No description available.

Thesis (M.S.)--Virginia Polytechnic Institute and State University, 1990. / Vita. Abstract. Includes bibliographical references (leaves 171-183). Also available via the Internet.

Thesis (M.Sc.) -- University of Adelaide, Dept. of Human Physiology and Pharmacology, 1976. / Typescript (photocopy).

Thesis (Ph. D.)--University of Washington, 1998. / Vita. Includes bibliographical references (leaves [214]-226).

Thesis (doctoral)--University of Stockholm, 1983. / Publications on which thesis is based are appended. Includes bibliographical references.

This thesis comprises an investigation into the reaction of halogenated xenobiotics and anaesthetic agents, with hepatic microsomal stearate desaturase. The levels of stearate desaturase in the hepatic microsomes were routinely elevated by re-feeding the experimental animals a high carbohydrate diet. The interaction of the xenobiotics with stearate desaturase was assessed by monitoring their effects on the redox steady state of hepatic microsomal cytochrome b₅, in the presence and absence of cyanide.

Previous experiments have demonstrated that the hepatoxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) involves synergism with iron. It has been postulated that it is storage iron that plays a role in toxic effects observed with TCDD poisoning. It was hypothesized that TCDD induction of the Ah gene locus in some way leads to mobilization of storage iron from the iron storage protein ferritin. Microsomal ferritin iron release was investigated in intact microsomes and in a reconstituted system. Evidence is presented which suggests that NADPH-cytochrome c (P450) reductase is capable of effecting the release of iron from flavin (FMN), and that at the same time, the reduced flavin thus generated is capable of effecting the release of iron from ferritin. While no direct evidence was obtained, the results do lend support to the hypothesis that TCDD toxicity could result from the mobilization of iron from ferritin by the TCDD induced microsomal electron transport system. / Thesis / Master of Science (MSc)

No description available.

Orientador: Rosangela Goncalves Peccinini / Resumo: A tuberculose é uma doença infectocontagiosa provocada pelo Mycobacterium tuberculosis que apesar de reconhecida a muitos anos, ainda tem ocorrência frequente na sociedade, assim como os casos de resistência aos medicamentos, que tem apresentado aumento significativo nos últimos anos. Na busca de novas estratégias para o tratamento, pesquisadores da Unifesp-Diadema desenvolveram novos compostos com potencial atividade antimicobacteriana, denominados pirazinoato de metila (I), pirazinoato de etila (II), pirazinoato de butila (III) e 2-(pirazina-2-carboniloxi)etill pirazina-2-carboxilato (IV), derivados do ácido pirazinóico, principal metabólito da pirazinamida. Ensaios in vitro como a avalição de propriedades físico-químicas e ensaios que avaliam a absorção, distribuição, metabolismo e excreção (ADME), auxiliam na predição das características farmacocinéticas em um estágio inicial do desenvolvimento, permitindo a seleção dos melhores candidatos a novos fármacos. O presente estudo teve como objetivo a realização de screening físico-químico (determinação do coeficiente de partição e da estabilidade química nos pHs de 1,2; 7,4 e 8,8) e ensaios de ADME (cálculo da permeabilidade aparente em monocamada de células Caco-2, a avaliação da estabilidade metabólica em microssoma de ratos e de humanos e avaliação da estabilidade em plasma de rato). Os compostos apresentaram logP de valor negativo, indicando hidrofilicidade e foi observada estabilidade frente os três pHs avaliados. A perme... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Tuberculosis is an infectious disease caused by Mycobacterium tuberculosis which, although recognized for many years, still occurs frequently in society, as well as cases of drug resistance, which has shown a significant increase in recent years. In the search for new treatment strategies, researchers at Unifesp-Diadema have developed new compounds with potential antimycobacterial activity called methyl pyrazinoate (I), ethyl pyrazinoate (II), butyl pyrazinoate (III) and 2- (pyrazine-2 -carbonyloxy) ethyl] pyrazine-2-carboxylate (IV), derivatives of pyrazinoic acid, pyrazinamide's main metabolite. In vitro assays such as the evaluation of physicochemical properties and assays that evaluate absorption, distribution, metabolism and excretion (ADME), aid in the prediction of pharmacokinetic characteristics at an early stage of development, allowing the selection of the best candidates for new drugs. The objective of the present study was the physical-chemical screening (determination of partition coefficient and chemical stability at pHs of 1.2, 7.4 and 8.8) and ADME tests (calculation of the apparent permeability in monolayer of Caco-2 cells, evaluation of metabolic stability in rat and human microsomes and evaluation of stability in rat plasma). The compounds presented logP negative value, indicating hydrophilicity and stability was observed the three pHs evaluated. The apparent permeability calculated for compounds I, II, III and IV resulted in values of 4.66 x10-6; 4.14 x10-... (Complete abstract click electronic access below) / Mestre

Orientador: Rosângela Gonçalves Peccinini / Resumo: Estudos precoces de ADME podem agilizar o processo de desenvolvimento de novos fármacos, selecionando os mais promissores para futuros estudos farmacocinéticos. Nesse sentido, e considerando a necessidade de novos tratamentos para a leishmaniose visceral e para a tripanossomíase americana, as moléculas LINS03006, LINS03011 e LINS03013 com ação sobre o Trypanosoma cruzi e a Leishmania infantum foram desenvolvidas por pesquisadores da UNIFESP/Diadema. O presente trabalho teve como objetivo realizar estudos físico-químicos e de ADME para a seleção das moléculas LINS mais promissoras para futuros estudos in vivo. Métodos analíticos e bioanalíticos por UHPLC/UV foram desenvolvidos para a quantificação dos compostos nos ensaios realizados. Foram realizados estudos de estabilidade química em diferentes pHs (1,2; 7,4 e 8,8), estabilidade metabólica em microssomos de rato e humano, estabilidade ex vivo, coeficientes de partição (log P) e permeabilidade em células Caco-2. Os compostos apresentaram estabilidade de até 24 horas em todos os pHs avaliados, levando à expectativa de que na administração oral não ocorrerá degradação decorrente do pH estomacal, sanguíneo e duodenal. O estudo em plasma de rato resultou, para todos os compostos, estabilidade em tempo suficiente – ao menos 6 horas – com expectativa de que ocorra efeito in vivo. Nos estudos de logP, os compostos apresentam características lipofílicas, favorecendo a permeabilidade e o clearance hepático. No ensaio de permeabilidade... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Early studies of ADME can speed up the development of new drugs, selecting the most promising for future pharmacokinetic studies. In this sense, and considering the need for new treatments for visceral leishmaniasis and american trypanosomiasis, the molecules LINS03006, LINS03011 and LINS03013 with action on Trypanosoma cruzi and Leishmania infantum were developed by researchers from UNIFESP/Diadema. The present work aimed to perform physical-chemical and ADME studies to select the most promising LINS molecules for future in vivo studies. Analytical and bioanalytical methods by UHPLC/UV were developed for the quantification of compounds in the assays performed. Chemical stability studies were performed at different pHs (1.2, 7.4 and 8.8), metabolic stability in rat and human microsomes, ex vivo stability, partition coefficients (log P) and permeability in Caco-2 cells. The compounds exhibited stability of up to 24 hours in all evaluated pHs, leading to the expectation that oral degradation will not occur due to stomach, blood and duodenal pH. The study in rat plasma resulted, for all compounds, stability in sufficient time - at least 6 hours - with the expectation that in vivo effect would occur. In logP studies, the compounds presented lipophilic characteristics, favoring permeability and hepatic clearance. In the permeability assay, the LINS compounds presented Papp > 5.0xE-06 cm/s, which can be classified as medium or high permeability, thus, there is an expectation of abs... (Complete abstract click electronic access below) / Mestre