Tesis sobre el tema "Disposion of"

This essay is based on a survey of student’s attitudes and knowledge about global warming. A survey was used to obtain answers. The questionnaire is divided into three different stages. Some whit knowledge- based questions, one whit self-assessing questions and some with selffulfilling questions. Several studies have been created to survey students’ attitudes and knowledge, to see if there are knowledge gaps among university student, and to see if the universities lack certain teaching components. In the results, it was noted that Karlstad’s students had relatively low level of knowledge and assessed their own knowledge relatively high to the actual knowledge they hold. The students felt that society cares about global warming to some extent, and they want to counteract global warming but at the same time adapt society to the climate of the future. As an Australian study, (Pfautsch . and Gray 2017), the Karlstad students had an equal view as the Australian students of how to evaluate various sources of global warming, for example, politicians, classic media and social media were ranked among all as very unreliable sources.

Biologics are an increasing class of pharmaceuticals that possess many therapeutic benefits over typical, small‐molecule drugs, such as; high specificity, reduced frequency of off‐target effects, and the ability to mimic the body’s own physiological system. Despite these advantages, biologics still suffer from limitations due in part to their inherent protein composition, including; rapid circulatory degradation, renal clearance, and immunogenicity. Consequently, methods to modify biologics have been sought that can ameliorate these limitations yet still maintain their efficacy. PEGylation, defined as the conjugation of polyethylene glycol (PEG) to biologics, is one such modification. The coupling of PEG increases the overall molecular weight (MW) of the biologic, resulting in reduced renal clearance, whilst simultaneously acting as a shield to protect against proteolytic degradation. Both of these effects extend the half‐life of coupled biologics and improve their bioavailability. Furthermore, the extended residence times of PEGylated agents leads to an increase in efficacy in comparison to the non‐PEGylated counterpart; since the therapeutic moiety has more opportunities to elicit a response. The shielding effect of PEG is also reported to reduce the immunogenicity of biologics through preventing immune recognition of antigenic epitopes present on the biologic’s surface. The benefits of PEGylation have been well validated and there are a number of PEGylated agents clinically available, with more in various stages of development. Despite this, however, there is still little known concerning the disposition, metabolism and biological fate of PEGylated proteins. Furthermore, whilst PEGylation can reduce the immunogenicity of a protein, this has not precluded the onset of a new immunogenicity raised against the PEG moiety itself, nor indeed has PEGylation been shown to universally reduce the immunogenicity of coupled proteins. Anti‐drug antibodies (ADAs) and hypersensitivity reactions have been reported in both animal studies and patients receiving PEGylated agents. Furthermore, these adverse drug reactions (ADRs) occur against both the PEG and protein moieties of the conjugate. Consequently, there is a real need to understand the fundamental mechanics behind the metabolism, disposition and biological fate of PEGylated biologics, as well as defining the effect of PEGylation on the immune recognition, processing and presentation of the coupled protein. The bioanalysis of PEGylated proteins is hindered by inherent difficulties associated with the PEG moiety. PEG is transparent, non‐fluorescent, contains no ultra‐violet (UV) chromophore, is polydisperse, and is not easily ionised; making analysis by spectroscopy and mass spectrometry difficult. The utility of radiolabeling is also limited due to issues arising from placement of the radiolabel within the conjugate. Consequently, alternative analytical tools are required for the comprehensive bioanalysis of PEGylated proteins. In light of these issues the studies described in this thesis aimed to develop methodologies that can: 1) provide quantitative information concerning the biological fate and disposition of both the PEG and protein moieties of a PEGylated protein, and 2) define the effect of PEGylation on the processes involved in generating an immune response. The first investigation in this thesis involved developing and optimising gel‐based methodology and 1H nuclear magnetic resonance (NMR) spectroscopy to monitor the kinetics, disposition and biological fate of a model PEGylated protein, 40KPEG‐insulin, in a rodent disposition study. Male Wistar rats were intravenously administered a single dose of 40KPEG‐insulin and maintained over a period of 28 days. Plasma and urine samples were collected almost daily and liver and kidneys harvested on days 14 and 28. 1H NMR and gelbased analysis, incorporating western blotting for both PEG and insulin, and a barium iodide (BaI2) stain for PEG, revealed that PEG persists in both biological tissues and fluids across 28 day days. However, the anti‐insulin western blots revealed that the insulin moiety was either metabolically cleaved or sequentially degraded from PEG to the extent that no immunodetectable insulin was detected by day 7 in urine, or by day 14 in plasma, and could not be detected at all in liver and kidney tissue on days 14 and 28. However, an in vitro plasma stability study found the insulin moiety of 40KPEG‐insulin to be stable in plasma over 7 days, indicating that the loss of insulin signal observed in vivo must be occurring following cellular internalisation; potentially allowing for the liberated protein to be immunologically processed. The second investigation in this thesis concerned the effect of PEGylation on in vitro cellular internalisation. A range of different PEG MWs were incubated with dendritic cells (DCs) – a model antigen presenting cell (APC) – and internalisation was assessed by flow cytometry and fluorescence microscopy. These data revealed that DC internalise PEG regardless of MW, suggesting that PEGylation, in terms of MW, may have little effect on the internalisation of a PEGylated biologic by APC – over the clinically relevant PEG MW range used in this study. Thirdly, the effect of PEGylation was assessed on the lysosomal and proteasomal pathways of antigen processing and presentation, events en route to producing an immune response which occur after cellular internalisation. Insulin was conjugated to a range of different MW PEGs and incubated with either lysosomes or proteasomes. PEG was shown to be stable to lysosomal proteolysis over a period of 7 days; however insulin was completely degraded within 2 hours. When coupled to PEG, the insulin moiety was again degraded completely within 2 hours regardless of PEG MW. No PEG MW effect was observed when analysing the peptide repertoires generated between the PEGylated insulin conjugates. Indeed, it was shown that PEGylation provides only local protection against lysosomal degradation at the site of attachment. However, when degraded by proteasomes a PEG MW‐dependent effect was observed. Over 48 hours, insulin was nearly degraded to completion when conjugated to 20 kDa PEG. But when coupled to either 30 or 40 kDa PEG, only ~50% of the insulin moiety was degraded. When analysing the peptide repertoires, again PEG, regardless of MW, provided partial protection at the site of attachment. However, there was much more variation in the peptides generated between each PEGylated insulin. In conclusion, the methods developed in this thesis represent facile, inexpensive analytical tools to comprehensively analyse the disposition, kinetics and biological fate of both the PEG and protein moieties of PEGylated proteins. Furthermore, the investigation presented in this thesis was the first of its kind to demonstrate that cleavage and/or degradation of a PEGylated protein can occur in vivo. Consequently, the methods described in this thesis could be easily used to provide a measure of the pharmacokinetics and tissue retention of PEGylated biologics in man. When analysing the effect of PEGylation on the processing of PEGylated proteins, there was shown to be little difference when processed via the lysosomal pathway of antigen processing. However, based on the peptide repertoires generated PEG did provide local protection against degradation at the site of attachment – suggesting that site‐specific PEGylation, tailored for individual biologics, may provide a viable route to reduce the immunogenicity of the attached protein. Future investigation is warranted to further elucidate the potential effects of PEGylation on immunological events occurring downstream of lysosomal/proteasomal processing.

Le corps humain est aujourd'hui utilisé à diverses fins (chirurgie esthétique, don d'organe, procréation médicalement assistée, recherches biomédicales, tatouages, interruption de grossesse. . . ). Il est donc mis à la disposition tant de l'individu que de la société. On constate alors que le législateur, malgré l'édification d'un statut protecteur du corps humain dans le Code civil, autorise certaines de ces utilisations (don d'organe ou chirurgie esthétique par exemple), en limite d'autres (comme l'interruption de grossesse) et enfin en interdit certaines autres (c'est le cas de l'euthanasie). Ces permissions de la loi, inscrites dans le code de la santé publique, ont pour fondement une liberté corporelle donnée à l'individu. En effet, malgré l'utilisation courante de l'expression « droit de disposer de son corps », la notion de « droit » ne peut avoir de réalité juridique en ce qui concerne cette disposition. La notion de « liberté » est alors mieux adaptée aux pouvoirs que peut exercer l'individu sur son corps. Ainsi, cette qualification emporte des conséquences importantes notamment en ce qui concerne les limites ou les interdictions apportées à cette liberté. Ces dernières reposent sur la notion d'ordre public corporel. Il apparaît que c'est l'intérêt général, l'intérêt de la société, et notamment la préservation de ses valeurs morales telles que le respect de la vie, qui vont commander cet ordre public
The human body is now being used for various purposes (plastic surgery, organ donation, invitro fertilisation, biomedical research, tattoos, termination of pregnancy, etc. ). And is thus place at the disposal of both the individual and society. Despite building a protective status of the human body in the Civil Code, allows some of those uses (organ donation or cosmetic surgery, for example), limit others (like the termination of pregnacy) and banned others (in the case of euthanasia). These permissions enshrined in the Public Health Code, are premised on the concept of an individual corporal freedom. Indeed, despite the common use of the term "right to hold mastery over ones body", the concept of "right" can have no real legal significance. The notion of "freedom" is better suited to qualify the powers that the individual carries over there body. Thus, this qualification carries significant consequences, particularly in regards to the limitations or prohibitions which nuances this freedom. These nuancing legal positions are based on the concpet of the general interest, "ordre public corporel". It appears that in the eyes of the law the general interest, that of society, and in particular the preservation of its moral values such as respect for life, will define this legal position of ordre public

Aggressiveness, nervousness, flightiness, gregariousness and overall disposition were evaluated in F2 Nellore-Angus embryo transfer calves (n = 443) from 13 full sib families and in half Bos indicus, half Bos taurus natural service calves (n = 259) from 4 paternal half sib families. Calves were born from 2003 to 2007, and evaluated shortly after weaning. Steers were evaluated shortly before slaughter for all 5 disposition traits and at slaughter for overall disposition. Heifers were evaluated for overall disposition at calving every year. Scores ranged from 1 to 9, with 1 being docile and 9 being unruly, except at calving where scores ranged from 1 to 5. Between sires for overall disposition, calves by 297J were lowest at weaning (2.83), before slaughter (2.84), and at slaughter (2.45) and second lowest in first calf heifers (2.27). Calves by 437J were highest at weaning (4.10), before slaughter (3.54), at slaughter (2.89) and in first calf heifers (3.10). Bulls had the lowest scores at weaning (2.54), although the number was small (n=10); females were the highest (4.01), and steers were intermediate (3.70). All 5 weaning traits were correlated (P < 0.05) with each other (0.73 to 0.96). The correlation of recipient disposition and weaning disposition of the calves was 0.12 (P < 0.05). Aggressiveness was not significantly correlated with other component traits before slaughter but was with overall disposition (0.19, P < 0.05). All other traits were significantly inter-correlated (0.60 to 0.97). Disposition at weaning was correlated with disposition before slaughter (0.43, P < 0.05). Slaughter disposition was correlated with weaning disposition (0.30, P < 0.001) and disposition before slaughter (0.27, P < 0.001). Disposition in first calf heifers was correlated with weaning disposition (0.34, P < 0.001) and disposition in second calf females (0.53, P < 0.0001). The results indicate that both genetics and recipient disposition affect calf disposition at weaning, calves with better dispositions at weaning have better dispositions later in life, and there is sufficient variability within and between these full sib and half sib families for use in QTL analysis for major genes for disposition in Nellore-Angus cross cattle.

Cocaine is a psychomotor stimulant which is widely abused. To understand the behavior of cocaine, the disposition kinetics of the compound were characterized using the rat as an animal model. A sensitive HPLC assay was developed to quantitate cocaine and metabolites (cocaethylene, norcocaine, benzoylecgonine, and benzoyl-norecgonine) in plasma and urine samples. Since ecgonine methyl ester has insufficient UV absorptivity, the quantitation of this compound in blood and urine was performed by a GC/NPD method. The effects of dose and route of administration on the disposition kinetics of cocaine were studied in male Sprague-Dawley rats. The total systemic clearance of cocaine following i.v. and s.c. administration are dose-independent. The clearance of cocaine (CL/F) following i.p. administration is dose-dependent. Cocaine absorption following subcutaneous injection was slow but complete (F = 1.0). The extraction ratio of cocaine in the lung (1-F) is about 0.18. The oral bioavailability of cocaine (F = 0.05) was low compared to i.p. administration (F = 0.35-0.63). Various properties of cocaine in the blood (blood clearance, blood to plasma ratio and plasma protein binding) were characterized using blood from the experimental animals and humans (male and female). Cocaine degradation in blood was dose-independent. In rat, cocaine degradation in blood was slow and due to the non-enzymatic degradation. In humans, cocaine is metabolized by a cholinesterase enzyme and this reaction can be inhibited by NaF. Ethanol had no influence on cocaine degradation either in human or rat blood. Cocaine blood to plasma ratio was dose-independent and was not influenced by NaF and ethanol. Plasma protein binding of cocaine in the rat was independent of concentration but depended upon plasma pH. Gender and time of the menstrual cycle had no influence on cocaine degradation, blood to plasma ratio or plasma protein binding in humans. A simple device has been modified for serial venous blood sampling which permits the simultaneous measurement of locomotor activity in the freely moving rat. The relationship between the locomotor activity following a single short i.v. infusion of cocaine and cocaine plasma concentrations can be adequately described by the Sigmoid-Emax model or by the same model coupled with an effect compartment.

La mise à disposition est une notion récente – à l’échelle du droit français – qui n’a réellement intégré le domaine juridique qu’au siècle dernier. A travers elle, c’est le phénomène d’évolution de la langue juridique qui peut être observé, les raisons et le processus de l’intégration d’un terme de la langue courante au sein du langage juridique. Par ailleurs, l’ampleur et la rapidité avec lesquelles la locution « mise à disposition » s’est répandue dans les textes du droit français montrent à quel point la formule répond à un besoin des praticiens. Pourtant, la notion de mise à disposition ne présente, à première vue, aucune cohérence et son utilisation normative recèle de nombreuses contradictions. L’étude approfondie de la mise à disposition permet toutefois de découvrir une notion homogène sous la forme d’une « licence d’utilisation », notion qui appelle un régime particulier. La mise en exergue par l’étude de la mise à disposition de certaines singularités juridiques ouvre d’ailleurs la voie à une réflexion plus large portant sur la pertinence de certaines classifications classiques, notamment quant aux catégories de choses et quant à la distinction droits réels / droits personnels
The provision is a recent notion - across the French law - which has really integrated the legal scope in the last century. Through it, the phenomenon of legal language evolution can be observed, the reasons and the process of integrating a term of the current language in the legal language. Moreover, the extent and speed with which the "provision" phrase has spread in the texts of French law show how the formula meets the need of practitioners. Yet the notion of providing presents, at first glance, no consistency and normative use conceals many contradictions.However, the comprehensive study of the provision give the opportunity to discover a homogeneous concept as a "license to use" concept that calls a special regime. The discovery of certain legal singularities also opens the way for a broader reflection on the relevance of certain conventional classifications, particularly as regards the categories of things and on the distinction real rights / personal rights

Smartphones are the most personalized and in the meantime the most anthropomorphized computing and communication technology in our society. Existing studies, especially Computers as Social Actors studies, on anthropomorphism and social interactions focus on how to implement and elicit positive anthropomorphic effects but fail to address the motivations and dispositional factors. Through an online survey that incorporates well-tested social psychological scales, this study provides empirical evidences that smartphone users’ social dispositions including chronic loneliness, attachment style, and cultural orientations are associated with their acceptance and awareness of anthropomorphism. Findings in this study suggest that existing studies are limited to method of choice and overlooked how people adapt to communication technologies differently in real life settings. Anthropomorphic design in communication technology and anthropomorphized message in advertising strategies need further examination when targeting a diversified or specified demographic.

La mise à disposition permet de designer une certaine forme de mobilité du salarié. C'est l'opération par laquelle un salarié, sur la base de son contrat de travail, accepte d'effectuer sa prestation au profit d'une autre personne morale ou physique que celle avec laquelle il est lié. La sous-utilisation de la mise à disposition comme mode de détermination des droits et obligations des parties impliquées dans une telle opération triangulaire tient au fait qu'elle n'est par caractérisée et que son mécanisme contractuel n'est pas identifié. A condition de combler ces lacunes, la mise à disposition pourrait constituer une qualification juridique permettant d'introduire plus de sécurité juridique et de réduire le contentieux lié à la mobilité du salarié. Le code du travail n'offre des cadres juridiques précis que lorsque la mise à disposition constitue le mode de ploiement exclusif d'une activité économique. Il procède alors à l'organisation et au contrôle de cette activité. Hormis ces champs d'application, la mise à disposition est illicite (répression pénale de toute opération ayant pour objet exclusif le prêt de main-d’œuvre à but lucratif). Mais loi et jurisprudence tendent à élargir le champ d'utilisation de la mise à disposition comme objet ou moyen d'exécution d'un contrat de prestation de services. Or cette forme d'emploi est essentiellement précaire puisque les conditions de travail et d'emploi du salarie sont en réalité déterminées par l'entreprise utilisatrice mais que la responsabilité de celle-ci reste insaisissable puisqu'elle n'endosse pas la qualité d'employeur. C'est pourquoi il est proposé de délaisser le schéma juridique actuel (conduisant à des mises à disposition avouées et cachées) pour construire un cadre juridique garantissant que la mise à disposition ne soit ni préjudiciable au salarié ni utilisée comme moyen d'éluder les dispositions légales ou conventionnelles
The salaried workers' purview implies some form of workers' mobility. In this particular case the salaried worker, according to his employment contract, accepts to work for a moral or physical entity different from the one he is bound to. This terminology is underused as means of defining the rights and obligations of the implied parties in such a triangular operation. This is due to the fact that it is not clearly characterized and also to the fact that is juridical bases have not been defines. Once this gap filled, the salaried worker's purview could serve as a juridical qualification aimed at providing more legal security and reducing the litigation linked to the worker's mobility. Precise legal frameworks are specified in the code du travail* when some economic activity uses this operating modality exclusively. This economic activity is then ruled and controlled. Apart from well-defined cases, the operation which consists in putting workers at firms disposal becomes illegal being considered as an operation whose only aim is manpower lending. Nevertheless, laws and jurisprudence tend to widen the field of the workers' purview as the object or the mode of execution of contracts used in service providing. But this kind of employment is precarious in most cases since the working and employment conditions are actually fixed by the host firm which is not the legal employer and hence not liable. Therefore we suggest to put the current legal scheme (leading to declared or converted workers' purview) aside, in order to design another juridical frame. Its purpose would be to guarantee that the workers’. .

Les mises à disposition de salariés répondent à des besoins économiques importants. Consistant pour un employeur à laisser un tiers bénéficier temporairement de la force de travail d’un ou plusieurs salariés, ces opérations permettent de répondre à un besoin ponctuel ou d’accompagner une opération économique. La réponse du législateur laisse perplexe. A la multiplication des formes réglementées de mises à disposition (travail temporaire, travail à temps partagé, etc), s’ajoute l’éparpillement de règles isolées, fruit de l’accumulation de textes non coordonnées. Or, les risques, civils et pénaux, attachés à ces opérations, nécessiteraient une approche globale des mises à disposition de salariés et une précision accrue des règles qui leur sont applicables. Ce changement d’approche suppose, au préalable, que les mises à disposition soient, en tant que telles, définies et reconnues. La réglementation, souvent précise, des formes réglementées, doit être assortie d’un droit commun applicable à toutes les mises à disposition de salariés ne relevant pas d’une catégorie particulière. En l’absence de telles règles, il est nécessaire de recourir aux mécanismes de droit civil pour appréhender ces opérations triangulaires ou d’adapter les règles applicables aux relations de travail classique

Collision warning systems represent a promising means to reduce rear-end crash involvement. However, these systems experience failures in the real-world that may promote driver distrust and diminish drivers' willingness to comply with warnings. Recent research suggests that not all false alarms (FAs) are detrimental to drivers. However, very few studies have examined how different alarms influence different driving populations. The purpose of this research was to examine how younger, middle-aged, and older drivers (with and without UFOV impairments) evaluated and responded to four different alarm contexts - false alarm (FA), nuisance alarm (NA), unnecessary alarm (UA) and true alarm (TA) - when they did and did not receive warnings. FA contexts represent out-of-path conflict scenarios where it is difficult for the driver to identify the source of the alarm. NA contexts represent out-of-path conflict scenarios that occur in a predictable manner that allows drivers to identify the source of the alarm. UA contexts are transitioning host conflict scenarios where the system issues an alert but the situation resolves itself before the driver needs to intervene. TA contexts represent in-host conflict scenarios where the situation requires the driver to intervene to avoid a collision. The results suggest that alarm context does matter. Compared to response data that differentiates FA and NA from UA and TA, subjective data shows greater sensitivity and differentiates between all four alarm contexts (FA Younger drivers indicated a high degree of confidence in their own ability across the different conditions. While they adopted a similar response pattern as middle-aged drivers during the TA contexts, these drivers responded less frequently than middle-aged and older drivers during the UA context. Diminished hazard perception ability and the tendency to consider these situations less hazardous likely account for the fewer responses made during these situations by younger drivers. Older drivers with and without UFOV impairments indicated similar hazard ratings for UA and TA contexts, yet drivers with UFOV impairments responded less frequently in both alarm contexts. Diminished hazard perception ability, slower simple response times, and degraded contrast sensitivity likely account for the fewer and slower responses. Interestingly older drivers with impairments did respond more frequently when warned during the TA context. They also rated FAs and NAs more positively than the other driver groups. The results of this study suggest applying signal detection theory without concern for the alarm context and driver characteristics is insufficient for understanding how different alarms influence operators and that subjective data can inform design. Researchers are encouraged to combine multiple perspectives that incorporate of both an engineering and human perspective.

Schizophrenia and schizoaffective disorders are chronic conditions with a significant impact on many functions. Positive, negative, cognitive and motor symptoms appear in different degrees and constellations. Antipsychotics are of fundamental importance to reduce symptoms. However, insufficient clinical effect and adverse drug reactions (ADRs) are important limitations of this drug therapy. Olanzapine (OLA) is a second-generation antipsychotic (SGA) drug widely used in the treatment of schizophrenia and schizoaffective disorder. The drug has well-documented effects against positive symptoms and has been claimed to be efficacious also against negative symptoms. This thesis comprises of two studies. The aim of study 1 was to investigate factors that may influence the inter- and intra-individual variability of steady-state trough concentrations of OLA and its N-desmethyl metabolite (DMO) in serum. This was done in a cohort of patients treated with oral OLA in a routine clinical setting. In study 2 steady-state trough serum OLA and DMO concentrations were studied in relation to cerebrospinal fluid (CSF) OLA and DMO concentrations in patients with schizophrenia or schizoaffective disorder, medicated with oral OLA as the only antipsychotic drug. We also analysed the effects of age, gender smoking and concomitant medication in both studies and in study 2 we also analysed polymorphisms in genes with suggested importance for OLA disposition. The drug metabolizing enzymes CYP1A2 and CYP2D6 have earlier been found to be of importance for OLA metabolism and one animal study has suggested a role for P-gp for the transport of OLA into the brain. Therefore we analysed the influence of single nucleotide polymorphisms in the CYP1A2 gene (-3860G>A, -2467T>delT, -739T>G, -729C>T, -163C>A, and in the CYP2D6 gene (*3, *4, *5,*6, and*41) and in the ABCB1 gene (1236C>T, 3435C>T, and 2677G>A/T). Study 1 started as a post-marketing surveillance project. In 1997 a high-performance liquid chromatography (HPLC)-based therapeutic drug monitoring (TDM) routine for serum OLA and DMO was established. During 1997–1999, a total of 753 TDM requests for a total of 545 Swedish patients were analysed. Additional patient information on certain clinical variables was collected on a specifically designed TDM request form. Samples from 194 patients were found to be eligible for further scrutiny. We found that the concentration-to-dose ratio (C/D) for OLA varied 25-fold and that of DMO 22-fold between individuals. The intraindividual variability over time was lower. Women had significantly higher median C/D ratio for OLA than men. However, the higher C/D ratio for OLA in women was statistically significant only in the non-smoking group. Non-smokers had significantly higher C/D ratio for OLA than smokers. Smokers received significantly higher daily doses of OLA than non-smokers. In the group with reported ADRs, the serum OLA concentration was 22% higher than in the group without ADRs. Patients co-medicated with carbamazepine had a 71% lower C/D ratio for OLA than patients who did not co-medicate with carbamazepine. Study 2 included 37 Caucasian outpatients (10 smokers and 27 non-smokers). CSF was collected from 29 out of them. Because of very low OLA and DMO concentrations in CSF, a new liquid chromatography/tandem mass spectrometry (LC-MS/MS) method for determination of OLA and DMO in serum and CSF was developed. We found a strong correlation between serum and CSF concentrations of OLA and a somewhat weaker corresponding correlation regarding DMO. The median CSF concentrations of OLA and DMO were on an average 13% and 16% of the serum levels. Non-smokers had higher (P <0.01) C/D ratio for OLA in serum and in CSF than smokers. Extensive metabolizers (EM) of CYP2D6 had higher daily OLA dosages than poor metabolizers (PM) when the influence of smoking was taken into account. EM smokers also showed lower CSF C/D for DMO than PM smokers. The DMO/OLA ratio in CSF showed a similar pattern, with a statistically significant combined effect of smoking and CYP2D6 genotype, EM smokers having the lowest and PM smokers the highest ratio. The combination of smoking and CYP2D6 genotype also affected the CSF/serum DMO ratio, PM smokers having the highest and EM smokers the lowest ratio (mean 20%, vs 9.5%). Patients co-medicating with benzodiazepines also showed higher CSF DMO/OLA ratio than patients without benzodiazepines. Moreover, DMO concentrations in CSF in relation to serum were higher in benzodiazepine users than in patients not comedicating with benzodiazepines (mean 24% vs 14.4%). Smoking habits did not affect these results. Carriers of the ABCB1 1236T/2677T/3435T haplotype had higher serum and CSF OLA concentrations than patients without this haplotype. The C/D ratios for serum DMO decreased with increasing age (P < 0.05). In summary, smoking habits and co-medication with carbamazepine should be taken into consideration when dosing OLA. In study 1 we noted that women had higher serum C/D OLA ratio than men among non-smokers. This could not be confirmed in study 2, probably due to the small study population. Polymorphisms in genes of importance for OLA metabolism (CYP1A2 and CYP2D6) and transport (ABCB1) over membranes have some, but probably a minor, effect on serum and CSF concentrations. Larger studies are needed to confirm these observations. Smoking in combination with CYP2D6 polymorphism and the use of benzodiazepines affected the DMO metabolism in the brain in this study. However, because of low precision in the method at low DMO concentrations and a low number of patients, these results must also be confirmed in larger studies. The strong correlation between serum and CSF OLA concentrations established in study 2 indicates that factors influencing serum concentrations (such as smoking) also influence these concentrations in CSF. When patients are non-responsive to treatment, not compliant, vulnerable to ADRs on standard doses, or when drug interactions are suspected, TDM serum-OLA concentrations can be used as a diagnostic tool. Therapeutic drug monitoring is also of value to optimize long-term treatment of patients as environmental factors such as smoking and drug interactions may differ over time and could markedly interact with a patient´s metabolic capacity and thereby the therapeutic outcome.
Schizofreni och schizoaffektiv sjukdom är livslånga tillstånd som oftast medför påtaglig funktionsnedsättning och betydande lidande både för patienten och närstående. Trots att antipsykotika är avgörande för behandlingsframgång vid dessa sjukdomar förekommer inte sällan problem med bristande behandlingseffekt och/eller biverkningar. Olanzapin (OLA) är ett läkemedel godkänt för akut- och underhållsbehandling av schizofreni och schizoaffektiv sjukdom. OLA blev godkänt för allmän förskrivning i Sverige 1996. Det övergripande syftet med detta projekt var att undersöka variation i omsättningen av OLA och dess metabolit N-desmetylolanzapin (DMO) vid behandling av patienter med schizofreni eller schizoaffektiv sjukdom. Projektet utgörs av två delstudier. Studie 1 syftade till att klargöra hur OLA- och DMO-koncentrationer varierar i blodet mellan individer och inom individer vid upprepade mätningar. Syftet med studie 2 var att utforska om det fanns någon korrelation mellan OLA- och DMO-koncentrationer i serum och i likvor hos patienter som behandlades med enbart OLA som antipsykotiskt läkemedel. Effekten av rökning, kön, ålder och eventuell annan pågående medicinering undersöktes i båda studierna. I arbete 2 analyserades även samband till varianter av gener som kodar för läkemedelsmetabolism (CYP2D6, CYP1A2) och läkemedelstransport (ABCB1). Materialet till studie 1 insamlades under 1997-1999. Med vätskekromatografi analyserades OLA- och DMO-koncentrationer i 753 serumprover från 545 patienter. Kliniska data registrerades enligt ett strukturerat protokoll. För de 194 patienter där provet var korrekt taget (jämvikt, dalvärde) och där relevant klinisk information fanns tillgänglig gjordes ytterligare dataanalys. Vi fann att förhållandet mellan serumkoncentration och OLA dos (C/D OLA) varierade 25-faldigt och C/D DMO varierade 22-faldigt mellan individer. Kvinnor hade signifikant högre C/D OLA än män och icke-rökare hade högre C/D OLA än rökare. Rökare ordinerades högre doser av OLA än icke-rökare. I gruppen med rapporterade biverkningar var medianvärdet av OLA i serum 22 % högre än i gruppen utan biverkningar. Patienter som samtidigt medicinerade med karbamazepin hade ett 71% lägre medianvärde av C/D OLA än patienter utan karbamazepinmedicinering. Variabiliteten av C/D OLA var lägre inom individer vid upprepade mätningar vid olika tillfällen än mellan individer. I studie 2 inkluderades 37 svenska polikliniska patienter (10 rökare och 27 icke-rökare). Från 29 avdessa erhölls likvor via lumbalpunktion. Vi fann stark korrelation mellan OLA-koncentration iserum och likvor och något svagare korrelation mellan serum- och likvorkoncentration av DMO. Likvorkoncentrationerna av OLA och DMO var i genomsnitt 12% respektive 16% avkoncentrationerna i serum. Icke-rökare hade högre C/D OLA i serum och likvor än rökare.Snabba metaboliserare via CYP2D6 förskrevs högre dagliga doser än långsammametaboliserare när hänsyn togs till rökvanor. Rökande långsamma metaboliserare hade högreC/D DMO i likvor, högre DMO/OLA ratio och högre likvor/serum DMO än rökande snabbametaboliserare. Även patienter som samtidigt medicinerade med bensodiazepiner hade högreCSF DMO/OLA ratio och högre likvor/serum DMO än patienter som inte medicinerade medbensodiazepiner. Bärare av haplotypen 1236T/2677T/3435T för ABCB1 hade högre serumochlikvorkoncentrationer av OLA än patienter utan denna haplotyp. C/D DMO minskademed ökande ålder. Sammanfattningsvis fann vi att rökvanor och samtidig medicinering med karbamazepin påverkar metabolismen av OLA, vilket ska beaktas vid dosering av OLA. I studie 1 visade serumanalyser högre C/D OLA hos kvinnor än hos män. Denna könsskillnad var statistiskt signifikant enbart för icke rökare. Genetiska varianter av de metaboliserande enzymerna CYP2D6 och CYP1A2 hade en viss, men till synes underordnad, effekt. De effekter vi noterade avseende likvoromsättningen av DMO hos rökande långsamma metaboliserare samt hos patienter som använde bensodiazepiner måste undersökas närmare i framtida studier pga. viss metodosäkerhet vid låga DMO-koncentrationer. Det fanns en stark korrelation mellan serum- och likvorkoncentrationer av OLA och en något svagare motsvarande korrelation för DMO. Resultaten talar för att koncentrationer av OLA i serum reflekterar dem i likvor. Den intraindividuella variabiliteten av C/D OLA var som väntat lägre än den interindividuella variabiliteten. OLA-behandling kan betraktas som förutsägbart i så måtto att vid ökad dosering ökar likvorkoncentrationen linjärt med koncentrationen i serum. Serumkoncentrationsmätning av OLA kan, förutom att vara vägledande avseende ordinationsföljsamhet, användas för optimering av OLA-behandling och för långsiktig individuell uppföljning. Omgivningsfaktorer, som t.ex. rökning eller samtidig medicinering med vissa andra läkemedel, kan interagera med genetiska faktorer avseende läkemedelsmetabolism. Detta kan i sin tur markant påverka individuell variation över tid. Ändrade rök- och medicineringsvanor kan därför kräva betydande justeringar av OLAdosering.

Plan for the investigation of pharmacokinetics of amphotericin B (AmB) in rats. The disposition kinetics of AmB as a function of dose was characterized in this research project to improve the therapeutic usage of this drug. Male Sprague-Dawley rats were randomly divided into three different dose groups, receiving high, medium and low dose of AmB. Serum samples and urine samples were collected and assayed by HPLC. There are no significant differences for half-life, volume of distribution or systemic clearance as a function of dose. However, renal clearance decreases when the total infused dose increases. Creatinine clearance decreases significantly in the high dose group, suggesting the occurrence of nephrotoxicity. We conclude that volume of distribution and systemic clearance are linear over the dose range studied. The dose-dependent renal clearance may be due to either the nephrotoxicity associated with AmB or saturable secretion.

The disposition kinetics of Amphotericin-B (Am-B) were investigated in rats in three different dose groups. Each group contained four rats. The serum and urine Am-B concentrations were analyzed by reversed-phase HPLC. There were no significant differences for total body clearance and half-lives as a function of dose. Those observations suggested systemic dose-independent behavior of Am-B. However, renal clearance of Am-B decreased significantly as Am-B dose increased; whereas, no renal damage was observed during the experiment. The present studies suggested that renal clearance was dose-dependent and that there may be a saturable tubular secretion process for Am-B renal excretion.

This thesis investigates the potential of some commonly used pharmaceutical excipients to alter drug pharmacokinetics. In breath test studies, 3.2ml/kg DMSO prolonged the half-life of 14C-aminopyrine, -erythromycin and -NDMA, indicating in vivo inhibition of metabolism by CYP3A (erythromycin), CYP2E1 (NDMA) and the variety of enzymes that metabolise aminopyrine (CYP 2C11, 2C12, 2B1 and 2B2). However, no effects were apparent at doses typically used in pre-clinical formulations. Aminopyrine and erythromycin breath tests were not affected by propylene glycol (PG) or Solutol HS15, however PG did significantly increase 14C02 exhalation half- life in the NDMA breath test, suggesting a specific effect on metabolism by CYP2E1. While two 2ml/kg doses of DMSO increased plasma ai-AGP levels, none of the excipients tested consistently affected plasma ai-AGP at doses commonly used in pre-clinical formulations, suggesting that they are unlikely to increase protein binding by this mechanism. Transport studies in MDCK-MDR1 cells demonstrated an inhibitory effect of 0.1% Tween 80 and Solutol HS15 on P-Gp. In vivo, Tween inhibited the biliary elimination of 99mTc-MIBI but not 99mTc-HIDA, indicating inhibition of P-Gp, while Solutol inhibited the biliary elimination of both radiopharmaceuticals, suggesting inhibition of MRP and possibly P-Gp. Pre-treatment with 4ml/kg DMSO substantially impaired the renal elimination of 99mTc-DTPA. In contrast, 20% 1.8ml/kg DMSO significantly increased 99mTc-DTPA uptake into the kidneys, suggesting an increase in GFR. Both Tween and Solutol delayed 99mTc-DTPA elimination from the kidneys in some rats, without affecting GFR. However, Solutol did not significantly affect the pharmacokinetics of OAT or OCT substrates, suggesting it did not affect active renal secretion by these transporters. These results demonstrate that excipients can influence drug pharmacokinetics in vivo, after a single acute dose at levels commonly used in pre clinical studies.

En procedant a l'opposition classique "pouvoir legislatif pouvoir reglementaire", la presentation des notions traditionnelles d'autorisation budgetaire et d'execution de la loi de finances occulte la place pourtant reelle du ministre dans l'ordonnancement budgetaire. Un concept nouveau peut retablir ce dernier a sa juste place : celui de "mise a disposition des credits budgetaires", qui se definit par rapport au destinataire des credits, le ministre, et par son objet, l'attribution de credits. Les pouvoirs competents, pour attribuer les credits sont soit conjointement, (dans le cadre de la mise a disposition initiale, c'est-a-dire l'autorisation budgetaire), soit concurremment, (en cours d'execution de la loi de finances dans le cadre de procedures secondaires de mises a disposition), les pouvoirs legislatif et reglementaire. Mais le concept de mise a disposition presente des limites au regard d'un autre concept, celui d'utilisation : les credits sont mis a la disposition du ministre pour qu'il les utilise, c'est-a-dire execute la depense publique. Il entre ainsi dans le domaine de la comptabilite publique et utilise ses credits dans des conditions qui prouvent sa dependance vis-a-vis du pouvoir reglementaire. Le ministre apparait fondamentalement comme le lien organique privilegie du droit budgetaire et de la comptabilite publique, du gouvernemental et de l'administratif. . .

Metoclopramide (MCP) is a potent antinauseant/ antiemetic and gastrointestinal motility modifier. MCP finds clinical use in a wide variety of situations and is administered on both an acute and chronic basis. This thesis examines the pharmacokinetics of MCP in both normal, healthy volunteers and in uremic subjects on a maintenance hemodialysis program. Specifically, in the normal, healthy volunteers, the dose-linearity, and absolute and relative bioavailabilities are examined. In the uremics, the effects of chronic renal failure on MCP kinetics, the removal of MCP by hemodialysis, and the effects of hemodialysis on MCP kinetics are examined. Based on early reports, the pharmacokinetics of MCP were claimed to be dose-dependent and the absolute bioavailability extremely variable. However, many of these early studies suffered from methodological problems which limit the credibility of their findings. Based on a four-way crossover study involving six normal, healthy volunteers we find, in contrast to previous results, that the kinetics of MCP are linear over the dose range of 5 -20 mg, the absolute bioavailability is 76 ± 38 %, and the relative bioavailability of a solution dosage form vs the tablet dosage form is approximately 1. Although renal clearance accounts for only about 20 % of the total body clearance of MCP in normals, uremia has been shown to substantially alter MCP kinetics in both rat and man. There appears to be at least a two-fold decrease in total body clearance with an attendent, proportional increase in elimination half-life and insignificant change in volume of distribution. Hemodialysis is relatively ineffective in clearing MCP from the body and this inefficiency is probably related to the relatively large volume of distribution of MCP. Hemodialysis also has no effects on the apparent kinetic parameters following its termination. In addition, results from a single patient who received a kidney transplant show that the renewed renal function is accompanied by an apparent reversion of all kinetic parameters to within normal limits within 15 days of transplantation.
Pharmaceutical Sciences, Faculty of
Graduate

Pharmacogenetics involves research into the hereditary basis for the different responses of individuals to drugs or other environmental pollutants. Several functional genetic polymorphisms of drug metabolising enzymes, transporters, receptors and other drug targets have been identified and characterised and these polymorphisms may be responsible for interethnic differences in drug disposition and disease risk. Few studies have focussed on ethnic African populations. Several genes that have known genetic polymorphism and have clinical implications for disease risk and/or treatment of patients were evaluated in a sample of the Ghanaian (West African) population. Catechol-O-methyltransferase (COMT) catalyses the 0-methylation of neurotransmitters, catechol hormones and drugs such as levodopa and methyldopa. Ethnic differences in COMT activity have been observed in several populations. Previous studies suggest that the homozygous low activity allele (COMT*L) is less common in individuals of African origin than Caucasians. COMT genotyping was performed using a mini-sequencing method in 195 healthy Ghanaians. The frequency of the homozygous low activity allele was 6%. In Caucasians it is 31%. This study provides confirmation that the low activity COMT allele is less common in individuals of African origin. This finding may be important clinically with regards to the treatment of many neuropsychiatric disorders and in the pathophysiology of various human disorders including oestrogen-induced cancers, Parkinson's disease, depression and hypertension. This thesis aimed to determine the allele frequency of therapeutically important genetic polymorphisms in an African (Ghanaian) population. The data was then compared to other ethnic populations. The marked racial and ethnic differences in the frequency of functional polymorphisms in these drug- and xenobiotic-metabolising enzymes, transporters, receptors and other drug targets shows that ethnic origin needs to be considered in studies aimed at discovering whether specific genotypes or phenotypes are associated with disease risk or drug toxicity. Genotyping prior to treatment may be essential, as 95% of the Ghanaian subjects genotyped had between one and four mutations in the therapeutically important genes analysed. Genotyping assays specific for predominant mutant alleles should be used in different ethnic groups.

Using radioimmunoassay, radiolabelling and subcellular fractionation techniques, further information as to the role of metallothionein in the disposition of cadmium in the rat and man, following exposure to this metal, was obtained. A radioimmunoassay for the specific measurement of mammalian metallothionein I and II was developed, using a sheep anti-(rat metallothionein) antibody. The assay had a large linear working range (6. 6ng - 1.0mg/ tube) and was capable of metallothionein measurement in the mammalian tissues and body fluids without the need for high dilutions. Chronic dietary administration of 75, 150 and 300ppm cadmium to rats lead to a dose- and time-related accumulation of this metal in the liver, kidney and small intestine. The highest cadmium concentrations were located in the kidney. This was accompanied by disturbances in zinc and copper concentrations in these tissues. Using the radioimmunoassay, metallothionein induction was seen to parallel cadmium accumulation in these tissues. Chromatographic separation of the cytosolic fractions of some of these tissue samples revealed that only 42% of the cadmium was associated with metallothionein in the small intestine, whereas about 90% of the cadmium was associated with this protein in the other tissues. Urinary excretion of cadmium was about 10 fold higher(3-4ug/day) in the 300ppm dose group than the lower dose groups. Copper and not cadmium was associated with metallothionein in the urine; cadmium was located in the lower molecular weight fraction. Urinary metallothionein appeared to be a good index of cadmium body burden and also a good indicator of recent exposure - being detected in the urine after 3 days cadmium exposure. Studies using the isolated perfused liver system, revealed the paralleled release of cadmium and metallothionein from the liver of rats exposed to cadmium. The profile of this release suggests an active mechanism. Using [109]Cd, [3]H-labelled metallothionein, an exponential uptake of [109]Cd by the liver of rats not previously exposed to cadmium, was observed. Tritium uptake was less rapid. Subcellular fractionation, revealed that most of the tritium was located in the membranous fraction of the liver, whereas [109]Cd was found mainly in the cytosol (associated with endogenous metallothionein). Intravenously injected [109]Cd,[3]H-labelled metallothionein into rats,showed that 30-40% of this protein was taken up by the renal cortex within 10 minutes. Subcellular fractionation studies indicated the lysosomal degradation of this protein. 109Cd was retained in the cortex- associated with endogenous metallothionein of the cytosol fraction. Tritium was lost from the cortex by 24 hours after injection. The biological half-life of the exogenous metallothionein was calculated to be between 10 and 30 minutes. A group of human volunteers repeatedly consumed "brown crabmeat" containing cadmium for up to 12 weeks. Plasma and urine cadmium concentrations showed a paralleled increase after 2 and 6 weeks suggesting a "cyclic" release of cadmium possibly from the liver to the kidney, bound to metallothionein. This is discussed in the light of the data obtained from the in vitro organ perfusion studies and animal studies in vivo. descibed previously.

This thesis sets out to examine the disposition of the tritone in Gregorian Chant, both as a 'filled-in' and as a disjunct interval, or 'leap'. By comparison with other periods of music history, the tritone's place in early medieval music has hitherto received scant attention; one noteworthy text even claims that it was shunned altogether. But, in general, it has been assumed that the tritone was considered undesirable only as a harmonic device. Intervallic perception is partially determined by the prevailing culture and context. (In respect of the tritone, this is no more demonstrable than in jazz. ) And since the melodic tritone contravenes ancient principles concerning harmonious proportion, the tritone's disposition in the chant may therefore be deemed significant. The primacy of liturgy is affirmed, and the early neume notations accorded an important role in the analyses. The tritone 'leap' seems only to appear in the Great Responsories of the night Office - particularly those of Passiontide - and may owe its existence partly to medieval superstition. Furthermore, modern scholarship has failed to acknowledge the gulf between contemporary theory and practice by adopting a 'theory-dominated view' (as proposed by Rankin in connection with organum at Winchester). Later attempts to edit the tritone from the Benedictine MSS were inconsistent, as illustrated through a comparative study with the Cistercian sources.

Millions of people across the globe invest in financial markets, hoping to increase their wealth or income. Investing is risky of course, but some investors seem to battle not only the market but also themselves. In recent decades behavioural economics has uncovered many patterns of trading behaviour which appear to work against the investors who display them, resulting in lower investment returns. For this reason, these patterns of behaviour are regarded as trading biases. This thesis investigates two main themes that follow from the observation of trading biases in financial markets, both ultimately related to helping investors make better investment decisions. First, to what extent do individual investors reliably demonstrate trading biases? Second, why do these biases occur and can their impact be mitigated? With respect to the first theme, is there evidence that some biases have trait-like characteristics, and predict investors’ behaviour across a range of situations? This theme is related to the “state vs trait” argument from personality psychology. Applied here, the question is whether variation in trading behaviour is better explained due to environmental differences when decisions are being made (state), or because people differ in their tendencies to behave in certain ways (trait-like). If the latter, investors who tend to express biases would benefit from understanding their own decision-making patterns. Note that the claim here is not that the biases are literally traits themselves, but that they have trait-like characteristics such as intra-individual stability and construct validity. The evidence presented in this thesis suggests that the biases examined possess these characteristics because their expression depends on some underlying behavioural tendencies; these underlying tendencies may be traits, though they are not directly investigated here. With respect to the second theme, a suspected cause of many trading biases is the influence of irrelevant emotions on decision making. This thesis investigates evidence for the role of emotions in trading biases. It also investigates the use of cognitive reappraisal as a de-biasing technique (i.e. a method to reduce the level of bias displayed in trading decisions), which works by reducing emotions during trading. The main bias which this thesis examines is the disposition effect. This occurs when investors are more eager to sell gains than losses, or stated another way, when they hold losses longer than gains. So, it is a bias that affects decisions about selling, based on the profit or loss made on each stock. Although the disposition effect is widely studied in behavioural finance, it has not been demonstrated to be a persistent pattern of an investor’s trading behaviour. Experimental studies measure a mathematically defined disposition effect in the lab, but assume that this research can provide insight into the disposition effect observed in financial markets. Meanwhile cognitive reappraisal, a form of emotion regulation, has been shown to reduce the disposition effect, but only in students and only using lab conditions that lack ecological validity. Furthermore, the mechanism for reappraisal’s effect has not been investigated. As well as investigating whether the disposition effect has trait-like characteristics, it also examines the “constituent biases” of the disposition effect, cutting gains and holding losses. Though the disposition effect is defined as a difference between selling gains and losses, the two are treated as two sides of the same behaviour rather than two separate trading patterns. This thesis argues that these constituent biases should be treated as separate biases, rather than two aspects of a unitary disposition effect. Building on the first theme, the constituent biases are also assessed for trait-like characteristics; building on the second theme, the effect of cognitive reappraisal on each constituent bias is examined. This thesis contains three studies, two involving retail investors and one with an adult novice sample. All three involve measuring trading biases with an ecologically realistic trading simulation, played multiple times. The two studies with retail investors also include a disposition effect scale. Cognitive reappraisal is tested in one of the two studies with retail investors and in the study with novices. I contribute to the literature in establishing that the disposition effect has trait-like characteristics aspects, by showing that it can be reliably measured in both an ecologically valid trading simulation and a self-report scale, and that these link to real-world trading behaviour. Furthermore, I show that the disposition effect is not a unitary bias but that its two constituent biases, cutting gains and holding losses, are independent of each other. They too have trait-like characteristics, and can also be reliably measured using the same ecologically valid trading simulation. However, levels of each bias in investors are not associated with each other. This contrasts with the conventional approach to the disposition effect that treats them as opposite sides of a unitary bias. I argue they are independent biases which are measured together in the disposition effect. Furthermore, as independent biases they are likely to be underpinned by different underlying traits. I build on the existing literature by showing that the disposition effect occurs in retail investors using this trading simulation. I find that cognitive reappraisal reduces the disposition effect, while I make improvements in the external validity of this test in both the measurement of the disposition effect and participants used. I extend knowledge of emotion regulation and trading biases by showing that cognitive reappraisal reduces the disposition effect by decreasing the tendency to hold losses. Lastly, I show that cognitive reappraisal is not effective under the same conditions in novices (as opposed to retail investors). This reminds us of the merit of testing de-biasing techniques with greater ecological validity, and suggests that implementing de-biasing techniques in real world decision making may be more difficult than it first appears.