Cerebral blood flow dynamics is an essential component for preserving cerebral integrity. Cerebral blood flow abnormalities are often seen in patients with central nervous system pathologies such as epilepsy, migraine, Alzheimer's Disease, vascular dementia, stroke, and even HIV/AIDS. There is increasing clinical and experimental evidence implicating cerebral hypoperfusion during ageing. The determination of cerebral perfusion has therefore become an important objective in physiological, pathological, pharmacological, and clinical investigations. The knowledge of regional cerebral blood flow further provides useful diagnostic information and/or data for a better understanding of the complex clinical presentations in patients with neurological and psychiatric disorders. Several cerebrovasoactive drugs have found application in the clinical setting of cerebrovascular diseases such as migraine and dementia. Due to the similarities between humans and non-human primates with respect to their brains, both structurally and behaviourally, numerous studies have been conducted and several non-human primate models have been developed for physiological, pathological, pharmacological, and clinical studies, amongst others in Parkinson's disease and diabetes. The relatively large size of the Cape baboon Papio Ursinus with a weight of 27-30 kg for a large male, makes this primate especially suitable for in vivo brain studies using radiotracers and Single Photon Emission Computed Tomography (SPECT). The main aim of the current study was therefore to develop a suitable radiotracer (99m Tc-hexamethylpropylene amine oxime (HMPAO) or 99m Tc_ethyl_cysteinatedimer (ECD) or 123l-iodoamphetamine (IMP)) for adapted in vivo cerebral blood flow measurements in a non-human primate (Papio ursinus) as an investigative model. The model was to be validated and applied in various drug studies for the evaluation of pharmacological interventions. The study design made use of split-dose methodology, whereby the radiopharmaceutical (radiotracer) was administered twice during each study. The first administration was injected soon after the induction of the anaesthesia, and was followed by the first SPECT data acquisition. The second administration of the radioligand, a double dose of radioactivity with respect to the first radioligand injection, was done at a specific time during the study, which took into account the pharmacodynamics of the drug. A second SPECT data acquisition followed subsequently. The drugs that were included in the study were acetazolamide, a carbonic acid anhydrase inhibitor (often used in nuclear medicine to determine cerebral reserve); sumaptriptan, a 5-HT (serotonin) agonist used for treatment of migraine; sodium valproate (an anti-epileptic drug); nimodipine, a calcium channel blocker and nitro-glycerine, a vasodilator used for angina. Arterial blood pressures were recorded from a catheter in the femoral artery and heart rates were concurrently monitored. The split-dose method was successfully applied to develop a non-human primate cerebral blood flow model under anaesthesia. The model showed differences in cerebral perfusion of the different anaesthesia regimes. These anaesthesia data sets were suitable as control/baseline results for drug intervention studies. Acetazolamide evaluation through the split-dose method in the baboon confirmed the sensitivity of the model by presenting comparable perfusion. This result compared to those already familiar prompted the model to be applied in pharmacological intervention studies. Subsequent results of these investigations showed increases in perfusion for single drug nimodipine treatment (25%). However, nimodipine attenuated the increases in perfusion when administered in combination with acetazolamide. Sumatriptan was able to decrease and normalise the increased perfusion after long duration anaesthesia. Decreased cerebral blood flow was observed for combinations of nimodipine with sodium valproate suggesting drug-drug interaction with important clinical implications. Similar decreases were found also for sumatriptan and nitro-glycerine when administered in combination with nimodipine. Studies with the various tracers (99m Tc_HMPAO or 99m Tc_ECD or 123l_IMP) showed clear differences in the perfusion data, confirming variation in the biochemical performance of the tracers. These differences, if not taken into consideration, caution for inappropriate clinical conclusions and subsequent erroneous therapeutic decisions. Improvement of radiotracer efficacy was subsequently attempted through application of the cyclodextrine complexation approach. Although cyciodextrine technology did not markedly improve the brain disposition of the 99m Tc-ECD, protection of the tracer against degradation was demonstrated. This study encouraged further exploration of this method for protection of the tracer against chemical and metabolic degradation. The current study was aimed to develop and effectively apply a non-human primate model with nuclear medicine technology for cerebral blood flow determinations after pharmacological interventions. This was achieved through the split-dose method and dedicated computer programming, which yielded a successful model with the non-human primate under anaesthesia. The model was validated with the application of acetazolamide to confirm familiar cerebrovascular reserve results, indicating that the model is sensitive to CBF changes. The model was also effectively applied in several pharmacological intervention studies, whereby cerebropharmacodynamics of selected drugs were investigated and established. This unique model of a non-human primate, Papio ursinus for cerebral blood flow determinations has served pharmacological research successfully during the past 12 years and could do so in the future, with scope to investigate new frontiers with improved technologies. / Thesis (Ph.D. (Pharmacology))--North-West University, Potchefstroom Campus, 2004.

Thesis (Ph.D.)--McMaster University, 2005. / Supervisor: John Fitzmaurice Valliant. Includes bibliographical references. Also available online.

Thesis (Ph.D.)--McMaster University, 2005. / Supervisor: John Fitzmaurice Valliant. Includes bibliographical references. Also available online.

Thesis (PhD) -- McMaster University, 1997. / Also available via World Wide Web.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2005. / Härtill 5 uppsatser.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2006. / Härtill 5 uppsatser.

Thesis (M.S.)--University of Missouri--Columbia, 2003. / "December 2003." Typescript. Vita. Includes bibliographical references (leaves 84-96). Also issued on the Internet.

Thesis (M.S.)--University of Missouri--Columbia, 2003. / "December 2003." Typescript. Vita. Includes bibliographical references (leaves 84-96). Also issued on the Internet.

Os radiofármacos são preparações farmacêuticas, que contém radionuclídeo, utilizados em medicina nuclear. O objetivo desse trabalho foi estudar as concentrações de elementos químicos, principalmente metais, em amostras de radiofármacos ALBUMINA-TEC, DEX 70-TEC, DEX 500-TEC, DISIDATEC, DMSA-TEC, EC-TEC, DTPA-TEC, FITATO-TEC, GHA-TEC, MDP-TEC, MIBI-TEC, PIRO-TEC, FDG-Flúor-18, GERADOR IPEN-TEC, IODO-131 SOLUÇÃO. As análises foram realizadas em equipamento Vista MPX simultâneo ICP-OES (Agilent, Australia). A validação do método foi realizado segundo os critérios descritos na RDC n° 899: Guia para validação de métodos analíticos e bioanalíticos de 29 de maio de 2003. De acordo com a Farmacopeia Americana (USP), as impurezas elementares com potencial toxicidade devem ser quantificados. Uma proposta de revisão USP 35 introduz a técnica de espectrometria de emissão atômica para a análise de elementos. Os resultados de validação das análises no ICP-OES indicam a necesidade de controle da limpeza e manutenção do equipamento, alterações do sample uptake delay e avaliação da robustez com as linhas do Mg. As curvas analíticas e faixas de concentracões analisadas foram lineares com r > 0,99. Os resultados de DPR foram abaixo de 5%. Todos os resultados dos parâmetros avaliados estão de acordo com os estabelecidos pela ANVISA. / Radiopharmaceuticals are pharmaceutical preparations containing radionuclide used in nuclear medicine. The aim of this work was to study the concentrations of chemical elements, especially metals, in samples of radiopharmaceuticals ALBUMINA-TEC, DEX 70-TEC, DEX 500-TEC, DISIDA-TEC, DMSA-TEC, EC-TEC, DTPA-TEC, FITATO-TEC, GHA-TEC, MDP-TEC, MIBI-TEC, PIRO-TEC, FDG-FLÚOR-18, GERADOR IPEN-TEC, IODO-131 SOLUÇÃO. The analyses were carried out simultaneously in an ICP-OES Vista MPX (Agilent). The method validation was performed according to the criteria defined in RDC No. 899 : Guide for validation of analytical and bioanalytical methods for May 29, 2003 of the ANVISA. According to the U.S. Pharmacopeia (USP), the elemental impurities with potential toxicity must be quantified. A proposed revision to USP 35 introduces the technique of atomic emission spectrometry for the analysis of elements. The validation results of the ICP- OES analyzes indicated the necessary to control the cleaning and maintenance of equipment, changes in sample uptake delay and robustness evaluation with the lines of Mg. The analytical curves and concentration ranges analyzed were linear with r > 0.99. The results of DPR were below 5%. All the parameters were below the established by ANVISA .

Made available in DSpace on 2014-10-09T12:35:12Z (GMT). No. of bitstreams: 0 / Made available in DSpace on 2014-10-09T13:56:12Z (GMT). No. of bitstreams: 0 / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / Dissertação (Mestrado) / IPEN/D / Instituto de Pesquisas Energeticas e Nucleares - IPEN-CNEN/SP / FAPESP:11/03138-8