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1
Cuervo, Alfredo Carabot. „Chemical studies on steroidal sapogenin producing plants of Venezuela“. Thesis, University of Portsmouth, 1990. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.255340.
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2
Robinson, David Thomas. „The metabolism of trilostane and epostane“. Thesis, University of Surrey, 1989. http://epubs.surrey.ac.uk/847952/.
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Trilostane and epostane are synthetic steroids which inhibit the 3beta-hydroxysteroid dehydrogenase enzyme. This enzyme is part of a system which catalyses an essential step in the synthesis of biologically active steroids. In animals and man trilostane preferentially inhibits adrenal steroid synthesis whilst epostane inhibits placental/ovarian steroid synthesis. The synthesis of radiolabelled trilostane and epostane are described. Stability investigations showed these radiolabelled compounds to be susceptible to degradation, although trilostane less so than epostane. Careful handling procedures were essential for metabolism studies. Animal studies showed no difference in the overall excretion and distribution of radioactivity for [[14]Cl-trilostane and [[14]C]-epostane. However the site specific localisation of active components within adrenals and ovaries reflected the in vivo organ selectivity observed for these compounds. In man a major plasma metabolite of trilostane was shown to be 17-ketotrilostane which is intrinsically twice as active as parent compound with regard to 3beta-hydroxysteroid dehydrogenase inhibition. A specific, sensitive and accurate HPLC assay was developed which enabled the measurement of trilostane and 17-ketotrilostane in plasma. Plasma concentrations of 17-ketotrilostane in male volunteers were approximately three-fold higher than trilostane, and consequently this metabolite may be an important contributor to the clinical efficacy of this drug. Micronisation of both trilostane and epostane was shown to be appropriate in order to maximise the oral systemic availability of these compounds. However even with micronised formulations considerable inter-and intra-subject variability was noted. For trilostane, variability in absorption, coupled with individual differences in the metabolism to the more active 17-ketotrilostane, may in part account for the variable efficacy encountered in clinical trials.
3
Parmar, Rina. „The interaction of a model steroid with phospholipid structures“. Thesis, University College London (University of London), 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.265759.
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4
Barr, J. „Sex differences in drug and steroid metabolism in rat liver : Biochemical basis“. Thesis, University of Glasgow, 1985. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.379310.
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5
Fiandaca, Maggie. „Ionic Liquid Formation and Characterization of a Non-steroid Anti-inflammatory Drug“. Thesis, University of the Sciences in Philadelphia, 2020. http://pqdtopen.proquest.com/#viewpdf?dispub=22620871.
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The present work focuses on modifying a non-steroid anti-inflammatory drug (NSAID) into an ionic liquid and evaluating the resulting thermal behavior and structural changes of the drug. Naproxen was chosen as the NSAID molecule due to thermal stability and limited examples of its use as an ionic liquid in current literature. Lidocaine was chosen as the counterion based on a screening study of potential ionic liquid formers. The screening included both potential protic and aprotic formation and counterions were included with consideration to pKa, hydrogen bonding ability, molecular size, diffuse charge distribution and functional groups. Analytical techniques used to evaluate the counterions included high performance liquid chromatography (HPLC), differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA). Naproxen and lidocaine were then combined in varying molar ratios to determine the thermal behavior of the mixtures. The samples with equimolar, or higher, ratio of naproxen showed a phase which had a melting point of 82–85 °C. The DSC data was analyzed using a modified Tamman plot, resulting in the unexpected and previously unreported behavior of ionic liquid formation at a 2:1 molar ratio of naproxen to lidocaine, referred to as IL1 in this research. This stoichiometry was confirmed through Fourier Transformed Infrared (FT-IR) and nuclear magnetic resonance (NMR) spectroscopy methods. The samples that contained a higher molar ratio of lidocaine than naproxen, resulted in material more consistent with higher-order complex clusters. Further characterization of IL1 found that the material demonstrated behaviors of an ionic liquid, including weak intermolecular forces and at least partial ionization of the drug and counterion.
6
Modak, Subhendu Bhusan. „Plant physiological investigation on production of steroid drug yielding solanum viarum dunal available in North Bengal“. Thesis, University of North Bengal, 1992. http://hdl.handle.net/123456789/901.
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7
Skårberg, Kurt. „Anabolic-androgenic steroid users in treatment : social background, drug use patterns, and criminality“. Doctoral thesis, Örebro universitet, Hälsoakademin, 2009. http://urn.kb.se/resolve?urn=urn:nbn:se:oru:diva-6249.
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8
Soto, Laveaga Gabriela. „Root of discord : steroid hormones, a wild yam, peasants and state formation in Mexico (1941-1986) /“. Diss., Connect to a 24 p. preview or request complete full text in PDF format. Access restricted to UC campuses, 2001. http://wwwlib.umi.com/cr/ucsd/fullcit?p3023452.
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Thesis (Ph. D.)--University of California, San Diego, 2001.Vita. Accompanying videorecording (14 min. : sd., col. ; 1/2 in.) has title: Barbasco, la raíz de la discordia. Includes bibliographical references (leaves 248-266).
9
Spence, John Cochrane. „Mood changes associated with anabolic-androgenic steroid use in male bodybuilders“. Thesis, McGill University, 1991. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=60580.
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The present study described the daily moods of male bodybuilders who self-administered large doses of anabolic-androgenic steroids (AS) through a full cycle of steroid use. Male bodybuilders (N = 13) who had been self-administering AS for 2.5 to 12 years served as subjects and participated in a 14 to 16 week experience sampling procedure wherein brief mood questionnaires were filled out twice daily.Findings revealed that 11 of the 13 subjects experienced self-reported mood changes in association with AS use. In particular, 2 subjects (subjects 4 & 11) experienced quite dramatic changes in mood. It is concluded that there is much variability with regards to the psychological effects that humans may display in association with AS use.
Data are discussed in terms of the effects that AS use may have on mental health.
10
Pennington, Cody W. „The Academic Steroid: Nonmedical Use of Prescription Stimulants at a North Texas University“. Thesis, University of North Texas, 2014. https://digital.library.unt.edu/ark:/67531/metadc699893/.
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The goal of this study was to determine the extent, motivations, and justifications of nonmedical prescription stimulant use among the population at a large public university in the North Texas region. Participants consisted of 526 undergraduate students enrolled at the studied university during the spring and summer 2014 semesters. The findings of the study suggest that the nonmedical use by students was higher than the findings in much of the current literature, but was within the parameters established in the literature. The primary motivation for nonmedical use was academic in nature and was justified by moderation of nonmedical use to strategic academic times.
11
Ahlbom, Eva. „Neuronal and endocrine cells' susceptibility to physiologic and toxic stimuli : a study on the effects of steroid hormones /“. Stockholm, 2000. http://diss.kib.ki.se/2000/91-628-4278-1/.
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12
Flood, Lars. „Glucocorticosteroid therapy and steroid resistance in inflammatory bowel disease /“. Stockholm, 2004. http://diss.kib.ki.se/2004/91-7140-020-6/.
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13
Petersson, Maria. „Short- and long-term cardiovascular and behavioural effects of oxytocin : mechanisms involved and influence of female steroid hormones /“. Stockholm, 1999. http://diss.kib.ki.se/1999/91-628-3503-3.
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14
LURAGHI, ANDREA. „Rational drug design and synthesis of new steroid derivatives for the treatment of chronic heart failure“. Doctoral thesis, Università degli Studi di Milano-Bicocca, 2021. http://hdl.handle.net/10281/302116.
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L’insufficienza cardiaca è una sindrome di grande rilevanza clinica nella quale il muscolo cardiaco non è in grado di pompare il sangue efficacemente nel corpo. Per il trattamento dei pazienti si ricorre, principalmente, ai glicosidi cardiaci o digitalici come la digossina, che svolgono la loro azione inibendo la pompa Na+/K+ e, conseguentemente, aumentando la concentrazione del calcio, favorendo una migliore contrazione. Il calcio viene però accumulato in alte concentrazioni nella cellula provocando nei pazienti cronici aritmie che possono portare, comunque, alla morte del paziente.
Pertanto, lo scopo di questa tesi tesi è stato quello di sintetizzare nuovi candidati farmaci (drug leads) per il trattamento dell’insufficienza cardiaca che abbiano la stessa attività dei digitalici con indice terapeutico maggiore e minor tossicità, garantendo l’assenza di aritmie nei pazienti cronici.
Il disegno delle molecole realizzate durante il periodo di tesi è partito dalla struttura chimica della molecola istaroxime: questo composto è attualmente in fase clinica III come farmaco cardiaco. Istaroxime è in grado di inibire efficacemente la pompa Na+/K+ evitando, allo stesso tempo, la comparsa di aritmie grazie alla sua azione stimolante su SERCA-2°, una proteina di membrana in grado di sequestrare il calcio citosolico durante il rilassamento cardiaco. Lo studio dei metaboliti di istaroxime ha portato all’identificazione di una molecola in cui il gruppo amminico della catena sull’ossima è stato ossidato a carbossile. Questa molecola, cosiddetta “PST3093”, è in grado di attivare selettivamente SERCA-2a senza inibire, invece, la pompa Na+/K+.
Attualmente, questo composto costituisce l’unico candidato farmaco in grado di stimolare il rilassamento cardiaco evitando la comparsa di aritmie. Tuttavia, sia istaroxime che il suo metabolita presentano delle criticità legate alla presenza della funzionalità ossima, a cui è associata una componente genotossica nei trattamenti cronici.
Pertanto, sono stati sintetizzate due classi di molecole, la prima ispirata a PST3093 in cui il gruppo funzionale responsabile della tossicità è stato rimosso. Queste molecole sono caratterizzate da un innovativo meccanismo di azione, in grado di stimolare efficacemente e selettivamente la proteina SERCA2a. In questa sezione sono state identificate due molecole come possibili candidati farmaci con e si sta procedendo con il loro sviluppo clinico. Il loro meccanismo di azione unico e non noto in letteratura, rappresenta un passo avanti verso lo sviluppo di nuove terapie contro l’aritmia.
Nella seconda sezione, invece, i composti sintetizzati sono ispirati ad istaroxime. Qui, per evitare la degradazione dell’ammina primaria ad acido carbossilico, è stata costruita una libreria di composti caratterizzati dalla presenza di una ammina ciclica. In questa sezione i composti hanno dimostrato di possedere sia capacità inibitorie sulla pompa Na/K che stimolatorie su SERCA2a ma con minor potenza rispetto ad istaroxime. Tuttavia, questi composti non posseggono le tossicità intrinseca di istaroxime.
Per proseguire nello sviluppo di queste molecole, nella terza sezione, realizzata in collaborazione con la Maastricht University, un sistema di drug delivery è stato realizzato grazie a processi di elettrofilatura. L’analisi preliminare di sistemi modello ha portato all’identificazione di sistemi polimerici composti da nanofibre ad alto grado di allineamento capaci di rilasciare nel medio studiato piccole quantità di molecole nel tempo, capaci di espletare la loro azione farmaceutica a livello locale, diminuendo i rischi associati al metabolismo di istaroxime. Questa sezione rappresenta l’inizio di uno sviluppo tecnologico volto al miglioramento della azione di istaroxime senza modificarne la struttura chimica.Heart failure (HF) is one of the major causes of death in the world. Patients affected by HF presents a pathophysiological state in which the heart is not cable of pumping the blood efficiently in the body due to a loss of contractility of the myocardium, leading to a chronic condition in which oxygen and nutritional need of the body are not satisfied. The most important therapy involves inotropic agents, such as digitals glycosides, capable of improving the cardiac output. The most known digitalis glycoside is Digoxin extracted from Digitalis purpurea. Such compounds acts as inhibitor of the Na+/K+ pump, an active transporter capable of expelling Na+ from the cardiac cells introducing K+ against the natural gradient. The inhibition causes an accumulation of Na+ inside the cell. Sodium is so used from the Na+/Ca++ pump to introduce Ca++ inside the cell. The high concentrations of Ca++ accumulated inside cardiac cells induce contraction of the myocardium. However, digitalis compounds present a small gap between the active concentration and the toxic one. In fact, the over intracellular accumulation for long periods of Ca++ could leads to arrhythmic situations. At today is known only one compound able to stimulate a better contraction without causing arrhythmias, such molecule, called “Istaroxime”. Istaroxime is now under development for the treatment of acute decompensated heart failure. Detailed studies highlighted that a metabolite of Istaroxime, the so-called “PST3093”, acts as a pure activator of SERCA-2a, a protein able to sequestrate Ca2+ from the cytosol, without any action on Na+/K+ pump. PST3093 is the only example in the literature of a pure SERCA-2a activator, making an interesting case of study and a possible first in class drug. Despite the promising activity and the unique characteristic of this compound, there is still the main issue due to the genotoxicity of the carboxy-hydroxylamine formed after oxime degradation by metabolism. Within this thesis, the work can be roughly divided in three parts. In the first part, the work is focused on the development of stable derivatives of “PST3093”, able to maintain the unique stimulatory effect over Serca-2a but, at the same time, substituting the non-metabolically stable oxime. Two compounds were identified, and will be further developed as first-in-class drugs, able to efficiently stimulate the activity of Serca-2a with potential application as anti-arrhythmic drugs. The second section is focused on the creation of compounds inspired to Istaroxime, able to acts as Na+/K+ inhibitors and Serca-2a stimulator. Here we developed analogues of Istaroxime, lacking the risks associated to the oxime group. The third section was developed in MERLN institute of Maastricht University. In this part of the work was developed a drug delivery systems based on electrospun polymeric scaffolds, able to deliver locally the drug reducing its toxicity.
15
Monaghan, Amy Elizabeth. „The amino terminal domain of steroid hormone receptors as a novel drug target : identification of small molecule inhibitors“. Thesis, University of Aberdeen, 2016. http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?pid=230709.
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Steroid hormone receptors (SHRs) are well validated therapeutic targets in a number of diseases. Current therapies competitively antagonise the ligand binding domain (LBD), blocking activation of the receptor and downstream signalling pathways. However cross-reactivity can be seen amongst the antagonists of different SHRs eliciting unwanted side effects. Additionally the acquisition of resistance to current therapies in diseases such as prostate cancer limits their use. The amino-terminal domain (NTD) of SHRs provides an alternative target for antagonism by allowing potential therapies to block receptor transactivation and inhibit interactions with co-activator proteins. Reduced homology between different SHR NTDs also increases the specificity of drug interactions. However development of targeted therapies using rational drug design has been hindered by its intrinsically disordered structure. Establishing cell lines which stably express a SHR responsive reporter gene alongside variants of SHRs lacking the LBD provides a method by which small molecules specifically targeting the NTD of each receptor can be identified. This assay has been designed to overcome the barriers to drug discovery that are presented by an intrinsically disordered protein. The project follows the design, development, optimisation and implementation of a high throughput screening assay with the potential to identify novel small molecule inhibitors of SHRs. The applications of these inhibitors are highlighted throughout, with specific reference to their potential to inhibit the androgen receptor in prostate cancer.
16
Rutecki, Jared W. „Enhancing the Agenda: A Content Analysis of Weekly Magazine Coverage of Performance-Enhancing Drug Use in Competitive Athletics, 1986-2006“. Ohio : Ohio University, 2009. http://www.ohiolink.edu/etd/view.cgi?ohiou1241446015.
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17
Lu, Wen An. „Analysis of athletes' nutritional supplements for their content of IOC-banned anabolic agents and evaluation of the supplements' effect upon exercise endurance and urinary steroid profiles“. Thesis, University of Portsmouth, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.271388.
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18
Sudji, Ikhwan Resmala [Verfasser], und Michael [Akademischer Betreuer] Wink. „Bioactivity of Steroid and Triterpenoid Saponins: Influence on Membrane Permeability and Drug Absorption / Ikhwan Resmala Sudji ; Betreuer: Michael Wink“. Heidelberg : Universitätsbibliothek Heidelberg, 2015. http://d-nb.info/1180613902/34.
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19
Zghebi, Salwa S. „Crystal engineering, Bio Pharmaceutics and Cell biology of active pharmaceutical ingredient (drug) nanoparticles. Formation and cell interaction of hydrocortisone and prednisolone nanoparticles“. Thesis, University of Bradford, 2010. http://hdl.handle.net/10454/5183.
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Nanotechnology applications have emerged enormously in recent times. Of particular interest is that area that overlaps the areas of nanotechnology, biology and medicine: nanomedicine. One advantage of nanomedicines is it that it can be used as an enabling technology by pharmaceutical researchers and industry to overcome issues associated with the low bioavailability of hydrophobic drugs. In the first part of the current study, nanosuspensions of two of hydrophobic steroid drugs: hydrocortisone and prednisolone were produced. Nanosuspensions were prepared using a bottom-up approach: the anti-solvent precipitation method using microfluidic reactors. Surface modification was carried out on these nanosuspensions using cationic surfactants to obtain nanoparticles with different levels of surface positive charge as indicated by ¿-potential values. Dynamic light scattering (DLS) and transmission electron microscope (TEM) techniques were used to characterize the prepared nanoparticles. Powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC) were also used to characterize hydrocortisone nanoparticles. In the second part, cellular uptake of both coated and uncoated nanoparticles by HaCaT keratinocytes cell line was examined and indicated by quantifying the anti- inflammatory effect of nanoparticles on the LPS-induced inflammation. Also, TEM was employed to evaluate the cellular uptake of hydrocortisone nanoparticles. Results showed higher ant-inflammatory effect of coated nanoparticles over uncoated nanoparticles. Furthermore, the anti-inflammatory effect of coated nanoparticles was correlated to the degree of positive surface charge.Libyan government
20
Durkin, Keith F. „Anabolic steroid use among non-competitive male bodybuilders : an application of two theories of deviant behavior /“. Thesis, This resource online, 1992. http://scholar.lib.vt.edu/theses/available/etd-03302010-020622/.
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21
Awah, Edmund Kpabi. „Regulation of the indoleamines by sex steroids“. Thesis, Rhodes University, 1992. http://hdl.handle.net/10962/d1004114.
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Alteration of serum tryptophan leads to parallel alterations in brain tryptophan levels. Such changes in brain tryptophan levels has been shown to lead to mood disturbances. The primary enzyme responsible for altering serum tryptophan levels is the liver cytosolic enzyme, tryptophan pyrrolase. Activation of this enzyme is responsible for the enhanced catabolism of circulating tryptophan. The purpose of the present study was firstly to establish whether there is a link between sex steroids and tryptophan pyrrolase activity especially since sex steroids are also known to cause mood disturbances and secondly to determine the effects of sex steroids on brain indolamine metabolism. The results show that all three sex steroids induce the activity of tryptophan pyrrolase implying that they decrease serum tryptophan levels by the activation of tryptophan pyrrolase, thus making less tryptophan available for uptake by the brain. It was also shown that the sex steroids enhance the uptake of ¹⁴C-tryptophan by brain synatopsomes. In addition, the sex steroids influenced the pattern of metabolism of serotonin by organ cultures of rat pineal glands. It is possible that the sex steroids regulate the availability and uptake of indoleamines in the brain.
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Löfgren, Magnus. „Behavioral effects of female sex steroid hormones : models of PMS and PMDD in Wistar rats“. Doctoral thesis, Umeå universitet, Obstetrik och gynekologi, 2009. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-22557.
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Background Animal models can be used to mimic human conditions of psychopathology, and also as pre-clinical models to evaluate candidate drugs. With hormonal treatment it is possible to produce behavior in the rat which corresponds to the mental symptoms of pre-menstrual syndrome (PMS), and pre-menstrual dysphoric disorder (PMDD). PMS affects 25-30 % of all women in fertile age and 3-8% are diagnosed with the more severe condition PMDD. The cardinal mental symptoms are; irritability, mood-swings, depression, anxiety, fatigue, insomnia, difficulties with concentration and memory and learning difficulties. The symptoms of PMS/PMDD occur in the luteal phase in conjunction with increasing concentrations of progesterone (P4) and P4-metabolites. In anovulatory cycles the symptoms are absent. The hormones which produce the monthly reoccurring negative symptoms on mood are foremost the neuroactive metabolites; allopregnanolone (ALLO) and tetrahydro-deoxycorticosterone (THDOC). ALLO is produced by the corpus luteum, but can also be synthesized in the brain, both ALLO and THDOC can also be released from the adrenal cortex during stress. These steroids are active on the inhibitory GABA neurotransmitter system through the GABAA receptor, and the effects are similar to that of alcohol and benzodiazepines. These steroids have strong sedative and hypnotic effects. A paradox is that some individuals seem to react with negative mood on sex steroids while all fertile women have the cyclical steroid changes during the menstrual cycle. Some individuals are more sensitive to neuroactive steroids with influences of personality, heritability and stress factors. Aims The thesis aims were to develop pre-clinical animal models of PMS/PMDD and to investigate induction of ALLO tolerance, individual sensitivity to neurosteroids and the interactions between chronic social stress and neurosteroids. Methods In these studies male and female Wistar rats were used to test steroid hormone effects on learning and memory and behaviors analogous to negative mood symptoms. This was accomplished through hormonal treatment and a subsequent withdrawal period from P4 (P4) + estradiol (E2) (PEWD), or ALLO. To assess tolerance, memory and learning in the Morris water maze (MWM) was studied. Anxiety-like behaviors were tested with the elevated plus maze (EPM), open field test (OFT), and the intruder test (IT). The EPM or OFT was used to classify the rats as high or low responders on risk-taking and explorative behavior (HR/LR). For social ranking order assessment the tube test (TT) and food competition test (FCT) were used. Chronic social stress was accomplished through co-habituation with two older rats (chronic subordination stress). In female rats the estrous cycle followed using staining of vaginal smears. Concentration of corticosterone (CORT) was measured by radio-immuno-assay (RIA). Results In the MWM ALLO pre-treatment produced tolerance to the acute negative ALLO effects. Both male and female rats showed behavioral correlations between the EPM and OFT tests, and correlations were also seen in CORT levels. Individuals with the stable trait of high risk-taking and explorative behavior (HR) were more sensitive to PEWD induction of anxiety-like behavior. These animals also showed decreased CORT levels during withdrawal. Chronic subordination stress enhanced the response to PEWD on measures of locomotor activity and social anxiety-like behavior. Conclusions It is possible to induce tolerance to the negative ALLO effects on learning and memory. The animal models of anxiety-like behavior show an individual PEWD response profile where HR rats are more sensitive. Exposure to chronic social stress enhanced the PEWD response. Hence there are both inherent and environmental factors behind the behavioral response to steroid hormones in rats.Stress- och könshormoners verkningar på centrala nervsystemet
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Smith, Christine. „Efficacy and Safety of Pharmacological and Non-Pharmacological Interventions in Juvenile Idiopathic Arthritis: A Series of Systematic Reviews and Network Meta-Analyses“. Thesis, Université d'Ottawa / University of Ottawa, 2017. http://hdl.handle.net/10393/35744.
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There is little head-to-head evidence comparing interventions available for juvenile idiopathic arthritis (JIA). This review involved a series of systematic reviews and network meta-analyses (NMAs) to evaluate the comparative efficacy and safety of pharmacological and non-pharmacological interventions among patients with JIA. Outcomes were the American College of Rheumatology Pediatric 30 (ACR Pedi 30) (disease response), its six composite outcomes, pain relief, health-related quality of life, and physical and emotional functioning. There was some evidence that etanercept had greater reduction in the number of joints with active arthritis compared to abatacept for polyarticular-course JIA and that canakinumab had improved ACR Pedi 30 over rilonacept. Non-pharmacological interventions showed no significant results for efficacy but were safe overall. Most included studies were low-quality and many were excluded from analysis because of unclear reporting or no results for outcomes of interest. As more studies are conducted this will improve the estimates from the NMAs.
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Alame, Ghina. „Étude de la réversion du phénotype de Multi Drug Resistance (MDR) par de nouveaux dérivés stéroïdiens, in vitro sur des lignées cellulaires humaines et murines résistantes et in vivo par xénogreffes“. Phd thesis, Université Claude Bernard - Lyon I, 2009. http://tel.archives-ouvertes.fr/tel-00877481.
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La chimiorésistance des cancers est caractérisée par une résistance pléïotropique à de multiples médicaments. Ce mécanisme est en partie causé par la surexpression des transporteurs à "ATP binding cassette" (Pgp, MRP1, BCRP...). Les inhibiteurs connus de ces transporteurs comme la cyclosporine A, le vérapamil et le RU486 sont toxiques à doses élevées. Dans cette étude, de nombreux dérivés stéroïdiens synthétisés au laboratoire à base de progestérone ou d'acides biliaires ont été évalués pour leur capacité à inhiber les transporteurs ABC et plus spécifiquement les fonctions de transport par la Pgp ou la BCRP. Plusieurs de ces dérivés synthétisés se sont avérés capables de restaurer complètement la sensibilité des cellules résistantes d'une manière plus importante que la cyclosporine A in vitro. De plus, le meilleur des nos dérivés testés s'est avéré capable in vivo de diminuer significativement la progression tumorale de xénogreffe sur les souris et d'augmenter la durée de survie des souris. Cette étude a ainsi permis d'ouvrir la voie au développement de nouveaux dérivés stéroïdiens peu toxiques ayant la capacité d'inhiber le phénotype MDR et de restaurer la sensibilité des cellules cancéreuses vis-à-vis des agents chimiothérapeutiques utilisés, avec un perspective d'application clinique
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Nippe, Stefanie [Verfasser]. „Injectable drug delivery systems for steroids / Stefanie Nippe“. Berlin : Freie Universität Berlin, 2015. http://d-nb.info/1068809787/34.
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Wang, Wei-qing. „Prevention therapy on bone loss in asthmatic patients on high dose inhaled steroids /“. Hong Kong : University of Hong Kong, 1997. http://sunzi.lib.hku.hk/hkuto/record.jsp?B18540028.
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Ngulube, Thabale Jack. „The interaction of anti-malarial drugs and steroid hormone metabolism“. Thesis, University of Leeds, 1989. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.329825.
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Ventura, Ventanachs Verònica. „In vitro metabolism and drug-drug interaction potential of irosustat, a steroidal sulfatase inhibitor“. Doctoral thesis, Universitat de Barcelona, 2013. http://hdl.handle.net/10803/124483.
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Irosustat is a first-generation, irreversible, steroid sulfatase inhibitor currently in development for hormone-dependent cancer therapy. Its structure is a tricyclic coumarin-based sulfamate that undergoes desulfamoylation in aqueous solution, yielding the sulfamoyl-free derivative, 667-coumarin.
The first aim of the present work was to study the in vitro metabolism of irosustat, including its metabolic profile in liver microsomes and hepatocytes, the potential species differences, and the identification of the main metabolites. And the second aim of the present work was to predict potential drug-drug interactions between irosustat and possible concomitantly administered medications through the investigation in vitro of the enzymes participating in the metabolism of irosustat and its inhibition/induction potential with the main drug-metabolizing enzymes. The interaction of aromatase inhibitors in the in vitro metabolism of irosustat was also studied.
Irosustat was extensively metabolized in vitro, showing similar metabolite profiles among rat, dog, monkey, and humans (both sexes). In liver microsomes, the dog was the species that metabolized irosustat most similarly to metabolism in humans. Marked differences were found between liver microsomes and hepatocytes, meaning that phase I and phase II enzymes contribute to irosustat metabolism. Various monohydroxylated metabolites of irosustat and of 667-coumarin were found in liver microsomes, which mostly involved hydroxylations at the C8, C10, and C12 positions in the cycloheptane ring moiety. 667-Coumarin was formed by degradation but also by non-NADPH-dependent enzymatic hydrolysis, probably catalyzed by microsomal steroid sulfatase. The main metabolites formed by hepatocytes were glucuronide and sulfate conjugates of 667-coumarin and of some of its monohydroxylated metabolites.
The major cytochrome P450 enzymes involved in the transformation of irosustat were CYP2C8, CYP2C9, CYP3A4/5, and CYP2E1. Moreover, various phase II enzymes (UDP-glucuronosyltransferases and sulfotransferases) were capable of conjugating many of the metabolites of irosustat and 667-coumarin; however, the clinically relevant isoforms could not be elucidated.
Irosustat inhibited CYP1A2 activity in human liver microsomes through the formation of its desulfamoylated degradation product and metabolite 667-coumarin. CYP1A2 inhibition by 667-coumarin was competitive, with a K(i) of 0.77 μM, a concentration exceeding by only 5-fold the maximal steady-state concentration of 667-coumarin in human plasma with the recommended dose of irosustat. In addition, 667-coumarin metabolites enhanced the inhibition of CYP1A2 activity. Additional clinical interaction studies of irosustat with CYP1A2 substrate drugs are strongly recommended. 667-Coumarin also appeared to be a competitive inhibitor of CYP2C19 (K(i) = 5.8 μM) in human liver microsomes, and this inhibition increased with assessment in human hepatocytes. Inhibition of CYP2C19 enzyme activity was not caused by repression of CYP2C19 gene expression. Therefore, additional mechanistic experiments or follow-up studies with clinical evaluation are recommended. Irosustat neither inhibited CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2D6, CYP2E1, CYP3A4/5, or UDP-glucuronosyltransferase 1A1, 1A4, or 2B7 activities nor induced CYP1A2, CYP2C9, CYP2C19, or CYP3A4/5 at clinically relevant concentrations. Results from human liver microsomes indicated that no changes in irosustat pharmacokinetics in vivo are expected as a result of inhibition of irosustat metabolism in cases of concomitant medication administration or irosustat-aromatase inhibitor combination therapy with letrozole, anastrozole, or exemestane.Irosustat és un inhibidor irreversible de la sulfatasa esteroidal, de primera generació, actualment en desenvolupament per al tractament del càncer dependent d'hormones. Els objectius d'aquest treball van ser estudiar el metabolisme in vitro d'irosustat, incloent el seu perfil metabòlic en microsomes hepàtics i hepatòcits, les diferències entre espècies, així com la identificació dels principals metabòlits. I també predir les possibles interaccions fàrmac-fàrmac entre irosustat i possibles medicaments administrats de forma concomitant, a través de la investigació in vitro dels enzims que participen en el metabolisme de irosustat i el seu potencial d'inhibició / inducció dels principals enzims metabolitzants de fàrmacs. La interacció dels inhibidors de l'aromatasa en el metabolisme in vitro del irosustat també es va estudiar. Irosustat és extensament metabolitzat in vitro, mostrant perfils metabòlics similars entre rates, gossos, micos i humans (ambdós sexes). En microsomes de fetge, el gos va ser l'espècie que metabolitza irosustat de forma més similar al metabolisme en humans. 667-coumarin es va formar per degradació, però també per hidròlisi enzimàtica no dependent de NADPH, probablement catalitzada per la sulfatasa esteroidal microsomal. Es van trobar grans diferències entre els perfils metabòlics de microsomes hepàtics i de hepatòcits, significant que tant enzims de fase I com de fase II contribueixen al metabolisme del irosustat. Els principals metabòlits formats pels microsomes de fetge van ser monohidroxilats del irosustat i de la 667-coumarin, mentres que en hepatòcits van ser conjugats glucurònids i sulfats de 667-coumarin i d'alguns dels seus metabòlits monohidroxilats. Els principals enzims del citocrom P450 involucrats en la transformació del irosustat van ser CYP2C8, CYP2C9, CYP3A4/5, i CYP2E1. D'altra banda, diversos enzims de fase II (UDP-glucuronosiltransferasas i sulfotransferasas) eren capaços de conjugar molts dels metabòlits de irosustat i 667-coumarin, però, les isoformes clínicament rellevants no es van poden dilucidar. Irosustat inhibeix les activitats dels CYP1A2 i CYP2C19 en microsomes de fetge humà a través de la formació de 667-coumarin. Es recomanen estudis clínics addicionals d'interacció entre irosustat i substrats del CYP1A2. Pel CYP2C19, aquesta inhibició va augmentar amb l'avaluació en hepatòcits humans, tot i que no va ser causada per la repressió de l'expressió del gen CYP2C19. Per tant, es recomanen experiments mecanistics addicionals o estudis de seguiment amb avaluació clínica. Irosustat no inhibeix CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2D6, CYP2E1, CYP3A4/5, UGT1A1, UGT1A4 ni UGT2B7. Tampoc indueix CYP1A2, CYP2C9, CYP2C19 o CYP3A4/5, a concentracions clínicament rellevants. Els resultats dels microsomes hepàtics humans van indicar que no s'espera canvis en la farmacocinètica del irosustat com a resultat de la inhibició del seu metabolisme en els casos d'administració concomitant d’inhibidors de l’aromatase: letrozole, anastrozole, o exemestane.
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Davies, Neal Maynard. „Toxicokinetics of non-steroidal antiinflammatory drug-induced gastrointestinal damage“. Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1996. http://www.collectionscanada.ca/obj/s4/f2/dsk3/ftp04/nq22150.pdf.
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Esume, C. O. „Pharmacogenomics of non-steroidal antiinflammatory drug-induced gastrointestinal complications“. Thesis, University of Liverpool, 2016. http://livrepository.liverpool.ac.uk/3004654/.
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Over 30 million people worldwide use aspirin and other non-aspirin non-steroidal antiinflammatory drugs (NSAID) on a daily basis. It is estimated that over 25% of patients treated for arthritis with NSAIDs have experienced gastrointestinal (GI) complications that required hospital admission and 60% of deaths from adverse drug reactions (ADRs) are attributable to NSAID use. Significant non-genetic risk factors for the development of NSAID-related gastrointestinal complications include gender, H. pylori infection, and concomitant medications. Three genes (UGT1A6, PAI-1 and EYA1) with biological plausibility for roles in NSAID-related ulcers were analysed. Our analysis of genetic risk factors for NSAID-related GI complications in 1197 case-control subjects showed no association between a UGT1A6 polymorphism and NSAIDinduced GI toxicity (p=0.052). Furthermore, a meta-analysis of UGT1A6 studies confirmed that there was no association between NSAID-related GI complications and UGT1A6. The PAI-1 4G/5G polymorphism was also not associated with NSAID-related ulcers and bleeding (n=756), while the EYA1 rs12678747 single nucleotide polymorphism (SNP) was significantly (p<0.05, OR 1.52; 95% CI 1.21, 1.91) associated with binary ulcer status. In healthy volunteers, EYA1 gene expression in gastric biopsies was not related to the carriage of this SNP; this contrasts with the difference observed in patients with ulceration suggesting that there may be a SNP-disease interaction, which needs further study. EYA1 was found to be expressed in atypical gastrin secreting (AGS) cells, but the relative expression was significantly (p < 0.05) lower than in healthy human gastric epithelial cells and in renal cortical epithelial cells. Functional assays performed to explore the mechanism of NSAID-related gastric cell death and validate a plausible role for EYA1 in this process showed that there are multiple cell death pathways occurring concurrently in this cell model depending on the concentration of aspirin. At lower concentrations (10-20mM), PARP cleavage was observed suggestive of an apoptotic process, while at 50mM, necrotic cell death was the predominant mode of cell death. There was a significant (p < 0.05) concentration-dependent decrease in the caspase 3 and 7 activity in AGS cells despite a significant (p < 0.05) fall in the viability of the cells compared to the controls, suggesting that there is a role for non-caspase dependent mechanisms in the cell death. In summary, the thesis has focused on the clinical, molecular and functional aspects of peptic ulceration caused by NSAIDs (including aspirin). A novel pathway involving EYA1 has been investigated; this needs further work to define the exact mechanisms by which EYA1 leads to cell death and gastrointestinal injury in patients taking NSAIDs (including aspirin).
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Davis, Brian Robert. „Non-Steroidal Anti-Inflammatory Drug Use in Collegiate Athletes“. PDXScholar, 2015. https://pdxscholar.library.pdx.edu/open_access_etds/2477.
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Non-steroidal anti-inflammatory drugs (NSAID) are a class of medications used in the treatment of pain, inflammation, and illness. These medications are common, affordable, and easy to access. For these reasons, NSAIDs are commonly used by athletes of all backgrounds for treating injuries and as ergogenic aids. However, despite these behaviors, NSAIDs have well-documented side effects and the efficacious nature of these medications has been brought into question. Despite this, many athletes continue to use these medications frequently and indiscriminately. It is not known why athletes use these medications in light of their questionable effectiveness and cited adverse effects. Therefore, this study was designed to (1) further investigate the prevalence of NSAID use in collegiate-level athletes, (2) investigate attitudes and behaviors toward the use of NSAIDs cross-tabulated by sport, gender, and competition level, and (3) investigate athletes' general knowledge of NSAIDs.
Subjects for this study included 79 student-athletes (44 male; 25 female) attending Portland State University (PSU). The majority of the athletes started taking NSAIDs before high school (72% of the males and 64% of the females). Thirty-three percent of males and 32% of females reported that they had been taking NSAIDs within the past week. High in-season use of NSAIDs was reported by 52% of the male athletes and 48% of the female athletes, whereas off-season use was reported by 21% and 12% of the males and females, respectively. Cited reasons for NSAID use both in-season and off-season were relief of pain due to injury, prevention, recovery, soreness, and tightness. In total, 83% of males and 76% of females reported obtaining NSAIDs primarily through means other than health-care professionals. With regard to dosage, athletes reported taking NSAIDs based on product directions, instructions of an athletic trainer or perceived pain levels. An overwhelming majority of athletes (83% male; 76% female) were not aware of any side-effects from taking NSAIDs
In summary, this study revealed a pattern of high NSAID use in athletes competing in-season compared to a high prevalence of low NSAID use in athletes off-season. It also revealed a high prevalence of non-prescription NSAID use. Additionally, there was a high prevalence of self-purchasing of NSAIDs, combined with self-medication and a long history of NSAID use. This study also revealed a general lack of knowledge about NSAIDs.
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Mamelle, Elisabeth. „Réhabilitation des surdités de perception par des thérapies locales Hyaluronic acid liposomal gel sustains delivery of a corticoid to the inner ear Assessment of the efficacy of a local steroid rescue treatment administered 2 days after a moderate noise-induced trauma in guinea pig“. Thesis, Sorbonne université, 2019. http://www.theses.fr/2019SORUS576.
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Le développement de thérapies locales pour traiter les pathologies de l’oreille interne est un domaine de recherche majeur en otologie, permettant de s’affranchir des barrières anatomiques et d’obtenir une concentration efficace de substance active dans la cochlée. Dans ce but, une formulation de gel d’acide hyaluronique contenant des liposomes encapsulant une substance active, a été développée pour être administrée par voie transtympanique. Le phosphate de dexaméthasone (anti-inflammatoire) était utilisé pour démontrer l'intérêt de cette formulation. Nous avons montré que ce gel était capable d’assurer une libération prolongée de dexaméthasone jusqu’à 30 jours dans la périlymphe de cobaye, grâce aux liposomes qui formaient des réservoirs capables de franchir la fenêtre ronde. Chez le cobaye normo-entendant implanté cochléaire, l’injection peropératoire de gel contenant du phosphate de dexaméthasone permettait une meilleure préservation de l’audition à sept jours de la chirurgie, comparé au groupe témoin, sans substance active. En revanche, lorsque le gel de phosphate de dexaméthasone était appliqué 48 h après un traumatisme sonore, aucune récupération auditive supplémentaire n'était observée par rapport à la récupération spontanée de l’audition chez le cobaye. Au total, le gel d’acide hyaluronique contenant des liposomes est un bon candidat pour traiter les pathologies de l’oreille interne avec des concentrations efficacesLocal drug delivery to the inner ear is a promising treatment to ensure a sustained release of therapeutic agents into the cochlea bypassing its anatomic barriers. A hyaluronic acid gel containing liposomes that encapsulate a therapeutic agent was designed for transtympanic injection. Anti-inflammatory dexamethasone phosphate was the encapsulated drug selected to demonstrate the interest of this formulation. Therapeutic concentrations of dexamethasone were determined in perilymph of guinea pig 30 days after the local application. Liposomes acted as reservoirs, able to cross the round window membrane. In cochlear implanted guinea pigs, with normal hearing, when the dexamethasone gel was applied immediately after the cochlear implantation, better hearing thresholds were observed compared to the control group without drug. However, after an acoustic trauma, local dexamethasone gel, administered 48 h after the trauma, failed to improve the hearing compared to the spontaneous recovery. Finally, the hyaluronic acid gel loaded with liposomes is a good candidate to reach effective concentration of drugs for inner ear therapy
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Harmzen, Magdalena Adriana. „Overview of the prescribing patterns of non-steroidal anti-inflammatory drugs : 2004-2006 / Magdalena Adriana Harmzen“. Thesis, North-West University, 2008. http://hdl.handle.net/10394/3719.
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Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used for systemic control of acute and chronic pain and inflammation (Lin et ah, 2000:1129), but usage problems and side-effects that occur during the post-marketing phase of these drugs are well documented (Thiefin & Beaugerie, 2005:287). Following the demonstration of the value of anti-inflammatory therapy in diseases like rheumatoid arthritis (Boardman & Dudley Hart, 1967:268), new NSAIDs appeared on the market (Dieppe et al., 2004:867), and the indications steadily broadened from inflammatory diseases to almost any painful condition. Studies have indicated that NSAID-associated serious upper gastro-intestinal (GI) adverse events result in 103 000 hospitalisations (Bombardier, 2002:4) and 165 000 deaths per year in the United States.
A study in South Africa in 2002 indicated that NSAID utilisation contributed considerably to the total cost of all medicine items from a medicine claim database in the private health care sector (Joubert, 2002:260).
The objective of this study was to determine the prevalence and cost of non-steroid anti-inflammatory drugs in a section of the private health care sector, and specifically to determine the prevalence, usage and cost of Coxib (Specific cyclo-oxygenase-2 inhibitor) medicine items before and after the withdrawal of Vioxx® from the market in September 2004 (Merck, 2004).
Data from two medicine claim databases for the years 2004, 2005 and 2006 (medicine claim database I) and the years 2005 and 2006 (medicine claim database M), were analysed by means of a retrospective drug utilisation review (DUR) study. The usage of Coxib medicine items was determined, and compared for the periods before and after the withdrawal of Vioxx® in September 2004.
It was found that between 9 and 10.5 per cent of prescriptions dispensed through both medicine claim database I and medicine claim database M during the study period were NSAID prescriptions. NSAID medicine items on medicine claim database I represented between 3.9 % (R25 942 986) and 2.9 % (R8 073 034) of the total cost of all medicine items claimed from 2004 to 2006. NSAIDs represented 3.1 % (R58 290 412) and 2.8 % (R57 752 267) of the cost of all medicine items claimed through medicine claim database M during 2005 and 2006 respectively, indicating similar trends in the two medicine claim databases.
The prevalence of Coxibs on medicine claim database I decreased from almost 20 % (47 938) in 2004 to 8.4 % (13 276) in 2005, but showed an increase again to 10.9 % (12 355) in 2006. The prevalence of both cyclo-oxygenase (COX) inhibitors, and Coxibs demonstrated a change during 1 September 2004 to 31 December 2004 when COX-inhibitors showed an increase in use, while Coxibs showed and almost equal but opposite trend with a decrease in use. This could possibly be related to perceptions of providers and public with regard to Coxibs and their related safety after the withdrawal of Vioxx® on 30 September 2004 (Merck, 2004) and other Coxibs such as Bextra® (FDA, 2005) in 2005 in USA.
It is concluded that most patients who were using Coxibs before the withdrawal of Vioxx®, substituted Coxibs for COX-inhibitors, that are known for their possible gastro-intestinal side-effects.
Recommendations for future research regarding NSAID use were also made, and included an investigation of the usage of Coxibs in different age groups, as well as the combination of NSAIDs with gastro-protective medicines in long-term use.Thesis (M.Pharm. (Pharmacy Practice))--North-West University, Potchefstroom Campus, 2009.
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Ingram, Matthew John. „Nitroxylated non-steroidal anti-inflammatory drugs“. Thesis, Liverpool John Moores University, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.400526.
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Gregg, Catherine Nicola. „Structure-activity studies in non-steroidal anti-inflammatory drugs“. Thesis, Liverpool John Moores University, 1989. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.238686.
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Cheung, Wai-Han. „Novel steroidal metal complexes with potential pharmaceutical applications“. Thesis, Loughborough University, 1992. https://dspace.lboro.ac.uk/2134/27879.
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A study to develop novel lipophilic metal ion complexes based on dihydrocholesterol was undertaken. Steroid ligands functionalised at the 2- and 3- positions were synthesized as possible bidentate ligands for complexation of metal ions. Condensation of 5α-cholestan-3-one with ethyl formate in the presence of base gave 2-hydroxymethylene-5α-cholestan-3-one, and 2- acetyl-5α-cholestan-3-one was obtained by the reaction between 3- trimethylsilyloxy-5α-cholest-2-ene and acetyl chloride. Attempts to synthesize 2,3-dioximino-5α-cholestane from 5α-cholestan-3-one and 2α-hydroxy-5α-cholestan-3-one were unsuccessful. Likewise 2- methylene-5α-cholestan-3-one, which was expected to lead to other bidentate ligands, could not be prepared satisfactorily from 5α-cholestan- 3-one or 3-trimethylsilyloxy-5α-cholest-2-ene.
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王衛慶 und Wei-qing Wang. „Prevention therapy on bone loss in asthmatic patients on high dose inhaled steroids“. Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 1997. http://hub.hku.hk/bib/B31214691.
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Gros, Ludovic. „Sterol 24-methyltransferase as a drug target in parasitic protozoa“. Thesis, Cardiff University, 2005. http://orca.cf.ac.uk/55386/.
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In order to investigate further the mode of action of these compounds, synthesis of proteomic probes was attempted. Synthetic design and attempts are presented chapter VII. To establish whether there was 24-SMT present in the blood stream form of T. b. brucei, a Northern blot was carried out. This confirmed transcription of the enzyme which was then cloned, over expressed and purified (Chapter VIII). Enzyme assays were carried out against the recombinant enzyme.
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Khundker, Sharmin. „Theory of solvation and its application to the supercritical fluid extraction/supercritical fluid chromatographic analysis of pharmaceuticals“. Thesis, Northumbria University, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.245283.
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The roam objectives of this PhD project were to relate anal~ te solubility in supercritical carbon dioxide via molecular structure and also to investigate the factors that influence the solubility and extraction of analytes in a supercritical fluid extraction (SFE) when using carbon dioxide as the solvent. The polarity of an analyte was selected as the key parameter to developing a means of estimating steroid solubility in supercritical carbon dioxide. Polarity can be estimated by the hydrophobicity term, log P (based on partition coefficients), and also of the solubility parameter, 0,. The use of partition coefficient in conjunction with a calculated solubility parameter was demonstrated as a reasonable means of estimating steroid solubility in supercritical carbon dioxide. Experimental determination of the solubility of several steroid compounds with a range in polarities in supercritical carbon dioxide was carried out in order to correlate solute polarity to the solute solubility. A chromatographic method was also investigated based on capacity factor measurements for the prediction of steroid solubility in supercritical carbon dioxide. The application of supercritical fluid extraction (SFE) \\
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Butler, Gregory James. „Non-steroidal anti-inflammatory drugs and skin cancer /“. [St. Lucia, Qld.], 2005. http://www.library.uq.edu.au/pdfserve.php?image=thesisabs/absthe19122.pdf.
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Campbell, William I. „Pain suppression using non-steroidal anti-inflammatory drugs“. Thesis, Queen's University Belfast, 1989. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.335935.
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Duffy, Judith Clare. „Design of novel non-steroidal anti-inflammatory drugs“. Thesis, Liverpool John Moores University, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.521744.
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Abu-Omar, Ghada M. „Drug interactions and metabolism of cyclosporin A and steroids by human liver microsomes in vitro“. Thesis, University of Aberdeen, 1992. http://digitool.abdn.ac.uk/R?func=search-advanced-go&find_code1=WSN&request1=AAIU545502.
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1) The purpose of this work is to study the enzymology of cyclosporin A (CsA) metabolism by human liver in vitro , in particular investigating the basis for interindividual variations and drug interactions involving CsA metabolism, and to apply this knowledge to the development of a non-invasive test for predicting an individual's ability to metabolise CsA in vivo . The ultimate aim is to help to improve CsA therapy by understanding the factors which determine its metabolism in patients. 2) Human liver microsomes metabolised cyclosporin A (Km 25M) to eight identifiable metabolites, which were detected following incubation with [3H]-CsA in the presence of NADPH and aerobic O2. An interindividual variation in the generation of CsA metabolites was also observed. In addition, the formation rates of primary and secondary CsA metabolites were induced to different extents by 2 and 4 fold respectively, in liver microsomes prepared from patients treated with anticonvulsant treatment. Metabolite M1 formation was also induced by anticonvulsant treatment. 3) A significant correlation was observed between the total rate of CsA metabolism and cytochrome P-450IIIA concentration as measured by Western blot analysis, in 9 human liver microsomal preparations; 6 were obtained from untreated individuals and 3 from anticonvulsant-treated patients. This correlation was also present when the primary and the secondary metabolite profiles were considered separately. The kinetics of CsA metabolism by human liver microsomes demonstrated different Km and Vmax values for the formation rates of primary and secondary CsA metabolites. This suggests the possible involvement of two enzymes within the P-450IIIA family, responsible for the formation of primary and secondary metabolites, respectively. 4) Anti P-450IIIA antibodies inhibited the total rate of CsA metabolism in microsomal preparations from anticonvulsant-treated patients but to a lesser extent than those from untreated individuals. This suggests an involvement of other form(s) of P-450in CsA metabolism, responsible for between 20-30&'37 of CsA metabolic activity in human liver microsomes. However, these are unlikely to be P-450IIB1, P-450IA1 or P-450IIC, as none of the antibodies raised against these P450s significantly inhibited the metabolism of CsA. 5) From induction, inhibition and correlation studies, cytochrome P-450IIIA has been confirmed as being responsible for the major part of CsA metabolism in human and rat liver microsomes.
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Omile, Clement Ibe. „Analysis and pharmacokinetics of non-steroidal anti-inflammatory drug combinations in man“. Thesis, University of Strathclyde, 1988. http://oleg.lib.strath.ac.uk:80/R/?func=dbin-jump-full&object_id=21283.
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High Performance Liquid Chromatographic methods for quantifying 11 commonly used non-steroidal antiinflammatory drugs in serum were developed. Rapid, specific and sensitive adaptations of the methods were achieved by extraction with chloroform : acetonitrile 3:2 or diethylether : n-hexane 1:1 , giving recoveries of 85-98 %. The methods were used to study the in-vivo kinetic properties of aspirin in healthy volunteers when aspirin (652mg) was taken alone (I), with paracetamol (l000mg) (II) or with indomethacin (l00mg) (III) The salicylate absorption rate for I was 0.75 ± 0.03 hr⁻¹ (mean ± S.E.M) but for II the absorption rate was 0.99 ± 0.03 hr⁻¹; for III the absorption rate was 1.14 ± 0.05 hr⁻¹.These constants for II and III were different (p = 0.05) from that for I but not from each other. Statistically significant differences were not found between other pharmacokinetic parameters viz: (mean ± S. E. M. ) I II II Distribution Volume ( L ) 8.60 ± 0.79 : 7.97 ± 0.57 : 7.27 ± 0.45 : Rate (hrp-1s) blood to tissue 0.07 ± 0.02 : 0.11 ± 0.02 : 0.23 ± 0.03 : Tissue to blood 0.15 ± 0.01 : 0.20 ± 0.02 : 0.23 ± 0.03 : Elimination rate (hr⁻¹) Pseudodistribution ( body) 0.08 ± 0.01 : 0.08 ± 0.01 : 0.09 ± 0.01 : Central compartment (plasma) 0.12 ± 0.01 : 0.13 ± 0.02 : 0.13 ± 0.01 Relating the findings to changes in electropotential differences across the gastric mucosa it is apparent that a reduced gastric mucosal distribution of aspirin with an increased intestinal mucosal transport of aspirin when combined with paracetamol or indomethacin confer protective effect on the gastric mucosa.
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Lara, Diana. „Cationic steroid antibiotics as potential chemotherapeutic agent against Trypanosoma cruzi and Leishmania major“. To access this resource online via ProQuest Dissertations and Theses @ UTEP, 2007. http://0-proquest.umi.com.lib.utep.edu/login?COPT=REJTPTU0YmImSU5UPTAmVkVSPTI=&clientId=2515.
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Dunagan, Fiona M. „Non-steroidal anti-inflammatory drugs : pharmacokinetics and clinical response in rheumatoid arthritis“. Thesis, University of Glasgow, 1986. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.236497.
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Gill, Julie C. „An investigation of potential steroidal carcinogens“. Thesis, Loughborough University, 1988. https://dspace.lboro.ac.uk/2134/11091.
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Various potential metabolites of steroids with alkylating properties were synthesised, with important cellular in order that their reaction constituents and their mutagenicity could be investigated by Dr. Grover of the Chester Beatty Research Institute. Promising compounds were also investigated by Dr. Traynor, of Loughborough University, as part of an ongoing project to find selectively toxic compounds to estrogen dependant tumours.
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Goold, Richard David. „Influence of endogenous female sex-steroids on mutagen metabolism“. Thesis, Rhodes University, 1985. http://hdl.handle.net/10962/d1004919.
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Cytochrome P-450, the terminal oxidase of the metabolic mono-oxygenase system, is thought to exist in multiple forms, which have differing substrate specificities, and are variably inducible by different enzyme inducers. Many mutagens, themselves unreactive, require metabolic activation by one or more of these cytochrome P-450-dependent microsomal enzymes for mutagenic activity. Such mutagens may be detected in the Salmonella mutagenicity test only by the incorporation of an hepatic microsomal (59) fraction into the assay (as a first approximation to in vivo metabolism). Induction of the microsomal enzymes by different agents enhances the metabolic activation of mutagens; in fact, many mutagens are only detected when the 59 fraction has been induced by appropriate agents. Inducers of the phenobarbital-type are known to enhance microsomal steroid hydroxylation when administered at supraphysiological levels, inducers of several mono-oxygenase activities. In turn, the steroids, have been reported to be The inductive effects of the female sex-steroids and the combined effects of steroid and phenobarbital (PB) pretreatment on the metabolic activation of four mutagens have been investigated using the Salmonella assay. Female Sprague-Dawley rats were pret reated with 17a-oestradiol (E2) or progesterone (PRG) , at a level of either 1 mg/kg or 20 mg / kg daily for 14 days. A duplicate set of similarly pretreated groups were also induced with PB. Hepatic microsomal fractions were prepared from each group and incubated with each of the te st mutagens in the presence of a tester strain known to detect each particular type of mutagen. Induction of the hepatic metabolizing system by PB increased the activation of the mutagens significantly (as reflected by an increased number of revertant prototrophic S .typhimurium colonies). The administration of PRG also caused significant, and dose-dependent, induction of the activation of af l atoxin B1, benzo(a)pyrene, and dimethylnitrosamine. In general, E2 exhibited no inductive effect, but it did produce an increase in the activation of aflatoxin B1 (a reaction which is known to be catalysed by a mono-oxygenase prefe rentially inducible by PB). When use was made of a microsomal fraction that was prepared from animals which were both steroidpretreated and induced by PB, mutagenic activation was of the same order of magnitude as that observed when induction was brought about by PB alone. The absence of additive effect, taken together with the observations already mentioned, indicate that steroids induce the same cytochrome isozymes that are induced by PB. The implications of sex-hormonal regulation of the metabolic activation of mutagens are briefly discussed.KMBT_363
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Green, K. L. „Studies on the mechanisms of action of some newly synthesised quaternary steroidal neuromuscular blocking compounds“. Thesis, University of Strathclyde, 1987. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.382348.
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Jacob, Molly. „Mechanism of non-steroidal anti-inflammatory drug induced damage in the small bowel“. Thesis, King's College London (University of London), 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.313890.
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