unfolded protein response (UPR). Second, we demonstrate that the antimicrobial oligopeptide thiostrepton displays dual activity as a selective prooxidant and proteasome inhibitor causing proteotoxic stress that preferentially targets malignant melanoma and multiple myeloma cells. Third, we demonstrate for the first time that the clinically used 4-aminoquinoline antimalarial amodiaquine causes autophagic-lysosomal and proliferative blockade sensitizing human melanoma cells to starvation- and chemotherapy-induced melanoma cell death. Taken together, our data indicate the chemotherapeutic potential of small molecule proteotoxic stress inducers and strongly suggest feasibility of repurposing specific non-oncological drugs for proteotoxic stress-directed antimelanoma intervention.
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Sollome, James Jerome. "Heregulin Activates a Novel HER2/HER3-MTK1-GIT1/ERK1/2 MAPK Signaling Pathway." Diss., The University of Arizona, 2014. http://hdl.handle.net/10150/315554.
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Human MAP3K4 (MTK1) functions upstream of mitogen activated protein kinases (MAPKs). In the studies presented herein, MTK1 is shown to be required for human epidermal growth factor receptor 2/3 (HER2/HER3)-heregulin beta1 (HRG) induced extracellular acidification and cell migration in MCF-7 breast cancer cells. Furthermore, it was shown that HRG stimulation leads to association of MTK1 with tyrosine phosphorylated HER3 in MCF-7 and T-47D breast cancer cells. The MTK1/HER3 association was dependent on HER2 activation and was decreased by pre-treatment with the HER2 inhibitor, lapatinib. Furthermore, HER2 does not directly associate with MTK1, but phosphorylates HER3 transiently. MTK1 also has a role in the ERK1/2 MAPK signaling pathway in response to heregulin (HRG) stimulation in T-47D and MCF-7 breast cancer cells. In addition to MTK1, Shc, Grb2 and GIT1 proteins are all involved in the ERK1/2 MAPK pathway in response to growth factor stimulation. MTK1 was also shown to associate with activated ERK1/2, GIT1, Shc, Grb2 and p85 of PI3K in response to heregulin stimulation. ERK1/2 kinase activity is involved in aberrant signaling that leads breast cancer progression. GIT1 is a scaffolding protein that is linked to growth factor mediated ERK1/2 signaling in cell migration. Moreover, we also identify the actin interacting region (AIR) on MTK1 and disruption of actin cytoskeletal polymerization with cytochalasin D inhibited the interaction between HER3 and MTK1, indicating that f-actin (which is needed for cell migration) is required for the MTK1/HER3 association. Additionally, HRG stimulation leads to extracellar acidification that is independent of cellular proliferation. HRG induced extracellular acidification is significantly inhibited when MTK1 is knocked down in MCF-7 cells. Similarly, pre-treatment with lapatinib significantly decreased HRG induced extracellular acidification. Extracellular acidification is linked with cancer cell migration. We performed scratch assays that show HRG induced cell migration in MCF-7 cells. Knockdown of MTK1 significantly inhibited HRG induced cell migration. Furthermore, pre-treatment with lapatinib also significantly decreased cell migration. Cell migration is required for cancer cell metastasis, which is the major cause of cancer patient mortality. We identify MTK1 in the HER2/HER3-HRG mediated extracellular acidification and cell migration pathway in breast cancer cells.
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Alamri, Mohammed A. "Syntheses and Evaluations of Bicycloheptylamines and Cyclohexylamines as Sigma-2 Receptor Ligands and Their Potential as Anticancer Agents." Thesis, University of the Sciences in Philadelphia, 2017. http://pqdtopen.proquest.com/#viewpdf?dispub=10631480.
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Sigma-2 receptors are a new target in cancer research. These receptors tend to be overexpressed in cancers compared to normal tissue, this expression is also high during proliferation. Fluorescent and radio-labeled sigma-2 receptors show increased uptake in tumors, and this uptake seems to be largely endocytotic. Many sigma-2 receptor ligands demonstrated anticancer properties either as sole treatments or adjunct therapies where they act as chemosensitizers that increase the activity of DNA-targeting drugs. Some sigma-2 receptors ligands have been utilized as cancer-selective, cargo-delivering moieties, showing potent cytotoxicity both in vitro and in vivo with minimal off target toxicity.
In this research, we synthesize sigma-2 receptor ligands based on previously discovered bicycloheptyl- and cyclohexylamines with high selectivity and affinity towards the sigma-2 receptors. The new novel ligands fall into two categories, fluorescent sigma-2 ligands, and doxorubicin-conjugated ligands. The compounds were synthesized, purified and analyzed in our laboratory. after which they were sent to the National Institute of Mental Health Psychoactive Drug Screening Program (NIMH-PDSP) where they underwent receptor binding studies to determine binding affinities on a panel of a 45 central nervous system receptors. The three synthesized fluorescent compounds displayed varying affinities to sigma-2 receptors ranging from high (32 nM) to medium (557 nM). Absorption and emission spectra for the fluorescent compounds were determined and showed consistency with other compounds in literature containing the same fluorescent moiety (NBD-chloride, i.e. 4-chloro-7-nitrobenzofurazan). Uptake into cancer cells (PANC-1, HT-29, and HCT-116 cells) known to express the sigma-2 receptors was assessed. Results show that higher sigma-2 affinity translates into increased uptake into these cancer cells. The doxorubicin-conjugated ligands showed superior anticancer activity compared to either doxorubicin alone or in combination with another sigma-2 ligand. This effect was significantly reduced by using a pan-caspase inhibitor (Z-VAD-FMK). Furthermore, the higher affinity conjugate (22) (MA-28C) was more active than the low affinity one (25) (MA-30C). These two conjugated ligands where submitted to the NCI-60 Human Tumor Cell Line Screen program. The results showed that in eight out of the nine cell lines known to overexpress sigma-2 receptors, the high affinity conjugate was much more potent than doxorubicin at reaching LC50 (lethal dose to 50% of cells), while both drugs were mostly comparable in their IG50, and TGI concentrations (concentration that reduce growth by 50% and total growth inhibition concentration, respectively).
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Tillotson, Joseph, and Joseph Tillotson. "Targeting Enzymes Involved in Protein Translation and Quality Control as Potential Cancer Therapeutics." Diss., The University of Arizona, 2016. http://hdl.handle.net/10150/621777.
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Activation of pathways resulting in an overexpression of oncoproteins, reliant on cap-dependent translation, or mutations of key proteins in a pathway can be advantageous to cancer cells but creates heightened protein quality control pressure. Because of this, there has been an interest in targeting enzymes involved in protein synthesis and protein quality control: such as the eukaryotic initiation factor, eIF4A, a DEAD-box RNA helicase involved in translation initiation, and p97, an AAA+ chaperone involved in protein quality control. Despite some successes in discovering both eIF4A and p97 inhibitors, many of these compounds have pharmacological setbacks. The work in this dissertation defines new inhibitors of eIF4A and p97 with unique mechanisms of action. As described in chapter 2, we demonstrated that a marine-derived sesquiterpene, elatol, can modulate the ATPase activity of eIF4A. We provide further evidence that this molecule inhibits cap-dependent translation. Because there is no clear consensus on the mechanism of action for elatol, we hypothesized that the mechanism of toxicity attributed to elatol is likely through inhibition of cap-dependent translation initiation by targeting eIF4A. In chapter 3, we adapted a colorimetric assay to identify natural products that modulate the ATPase activity of p97 from which withaferin A (WFA) was identified. Because proteostasis modulation can connect each of the reported modes of action of WFA, we hypothesized that the primary mode of cytotoxic action of WFA is through inhibition of protein quality control machinery. Through medicinal chemistry efforts, we were able to improve WFA's biochemical and cellular activities as well as shifting the activity toward p97 and away from the proteasome. The work described in chapter 4 reports that dehydrocurvularin (DHC) and its chlorinated analogs are covalent modifiers of p97 and that the selectivity toward p97 can be attributed, in part, to the electronic effects of the chlorines. Taken together, this work highlights the significance of targeting protein translation and quality control, by modulation of eIF4A and p97 activity respectively, as promising anticancer therapeutics.
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Hume, Wyatt Roderic. "Studies on the pharmacology and toxicology of materials applied to dentine /." Title page, contents and abstract only, 1988. http://web4.library.adelaide.edu.au/theses/09D/09dh922.pdf.
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MONTGOMERY, DAVID WESLEY. "IMMUNOLOGY, PHARMACOLOGY AND TOXICOLOGY OF THE IMMUNOSUPPRESSIVE CYCLIC PEPTIDE, DIDEMNIN B." Diss., The University of Arizona, 1986. http://hdl.handle.net/10150/183982.
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Didemnin B (DB) is a seven amino acid cyclic polypeptide (NSC-325319), MW 1112, isolated from a Caribbean tunicate of the family didemnidae (Trididemnum genus). In vitro assays of murine splenic mononuclear cell (MNC) proliferation showed that DB potently inhibited the mixed lymphocyte reaction (IC₅₀ = < 10 pg/ml), concanavalin A (Con A; IC₅₀ = 50 pg/ml) and lipopolysaccharide (IC₅₀ = < 100 pg/ml) mitogenesis. Proliferation induced by phorbol esters, calcium ionophore and Con A were equipotently inhibited by DB, suggesting that the drug acts upon an intracellular pathway common to these mitogens. Since DB did not produce lymphocytotoxicity, nor inhibit ongoing DNA, RNA or protein synthesis at immunosuppressive concentrations, it was concluded that this agent may affect lymphocyte activation processes. Investigation of the mechanisms of DB action showed that it failed to alter interleukin 2 (Il-2) production by MNC in vitro. However DB was found to block binding of the hormone prolactin (PRL) to both human lymphocytes and a PRL-dependent cell line, the Nb 2 node lymphoma. As PRL plays an important regulatory role in the immune response, abrogation of PRL-MNC interaction may represent a site of DB immunosuppressive action. In vivo, DB demonstrated a potent, inhibitory effect upon alloantigen-driven proliferation in the murine graft-versus-host reaction but hemagglutinating antibody responses in mice to sheep red blood cells were strongly enhanced by DB treatment (4.6-fold). Further, DB treatment of mice in vivo was not bone marrow suppressive, but increased organ cellularity, ongoing DNA synthesis and circulating levels of lymphocytes and granulocytes. DB also exerted significant toxicity in vivo. High doses caused losses in body weight (18%) and mortality (20%), but no mortality occurred at doses of 0.1 mg/kg/day x 7 days. DB did not significantly alter indices of renal function but high dose treatment produced significant but reversible hepatotoxicity. DB also induced ornithine decarboxylase activity in various rat tissues, with adrenal > liver > kidney = spleen > thymus > heart. This correlated with increased organ to body weight ratios for liver and spleen, suggesting a trophic response of these organs to DB. The data presented here show that DB exerts potent inhibitory activity toward cell mediated immunity in vivo and in vitro suggesting that DB might also inhibit rejection of solid organ grafts. In addition, humoral responses and bone marrow function are markedly enhanced by DB treatment in vivo, suggesting that resistance to infectious organisms might be increased by this drug.
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Ruscoe, Julie Elizabeth. "The effect of disposition on the pharmacology and toxicology of antimalarials." Thesis, University of Liverpool, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.337126.
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Vander, Werf Karie. "Pharmacokinetics and pharmacodynamics of oral meloxicam tablets in healthy horses." Thesis, Kansas State University, 2013. http://hdl.handle.net/2097/15314.
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Master of ScienceDepartment of Clinical Sciences
Elizabeth Davis
The first aim of the current study was to investigate the pharmacokinetics of oral meloxicam tablets and the gastrointestinal and renal effects after a 14-day treatment period. Meloxicam was orally administered to six adult horses once daily at a dosage of 0.6 mg/kg for 14 consecutive days. Blood was collected prior to each administration and at 20 and 40 min, and 1, 2, 4, 8, 12, and 24 hours after administration on days 1, 7, and 14 for the determination of meloxicam plasma concentrations by mass spectrometry. In addition, trough samples were taken on days 3 and 10. Complete blood count, serum biochemical analysis, urinalysis, and gastroscopy were performed at baseline and conclusion of the investigation. Complete blood count, serum chemistry, and urinalysis results were unchanged through the study period. Gastroscopy scores were not significantly increased. The Cmax was 1.82 ± 0.80 µg/mL at Tmax 3.48 ± 3.30 hr on day 1, 2.07 ± 0.94 µg/mL at Tmax 1.24 ± 1.24 hr on day 7, and 1.81 ± 0.76 µg/mL at 1.93 ± 1.30 h on day 14 (p = 0.30). The mean half-life was 4.99 ± 1.11 h. The second aim of the study was to compare the analgesic effects and gastrointestinal and renal adverse effects of oral meloxicam tablets (0.6 mg/kg) to oral phenylbutazone tablets (4.4 mg/kg) orally once daily for 4 days in induced and naturally occurring lameness in adult horses. The study was performed on 4 healthy but lame adult horses. Complete blood count, serum biochemistry, urinalysis, and gastroscopy were performed prior to entrance to the study. Lameness was exacerbated in two horses using lipopolysaccharide (LPS; E. coli O55:B5) injected into the right metacarpophalangeal joint. The remaining two horses had Grade 3 or Grade 4 lameness due to naturally occurring laminitis. Meloxicam or phenylbutazone was administered to two horses each in a blinded, randomized manner once daily for four days. Lameness was evaluated using a pressure mat system and contact pressure, force, and stride length were evaluated at baseline and twice daily. Complete blood count, serum chemistry, and urinalysis were unremarkable for all four horses except one horse with an increased GGT. This horse experienced hepatic rupture secondary to amyloidosis the final day of the study. Gastric ulcer scores did not change during the study period. Phenylbutazone administration resulted in a greater response (force and contact area) in the right front and left hind limbs compared to meloxicam administration. There were not enough data points to evaluate the other two limbs. A third aim of the study was two-fold and first evaluated the effects of ex vivo stimulation of peripheral blood mononuclear cells (PBMCs) with LPS on cyclooxygenase (COX) messenger RNA (mRNA) expression. The second portion documented the effects of LPS-induced joint inflammation and treatment with non-steroidal anti-inflammatory drugs on the mRNA and protein expression of COX-2 in PBMCs. The results indicate that LPS upregulates COX-2 gene expression in PBMCs. Additionally, injection of LPS into the metacarpophalangeal joint increases both COX-2 mRNA and protein expression in PBMCs at 24 hours after injection. The relative expression of COX-2 after treatment with meloxicam or phenylbutazone indicates a stronger inhibition with phenylbutazone; however, further study with additional horses is needed. Pharmacokinetic analysis of the oral tablet formulation of meloxicam indicates the pharmacokinetics are similar to the oral suspension formulation. Meloxicam appears to be inferior to phenylbutazone in its analgesic properties for induced lameness and naturally occurring laminitis, however the small sample size used in the study makes interpretation difficult.
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Schumacher, Stephen A. "The pharmacokinetics and pharmacodynamics of intravenous magnesium sulfate in horses." The Ohio State University, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=osu1562104626668678.
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Locke, Sara Lindsey. "Effect of cytochrome P450 inhibition on pharmacokinetics and toxicity of diclofenac in chickens : unravelling toxicity in Gyps vultures." Diss., University of Pretoria, 2020. http://hdl.handle.net/2263/75858.
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The nonsteroidal anti-inflammatory drug (NSAID) diclofenac was responsible for the decimation of Gyps vulture species on the Indian subcontinent over the last two decades of the 20th century. For an unknown reason, Gyps vultures were extremely sensitive to diclofenac (LD50 ~ 0.1-0.2 mg/kg), with toxicity appearing to be linked to a metabolic deficiency, demonstrated by the long T1/2 (~12-17 h) and low Cl (0.0001-0.0002 L/h*kg). This was in striking comparison to other bird species such as the domestic chicken (Gallus gallus domesticus), where the LD50 is ~10 mg/kg, the T1/2 is ~1 h and the Cl values are ~0.1-0.2 ml/h*kg. The aim of this study was to determine if Cytochrome P450 2C9 (CYP2C9) homolog pharmacogenomic differences among avian species is driving diclofenac toxicity in Gyps vultures. For this evaluation, we exposed each of 10 CYP-inhibited (fluconazole) test group domestic chickens to a unique dose of diclofenac, centred on the LD50 of 9.8 mg/kg, as per OECD toxicity testing guidelines. The toxicity and pharmacokinetic results were compared to control group birds that received no fluconazole.
The birds showed typical clinical and post mortem signs of diclofenac toxicity; depression, lethargy and anorexia within 48 -56 h and visceral gout with varying degrees of nephrosis. Though no differences were noted in the LD50 values for each group (11.92 mg/kg in the CYP-inhibited test group and 11.58 mg/kg in the control group), the pharmacokinetic profile of the test group was suggestive of partial inhibition of CYP metabolism. This was evident in the geomean values for Cmax (0.61 vs. 0.41 ug/ml), AUClast (0.5 ug/ml*h vs. 0.4 ug/ml*h) and clearance (1.52 L/h*kg vs. 1.59 L/h*kg), despite CYP-inhibited birds at the two highest doses succumbing without a definable pharmacokinetic curve. In contrast both birds dosed at the two highest doses from the control group demonstrated high T1/2 and MRT values, consistent with expectations.
Evaluation of the metabolite peaks produced also suggested partial inhibition of CYP enzymatic metabolism in test group birds as they produced lower amounts of metabolites for one of the 3 peaks demonstrated and had higher diclofenac exposure. Furthermore, though the general trend was that birds that produced less metabolites and that died tended to be those dosed towards the higher end of the dose range, the results were not consistent. One bird in the test group, dosed at a much lower dose, exhibited very low metabolite production compared to birds in both treatment groups. This bird also exhibited pharmacokinetic data suggestive of metabolic constraint. These findings, coupled with the high variation in levels of metabolites produced across both treatment groups, indicates that there is a degree of natural variation in metabolism which is independent of dose in chickens, and which would also explain the higher LD50 in the chicken in comparison to the vulture.
This pilot study supports the hypothesis that CYP metabolism is varied among bird species and may explain the higher resilience to diclofenac in the chicken vs. Gyps vultures. Further studies using a larger sample size and a single dose of diclofenac may provide more conclusive results.Mini Dissertation (MSc)--University of Pretoria, 2020.
Paraclinical Sciences
MSc
Unrestricted
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Javanmard, Sahar. "Synthesis and pharmacology of site-specific cocaine abuse treatment agents." Diss., Georgia Institute of Technology, 2002. http://hdl.handle.net/1853/30952.
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Thurmond, Thane S. "Indomethacin Reduces Splenic Red Pulp Macrophage Populations in Female New Zealand White Rabbits." Digital Commons @ East Tennessee State University, 1995. https://dc.etsu.edu/etd/2807.
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In an effort to elucidate the mechanism by which indomethacin (IN) attenuates the stimulatory effect of estradiol (E$\sb2$) on rabbit splenic red pulp macrophages (RPM), thirty-nine female New Zealand White rabbits were divided into 10 groups: ovariectomized (OVX), OVX/IN at 0.1 and 5.0 mg/kg body weight (bw)/day; sham OVX (SOVX), SOVX/IN at 0.1 and 5.0 mg/kg bw/day; OVX/25 mg E2, OVX/25 mg E$\sb2$/IN at 0.1 and 5.0 mg/kg bw/day; intact Control. Quantitative changes in RPM population in response to the treatments were measured using a 0 to 4 histologic grading scale. Estradiol treatment resulted in increased RPM grade when compared to the OVX non-E$\sb2$ groups. Indomethacin addition decreased mean RPM grade in the SOVX/IN 5.0 group when compared to its E$\sb2$ control group. Indomethacin administration had no significant effect on levels of PGE$\sb2$ in the spleen, blood or urine (p $>$.05). Hematocrits were reduced in both OVX and OVX/E$\sb2$ groups and this decrease was exacerbated by the high IN dose. The results from this study suggest that the effect of IN on E$\sb2$-induced RPM activation may be mediated through a non-prostaglandin pathway. The observed hematocrit changes are possibly the result of direct action of IN and E$\sb2$ on erythrocytes. To further investigate whether a direct interaction of IN and E$\sb2$ with rabbit erythrocytes may be responsible for the decreases in hematocrit observed in vivo, an in vitro study was conducted to determine the effect of these drugs on erythrocyte fragility characteristics. Two ml aliquots of treated New Zealand White rabbit whole blood were assayed as; Control, IN (9.6 $\mu$g/ml), E$\sb2$ (500 pg/ml) and IN plus E$\sb2$, for changes in erythrocyte fragility. Osmotic (OF) and mechanical (MF) fragility were evaluated under approximate physiological conditions by measurement of hemoglobin release at 545 nm. Blood samples at 39.5$\sp\circ$C were assayed immediately after drug addition (initial) and again 4 hours after incubation (final). Eight replicates of each experiment were run. Results of the OF assays showed a significant increase (p $<$.05) in mean 50% hemolysis point between IN (final) and IN plus E$\sb2$ (final) when compared to their mean initial values and to the mean final Control value. The OF hemolysis dispersion was increased by IN and IN plus E$\sb2$ treatment when final values were compared to initial values. The mean final values for MF increased with IN, E$\sb2$ and IN plus E$\sb2$ treatment versus the mean final Control value (p $<$.05). While the increase in MF from IN was greater than that from E$\sb2$, the MF from the combination (IN plus E$\sb2$) was not greater than from IN alone (p $>$.05). The IN-induced increases in both OF and MF indicate a difference in degrees of interaction with the erythrocyte from that of E$\sb2$, which only affected MF and whose effect was not additive or synergistic with that of IN. The in vitro experimental results demonstrate that the increased fragility produced by IN and E$\sb2$ on rabbit erythrocytes may account for the observed in vivo reduction in hematocrit. Increased erythrocyte fragility would also lead to their accelerated clearance from the circulation by splenic RPM and subsequent increases in activity of these macrophages. This elevation in splenic RPM population may also be enhanced by direct E$\sb2$ stimulation of macrophage proliferation.
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ROSA, GUSTAVO A. B. "Estudo dos efeitos do fármaco propranolol para Ceriodaphnia silvestrii (Cladocera, crustacea) com ênfase em efeitos nas populações." reponame:Repositório Institucional do IPEN, 2008. http://repositorio.ipen.br:8080/xmlui/handle/123456789/11679.
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Made available in DSpace on 2014-10-09T12:54:40Z (GMT). No. of bitstreams: 0Made available in DSpace on 2014-10-09T14:07:21Z (GMT). No. of bitstreams: 0
Dissertação (Mestrado)
IPEN/D
Instituto de Pesquisas Energéticas e Nucleares - IPEN/CNEN-SP
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Vernetti, Lawrence Allen. "The effect of cyclosporine A on cytokeratin intermediate filament phosphorylation." Diss., The University of Arizona, 1991. http://hdl.handle.net/10150/185577.
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MCF7 cell cultures exposed to cyclosporine A (CsA) from 1-5 μM and from 0-48 hr have decreased viability and clonogenic ability. When these cells are examined by indirect immunofluorescence for cytoskeletal filaments, there is altered cell shape, but no alteration in microfilaments or microtubules. However, there is a collapse in cytokeratin intermediate filament arrays resulting in a peri-nuclear reorganization at 24-48 hr incubation (5 μM). When MCF7 cells are pre-treated in 5 μM CsA for 24 hr, and then placed in non-drug media for 12-24 hr, there is recovery of cytokeratin arrays and cell shape. Analysis of cytokeratin proteins by 2-D electrophoresis depict decreased phosphorylated proteins at 2-5 μM CsA (24 hr). CsA (1-5 μM CsA, 1-48 hr) inhibits phosphate content on cytokeratin protein to 35% levels on cytokeratin #8, and to 50% levels on cytokeratins #18, and #19. CsA decreases phosphate content on cytokeratin protein during incorporation, at steady state, and during turnover. Determinations of phosphate loss indicate that CsA increases turnover at greater levels than it inhibits incorporation, suggesting the activation of a phosphatase enzyme. CsA-induced decreased phosphorylation levels can be rescued by addition of 100 nM 12-o-tetradecanoylphorbol-13-acetate (TPA), but not upon addition of 50 μM forskolin. This indicates a CsA-sensitive protein kinase C site on cytokeratin protein. An in vitro urea assay was utilized to examine assembly and disassembly or cytokeratin protofilaments. CsA (5 μM, 48-72 hr) does not alter assembly of cytokeratin protofilaments from monomeric proteins. Analysis of disassembly of protofilaments into monomeric units resulted in CsA-induced (5 μM, 48-72 hr) inhibition of disassembly. Regulation of phosphorylation may therefore be important in the assembly and disassembly of cytokeratin filaments, and a resistance to disassembly may indicate a CsA interaction that is toxic to the cell.
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Gunawardhana, Lhanoo. "The role of metabolic activation and oxidant injury in the hepatotoxicity of 1,2-dichlorobenzene in the rat." Diss., The University of Arizona, 1992. http://hdl.handle.net/10150/186039.
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1,2-Dichlorobenzene (1,2-DCB) is a potent hepatotoxicant in the Fischer-344 (F344) rat. Phenobarbital (PB), a known inducer of cytochrome P-450, enhanced the metabolism and covalent binding of 1,2-DCB in F344 rat liver microsomes. Identification of 2,3-dichlorophenol, 3,4-dichlorophenol and dichlorobenzene dihydrodiol indicated the formation of dichlorobenzene epoxides in PB induced microsomes. Moreover, modulation of microsomal metabolism and covalent binding using glutathione, trichloropropene oxide, ascorbic acid and superoxide dismutase implicated quinones as the major covalent binding species of 1,2-DCB. These findings indicate that 1,2-DCB is activated by cytochrome P-450 to reactive intermediates that may initiate hepatocellular injury. The hepatotoxicity of 1,2-DCB was also studied in normal F344 rats administered methyl palmitate (MP) to inhibit Kupffer cell function or superoxide dismutase (conjugated to polyethylene glycol, i.e. PEG-SOD) to scavenge superoxide anions. Both agents markedly reduced the severity of 1,2-DCB induced liver injury in normal rats. However, MP and PEG-SOD did not inhibit the PB potentiated hepatotoxicity of 1,2-DCB. In summary, the data presented in this dissertation strongly support a role for Kupffer cell derived superoxide anions in the hepatotoxicity of 1,2-DCB in normal F344 rats. Since Sprague-Dawley (SD) rats are less susceptible to the hepatotoxicity of 1,2-DCB than F344 rats, markers of oxidant injury were assessed in both strains of rats following administration of 1,2-DCB. 1,2-DCB treatment did not deplete hepatic vitamin E in F344 or SD rats. However, 1,2-DCB treated F344 rats exhibited greater ethane exhalation than SD rats, at a time when differences in GSH depletion between the two strains were most prominent and prior to the initial appearance of toxicity in F344 rats. The results further confirmed the involvement of oxidative injury in the hepatotoxicity of 1,2-DCB. It is concluded that two key events are involved in the hepatotoxicity of 1,2-DCB (1) metabolism of 1,2-DCB by cytochrome P-450 to reactive intermediates that initiate cell injury (2) oxidative injury induced by Kupffer cell derived active oxygen species, that contributes to the progression of the injury.
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Brown, Alan Perry. "Generation and expression of halothane derived protein adducts in the guinea pig liver." Diss., The University of Arizona, 1993. http://hdl.handle.net/10150/186218.
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The volatile anesthetic halothane can be bioactivated in the liver to the reactive intermediate, trifluoroacetyl chloride, which is capable of covalently modifying liver protein. The product of this reaction is trifluoroacetyl-N-ε-amino lysine, which can act as a foreign epitope in altering both protein immunogenicity and antigenicity. Protein adduct formation appears to be responsible for the development of both an acute and an immune-mediated hepatotoxicity. The goal of this research project was to detect, quantify, and characterize the formation of protein adducts in the guinea pig liver, following exposure to halothane. This species provides the most accurate animal model for halothane hepatitis to date. An in vitro liver slice system was used to study the conditions for the production of protein adducts during halothane exposure. Covalent binding to slice protein occurred in a linear fashion over the time course of exposure, and was concentration dependent. Oxidative metabolism of halothane was required for adduct production. Adduct formation occurred to specific and identifiable proteins. The majority of the protein adducts in the liver slice were localized to cytosolic glutathione-S-transferase (GST). GST can be released from the liver slice, transporting the adduct to the extracellular environment. Guinea pigs were anesthetized with halothane to compare the results obtained in vitro, with what occurs in the whole animal. Covalent binding to liver protein occurred predominately in the microsomal fraction. The protein adducts identified in the guinea pigs corresponded to those seen in liver slices. GST was identified as a target for the acid chloride intermediate in the liver of these animals. Covalent binding to cytosolic protein was dependent on liver glutathione content. A specific relationship between adduct formation to cytosolic protein and glutathione concentration was further demonstrated using an in vitro bioactivation system. GST may catalyze the reaction between the electrophile and glutathione. Liver glutathione content appears to mediate the degree and selectivity of covalent binding to target proteins. The development of halothane induced hepatotoxicity may be related to the interactions between its reactive intermediate, glutathione, and GST.
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Mobley, Scott Alven. "Retinol activation of Kupffer cells: A mechanism for potentiation of chemically-induced liver injury." Diss., The University of Arizona, 1993. http://hdl.handle.net/10150/186234.
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The mechanism by which vitamin A (VA, retinol) potentiates the hepatotoxicity of carbon tetrachloride (CCl₄) in male Srague-Dawley rats was investigated. The toxicity of single and repeated doses of CCl₄ was potentiated in rats following VA treatment. CCl₄-induced hepatotoxicity was completely eliminated in control and VA-treated rats by 1-aminobenzotriazole, a cytochrome P-450 inhibitor, indicating that CCl₄ metabolism was necessary to achieve potentiation. To determine if VA-potentiated CCl₄ hepatotoxicity involves retinol activation of Kupffer cells (KC), various parameters were measured as indicators of KC function. In vitro assays using populations of KC demonstrated that phagocytosis and free radical release were increased in KC isolated from VA-treated rats. A novel electrooptical technique for measuring release of superoxide anion (•O₂-) from individual KC was developed. It was demonstrated that KC are a heterogeneous population, each responding separately to a common stimulus. To examine if the mechanism by which VA potentiates CCl₄ hepatotoxicity is common to model systems in addition to Sprague-Dawley rats, four separate mice strains were also tested. VA pretreatment dramatically protected against CCl₄ toxicity in each mouse strain tested. These data support the hypothesis that in rats, release of reactive oxygen intermediates from KC is intimately involved in the mechanism by which VA potentiates CCl₄ hepatotoxicity.
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Wild, Stacie Lynn. "Pyrrolizidine alkaloids: Hepatic metabolism and extrahepatic toxicity." Diss., The University of Arizona, 1994. http://hdl.handle.net/10150/186599.
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Pyrrolizidine alkaloids are proposed to be metabolized in the liver to reactive pyrrole species, or dehydroalkaloids. These reactive pyrroles are hypothesized to be responsible for pyrrolizidine alkaloid toxicity. This dissertation research has established that dehydroalkaloids are, in fact, metabolites of pyrrolizidine alkaloids. It was first determined that dehydromonocrotaline is produced during hepatic microsomal metabolism of monocrotaline and that it has the ability to bind in vitro with a synthetic thiol-containing resin, Thiopropyl Sepharose 6B. Similarly, synthetic dehydromonocrotaline binds to this resin. Dehydromonocrotaline was identified as a pyrrolizidine alkaloid metabolite based upon its resin cleavage products. When resin-bound pyrrole, synthetic or microsomally generated, was cleaved in a buffered, ethanolic silver nitrate solution, O⁷-ethyl dehydroretronecine was the major product, supporting the suggestion that the pyrrole generated by hepatic microsomes is dehydromonocrotaline. This system was then used to determine the formation of dehydroalkaloids from other pyrrolizidine alkaloids. These other alkaloids--trichodesmine, retrorsine, senecionine and heliotrine--cause toxicity to the liver as well as to extrahepatic organs. Their metabolism in this system reveals that alkaloids which produce extrahepatic toxicity have an increased percentage of reactive metabolites formed by phenobarbital-induced hepatic microsomes. Therefore, this system in vitro can be a good predictor of alkaloids which may produce extrahepatic toxicity in vivo. Trichodesmine is a pyrrolizidine alkaloid that is unique in its neurotoxicity. It is structurally similar to monocrotaline, yet it varies widely in its toxicity. It was determined that trichodesmine is more toxic in the rat than monocrotaline as indexed by LD₅₀ values. The distribution of pyrrolic metabolites reveals that trichodesmine treatment results in brain pyrrole levels 4 times higher than monocrotaline, retrorsine, or control. Histopathologic investigation of trichodesmine-treated animals reveals severe neuronal death in the cerebral cortex. These results suggest that neurotoxicity observed with trichodesmine is a result of pyrrole metabolites reaching the brain, thus providing further evidence for the involvement of pyrrole metabolites in pyrrolizidine alkaloid-induced extrahepatic toxicity.
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Collins, Stuart A. "3,4-methylenedioxy-methamphetamine(MDMA)-induced Increases in Hippocampal Glutamate Concentrations and Its Impact on the Dentate Gyrus." University of Toledo Health Science Campus / OhioLINK, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=mco1438598527.
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Poletti, Jabbour Jamil, Rospigliosi Andrés Wiegering, Elías Reneé Pereyra, and Barrera Carmen Cecilia Elías. "Carbamazepine and oxcarbazepine: reflections after an oxcarbazepine-induced Stevens-Johnson syndrome/toxic epidermal necrolysis overlap." Springer International Publishing, 2016. http://hdl.handle.net/10757/609483.
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Subhahar, Michael. "Pharmacokinetics and pharmacodynamics of some NSAIDs in horses : a pharmacological, biochemical and forensic study." Thesis, University of Central Lancashire, 2013. http://clok.uclan.ac.uk/9244/.
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Non-steroidal anti- inflammatory drugs (NSAIDs) have been in use for over 100 years to treat pain, exerting their analgesic effect by inhibiting prostaglandin (PG) synthesis via the COX pathway. Some of the NSAIDs have adverse side effects including ulceration of the stomach and cardiovascular events which are associated with bleeding. Search is still going on to find a safe NSAID. Two new coxib NSAIDs, namely celecoxib and etoricoxib have been developed and they exert marked beneficial effects in reducing pain in humans and other small animals with little or no side effects. No such study has been done on horses to see if they can tolerate the drug as an analgesic pain killer. This study was designed to investigate the effects of the two coxib NSAIDs, celecoxib and etoricoxib in six retired race horses to determine any adverse side effects of the drugs, the time course changes in their metabolism and elimination once administered orally in known physiological doses and the metabolites produced by each drug over time. The study employed well established clinical and biochemical techniques to measure blood-borne parameters and the metabolism of each drug. The results show that either etoricoxib or celecoxib had no adverse side effects on blood borne parameters and the stomach of the horses. Pharmacokinetic study following oral administration of 2 mg/kg b wt of either celecoxib or etoricoxib to the six race horses showed a Cmax of 1.15 ± 0.3 µg/ml, tmax, to be 4.09 ± 1.60 hr and a terminal half- life of 15.52 ± 1.99hr for celecoxib and a Cmax of 1.0± 0.09 µg/ml, tmax of 0.79 ± 0.1 hr and, terminal half- life of 11.51 ± 1.56 hr, respectively for etoricoxib. The results also show that each coxib is metabolized in the horse and both the parent drug and its metabolites are found in the urine, plasma and faeces. The results have also shown that even small traces of either drug or its metabolites can be measured in urine samples even 120 hours following oral administration. The main metabolites found in plasma, urine and faeces are hydroxyl celecoxib and carboxycelecoxib when celecoxib was administered orally to the 6 retired race horses. Similarly, hydroxymethyletoricoxib, carboxylic etoricoxib, hydroxymethyl-1-N-oxide metabolite of etoricoxib and hydroxymethyletoricoxib glucuronide were also found in plasma, urine and faeces following oral administration etoricoxib .to the animals. The results for either horse haeptocytes or camel liver show to some extend similar metabolites. In conclusion, the results show that both drugs have no adverse side effects in the horse and their metabolites are completely eliminated within 120 hours following oral administration.
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Keefer, Edward W. "Unique applications of cultured neuronal networks in pharmacology, toxicology, and basic neuroscience." Thesis, University of North Texas, 2001. https://digital.library.unt.edu/ark:/67531/metadc2797/.
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This dissertation research explored the capabilities of neuronal networks grown on substrate integrated microelectrode arrays in vitro with emphasis on utilizing such preparations in three specific application domains: pharmacology and drug development, biosensors and neurotoxicology, and the study of burst and synaptic mechanisms. Chapter 1 details the testing of seven novel AChE inhibitors, demonstrating that neuronal networks rapidly detect small molecular differences in closely related compounds, and reveal information about their probable physiological effects that are not attainable through biochemical characterization alone. Chapter 2 shows how neuronal networks may be used to classify and characterize an unknown compound. The compound, trimethylol propane phosphate (TMPP) elicited changes in network activity that resembled those induced by bicuculline, a known epileptogenic. Further work determined that TMPP produces its effects on network activity through a competitive inhibition of the GABAA receptor. This demonstrates that neuronal networks can provide rapid, reliable warning of the presence of toxic substances, and from the manner in which the spontaneous activity changes provide information on the class of compound present and its potential physiological effects. Additional simple pharmacological tests can provide valuable information on primary mechanisms involved in the altered neuronal network responses. Chapter 3 explores the effects produced by a radical simplification of synaptic driving forces. With all synaptic interactions pharmacologically limited to those mediated through the NMDA synapse, spinal cord networks exhibited an extremely regular burst oscillation characterized by a period of 2.9 ± 0.3 s, with mean coefficients of variation of 3.7, 4.7, and 4.9 % for burst rate, burst duration, and inter-burst interval, respectively (16 separate cultures). The reliability of expression of this oscillation suggests that it may represent a fundamental mechanism of importance during periods of NMDA receptor dominated activity, such as embryonic and early postnatal development. NMDA synapse mediated activity produces a precise oscillatory state that allows the study of excitatory-coupled network dynamics, burst mechanisms, emergent network properties, and structure-function relationships.
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Nylander, Martina. "The thrombin receptors PAR1 and PAR4 and their relative role in platelet activation." Licentiate thesis, Pharmacology, 2009. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-19958.
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Many blood cell mechanisms in the human body are working all the time to maintain haemostasis in the blood vessels. Once a wound arises platelets are alerted via different substances to cover the wound and prevent loss of blood. Most of the times these mechanisms do stop the blood, and further heal the wound. During other circumstances the platelet-covering continues to form a thrombus, preventing the blood to flow and instead causes myocardial infarction or stroke. There are several risk factors triggering development of circulatory diseases such as obesity, lack of exercise, smoking, infection and stress.
This thesis describes the interaction between the two platelet thrombin receptors PAR1 and PAR4, together with the interaction of the oral pathogen Porphyromonas gingivalis (with thrombin-like gingipains), and the cross talk with the stress hormone epinephrine and its α2A adrenergic receptor. Until now PAR1 is thought to be the most important thrombin receptor due to its high affinity for thrombin. From a phylogenetical and patophysiological point of view there must be a reason why platelets express two different thrombin receptors. Today PAR4 is considered less important, but this thesis implies that PAR4 plays an important role in platelet signaling and haemostasis.
The results show that bacteria pre-stimulated platelets, followed by epinephrine gives a strong and full aggregation and calcium mobilization, in both aspirinated and non-aspirinated human platelets. The amount of bacteria does not itself, or epinephrine alone give aggregation or calcium mobilization. This mechanism is dependent on both Rgp type gingipain released from P. gingivalis, and PARs in an interaction with the α2A adrenergic receptor.
Further, results reveal that PAR4 interacts and cross talks with the platelet α2A-adrenergic receptor in aspirinated platelets. Neither of the two platelet purinergic P2Y-receptors (P2Y12 and P2Y1) contribute to this action, but the purinergic P2X1 does. In aggregation studies a low dose of PAR4 activating peptide (AP), but not PAR1-AP, followed by epinephrine results in a strong aggregation and in a calcium mobilization. ATP secretion measurements did reveal that ATP was released during epinephrine stimulation, which indicate that ATP and P2X1 have a key role in this event. By blocking P2X1 both aggregation and calcium mobilization were abolished, but not by blocking P2Y12 and P2Y1. Inhibition of PI3-kinase, both epinephrine-induced calcium mobilization and aggregation were significant reduced. In non-aspirinated platelets PAR1 synergizes with the α2A adrenergic receptor and P2X1.
In conclusion, this thesis suggests that PAR4 plays an intriguing and important role in platelets with inactived cyclooxygenase 1. The results described in this thesis contribute to an increased knowledge of the platelet thrombin receptors.
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Gunter, Bryan. "Localization and Expression of GFRα2 Receptors in Neonatal and Adolescent Mouse Heart." Digital Commons @ East Tennessee State University, 2012. https://dc.etsu.edu/honors/134.
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Neurturin (NRTN), a member of the glial cell-line derived neurotrophic factor(GDNF) family, is required in the development of parasympathetic cholinergic neurons. It signals through binding to a glycosyl-phophatidyl inositol (GPI)-linked receptor, GDNF family receptor α2 (GFRα2), which couples to Ret tyrosine kinase. Studies of NRTN knockout mice have shown that NRTN is essential for normal cholinergic innervation of the heart, but the precise role of NRTN remains unknown. For NRTN to evoke a biological response, GFRα2 must be localized to the surface of target neurons. The aim of this study was to determine the expression and localization of GFRα2 at two developmental time points in the atria of mouse hearts, postnatal day (P)1 and P18. Atria were used because of their extensive cholinergic innervation, particularly at the sinoatrial node and the right atrium. By P21, neurons are adult sized and substantial growth of cholinergic nerve fibers has occurred; therefore, it was hypothesized that GFRα2 signaling would be higher in P1 neuronal fibers than in P18 fibers. Because NRTN only activates surface receptors, and once activated, internalization occurs, we further hypothesized that GFRα2 would be cytoplasm localized when treated with NRTN. Atria were analyzed for GFRα2 expression in cholinergic neurons by immunohistochemistry with and without Triton X-100, a cell membrane permeabilizing detergent, to visualize cytoplasmic localization in one group and cell membrane localization in the other. In an additional group, excised P1 atria were cultured in petri dishes with and without NRTN (400 ng/ml, 3h) to determine if GFRα2 was internalized in response to NRTN treatment. Stained atria were viewed using a fluorescence microscope, and digital images were collected using a confocal microscopy system. Within each age group, Triton X-100 treated tissues exhibited cytoplasmic localization within ganglia; however, P1 neurons had distinct membrane staining, whereas in the P18 model, the majority of the GFRα2 was localized to the cytoplasm. NRTN-treated P1 ganglia showed a substantial decrease in membrane localization in central cell bodies and an increase in localization in perimeter cell bodies compared to the non-NRTN group. The results from this study show that GFRα2 is extensively localized to the cell membrane in P1 cholinergic neurons and is primarily localized to the cytoplasm in P18 cholinergic neurons. NRTN treatments lead to internalization of GFRα2 and may lead to a better understanding of GFRα2 trafficking. These findings suggest that GFRα2 cellular localization may be increased in periods of elevated nerve fiber growth and may serve as a regulator of responsiveness to NRTN.
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Amann, Maria. "Anti-tumor activity, pharmacology and toxicology of EpCAM/ CD3-bispecific single-chain antibodies." Diss., lmu, 2009. http://nbn-resolving.de/urn:nbn:de:bvb:19-109478.
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Jodrell, Duncan Ian. "The pharmacology and toxicology of novel thymidylate synthase inhibitors, potential new anticancer agents." Thesis, University of Southampton, 1990. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.296525.
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