Thesis (doctoral)--Ludwig-Maximilians-Universität zu München, 1979.

Thèse d'exercice : Médecine. Anesthésie, réanimation chirurgicale : Université de Nantes : 2005. / Bibliogr. f. 70-75 [71 réf.].

Part I. In order to determine the effect of dose size on the bioavailability of phenytoin (Dilantinᴿ), a single intravenous dose of 15 mg/kg, single oral doses of 400, 800, 1600 mg, and 1600 mg in divided doses (i.e. 400 mg every three hours) were administered to six healthy male subjects. Values of V(max) and K(m) obtained from the intravenous dose were used to determine the extent of absorption from the oral doses. Although no statistically significant difference in extent of phenytoin absorption was observed, the time to reach maximum phenytoin serum concentrations increased significantly from 8.4 hours for the 400 mg dose and 13.2 hours for the 800 mg dose to 31.5 hours for the 1600 mg dose. Peak serum concentrations of 3.9, 5.7, 10.7, and 15.3 mg/1 were observed after the 400, 800, 1600 and 1600 mg divided doses, respectively. It is suggested that the prolonged, but complete, absorption of large phenytoin doses is due to a slow dissolution and continued absorption from the colon. Owing to the prolonged absorption of phenytoin, it may be necessary to use a larger oral than intravenous loading dose to produce similar maximum phenytoin serum concentrations. Part II. The effects of age and obesity on the pharmacokinetics of thiopental were studied in 7 morbidly obese (aged 25 to 46 years) and 22 lean patients (aged 25 to 83 years), who were primarily undergoing abdominal surgery. In all 29 patients, serum thiopental concentrations were determined by gas-liquid chromatography using a nitrogen-selective detector. Based upon total (bound+free) thiopental concentrations, the average (±S.E.) volumes of distribution (Vᵦ and V(ss)) were significantly larger in the obese (7.94 ± 1.72 1/kg and 4.72 ± 1.03 1/kg, respectively) than in the age-matched lean patients (1.95 ± 0.22 1/kg and 1.40 ± 0.16 1/kg, respectively). Clearance based on total thiopental concentrations normalized to total body weight (TBW) was not significantly different between the obese (0.18 ± 0.03 1/hr/kg) and lean patients (0.21 ± 0.02 1/hr/kg). However, total body clearance not normalized to TBW was significantly larger in the obese (24.98 ± 5.62 1/hr) than in the lean patients (11.86 ± 1.29 1/hr). The half-life of thiopental was significantly larger in the obese (31.87 ± 4.53 hours) than in the lean patients (6.61 ± 0.52 hours) and was primarily a function of the larger apparent volume of distribution for thiopental. The unbound fraction of thiopental in serum (range, 17.8% to 27.6%) did not depend on the degree of obesity, but was found to be greater with advancing age. The apparent volumes of distribution, Vᵦ and V(ss), were also related to age. No significant relationship was found between total body clearance with increasing age. Thus, the half-life of thiopental was positively correlated with age, and as in the obese study, was found to be primarily influenced by the apparent volume of distribution.

Orientador: Aricio Xavier Linhares / Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Biologia / Made available in DSpace on 2018-08-10T18:18:35Z (GMT). No. of bitstreams: 1 Soto_DoraAmparoEstrada_D.pdf: 2535722 bytes, checksum: 550a33ae626a5a9a30ff32773e785904 (MD5) Previous issue date: 2008 / Resumo: A Entomologia Forense utiliza dados de desenvolvimento e aspectos ecológicos de insetos necrófagos com o objetivo de auxiliar as investigações criminais, entre outros, no cálculo da estimativa do intervalo pós-morte (IPM). Igualmente, pode-se caracterizar a causa da morte quando essas drogas são detectadas em insetos imaturos que se alimentam dos corpos em decomposição. Além disso, os insetos podem servir como uma ferramenta alternativa para análises toxicológicas na ausência de tecidos e fluídos coletados habitualmente para este fim. Trabalhos recentes têm demonstrado que a presença de drogas ou toxinas em tecidos em decomposição pode alterar a taxa de desenvolvimento de insetos que usam este recurso como fonte alimentar. A ausência de conhecimentos dos possíveis interferentes no ciclo biológico pode gerar dados imprecisos sobre a idade do inseto, o que prejudicaria a estimativa do IPM. O ramo da Entomologia Forense que estuda os aspectos acima mencionados é denominado Entomotoxicologia. Rotineiramente, é necessário fazer testes preliminares em laboratório com dieta artificial e com certas substâncias para criar um banco de dados que possa ser útil como um padrão para investigar e quantificar as modificações que podem ocorrer com insetos coletados numa cena criminal. O objetivo principal deste estudo foi observar o efeito dos barbitúricos, fenobarbital (Gardenal®) e tiopental (Thiopentax®) em diferentes dosagens no desenvolvimento de imaturos de três espécies de califorídeos ¿ Chrysomya albiceps (Wiedemann), Chrysomya megacephala (Fabricius) e Chrysomya putoria (Wiedemann) (Diptera). Foi observado que os dois barbitúricos afetaram significativamente o desenvolvimento larval das três espécies, sendo que na maior dosagem a taxa de mortalidade foi elevada e na menor, o desenvolvimento retardou em até duas vezes, quando comparado ao grupo controle (sem adição de substância química). O conhecimento da ação destes barbitúricos no desenvolvimento dos imaturos dessas espécies de interesse forense pode contribuir para evitar erros no cálculo da estimativa do IPM. Também foi avaliada a taxa de desenvolvimento de Chrysomya albiceps (Wiedemann) e Chrysomya megacephala (Fabricius) (Diptera) criadas em diferentes dietas artificiais contendo tecidos de origem animal e comparadas a uma dieta já descrita em literatura, a qual não contém tecido animal, e a um grupo controle, onde foi usada somente a carne moída. A eficiência de cada dieta foi observada levando em conta o ganho de massa dos imaturos, o tempo de desenvolvimento larval, a taxa de sobrevivência de pupas e adultos, o intervalo de emergência e o tamanho dos adultos. Assim, foi proposta uma nova dieta artificial proporcionando uma melhor uniformidade para a adição de drogas e sobrevivência das espécies estudadas, tornando mais eficiente a criação e os testes biológicos com os dípteros necrófagos em laboratório / Abstract: The Forensic entomology utilizes developmental data and ecological aspects of necrophagic insects with the aim of helping criminal investigations, being able to, for instance, estimate the post mortem interval (PMI). Likewise, the death cause may be detected when these drugs are detected in immature insects from the same substrate. Besides, the insects can work as an alternative tool for toxicological analyses in the absence of tissues and fluids usually collected for this purpose. Recent investigations have been demonstrating that the presence of drugs or toxins in decomposing tissues may alter the development rate of insects that use such resource as a food substrate. The non-observance of this knowledge may lead to imprecise conclusions on the insect age, producing mistakes on the PMI estimative. This field of forensic entomology is named entomotoxicology. On routine basis, laboratory preliminary tests using artificial diet and certain substances are necessary to create a data bank that could be useful as a pattern to investigate and quantify the modifications that may occur with insects collected from death scenes. The present study aimed to verify the effect of the barbiturics phenobarbital (Gardenal®) and thiopental (Thiopentax®) in three concentrations, in the development of immatures of three Calliphoridae species ¿ Chrysomya albiceps (Wiedemann), Chrysomya megacephala (Fabricius) and Chrysomya putoria (Wiedemann) (Diptera). The barbiturics significantly affected the larval development of the three species, when the highest mortality rate occurred with the highest concentrations, and in the other concentrations the development retarded twice as much compared to the control group (without chemic substance). The knowledge on the action of these barbiturics in the immature development of these species of forensic interest can contribute to minimize the errors in the estimative of the PMI. A comparison of the developmental rate of the blowflies Chrysomya albiceps (Wiedemann), and Chrysomya megacephala (Fabricius) (Diptera) reared on: a) artificial diets containing animal tissues; b) artificial diet without animal tissue; and c) a control group (which contained only meat) was thus carried out. The efficiency of each diet was evaluated by observing the gain of immatures¿ weight, larvae developmental time, viability percentage obtained from pupae and adults, emergence interval and adult size. To make the rearing and biological tests with the necrophagic dipterans in laboratory more efficient, a new artificial diet was proposed, leading to a better uniformity and increased survivorship of the species studied. / Doutorado / Parasitologia / Doutor em Parasitologia

Abstract Functional magnetic resonance imaging (fMRI) has become a leading tool in the evaluation of the human brain function. In fMRI the activation induced blood oxygenation changes in the brain can be detected with an inherent blood oxygen level dependent (BOLD) contrast. Even small blood oxygen fluctuations in a resting brain can be depicted with the BOLD contrast. This thesis focuses on characterizing spontaneous oxygenation fluctuations of the brain by using BOLD fMRI. The effects of anesthetics on blood oxygen fluctuations were assessed in 38 children and 12 adults. The spatial distribution, frequency, synchrony, and statistical independence of the spontaneous oxygenation changes were analyzed. The role of imaging artifacts in the generation of BOLD signal fluctuations was investigated. The study aimed to develop and compare methods of detecting the nondeterministic oxygenation fluctuations of the brain. VLF BOLD signal fluctuation in the brain cortex is induced by physiological oscillation instead of imaging artifacts. This study shows for the first time how the power and synchrony of very low frequency (VLF <  0.05 Hz) blood oxygen fluctuation significantly increases after sedation. In deeper anesthesia, the VLF fluctuation overpowers other sources of blood oxygen variation as a sign of reduced blood flow and altered hemodynamic control. Regional hemodynamic mechanisms induce non-Gaussian features on the VLF blood oxygen fluctuation that can be depicted effectively with independent component analysis. Combined use of frequency, time, and spatial domain analysis guarantees a more complete picture of brain oxygenation fluctuations. The results of this thesis have a dualistic impact on fMRI research. First of all, VLF fluctuation alters the BOLD activation and connectivity results after sedation. Thus it has to be accounted for in the fMRI of sedated subjects. Secondly, by using the methods developed in this thesis, VLF fluctuation and other physiological BOLD signal sources can now be used in characterizing physiological alterations and pathology of the brain.

The neurotoxic potential of intravenous administered benzylpenicillin (BPC) was studied in rabbits with intact blood-CNS barriers and rabbits with experimental E. coli meningitis. At onset of epileptogenic EEG activity or seizures, serum, CSF and brain tissue were collected for assay of BPC. Based on the fact that, in tissues, BPC seems to remain extracellularly, brain concentrations of BPC were expressed as brain tissue fluid (BTF) levels, calculated as lOx the concentration in whole brain tissue. Neurotoxicity could be precipitated in all rabbits. In normal rabbits BTF levels of BPC were considerably higher than those in CSF indicating a better penetration across the blood-brain barrier (BBB). BPC penetrated better to CSF and BTF in meningitic rabbits than in normal controls, suggesting some degree of damage of the BBB concomitant with meningeal inflammation. E. coli meningitis did not increase the neurotoxicity of BPC. In control rabbits the intracistemal injection of saline resulted in some degree of pleocytosis. Unmanipulated animals are therefore preferable as controls. Epileptogenic EEG-changes was the most precise of the two variables used for demonstration of neurotoxicity. EEG-changes were therefore used as neurotoxicity criterion in the following rabbit experiments. To evaluate the effect of uraemia alone and uraemia plus meningitis on the neurotoxity of BPC in rabbits, cephaloridine was used to induce uraemia. Meningitis was induced by intracistemal inoculation of a cephalosporinresistant strain of E. cloacae. Untreated  rabbits were used as controls. Uraemia resulted in increased BTF penetration of BPC, possibly explained by permeability changes in the BBB and/or decreased binding of BPC to albumin. Uraemia did not result in increased penetration of BPC into the CSF of non-meningitic rabbits. Uraemic non-meningitic rabbits had the highest BTF levels of BPC at the criterion, indicating that cephaloridine-induced renal failure increased the epileptogenic threshold in these rabbits. The combination of uraemia and meningitis increased the neurotoxicity of BPC since the criterion was reached at considerably lower BTF levels of BPC. Meningitis, either alone or together with uraemia, did not increase the neurotoxicity in comparison to control rabbits. Higher BTF levels of BPC were found in meningitic rabbits than in controls with intact blood-CNS barriers at onset of EEG-changes. In all groups of rabbits there was a pronounced variability of BPC levels in the CSF while the intra-group variations in BTF levels were much smaller. Thus, BTF and not CSF levels were decisive for the neurotoxicity of BPC. Using   the same EEG-model, the neurotoxic potential of imipenem/cilastatin (I) and a new penem derivative, FCE 22101 were compared in a cross-over study. Both I and FCE 22101 were significantly more neurotoxic than BPC. While BTF levels of the three antibiotics could be detected in all tested rabbits, detectable CSF levels were only found in one of twelve rabbits treated with I or FCE 22101, indicating that BTF concentrations rather than CSF ones are decisive for neurotoxicity of ß-lactam antibiotics. The EEG-model used was found to be a suitable model for cross-over studies of intravenously administered antibiotics. Using the "silent-second" as EEG-threshold, a CNS interaction between intraperitoneally administered BPC and intravenous thiopental was demonstrated in rats. The most probably site for this interaction is the organic acid transport system out of the CNS. Thiopental distribution in the rat brain seemed to depend not only on its lipid solubility. / <p>Diss. (sammanfattning) Umeå : Umeå universitet, 1988, härtill 5 uppsatser.</p> / digitalisering@umu

Abstract The purpose of the present study was to gain more insight into the blood oxygen level-dependent (BOLD)-contrast functional MRI (fMRI) in the brain and its connection to EEG, both in global and local scales of their temporal and spatial relations. BOLD signal changes were studied during hyperventilation (HV) induced EEG reactivity of intermittent rhythmic delta activity (IRDA). The BOLD signal in gray matter decreased 30% more in subjects with IRDA (N = 4) than in controls (N = 4), during the first two minutes of HV. This difference disappeared during IRDA in EEG. BOLD signal changes may provide additional information about dynamic hemodynamic changes relative to HV induced EEG reactivity. BOLD signal changes were investigated during sudden deepening of thiopental anesthesia into EEG burst-suppression level in pigs (N = 5). Positive (6–8%) or negative (-3– -8%) group average BOLD signal changes correlated to the thiopental bolus injection were seen. Positive and negative responses covered 1.6% and 2.3% of the brain voxels, respectively. BOLD signal changes in brain are associated with sudden deepening of thiopental anesthesia into EEG burst-suppression level, but they are spatially inconsistent and scarce. Somatosensory BOLD response was studied in brain before and after globally induced methotrexate (MTX) exposition in pigs (N = 4). After the MTX exposure, reduced (from 2–4% to 0–1%) or negative (-2% to -3%) BOLD responses were detected. Somatosensory BOLD-contrast response shows a slight difference in brain before and after globally induced MTX exposition. An experimental epilepsy model for development of simultaneous EEG and BOLD-contrast fMRI in the localization of epilepsy was developed and tested. Dynamic penicillin induced local epilepsy was applied in deep isoflurane anesthesia in pigs (N = 6). Relatively high (10–20%) and localized BOLD signal increase was found. The dynamic penicillin induced focal epilepsy model in deep isoflurane anesthesia with simultaneous EEG and BOLD-contrast fMRI is feasible for the development of these methods for localization of epileptic focus or foci. In conclusion, with careful experimental design and analysis, BOLD-contrast fMRI with EEG provides a potential tool for monitoring and localising functional changes in the brain.