Neural tube defects (NTD) result from the failure of the neural tube to close properly very early in gestation. A child born with an NTD may experience an early death or life-long disability. In the 1990s, the critical role of folic acid in the prevention of NTDs was confirmed and as a strategy to increase blood folate concentrations of women of childbearing age, folic acid fortification programs were mandated in Canada and the US. However, this change impacted the entire population not just women of childbearing age and not everyone may benefit from the increased folate intake. The objective of this research was to investigate the impact of higher intakes of folates on the mortality rates of children with acute lymphoblastic leukemia (ALL) and the risk of colorectal cancer (CRC) in adult populations. To address the impact in children with ALL, a comparison of the mortality rates between the pre- and post-fortification time periods in Ontario was performed using data from the Pediatric Oncology Group of Ontario. A second comparison between the mortality rates in these children in non-folic acid fortifying countries and the US was also completed. These analyses suggest that folic acid fortification is not negatively impacting mortality. With respect to CRC, one systematic review and two meta-analyses were conducted investigating folate intake and the risk of CRC or adenoma recurrence. The first analysis, in observational studies, compared high versus low folate intake and the risk of CRC. The second examined folate intake within the various polymorphisms of the methylene tetrahydrofolate reductase enzyme. The final study examined the impact of supplementation of 1 milligram or more per day of folic acid and the risk of colorectal adenoma recurrence in those adults with a history of colorectal adenomas. The findings from the completed observational studies suggest that there is an associated risk reduction in colorectal cancer from the intake of higher levels of folates. The investigations into the impact of the folic acid fortification program suggest that the program is not associated with having a negative impact on mortality of children with ALL or on the risk of colorectal cancer.

Neural tube defects (NTD) result from the failure of the neural tube to close properly very early in gestation. A child born with an NTD may experience an early death or life-long disability. In the 1990s, the critical role of folic acid in the prevention of NTDs was confirmed and as a strategy to increase blood folate concentrations of women of childbearing age, folic acid fortification programs were mandated in Canada and the US. However, this change impacted the entire population not just women of childbearing age and not everyone may benefit from the increased folate intake. The objective of this research was to investigate the impact of higher intakes of folates on the mortality rates of children with acute lymphoblastic leukemia (ALL) and the risk of colorectal cancer (CRC) in adult populations. To address the impact in children with ALL, a comparison of the mortality rates between the pre- and post-fortification time periods in Ontario was performed using data from the Pediatric Oncology Group of Ontario. A second comparison between the mortality rates in these children in non-folic acid fortifying countries and the US was also completed. These analyses suggest that folic acid fortification is not negatively impacting mortality. With respect to CRC, one systematic review and two meta-analyses were conducted investigating folate intake and the risk of CRC or adenoma recurrence. The first analysis, in observational studies, compared high versus low folate intake and the risk of CRC. The second examined folate intake within the various polymorphisms of the methylene tetrahydrofolate reductase enzyme. The final study examined the impact of supplementation of 1 milligram or more per day of folic acid and the risk of colorectal adenoma recurrence in those adults with a history of colorectal adenomas. The findings from the completed observational studies suggest that there is an associated risk reduction in colorectal cancer from the intake of higher levels of folates. The investigations into the impact of the folic acid fortification program suggest that the program is not associated with having a negative impact on mortality of children with ALL or on the risk of colorectal cancer.

Made available in DSpace on 2014-12-17T14:16:37Z (GMT). No. of bitstreams: 1 EdileneGO_DISSERT.pdf: 1950686 bytes, checksum: 88f16924cd116b850ade306c274f71ac (MD5) Previous issue date: 2014-12-20 / Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior / New drug delivery systems have been used to increase chemotherapy efficacy due the possible drug resistance of cancer cells. Poly (lactic acid) (PLA) microparticles are able to reduce toxicity and prolong methotrexate (MTX) release. In addition, the use of PLA/poloxamer polymer blends can improve drug release due to changes in the interaction of particles with biological surfaces. The aim of this study was developing spray dried biodegradable MTX-loaded microparticles and evaluate PLA interactions with different kinds of Pluronic? (PLUF127 and PLUF68) in order to modulate drug release. The variables included different drug:polymer (1:10, 1:4.5, 1:3) and polymer:copolymer ratios (25:75, 50:50, 75:25). The precision and accuracy of spray drying method was confirmed assessing drug loading into particles (75.0- 101.3%). The MTX/PLA microparticles showed spherical shape with an apparently smooth surface, which was dependent on the PLU ratio used into blends particles. XRD and thermal analysis demonstrated that the drug was homogeneously dispersed into polymer matrix, whereas the miscibility among components was dependent on the used polymer:copolymer ratio. No new drug- polymer bond was identified by FTIR analysis. The in vitro performance of MTX-loaded PLA microparticles demonstrated an extended-release profile fitted using Korsmeyer- Peppas kinetic model. The PLU accelerated drug release rate possible due PLU leached in the matrix. Nevertheless, drug release studies carried out in cell culture demonstrated the ability of PLU modulating drug release from blend microparticles. This effect was confirmed by cytotoxicity observed according to the amount of drug released as a function of time. Thus, studied PLU was able to improve the performance of spray dried MTX-loaded PLA microparticles, which can be successfully used as carries for modulated drug delivery with potential in vivo application / Novos sistemas de libera??o de f?rmacos v?m sendo utilizados para aumentar a efic?cia de quimioter?picos devido ? poss?vel resist?ncia de c?lulas cancer?genas. As micropart?culas de poli (?cido l?ctico) (PLA) constituem uma alternativa para diminuir a toxicidade e prolongar a libera??o do metotrexato (MTX). Al?m disso, o uso de blendas polim?ricas PLA-polox?meros pode melhorar o perfil de libera??o do f?rmaco devido a mudan?as nas intera??es das part?culas com superf?cies biol?gicas. O objetivo do estudo foi desenvolver micropart?culas biodegrad?veis de MTX produzidas por spray drying e avaliar intera??es PLA-Pluronic? (PLA-PLU) para modular a libera??o do f?rmaco, utilizando diferentes tipos de Pluronic? (PLUF127 e PLUF68). As vari?veis de composi??o inclu?ram raz?es f?rmaco:pol?mero (1:10; 1:4,5; 1:3) e pol?mero:copol?mero (25:75, 50:50, 75:25). A reprodutibilidade e a efic?cia do m?todo de produ??o foram confirmadas pela alta efici?ncia de incorpora??o dos sistemas (75,0-101,3%). As micropart?culas de MTX/PLA apresentaram-se esf?ricas com superf?cie aparentemente lisa. Este formato mostrou-se dependente da raz?o pol?mero:copol?mero nas part?culas contendo blendas. A an?lise t?rmica e a difra??o de raios-X sugerem que h? dispers?o do f?rmaco por toda a matriz, enquanto que a miscibilidade entre os componentes foi dependente da raz?o pol?mero:copol?mero. Nenhuma liga??o qu?mica entre o f?rmaco e o pol?mero foi identificada pela an?lise de FTIR. As micropart?culas de PLA contendo MTX apresentaram perfil de libera??o prolongada com um prevalente modelo cin?tico de Korsmeyer-Peppas. O PLU acelerou a taxa de libera??o do f?rmaco devido a sua poss?vel sa?da da matriz polim?rica. Por outro lado, estudos de libera??o do f?rmaco realizados em cultura de c?lulas demonstraram que o PLU modula a taxa de MTX liberado a partir de micropart?culas contendo blendas. Este efeito foi confirmado pela citotoxicidade dos sistemas estudados, de acordo com a quantidade de f?rmaco liberado em fun??o do tempo. Portanto, o uso de PLU foi capaz de melhorar o perfil de libera??o de micropart?culas de PLA contendo MTX, o qual pode ser utilizado como carreador para modular a libera??o do f?rmaco com potencial aplica??o in vivo

Conselho Nacional de Desenvolvimento CientÃfico e TecnolÃgico / A mucosite induzida por quimioterÃpicos à um efeito colateral importante e limitante da terapia do cÃncer, cuja fisiopatologia nÃo à completamente compreendida. O presente estudo visa investigar o papel do Ãxido nÃtrico (NO) na patogÃnese das mucosites oral e intestinal induzidas por 5-fluorouracil (5-FU) e metotrexato (MTX) e os efeitos da glutamina (GLU) e alanil-glutamina (AL-GLU) na mucosite oral induzida por 5-FU. A mucosite oral foi induzida por duas administraÃÃes intraperitoneais (i.p.) de 5-FU nos 1 e 2 dias (60 e 40 mg/kg respectivamente), em hamsters. Os animais foram tratados subcutaneamente (s.c.) com os inibidores da Ãxido nÃtrico sintase (NOS), N-(3-(Aminomethyl)benzyl)acetamidina (1400W; 1 mg/kg), aminoguanidina (AG; 5 or 10 mg/kg), Nφ-Nitro-L-Arginina Methyl Ester (L-NAME; 5, 10 or 20 mg/kg) ou salina (0,4 ml), uma hora antes do 5-FU e, diariamente, atà o sacrifÃcio, no 10 dia. Em outro ciclo de experimentos, os animais receberam salina, suspensÃo de GLU ou de AL-GLU (100 mM) uma hora antes do 5-FU e, diariamente, atà o sacrifÃcio, nos 10 e 14 dias. A mucosite intestinal foi induzida pela administraÃÃo de MTX (2,5 mg/kg; s.c.) nos primeiros trÃs dias de experimentos, em ratos Wistar. Os animais foram tratados com AG (10 mg/Kg; i.p.), ou L-NAME (20 mg/Kg; i.p.), uma hora antes do MTX e, diariamente, atà o sacrifÃcio, no 5 dia. Na investigaÃÃo do papel do NO na mucosite oral induzida por 5-FU, os seguintes parÃmetros foram avaliados: anÃlises micro e macroscÃpica, atividade de mieloperoxidade (MPO) e da NOS, nÃveis teciduais de nitrito, imunohistoquÃmica para NOSi e detecÃÃo de morte celular. O efeito do 5-FU na produÃÃo salivar tambÃm foi avaliado. No estudo dos efeitos da GLU e AL-GLU, anÃlises micro e macroscÃpicas, atividade de MPO, detecÃÃo de morte celular, estoques teciduais de glutationa e concentraÃÃo sÃrica de glutamina foram os parÃmetros avaliados. No estudo do papel do NO na mucosite intestinal, foram realizados anÃlise histopatolÃgica, medida da altura de vilos nos trÃs segmentos do intestino delgado, atividade de MPO, detecÃÃo de apoptose, assim como, western blot e imunohistoquÃmica para NOSi. 1400W e AG, contrariamente ao L-NAME, reduziram os parÃmetros macro e microscÃpicos da mucosite oral e a infiltraÃÃo de cÃlulas inflamatÃrias, detectada na histopatologia e na atividade de MPO. Foram observados ainda, no 10 dia, maior atividade da NOS e marcaÃÃo imunohistoquÃmica para NOSi. 1400W reverteu a diminuiÃÃo da secreÃÃo salivar induzida por 5-FU. A mucosite oral induzida por 5-FU resultou na diminuiÃÃo dos nÃveis sÃricos de glutamina, bem como dos estoques teciduais de glutationa, no 10 dia, efeitos que foram revertidos pela administraÃÃo de GLU e AL-GLU. Apesar de nÃo ter prevenido a mucosite oral no 10 dia, o tratamento com GLU ou AL-GLU reduziu os parÃmetros macro e microscÃpicos da mucosite oral, e a atividade de MPO, no 14 dia. Na mucosite intestinal, AG e L-NAME preveniram o encurtamento de vilos e reduziram a necrose de criptas, assim como o infiltrado inflamatÃrio, efeitos induzidos pelo MTX, sendo esse Ãltimo constatado pela anÃlise histopatolÃgica e atividade de MPO. Foi detectado maior marcaÃÃo imunohistoquÃmica para NOSi no jejuno de ratos submetidos à mucosite intestinal. Esses resultados sugerem o papel relevante do NO na fisiopatologia das mucosites oral e intestinal. O presente estudo demonstrou ainda que a GLU e AL-GLU aceleraram a recuperaÃÃo da mucosa dos animais submetidos a mucosite oral por 5-FU, aumentando os nÃveis teciduais de glutationa, reduzindo a inflamaÃÃo e promovendo reepitelizaÃÃo / Mucositis induced by antineoplastic drugs is an important, dose-limiting and costly side effect of cancer therapy, which pathophysiology is not completely understood. The aim of the present study was to investigate the role of nitric oxide (NO) on the pathogenesis of oral and intestinal mucositis induced by 5-fluorouracil (5-FU) and methotrexate (MTX) and the effect of glutamine (GLU) and alanyl-glutamine (AL-GLU) on 5-FU-induced experimental mucositis. Oral mucosistis was induced by two intraperitoneal (i.p) administrations of 5-FU on the 1st and 2nd days (60 and 40 mg/kg, respectively) in hamsters. Animals were treated subcutaneously (s.c.) with the nitric oxide synthase (NOS) inhibitors N-(3-(Aminomethyl)benzyl)acetamidine (1400W; 1 mg/kg), aminoguanidine (AG; 5 or 10 mg/kg), Nφ-Nitro-L-Arginine Methyl Ester (L-NAME; 5, 10 or 20 mg/kg) or saline (0.4 ml), one hour before the injections of 5-FU and daily until sacrifice, on the 10th day. In another set of experiments, animals received saline, GLU or AL-GLU suspension (100 mM) one hour before the injections of 5-FU and daily until sacrifice, on the 10th or 14th day. Intestinal mucositis was induced by three administrations of MTX (2.5 mg/kg; s.c.) on the first three days of the experiment, in Wistar rats. Animals were treated i.p. with AG (10 mg/Kg), or L-NAME (20 mg/Kg), one hour before the injections of MTX and daily until sacrifice, on the 5th day. In the investigation of the role of NO on 5-FU induced oral mucositis, the following parameters were evaluated: microscopic and macroscopic analysis, myeloperoxidade (MPO) and NOS activities, nitrite level, immunohistochemistry for NOSi, salivary secretion, and cell death. In order to study the effect of GLU and AL-GLU, microscopic and macroscopic analysis, MPO activity, cell death, glutathione stores and the serum concentration of glutamine, were evaluated. In the MTX-induced intestinal mucositis, histopathological analysis was evaluated and the villus height in all three small intestine segments was measured. MPO activity, cell death, as well as, western blot and immunohistochemistry to evaluated the expression of the NOSi, were also conducted. 1400W or AG, but not L-NAME, reduced macroscopic and histological parameters of oral mucositis, and reduced the inflammatory cell infiltration as detected on histopathology and by MPO activity. Increased NOS activity and immunostaining for NOSi were detected. 5-FU induced a decrease in salivary secrection, observed on 4th day, and this effect was prevented by 1400W. The 5-FU-induced oral mucositis significantly decreased the serum GLU level as well as the cheek pouch glutathione stores, observed on day 10. GLU or AL-GLU reversed the 5-FU effects, restoring serum GLU levels and cheek pouch glutathione stores, observed on day 10, but did not prevent oral mucositis at this time. However, GLU and AL-GLU reduced macroscopic and histological parameters of oral mucositis, and reduced the MPO activity on day 14. In the MTX-induced mucositis, AG and L-NAME significantly prevented villous blunting, lamina propria cell death, and reduced crypt necrosis induced by MTX, decreasing neutrophil infiltration as detected by histopathology and by MPO activity. These data were associated with the detection of iNOS expression by Western blot and by immunohistochemistry in the jejunum tissue. These results suggest an important role of NO in the pathogenesis of oral and intestinal mucositis induced by 5-FU and MTX. The present study also demonstrated that GLU or AL-GLU hastens mucosal recovery increasing mucosal tissue glutathione stores, reducing inflammatory parameters and speeding reepithelization

Introdução: A doença vascular do coração transplantado, consiste em um processo inflamatório proliferativo que compromete o sucesso a longo prazo do transplante cardíaco e não há prevenção ou tratamentos efetivos. Uma nanoemulsão lipídica (LDE) pode carregar agentes quimioterápicos na circulação e concentrá-los nos enxertos cardíacos dos coelhos. O objetivo deste estudo foi investigar os efeitos do paclitaxel combinado a LDE;do metotrexate combinado ao LDE e a associação de ambos quimioterápicos ao LDE nos corações transplantados. Método: 28 coelhos alimentados com dieta com teor de 0,5% de colesterol e submetidos a transplante cardíaco herotópico foram tratados com ciclosporina (dose 10 mg/kg/ dia por via oral) e alocados em 4 grupos de 7 animais.Um grupo recebeu a associação de Metotrexate e LDE endovenosa (4 mg/kg/semana); segundo grupo recebeu por via endovenosa a combinação de Paclitaxel e LDE; o terceiro grupo recebeu a associação de LDE com metotrexate e paclitaxel; grupo controle que recebeu somente solução salina intravenosa. Os animais foram sacrificados 6 semanas após o procedimento. Foram realizadas análises da morfologia,histologia,imunohistoquímica e análise da expressão gênica do enxerto e dos corações nativos. Resultado: Em comparação com o grupo controle,coelhos transplantados e tratados com paclitaxel associado ao LDE apresentaram redução em 50% de estenose em artérias coronárias. Já nos grupos que usaram metotrexate associado a LDE ou paclitaxel combinado com metotrexate e associado a LDE, houve redução em 18% da estenose coronariana em relação ao grupo controle,mas a diferença não apresentou significância estatística.Nos três grupos tratados, houve redução do infiltrado macrofágico. No grupo que recebeu metotrexate associado a LDE,a expressão gênica de fatores pró-inflamatórios( TNF-alfa; MCP1; IL 18; VCAM-1 e MMP-12) foi reduzida drasticamente; enquanto a expressão de agentes anti-inflamatórios(IL 10 por exemplo) aumentou. Nos outros dois grupos (LDE+paclitaxel e LDE+paclitaxel e metotrexate) não houve influência consistente na expressão de genes pró e anti-inflamatórios. Conclusão: A associação paclitaxel e LDE promoveu melhora importante na vasculopatia dos enxertos.A associação metotrexate e LDE e a metotrexate mais palcitaxel e LDE reduziram a estenose de coronárias porém sem significância estatística. O infiltrado macrofagocítico foi reduzido nos três grupos tratados. Tais resultados podem servir de ponte para novos ensaios clínicos / Background: Coronary allograft vasculopathy is an inflammatory-proliferative process that compromises the long-term success of heart transplantation and currently has no effective prevention and treatment. A lipid nanoemulsion (LDE) can carry chemotherapeutic agentsin the circulation and concentrates them in the heart graft in rabbits. The aim of this study was to investigate the effects of paclitaxel (PACLI) binded tire parentesis to LDE, methotrexate (MTX) binded to LDE and the association of both particles in transplanted heart. Methods: Twenty eight rabbits fed 0,5% cholesterol diet and submitted to heterotopic heart transplantation were treated with cyclosporine A (10mg/kg/daily orally) and allocated to four groups of 7 animals. One group was treated with intravenous LDE-MTX (4mg/kg B.W., weekly); a second with LDE-paclitaxel, the third one with association of LDE-PACLI with LDE-MTX and the control group received only weekly intravenous saline solution. Animals were sacrificed 6 weeks later for morphometric, histological, immunohistochemical and gene expression analysis of the graft and native hearts. Results: Compared to controls, grafts of LDE-PACLI treated rabbits showed 50%reduction of coronary stenosis and in the LDE-MTX and LDE-MTX/PACLIstenosiswas around 18% less than control but this difference was not statistically significant. In the 3 treatment groups macrophage infiltration was decreased. In LDE-MTX group, gene expression of pro-inflammatory factors TNF-?, MCP-1, IL-18 and VCAM-1, and MMP-12 was strongly diminished whereas expression of anti-inflammatory IL-10 increased. In the other two treatment, groups (LDE-PACLI and LDE-PACLI/MTX) there was not a consistent influence in pro and anti-inflammatory gene expression. Conclusions: LDE-PACLI promoted strong improvement of the cardiac allograft vasculopathy. LDE- MTX and LDE -MTX/PACLI decreased coronary stenosis but without statistic significance. Macrophage infiltration was decrease in the three treatment groups. This new preparation maybe candidate for future clinical trials

Em estudos anteriores, mostramos que uma nanoemulsão artificial (NEm) de composição semelhante à da lipoproteína de baixa densidade se liga a receptores de lipoproteínas de baixa densidade após sua injeção na corrente sanguínea. Como tais receptores estão superexpressos em células com altas taxas de proliferação, como ocorre no cancer e na aterosclerose, a NEm pode ser utilizada como veículo para direcionar drogas a estas células, diminuindo sua toxicidade e aumentando sua ação farmacológica. Recentemente, reportamos que a associação de um derivado do agente antiproliferativo paclitaxel, o oleato de paclitaxel (OPTX) à NEm reduziu em 60% a área lesionada de aortas de coelhos submetidos à dieta rica em colesterol. Neste estudo, testamos o efeito sinérgico da terapia combinada do OPTX-NEm com um derivado do metotrexato, o di-dodecil metotrexato (DMTX), também associado à NEm. O MTX, além de sua ação antiproliferativa, também possui propriedades imunossupressoras. Coelhos machos da raça Nova Zelândia foram submetidos à dieta enriquecida com 1% de colesterol durante 8 semanas. A partir da quinta semana de consumo da dieta, 8 animais foram injetados semanalmente com solução salina por via endovenosa (grupo controle) e 8 receberam o tratamento combinado de OPTX-NEm (4mg/Kg) com DMTX-NEm (4mg/Kg), por 4 semanas. Ao final das 8 semanas, os animais foram sacrificados. As aortas dos animais foram retiradas, abertas longitudinalmente, fixadas em formalina tamponada a 10% e coradas com Escarlate R para a análise macroscópica da lesão. Os arcos aórticos foram seccionados em fragmentos de 5mm, embebidos em parafina e os cortes realizados foram corados com hematoxilina-eosina, para a determinação da área das camadas íntima e média. O tratamento combinado de OPTX-NEm com DMTX-NEm reduziu a área das lesões em 82%, em comparação ao grupo controle, e a razão da área da lesão/área total diminuiu de 0,82±0,08 para 0,08±0,06 (p<0,01). Por meio das avaliações da variação do consumo de ração, peso corporal e contagem de leucócitos totais (p>0,05), pode-se afirmar que os tratamentos não apresentaram toxicidade significativa, exceto pela queda na contagem de eritrócitos (p<0,05). Como conclusão, a quimioterapia combinada de OPTX e DMTX associados à NEm como veículo mostrou-se eficaz na redução da área de lesão aterosclerótica em coelhos e a toxicidade relacionada aos fármacos foi nitidamente reduzida. / In previous studies we have shown that an artificial nanoemulsion (NEm) that resemble LDL composition are taken-up by LDL receptors after injection into the bloodstream. As those receptors are upregulated in cells with higher proliferation rates, as occurs in cancer and atherosclerosis, NEm can be used as vehicle to direct drugs against those cells, diminishing toxicity and increasing pharmacological action. Recently, we reported that association of antiproliferative agent paclitaxel derivative, paclitaxel oleate (OPTX) to NEm reduced by 60% the lesion area of cholesterol-fed rabbits. In this study, the combined chemotherapy of OPTX-NEm with a methotrexate derivative, di-dodecil methotrexate (DMTX), also associated with NEm, was tested for synergistic effects. MTX, besides antiproliferative action, has also immunosuppressant properties. Male New Zealand rabbits were fed a 1% cholesterol diet for 60 days. Starting from day 30, 8 animals were treated with 4 weekly I.V. saline solution injections (control group) and 8 with combined OPTX-NEm (4 mg/kg) plus DMTX-NEm (4 mg/kg) for additional 30 days. On day 60, the animals were sacrificed for analysis. Aorta was excised, open longitudinally, placed in 10% buffered formalin and stained in Scarlet R for lesion macroscopic analysis. Segments of 5mm of the aortic arch were embedded in paraffin and sections were taken and stained in hematoxylin-eosin for intima and media area measurement. In comparison with controls, treatment with combined OPTX-NEm plus DMTX-NEm reduced the lesion area by 82% and the lesion/total area ratio was decreased from 0,82±0,08 to 0,08±0,06 (p<0.01). Except for decrease in erythrocyte count (p<0.05), treatments were devoid of significant toxicity, as evaluated by food intake, body weight and leucocyte count (p>0.05). In conclusion, this novel approach consisting in combined chemotherapy of OPTX and DMTX using NEm as a drug-targeting vehicle showed effective lesion area regression in rabbits and marked toxicity reduction.

Submitted by Fabiana Gonçalves Pinto (benf@ndc.uff.br) on 2017-04-04T17:45:28Z No. of bitstreams: 1 Leandro Silva Dias.pdf: 1153525 bytes, checksum: 8458e50ad0b542866cb54c89ea0006de (MD5) / Made available in DSpace on 2017-04-04T17:45:28Z (GMT). No. of bitstreams: 1 Leandro Silva Dias.pdf: 1153525 bytes, checksum: 8458e50ad0b542866cb54c89ea0006de (MD5) Previous issue date: 2012 / Conselho Regional de Enfermagem - RJ / Mestrado Profissional em Enfermagem Assistencial / A terapia com vários fármacos é a regra na quimioterapia antineoplásica e no tratamento de determinadas doenças infecciosas. Nesses casos os objetivos consistem na melhora da eficácia terapêutica e no retardo da emergência de células malignas ou de microrganismos resistentes aos efeitos dos fármacos disponíveis. Nas prescrições, das crianças internadas com patologias oncológicas, identificou-se como principal quimioterápico o Metotrexato (MTX), perfazendo um total de 3 a 4 doses por prescrição no tratamento de linfomas não Hodgkin e leucemias linfoides agudas. A interação farmacológica ocorre, quando um fármaco interfere com outros, alterando o efeito esperado, podendo ser prejudicial, á medida que causa aumento de riscos ao paciente. As interações farmacêuticas, também chamadas incompatibilidades medicamentosas, caracterizam-se por ocorrerem in vitro, isso é antes da administração no organismo, quando misturado dois ou mais fármacos em uma mesma seringa, equipo de soro ou outros recipientes. Objeto de estudo: As incompatibilidades físico-químicas dos medicamentos durante o ciclo de infusão do MTX endovenoso na clientela pediátrica com LLA e Linfoma não Hodgkin. Hipotese: O aprazamento de medicamentos concomitante a infusão do Metotrexato (MTX), realizado pelo enfermeiro, podem causar incompatibilidades que diminuem ou potencializam o efeito terapêutico deste quimioterápico. Objetivos: Traçar o perfil do tratamento farmacológico das crianças com LLA e LNH, durante o ciclo do MTX internadas na unidade pediátrica; verificar a prevalência das incompatibilidades físico-químicas entre os medicamentos administrados via endovenosa nas crianças com LLA e LNH, internadas na UP; estabelecer diretrizes para a Gerência do Cuidado de Enfermagem à crianças com LLA e LNH em uso de MTX endovenoso com a criação de um protocolo de aprazamento e administração. Foi um estudo observacional transversal, com abordagem quantitativa dos dados. A mostra foi composta por 13 pacientes com LLA e LNH, que atenderam os critérios de inclusão deste estudo, dos quais emergiram 86 prescrições. Os dados foram coletados no período de janeiro de 2008 à dezembro de 2011 e sofreram estatística descritiva e foi calculado a prevalência das incompatibilidades medicamentosas. O sexo masculino apresentou 61,5% da amostra, enquanto o feminino 38,5%; LLA com 85,6% e LNH com 15,2%; 100% de acessos centrais monolumen. Os eletrólitos apresentaram o maior numero de doses administradas, seguido do antiemético, e dos quimioterápicos. A interação medicamentosa do tipo farmacêutica, de maior prevalência foi a entre o cloridrato de ondansetrona e o bicarbonato de sódio a 8,4%, seguida da entre o cloridrato de midazolan e o bicarbonato de sódio. A pesquisa contribui para que o enfermeiro, se aproprie ainda mais dos conhecimentos relacionados a farmacocinética, farmacodinâmica e farmacêutica, assim como sobre as reações adversas medicamentosas, para que possam realizar a gerência do cuidado, no que tange toda a dinâmica da terapia medicamentosas, ou seja, uma assistência de enfermagem segura, livre de danos, sejam eles temporários ou permanentes, assegurando que os pacientes permaneçam o mínimo possível no ambiente hospitalar, assim como ter uma terapêutica medicamentosa com o resultado final que é a prevenção ou cura de doenças, e também eficácia nos tratamentos paliativo / Therapy with multiple drugs is the rule in cancer chemotherapy and in the treatment of certain infectious diseases. In such cases the objectives consist in improving the therapeutic efficacy and delay the emergence of malignant cells or microorganisms resistant to the effects of available drugs. In the prescriptions of children with oncological diseases, was identified as the main chemotherapeutic methotrexate (MTX), making a total of 3 to 4 doses per prescription in the treatment of non-Hodgkin lymphomas and acute lymphoid leukemias. The pharmacological interaction occurs, when a drug interferes with other, changing the desired effect and may be harmful, as will cause the patient to increased risks. The drug interactions, also called drug incompatibilities, characterized by occur in vitro that is prior to administration in the body, when two or more components mixed in one syringe, serum catheter or other containers. Object of study: The physico-chemical incompatibilities of drugs during the course of intravenous infusion of MTX in pediatric clients with ALL and non-Hodgkin's lymphoma. Hypothesis: The scheduling of drugs concomitant infusion of methotrexate (MTX), performed by the nurse, can cause incompatibilities that reduce or enhance the therapeutic effect of chemotherapy. Objectives: To describe the pharmacological treatment of children with ALL and NHL, during the cycle of MTX admitted to the pediatric unit and verify the prevalence of physical and chemical incompatibilities between drugs administered intravenously in children with ALL and NHL, admitted in UP; establish guidelines for the Management of Nursing Care for children with ALL and NHL in MTX intravenously with the creation of a protocol for scheduling and administration. It was an observational cross-sectional quantitative data approach. The show was comprised of 13 patients with ALL and NHL, who met the study inclusion criteria, 86 of which emerged prescriptions. Data were collected from January 2008 to December 2011 and suffered descriptive statistics and calculated the prevalence of drug incompatibilities. The male group showed 61.5% of the sample, while females 38.5%, 85.6% with ALL and NHL with 15.2%, 100% hits central monolumen. Electrolytes showed the highest number of doses administered, followed by an anti-emetic, and chemotherapy. The type of pharmaceutical drug interaction, was the most prevalent of the ondansetron hydrochloride and sodium bicarbonate to 8.4%, followed by between midazolam hydrochloride and sodium bicarbonate. The research contributes to the nurse, to appropriate further knowledge related to pharmacokinetics, pharmacodynamics, and pharmaceutical, as well as on adverse drug reactions so that they can carry out care management, regarding the dynamics of drug therapy, or is a safe nursing care, free of damage, whether temporary or permanent, ensuring that patients remain as little as possible in the hospital environment, as well as having a drug therapy with the end result is the prevention or cure of diseases, and also effective in the palliative treatment

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.

Abstract In the Nordic countries, event-free survival (EFS) exceeds 80% in certain groups of children treated for acute lymphoblastic leukaemia (ALL). With the improved cure rates, however, there are more children suffering from neurological late effects, especially due to therapy directed at the central nervous system (CNS). The aim of this study is to examine the changes taking place in the nervous system after leukemia treatment and to evaluate the role of treatment in these changes in patients and in an animal model. Twenty-seven ALL survivors and healthy controls were examined by means of motor evoked potentials (MEPs). ALL survivors were also examined clinically. The children with ALL continued to show decreased motor nerve conduction in the peripheral nerves, but not within the CNS, five years after the cessation of treatment. Clinical neurological findings were obtained in 33% of the cases. The MEP results indicated reversibility of the motor injury due to CNS effects. Nineteen patients underwent perfusion magnetic resonance imaging (MRI) at the cessation of treatment or 4-8 years after the treatment. Seventeen of them also underwent single-photon emission computed tomography (SPECT). The studies showed small perfusion defects in SPECT, which were not visible by perfusion MRI. Methotrexate (Mtx) neurotoxicity was studied in a swine model using functional MRI, brain perfusion SPECT, iodine-123 labelled 2β-carbomethoxy-3β-(4-iodophenyl) tropane ([123I]β-CIT) SPECT and whole-hemisphere autoradiography with [125I]β-CIT in ten Mtx-treated animals and five control animals. Mtx-related changes in the brain could be detected as reduced or negative blood-oxygen-level-dependent (BOLD) responses to somatosensory activation in BOLD contrast MRI, which indicates changes in flow metabolism coupling. Perfusion defects in brain SPECT were seen in the Mtx group and the control group, which suggests that the perfusion defects seen in brain SPECT are probably multifactorial. The change in dopamine transporter (DAT) density in the Mtx group was not different from that in the controls. The abnormalities in nerve conduction after treatment in survivors of ALL were partly reversible years after the treatment. The patients had perfusion defects in SPECT imaging which were not seen in perfusion MRI. The clinical significance of these defects remains obscure. The animal model suggested perfusion defects to be multifactorial.

Le dihydrofolate réductase (DHFR) est la principale cible du méthotrexate, un important composant du traitement de la leucémie lymphoblastique aiguë (LLA). Une association des polymorphismes du promoteur de DHFR avec l’issue de la LLA a été mise en évidence au laboratoire. Une survie sans événement (EFS) réduite corrélait avec les allèles A -317 et C -1610, et l’haplotype *1, défini par ces allèles. L’haplotype *1 était aussi associé à une expression élevée du DHFR. Dans cette étude, nous étendons l’analyse à la région régulatrice adjacente, d’environ 400 pb, correspondant au transcrit mineur non-codant du DHFR, qui joue un rôle essentiel dans la régulation de la transcription au niveau du promoteur majeur. Six polymorphismes ont été identifiés, parmi lesquels 5 étaient des SNPs et un polymorphisme de longueur composé d’un nombre variable d’éléments de 9 pb et d’une insertion/délétion de 9 pb. L’analyse d’haplotype, incluant tous les polymorphismes promoteurs, a révélé une diversification de l’haploytpe *1 en 5 sous-types (*1a à *1e). Les variations du promoteur majeur et les sous-types de l’haplotype *1 ont été par la suite analysés pour l’association avec l’issue de LLA. Un EFS réduit corrélait avec l’allèle A du polymorphisme G308A (p=0,02) et avec l’haplotype *1 (p=0,01). Des niveaux élevées d’ARNm étaient trouvés chez les porteurs de l’haplotype *1b (p=0,005) et pas pour les autres sous-types de l’haplotype *1. Alors, la mauvaise issue de LLA associée avec l'haplotype *1 est en effet déterminée par le sous-type *1b. Cette étude donne un nouvel aperçu des polymorphismes régulateurs du DHFR définissant plus précisément les variations du DHFR prédisposant un événement. / Dihydrofolate reductase (DHFR) is the major target of methotrexate, a key component in childhood acute lymphoblastic leukemia (ALL) treatment. We recently reported an association of DHFR promoter polymorphisms with ALL outcome. Lower event free survival (EFS) correlated with the alleles A -317 and C -1610, and with haplotype *1, defined by these alleles. Haplotype*1 was also associated higher DHFR expression. Here we extended the analysis to adjacent 400bp regulatory region corresponding to non-coding minor DHFR transcript which plays an essential role in the regulation of transcription from the major promoter. Six polymorphisms were identified, of which 5 were SNPs and one length polymorphism composed of variable number of 9bp elements and 9bp insertion/deletion. Haplotype analysis including all promoter polymorphisms revealed diversification of haplotype *1 into 5 subtypes (*1a to *1e). Major promoter variations and haplotype *1 subtypes were subsequently analyzed for the association with ALL outcome. Lower EFS correlated with an A allele of G308A polymorphism (p=0.02) and with *1b haplotype (p=0.01). Higher mRNA levels were found in the carriers of *1b haplotype (p=0.005) and not for remaining haplotype *1 subtypes. So, the worse ALL outcome associated with haplotype *1 is actually determined by the subtype *1b. The study provides a new insight into DHFR regulatory polymorphisms defining more precisely event–predisposing DHFR variations.