Análise do perfil das solicitações de medicamentos por demanda judicial no estado de Santa Catarina no período de 2005 a 2008

Dissertação (mestrado) - Universidade Federal de Santa Catarina, Centro de Ciências da Saúde, Programa de Pós-Graduação em Farmácia, Florianópolis, 2010A Constituição Federal de 1988 reconheceu o direito à saúde como direito fundamental a ser garantido pelo Estado aos cidadãos. Com base neste entendimento, ações judiciais, demandando medicamentos, vêm sendo impetradas contra o Estado, comprometendo o planejamento de políticas públicas e onerando os cofres públicos. Este trabalho teve como objetivo analisar o perfil das solicitações de medicamentos por demanda judicial no Estado de Santa Catarina, nos anos de 2005 a 2008. Realizou-se estudo descritivo, transversal, quantitativo, complementar ao desenvolvido em 2003 e 2004 por Pereira (2006). Os dados foram coletados na Diretoria de Assistência Farmacêutica em Santa Catarina. O perfil geral das demandas foi obtido por meio da análise total dos processos. O número de solicitações no período de 2003 a 2008 foi correlacionado com as alterações normativas do Ministério da Saúde. Os produtos foram categorizados pela Classificação Anatômica Terapêutica Química e quanto à pertinência nos Componentes da Assistência Farmacêutica. Por meio de consulta ao banco de dados da Agência Nacional de Vigilância Sanitária (ANVISA), foi possível analisar a situação do registro. Calculou-se amostra aleatória, estratificada por ano de início da ação. Realizou-se consulta manual em 716 processos a fim de caracterizá-los. O número de processos impetrados contra o Estado de Santa Catarina passou de 762, no ano de 2005, para 2875, em 2008. De 2005 a 2008, foram gastos, aproximadamente, R$151 milhões, com a aquisição de medicamentos. Mais de 60$ 3,00 a R$ 38.000,00. Predominaram prescrições provenientes do SUS (52,5%) e 46,2% não foram prescritas, conforme Denominação Comum Brasileira/Denominação Comum Internacional. Concluiu-se que, ao longo do período analisado, houve aumento no número de ações judiciais bem como no volume financeiro gasto pelo Estado para atendê-las. Um percentual de solicitações é pertinente. Por outro lado, existem demandas questionáveis como o custeio de tratamentos experimentais, não padronizados ou sem registro na ANVISA. O diagnóstico e análise do fenômeno da judicialização podem gerar parâmetros e indicadores hábeis à reformulação da política e gestão da Assistência Farmacêutica, de forma a minimizar seus efeitos e melhorar o atendimento ao cidadão

Peroxidasin-mediated crosslinking of collagen IV is independent of NADPH oxidases

Collagen IV is a major component of the basement membrane in epithelial tissues. The NC1 domains of collagen IV protomers are covalently linked together through sulfilimine bonds, the formation of which is catalyzed by peroxidasin. Although hydrogen peroxide is essential for this reaction, the exact source of the oxidant remains elusive. Members of the NOX/DUOX NADPH oxidase family are specifically devoted to the production of superoxide and hydrogen peroxide. Our aim in this study was to find out if NADPH oxidases contribute in vivo to the formation of collagen IV sulfilimine crosslinks. We used multiple genetically modified in vivo model systems to provide a detailed assessment of this question. Our data indicate that in various peroxidasin-expressing tissues sulfilimine crosslinks between the NC1 domains of collagen IV can be readily detected in the absence of functioning NADPH oxidases. We also analyzed how subatmospheric oxygen levels influence the collagen IV network in collagen-producing cultured cells with rapid matrix turnover. We showed that collagen IV crosslinks remain intact even under strongly hypoxic conditions. Our hypothesis is that during collagen IV network formation PXDN cooperates with a NOX/DUOX-independent H2O2 source that is functional also at very low ambient oxygen levels. © 201

Cytochrome c-promoted cardiolipin oxidation generates singlet molecular oxygen

The interaction of cytochrome c (cyt c) with cardiolipin (CL) induces protein conformational changes that favor peroxidase activity. This process has been correlated with CL oxidation and the induction of cell death. Here we report evidence demonstrating the generation of singlet molecular oxygen [O-2((1)Delta(g))] by a cyt c-CL complex in a model membrane containing CL. The formation of singlet oxygen was directly evidenced by luminescence measurements at 1270 nm and by chemical trapping experiments. Singlet oxygen generation required cyt c-CL binding and occurred at pH values higher than 6, consistent with lipid-protein interactions involving fully deprotonated CL species and positively charged residues in the protein. Moreover, singlet oxygen formation was specifically observed for tetralinoleoyl CL species and was not observed with monounsaturated and saturated CL species. Our results show that there are at least two mechanisms leading to singlet oxygen formation: one with fast kinetics involving the generation of singlet oxygen directly from CL hydroperoxide decomposition and the other involving CL oxidation. The contribution of the first mechanism was clearly evidenced by the detection of labeled singlet oxygen [O-18(2)((1)Delta(g))] from liposomes supplemented with 18-oxygen-labeled CL hydroperoxides. However quantitative analysis showed that singlet oxygen yield from CL hydroperoxides was minor (<5%) and that most of the singlet oxygen is formed from the second mechanism. Based on these data and previous findings we propose a mechanism of singlet oxygen generation through reactions involving peroxyl radicals (Russell mechanism) and excited triplet carbonyl intermediates (energy transfer mechanism).FAPESP (Fundacao de Amparo a Pesquisa do Estado de Sao Paulo)Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP)Conselho Nacional para o Desenvolvimento Cientifico e Tecnologico (CNPq)CNPq (Conselho Nacional para o Desenvolvimento Cientifico e Tecnologico)CAPES/PROCAD-NF (Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior/Programa Nacional de Cooperacao Academica Novas Fronteiras)CAPES/PROCADNF (Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior/Programa Nacional de Cooperacao Academica Novas Fronteiras)INCT de Processos Redox em Biomedicina - RedoxomaINCT de Processos Redox em Biomedicina RedoxomaNAPRedoxomaNAP-RedoxomaL'OREAL-UNESCO for Women in ScienceLOREALUNESCO for Women in ScienceJohn Simon Guggenheim Memorial FoundationJohn Simon Memorial Guggenheim Foundatio

Antioxidants inhibit low density lipoprotein oxidation less at lysosomal pH: a possible explanation as to why the clinical trials of antioxidants might have failed

Oxidised low density lipoprotein (LDL) was considered to be important in the pathogenesis of atherosclerosis, but the large clinical trials of antioxidants, including the first one using probucol (the PQRST Trial), failed to show benefit and have cast doubt on the importance of oxidised LDL. We have shown previously that LDL oxidation can be catalysed by iron in the lysosomes of macrophages. The aim of this study was therefore to investigate the effectiveness of antioxidants in preventing LDL oxidation at lysosomal pH and also establish the possible mechanism of oxidation. Probucol did not effectively inhibit the oxidation of LDL at lysosomal pH, as measured by conjugated dienes or oxidised cholesteryl esters or tryptophan residues in isolated LDL or by ceroid formation in the lysosomes of macrophage-like cells, in marked contrast to its highly effective inhibition of LDL oxidation at pH 7.4. LDL oxidation at lysosomal pH was inhibited very effectively for long periods by N,N'-diphenyl-1,4-phenylenediamine, which is more hydrophobic than probucol and has been shown by others to inhibit atherosclerosis in rabbits, and by cysteamine, which is a hydrophilic antioxidant that accumulates in lysosomes. Iron-induced LDL oxidation might be due to the formation of the superoxide radical, which protonates at lysosomal pH to form the much more reactive, hydrophobic hydroperoxyl radical, which can enter LDL and reach its core. Probucol resides mainly in the surface monolayer of LDL and would not effectively scavenge hydroperoxyl radicals in the core of LDL. This might explain why probucol failed to protect against atherosclerosis in various clinical trials. The oxidised LDL hypothesis of atherosclerosis now needs to be re-evaluated using different and more effective antioxidants that protect against the lysosomal oxidation of LDL

The Mechanism of Formation of N-Formylkynurenine by Heme Dioxygenases

[Image: see text] Heme dioxygenases catalyze the oxidation of l-tryptophan to N-formylkynurenine (NFK), the first and rate-limiting step in tryptophan catabolism. Although recent progress has been made on early stages in the mechanism, there is currently no experimental data on the mechanism of product (NFK) formation. In this work, we have used mass spectrometry to examine product formation in a number of dioxygenases. In addition to NFK formation (m/z = 237), the data identify a species (m/z = 221) that is consistent with insertion of a single atom of oxygen into the substrate during O(2)-driven turnover. The fragmentation pattern for this m/z = 221 species is consistent with a cyclic amino acetal structure; independent chemical synthesis of the 3a-hydroxypyrroloindole-2-carboxylic acid compound is in agreement with this assignment. Labeling experiments with (18)O(2) confirm the origin of the oxygen atom as arising from O(2)-dependent turnover. These data suggest that the dioxygenases use a ring-opening mechanism during NFK formation, rather than Criegee or dioxetane mechanisms as previously proposed