A exposição à radiação ultravioleta (RUV) pode levar a um desequilíbrio no balanço oxidante/antioxidante da pele causando prejuízos à sua integridade e levando a diversas alterações, entre as quais o envelhecimento precoce e o câncer de pele. Na tentativa de diminuir os efeitos biológicos mediados pelos radicais livres gerados pela RUV na pele, tem sido proposto a fotoquimioproteção com a utilização de antioxidantes tópicos. Dentre a gama de compostos disponíveis para serem empregados na fotoquimioproteção, a própolis, por sua pronunciada atividade antioxidante, entre suas inúmeras atividades biológicas, é uma matéria-prima com promissora ação tópica. Desta forma, extratos de própolis alcoólico e glicólico (EPA e EPG) foram caracterizados quanto à sua composição polifenólica e quanto à sua capacidade antioxidante frente a diversos radicais livres. Formulações adicionadas destes extratos foram desenvolvidas e submetidas a estudos de estabilidade física e funcional, estudos de liberação, permeação e retenção cutânea in vitro, bem como estudos preliminares de eficácia in vivo. Os resultados demonstraram que os extratos de própolis são capazes de seqüestrar eficientemente diversos radicais livres, principalmente radicais superóxido. Quando estes extratos foram adicionados em formulações de produtos para uso tópico, a atividade antioxidante foi mantida. Nos estudos prévios de estabilidade física foi observado que as formulações mais estáveis foram desenvolvidas com Hostacerin® SAF (menor conteúdo graxo) e Polawax® (maior conteúdo graxo). No entanto, somente a formulação desenvolvida com Polawax® apresentou estabilidade satisfatória por 1 ano quando armazenada à temperatura ambiente e a 40º.C 2º.C/70%UR 5%. Nos estudos de liberação, permeação e retenção cutânea foi observado a influência do conteúdo graxo na performance das formulações. A cinética de liberação das formulações tanto do ácido p-cumárico (utilizado como marcador), como dos compostos equivalentes ao extrato de própolis (EEP) demonstraram seguir o modelo de Higuchi. A formulação desenvolvida com Polawax® apresentou a melhor retenção cutânea, com retenção de 0,013 e 0,030 µL de EEP.cm-2 para as peles de camundongo e de porco, respectivamente. Em adição, esta formulação apresentou baixos níveis de permeação cutânea, sendo adequada para aplicação tópica fotoquimioprotetora. Nos estudos in vivo, esta formulação adicionada de EPA, foi capaz de diminuir o eritema, inibir o edema e aumentar a cicatrização de camundongos sem pêlo expostos à radiação UVB. Além disso, também foi observado a proteção da depleção da glutationa endógena (GSH). Os resultados preliminares de eficácia in vivo sugerem que formulações contendo o extrato de própolis apresentam boas perspectivas para serem utilizadas para prevenir e tratar os danos causados na pele pela radiação UV. / The ultraviolet radiation (UVR) exposition may lead to the skin oxidant/antioxidant imbalance injuring its integrity and leading to several disorders, such as ageing and skin cancer. In order to improve the biological effects caused by free radicals generated by UVR in skin, it has been suggested the photochemoprotection by using topical antioxidants. Among the available compounds to be employed in hotochemoprotection, propolis, due to its important antioxidant activity, among its innumerous biological activities, is a promising topical raw-material. Next, ethanolic and glycolic propolis extracts (EPE, GPE) were characterized in relation to their polyphenolic composition, and in relation to their antioxidant activity against several free-radicals. Formulations added with these extracts were developed and undergone to physical and functional stability studies, in vitro release and skin permeation and retention studies, as well as in vivo preliminary efficacy studies. The results showed that the propolis extracts are able to scavenge several free radicals efficiently, mainly superoxide radicals. When these extracts were added to formulations of topical products, their antioxidant activity were maintained. In the physical stability studies, it was observed that the most stable formulations were developed with Hostacerin® SAF (lower fat content) and Polawax® (higher fat content). However, only the formulation developed with Polawax® showed satisfactory stability for 1 year stored at room temperature and at 40º.C 2º.C/70%UR 5%UR. In the release, permeation and retention studies, it was observed the fat content influence in the formulation performance. The release profile of p-coumaric acid (used as marker compound) and the compounds equivalent to propolis extract (EPE) followed the Higuchi model. The formulation developed with Polawax® showed the best skin retention, retaining 0,013 and 0,030 L EPE.cm-2 in hairless mouse skin and in pig skin, respectively. In addition, this formulation presented low permeation, which is desired for photochemoprotective topical employment. In the in vivo studies, this formulation added with EPE was able to diminish erithema, inhibit oedema and increase cicatrisation in hairless mice exposed to UVB radiation. In addition, it was also observed the protection of the endogenous glutathione (GSH) depletion. The in vivo preliminary efficacy results suggest that formulations added with propolis extract present good perspectives to be employed to prevent and treat the injuries caused in skin by UV radiation.

In Thailand, Acanthus ebracteatus Vahl and Clerodendrum petasites S. Moore have been prescribed to treat skin diseases, such as rash, abscess, and urticaria, for at least 30 years. However, there is limited scientific support and no clinical trials that identify and verify the compounds that elicit useful pharmacological effects following their topical delivery. Vanillic acid was identified for the first time in A. ebracteatus together with verbascoside; furthermore, nine phenolic compounds, vanillic acid, 4-coumaric acid, ferulic acid, verbascoside, nepetin, luteolin, chrysin, naringenin, and hesperetin, and two reported, apigenin and hispidulin, were found in C. petasites. C. petasites (CP) was therefore chosen as the principal plant to be studied in this thesis. Hispidulin was quantified as a predominant compound, being present at 39 μmol/g (1.2% w/w) in a dried ethanolic extract. Various formulations of CP extracts were examined (a) in in vitro skin penetration experiments using Franz diffusion cells, and (b) in vivo using the tape-stripping method. Hispidulin penetrated through the skin within 3 hours; vanillic acid and nepetin were absorbed after 6 hours. In contrast, verbascoside was only taken up into the superficial layers of SC. There was no difference in the permeation of hispidulin, nepetin and vanillic acid from 10% w/w CP cream and lotion formulations. Hispidulin was percutaneously absorbed through the skin and taken up into the stratum corneum in the greatest amount, followed by vanillic acid and nepetin. It was found that the in vitro model was useful for preliminary formulation development, and that the tape-stripping method was robust and effective. Verbascoside, although a poor penetrant, was well released from the formulations in an in vitro release test, suggesting that it might be a potential skin surface-active compound, such as an antimicrobial. Hispidulin, nepetin and vanillic acid, based on their uptake and penetration into the skin, together with their known biological activities, may be considered as feasible candidates for the development of novel and effective antimicrobial, anti-inflammatory, and antioxidant formulations.

Made available in DSpace on 2017-07-24T19:22:14Z (GMT). No. of bitstreams: 1 Jose Laufer.pdf: 1246261 bytes, checksum: 67bab31b5ee267fca6c8c43076e3729b (MD5) Previous issue date: 2006-02-22 / The no invasive anesthesia by application of an anesthetic gel in the interior of the periodontal pocket appears as an alternative in the periodontal treatment. The objective of this study was to manipulate, to test the physical-chemical properties, the percutaneous absorption of a gel thermosetting topical anesthetic lidocaine/prilocaine 5 Test) and evaluates its biocompatibility. Preformulation studies, microbiological and percutaneous absorption (PA) in vitro and in vivo, has been done. To evaluate aspects of biocompatibility 2 techniques had been done: vascular permeability (VP) and descriptive histological analyses (HA). In the PV, 60 rats and 3 periods of observation had been used (3, 6, 9 hours) and were evaluated,visually, for the area of the inflammation and for dye concentration applied, by spectrophotometric analysis, after mplantation of 0,1 mL of the substances: G1- Teste; G2-Emla; G3-Poloxamer; G4-Controle. In AH, 60 rats, were divided in 4 groups (in the same way cited before) with subcutaneous implantation of polyethylene tubes with substances had been used, in periods of 2, 5 and 15 days. The pharmacotechnical results had shown values of pH 7,71, density (gel 1,020),not occurring microorganisms growth (gram+, gram- and fungi) in the substance Test and showing a good viscosity, adjusted for use in oral cavity. AP did not show significant differences between the GI and GII, with p>0,05 (Mann-Whitney) for the experiments in vitro and in vivo. In the PV, G1 and G2 had bigger values (p< 0,05) than G3 and G4. The histological analysis did not show areas of necrosis, nor severe inflammatory response. It is concluded that the gel Test presents adequate properties and showed not to induce severe inflammatory response in the subcutaneous, showing biocompatibility when compared with the control group. / A anestesia não invasiva com a aplicação de gel anestésico no interior da bolsa periodontal surge como uma alternativa no tratamento periodontal. Esse estudo teve como objetivo manipular, testar as propriedades físico-químicas, de absorção percutânea de um gel anestésico tópico termosensível (lidocaína/prilocaína 5 - Teste) e avaliar a sua biocompatibilidade. Foram realizados estudos de préformulação, microbiológicos e absorção percutânea (AP) in vitro e in vivo do fármaco. Para biocompatibilidade foram utilizadas 2 técnicas: permeabilidade vascular (PV) e análise histológica descritiva (AH). Na PV foram utilizados 60 ratos e 3 períodos de observação (3, 6, 9 horas) em que avaliou-se a área da inflamação visualmente e por quantificação do corante aplicado sob análise de espectrofotometria após implantação de 0,1 mL das substâncias sendo: G1-Teste; G2-EMLA; G3-Poloxamer; G4-Controle. Na AH foram utilizados 60 ratos divididos em 4 grupos (os mesmos supra citados) com implantação subcutânea de tubos de polietileno preenchidos com as substâncias, em períodos de 2, 5 e 15 dias. Os resultados de farmacotécnica mostraram valores de pH 7,71, densidade (gel 1,020), não ocorrendo crescimento microbiano (gram+, gram- e fungos) na substância Teste e mostrando uma boa viscosidade, adequada para uo em cavidade bucal. A AP não mostrou diferenças significativas entre o GI e GII com p>0,05 (Mann-Whitney) para os experimentos in vitro e in vivo. Na PV G1 e G2 tiveram valores maiores (p< 0,05) que G3 e G4. A análise histológica não mostrou áreas de necrose, nem resposta inflamatória severa. Conclui-se que o gel Teste apresenta propriedades adequadas e mostrou não induzir resposta inflamatória severa no subcutâneo de ratos, mostrando-se biocompatível quando comparado com o grupo controle .

de pele é o tipo mais frequente, correspondendo a cerca de 25% de todos os tumores malignos registrados no Brasil. Há que se destacar que uma formulação de uso tópico foi desenvolvida pelo grupo para uso contra câncer de pele e o estudo da estabilidade acelerada desta formulação foi avaliado nesse trabalho. Os frutos da espécie S. lycocarpum foram coletados, secos, triturados, submetidos à extração ácido-base e o precipitado foi suspenso em etanol e filtrado. Os heterosídeos alcaloídicos, SS e SM, foram isolados por cromatografia em coluna a vácuo e purificados em CLAE semipreparativa. A formulação contendo extrato alcaloídico armazenada em temperatura ambiente (27 ± 2 oC) apresentou a melhor estabilidade física. Ensaios para avaliação da atividade antifúngica in vitro do extrato alcaloídico, SS, SM e aglicona (SD) foram realizados com cepas de fungos dermatófitos e Candida spp., sendo que a SM apresentou o menor valor de concentração inibitória. No ensaio de citotoxidade em células humanas de carcinoma espinocelular (A431) e células de fibroblastos de camundongos (L929) foi possível observar a toxidade do extrato alcaloídico e das substâncias, SS, SM e SD frente às células cancerígenas. No ensaio in vivo, os animais foram induzidos ao câncer de pele não-melanoma do tipo espinocelular com células A431 e verificou-se que apenas o grupo de animais tratados com a formulação Curaderm BEC 5 apresentou redução tumoral. Em contrapartida, o grupo tratado com formulação contendo extrato alcaloídico se comportou da mesma maneira que os grupos controle da formulação e controle negativo. Com auxílio da histologia confirmou-se que o câncer de pele induzido nos animais foi do tipo espinocelular. No ensaio imunoistoquímico foi utilizado o anticorpo caspase-3 para marcar as células em apoptose nos tumores, sendo que o maior número de células apoptóticas foi verificada no grupo tratado com a formulação Curaderm BEC 5. / Solanum lycocarpum A. Saint-Hilaire (Solanaceae), commonly known as wolf apple or wolf´s fruit, is a plant native of Brazil very common in the Brazilian savanna. High concentrations of steroidal alkaloids are found in S. lycocarpum fruits, and solasonine (SS) and solamargine (SM) are the most important ones. These two alkaloids present potential antifungal and anticancer activities. Dermatophytic fungi are the most common agents responsible for superficial mycoses in humans and animals, by infecting exclusively the stratum corneum of skin, hair and nails. Skin cancer is the most frequent type corresponding to roughly 25% of all the malignant tumors registered in Brazil. A topical formulation for skin cancer treatment was developed by our research group and its stability tests are reported in this work. The S. lycocarpum fruits were collected, dried, milled and submitted to acid-base extraction furnishing a precipitate, which was solubilized in ethanol and then filtered. The heterosidic alkaloids SS and SM were isolated by using vacuum column chromatography and purified by semi-preparative HPLC. The formulation containing the alkaloidic extract stored at room temperature (27 ± 2 oC) was more stable than the ones in other conditions. Antifungal in vitro test of the alkaloidic extract, SS, SM and the aglycone (SD) were performed with Candida spp and dermatophytic fungi strains. The alkaloid SM displayed the lower inhibitory concentration. The toxicity of the alkaloidic extract, SS, SM and SD was verified in a cytotoxicicity test performed with both cultured human cells of spinocellular carcinoma (A431) and mice fibroblast cells (L929). An in vivo cytotoxicicity test was performed by inducing non-melanoma skin cancer in mice with spinocellular cells A431, in which only the animals treated with a commercial formulation Curaderm BEC 5, showed tumor reduction. There was no statistical difference between the group treated with the formulation containing the alkaloidic extract and control groups. Histological analysis confirmed that the skin cancer induced in the animals were spinocellular type. In an immunohistoquimic test, caspase-3 antibody was employed to stain the cells in apoptosis in the tumors, showing that apoptotic cells were more numerous in the group treated with the formulation Curaderm BEC 5.

O objetivo deste estudo foi investigar o potencial inibidor de desgaste dentário ocasionado por erosão e abrasão de um novo produto, o verniz ClinPro XT Varnish, em comparação com vernizes fluoretados convencionais à base de TiF4 e NaF. Sessenta amostras de esmalte bovino (n=15/grupo) com microdureza superficial entre 300-380KHN foram selecionadas e aleatoriamente tratadas com: verniz de NaF (Duraphat®, 2,26% F-), verniz de TiF4 (2,45% F-), ClinPro XT varnish (fluoraluminiosilicato e glicerofosfato de cálcio) e controle (sem tratamento). Após receberem os respectivos tratamentos, as amostras foram submetidas a 3 dias de desafios erosivos de 4x5 min/dia (Sprite® Zero) e a abrasão 2x15s/dia, utilizando uma máquina de escovação. Entre os ciclos de erosão e abrasão, as amostras permaneceram em saliva artificial. A perda de esmalte foi medida com perfilômetro óptico. Os dados foram submetidos ao teste Kruskal-Wallis seguido pelo Dunn (p<0,05) .Ambos vernizes de NaF (-5,84m [-12,06; 1,64]b) (mediana ± 95%IC) e TiF4 (-3,60m [-8,72; -0,45]b) foram eficazes em reduzir o desgaste do esmalte quando comparados ao grupo controle (-16,60m [-19,92; -10,04]a). O ClinPro XT varnish permaneceu na superfície do esmalte (106,21m [30,67; 126,22]c), impedindo completamente o desgaste. Assim foi possível concluir que o ClinPro XT teve um efeito superior aos outros vernizes, impedindo completamente a erosão e abrasão do esmalte por 3 dias in vitro. / The purpose of this study was to investigate the erosion and abrasion inhibiting effect of a newly released product, Vanish XT varnish, and compare it to conventional TiF4 and NaF varnishes. Sixty bovine enamel blocks (300-380 KHN) were selected and randomly allocated into 4 treatment groups (n=15/group): NaF varnish (Duraphat®, 2.26% F-), TiF4 varnish (2.45% F-), Vanish XT varnish (fluoroaluminosilicate and calcium glycerophosphate), and control (no treatment). The samples received their respective treatments one single time at the beginning of the experiment. During a total of 3 days, erosive challenges were done 4x5min/day (Sprite Zero®) and abrasion 2x15s/day using a brushing machine. In between the erosive and abrasive challenges and overnight the samples remained immersed in artificial saliva. Enamel loss was measured using a non-contact profilometer. The data were subjected to Kruskal-Wallis and Dunn tests (p<0.05). Both NaF (-5.84m [-12.06; 1.64]b) (median ± 95%CI) and TiF4 (-3.60m [-8.72; -0.45]b) varnishes were able to reduce enamel wear when compared to the control group (-16.60m [-19.92; -10.04]a). Vanish XT varnish remained on the enamel surface (106.21m [30.67; 126.22]c), completely preventing enamel wear. Therefore, we concluded that Vanish XT presented a superior effect when compared to conventional varnishes, completely preventing enamel erosion and abrasion for 3 days in vitro.

A exposição à radiação ultravioleta (RUV) pode levar a um desequilíbrio no balanço oxidante/antioxidante da pele causando prejuízos à sua integridade e levando a diversas alterações, entre as quais o envelhecimento precoce e o câncer de pele. Na tentativa de diminuir os efeitos biológicos mediados pelos radicais livres gerados pela RUV na pele, tem sido proposto a fotoquimioproteção com a utilização de antioxidantes tópicos. Dentre a gama de compostos disponíveis para serem empregados na fotoquimioproteção, a própolis, por sua pronunciada atividade antioxidante, entre suas inúmeras atividades biológicas, é uma matéria-prima com promissora ação tópica. Desta forma, extratos de própolis alcoólico e glicólico (EPA e EPG) foram caracterizados quanto à sua composição polifenólica e quanto à sua capacidade antioxidante frente a diversos radicais livres. Formulações adicionadas destes extratos foram desenvolvidas e submetidas a estudos de estabilidade física e funcional, estudos de liberação, permeação e retenção cutânea in vitro, bem como estudos preliminares de eficácia in vivo. Os resultados demonstraram que os extratos de própolis são capazes de seqüestrar eficientemente diversos radicais livres, principalmente radicais superóxido. Quando estes extratos foram adicionados em formulações de produtos para uso tópico, a atividade antioxidante foi mantida. Nos estudos prévios de estabilidade física foi observado que as formulações mais estáveis foram desenvolvidas com Hostacerin® SAF (menor conteúdo graxo) e Polawax® (maior conteúdo graxo). No entanto, somente a formulação desenvolvida com Polawax® apresentou estabilidade satisfatória por 1 ano quando armazenada à temperatura ambiente e a 40º.C 2º.C/70%UR 5%. Nos estudos de liberação, permeação e retenção cutânea foi observado a influência do conteúdo graxo na performance das formulações. A cinética de liberação das formulações tanto do ácido p-cumárico (utilizado como marcador), como dos compostos equivalentes ao extrato de própolis (EEP) demonstraram seguir o modelo de Higuchi. A formulação desenvolvida com Polawax® apresentou a melhor retenção cutânea, com retenção de 0,013 e 0,030 µL de EEP.cm-2 para as peles de camundongo e de porco, respectivamente. Em adição, esta formulação apresentou baixos níveis de permeação cutânea, sendo adequada para aplicação tópica fotoquimioprotetora. Nos estudos in vivo, esta formulação adicionada de EPA, foi capaz de diminuir o eritema, inibir o edema e aumentar a cicatrização de camundongos sem pêlo expostos à radiação UVB. Além disso, também foi observado a proteção da depleção da glutationa endógena (GSH). Os resultados preliminares de eficácia in vivo sugerem que formulações contendo o extrato de própolis apresentam boas perspectivas para serem utilizadas para prevenir e tratar os danos causados na pele pela radiação UV. / The ultraviolet radiation (UVR) exposition may lead to the skin oxidant/antioxidant imbalance injuring its integrity and leading to several disorders, such as ageing and skin cancer. In order to improve the biological effects caused by free radicals generated by UVR in skin, it has been suggested the photochemoprotection by using topical antioxidants. Among the available compounds to be employed in hotochemoprotection, propolis, due to its important antioxidant activity, among its innumerous biological activities, is a promising topical raw-material. Next, ethanolic and glycolic propolis extracts (EPE, GPE) were characterized in relation to their polyphenolic composition, and in relation to their antioxidant activity against several free-radicals. Formulations added with these extracts were developed and undergone to physical and functional stability studies, in vitro release and skin permeation and retention studies, as well as in vivo preliminary efficacy studies. The results showed that the propolis extracts are able to scavenge several free radicals efficiently, mainly superoxide radicals. When these extracts were added to formulations of topical products, their antioxidant activity were maintained. In the physical stability studies, it was observed that the most stable formulations were developed with Hostacerin® SAF (lower fat content) and Polawax® (higher fat content). However, only the formulation developed with Polawax® showed satisfactory stability for 1 year stored at room temperature and at 40º.C 2º.C/70%UR 5%UR. In the release, permeation and retention studies, it was observed the fat content influence in the formulation performance. The release profile of p-coumaric acid (used as marker compound) and the compounds equivalent to propolis extract (EPE) followed the Higuchi model. The formulation developed with Polawax® showed the best skin retention, retaining 0,013 and 0,030 L EPE.cm-2 in hairless mouse skin and in pig skin, respectively. In addition, this formulation presented low permeation, which is desired for photochemoprotective topical employment. In the in vivo studies, this formulation added with EPE was able to diminish erithema, inhibit oedema and increase cicatrisation in hairless mice exposed to UVB radiation. In addition, it was also observed the protection of the endogenous glutathione (GSH) depletion. The in vivo preliminary efficacy results suggest that formulations added with propolis extract present good perspectives to be employed to prevent and treat the injuries caused in skin by UV radiation.

Made available in DSpace on 2014-06-11T19:22:20Z (GMT). No. of bitstreams: 0 Previous issue date: 2007-12-14Bitstream added on 2014-06-13T20:48:46Z : No. of bitstreams: 1 vignoli_jcs_me_sjrp.pdf: 1219435 bytes, checksum: 616ec96df3d296bc6af6cf7ec0528071 (MD5) / Seed - Secretaria de Educação do Estado de São Paulo / A presente dissertação filia-se à Lingüística Textual, mais precisamente a uma abordagem sociocognitiva-interacionista, elegendo para objeto de estudo o texto, entendido como lugar de interação. Justificamos nosso recorte teórico pela opção de analisarmos, de maneira comparativa, as condições de produção e os textos delas resultantes, conjugando, portanto, o processo e seu produto. Nosso objetivo, então, é encontrar pistas nas produções escolares que remetam às orientações dadas em sala de aula, isto é, buscamos nos textos marcas que sinalizem as informações fornecidas em aulas de redação. Para tanto, observamos aulas em duas escolas particulares de São José do Rio Preto, ambas de terceiro ano do Ensino Médio, e relatamos os encaminhamentos dados para a produção textual. Essa descrição se baseou nos quatro sistemas cognitivos necessários para a produção textual – lingüístico, interacional, enciclopédico e sobre modelos textuais globais – descritos pela corrente sociocognitivista da Lingüística Textual, aos quais nós acrescentamos um outro saber - o conhecimento sobre organização tópica, pautado pelas propriedades da centração e da organicidade. Os textos coletados foram analisados a partir da categoria de tópico discursivo, com o intuito de observarmos a (des)organização tópica existente nas redação escolares. Quanto aos textos reescritos, além das aulas de orientação, levamos em conta as correções efetuadas pelos professores nos textos originais, a fim de verificar se esses novos direcionamentos contribuíam para a obtenção de textos organizados topicamente. Como resultado, percebemos que, apesar de algumas diferenças quanto ao modo de as aulas serem dadas nas duas salas informantes, a maioria dos textos não se apresentou dotado de organização tópica, fato que pôde ser explicitado pela natureza das orientações dadas em sala de aula. / The current dissertation joins to the Textual Linguistics with a sociocognitive – interacting approach, choosing as study goal the text, seen as the interaction place. The theoretical clipping is justified by the comparative analysis of the production conditions and the resulting texts, therefore joining the process and the product. The goal is to find clues in the school productions that rely on the classroom orientation, that is, we seek for signs from the composition classes. So that we observed classes in two private school groups in Sao Jose do Rio Preto, both in the third year of High School, and enrolled the directions given to textual production – linguistics, interactive, encyclopedic and about the global textual models – as described by the sociocognitivist running of Textual Linguistics, to which we added another knowledge – about topical organization, regulated by the properties of “centration” and “organicity”. The collected texts were analysed in the category of discursive topic, with the intention of observing the topical (dis)organization in the school compositions. As for the rewritten texts, besides the orientation classes, the corrections made by the teachers into the original texts were taken into account, in order to verify if the new orientations contributed in obtaining texts with topical organization. As a result, it was noticed that, in spite of some differences in the way the classes were given in the two observed groups, most of the texts weren’t endowed with topical organization and this result could be explained by the nature of orientation that were given in the classes.

Les acides biliaires sont depuis longtemps connus pour leur propriété d’agents solubilisant des graisses et des vitamines liposolubles, permettant ainsi une absorption efficace de ces nutriments lors de la digestion. Depuis les années 2000, plusieurs équipes ont montré que ces molécules étaient également dotées de propriétés de signalisation, en particulier via l’activation de deux récepteurs : le récepteur nucléaire FXR, et le récepteur membranaire TGR5. Le récepteur TGR5 est exprimé dans de très nombreux tissus, dont les muscles lisses et squelettiques, le tissu adipeux brun, la vésicule biliaire, mais aussi certaines cellules immunitaires et certaines populations cellulaires intestinales telles que les cellules entéroendocrine L. Selon le tissu étudié, l’activation de TGR5 peut être suivie de nombreux effets biologiques. En particulier, au niveau intestinal, l’activation de ce récepteur stimule la sécrétion de l’hormone incrétine GLP-1.Les hormones incrétines sont impliquées dans la régulation de la glycémie, en particulier dans la phase postprandiale, où elles concourent à potentialiser l’action de l’insuline, hormone hypoglycémiante majeure. Or, dans un contexte de diabète, et en particulier de diabète de type 2, l’organisme est devenu moins sensible à l’insuline, ce qui se traduit par un défaut de gestion de la glycémie, pouvant entrainer à terme des complications graves, telles que des amputations, une cécité, ou encore des problèmes cardiovasculaires. La prévalence et l’incidence de cette pathologie ont conduit l’OMS à la considérer comme la première épidémie d’origine non-infectieuse, ce qui illustre son impact sur la santé publique et le besoin médical constant qu’elle génère.Dans ce contexte, TGR5 apparait comme cible thérapeutique potentielle attrayante, de par l’effet GLP-1 sécrétagogue consécutif à son activation. En effet, parmi les thérapies antidiabétiques, deux classes de molécules basent leur efficacité sur une augmentation de la signalisation de la voie incrétine : les incrétinopotentiateurs (inhibiteurs de la DDP4, enzyme responsable de la faible demi-vie du GLP-1) et les incrétinomimétiques (agonistes synthétiques du récepteur au GLP-1). Récemment, cette dernière classe a également fait son apparition dans l’arsenal thérapeutique de l’obésité, confirmant l’intérêt de cette voie de signalisation dans les pathologies issues d’un désordre métabolique. L’obtention de composés GLP-1 sécrétagogues s’avère ainsi prometteuse et représente une approche complémentaire aux deux autres classes.L’objectif de ce travail était donc d’obtenir des agonistes puissants, sélectifs et originaux du récepteur TGR5. Afin de diminuer les risques d’effets indésirables, on-target ou off-target, nous avons choisi de profiter de la localisation intestinale de notre cible d’intérêt en concevant nos composés de manière à limiter l’exposition au seul tractus gastro-intestinal, en limitant leur absorption. Ainsi, nous avons cherché à obtenir des composés non systémiques GLP-1 sécrétagogues.La stratégie employée pour aboutir à ces composés a été le développement de molécules chimériques constituées d’une partie agoniste de TGR5, le pharmacophore, liée à un groupement permettant de limiter la perméabilité membranaire et donc l’absorption intestinale, le kinétophore. Après avoir optimisé la partie pharmacophore et identifié une position permettant l’ajout de différents types de kinétophores sans impact majeur sur l’activité du composé, nous avons pu obtenir plusieurs agonistes de TGR5 puissants, originaux, et dotés d’une très faible perméabilité membranaire. L’étude in vivo de ces molécules a ensuite permis de valider d’une part leur activité GLP-1 sécrétagogue, et d’autre part leur faible exposition systémique. Enfin, l’évaluation du potentiel thérapeutique d’un des meilleurs composés dans des modèles murins de diabète a récemment pu être initiée. / Bile acids have long been known as lipid solubilizing agents, enabling efficient absorption of nutrients and vitamins during digestion. Since 2000, several teams have demonstrated the signaling properties of these molecules, especially through the activation of two receptors : the nuclear receptor FXR and the membrane receptor TGR5.The TGR5 receptor is expressed in various tissues, such as smooth and skeletal muscles, brown adipose tissue, gallbladder, but also on some immune or intestinal cell lines such as the enteroendocrine L cells. Depending on the studied tissue, TGR5 activation can trigger various biological effects. In the intestine, its activation can stimulate the secretion of an incretin hormone, the GLP-1.Incretin hormones play a role in glycaemia regulation, especially during the postprandial phase during which they potentiate the action of the insulin, the main hypoglycemic hormone. Diabetes mellitus correspond to a decreased response of the organism to insulin signaling. This leads to a default in the glycaemia handling that can lead to serious complications, such as amputation, blindness, or cardiovascular problems. Prevalence and incidence of this disease have lead the WHO to define diabetes as the first non-infectious epidemic, illustrating its impact on public health and the constant need for new therapeutic opportunities.In this context, TGR5 appears as an appealing potential therapeutic target, especially because of the GLP-1 secretagogue effect triggered by its activation. Indeed, among the antidiabetic therapeutic options, two classes of drugs work by increasing the incretin signaling: the incretinopotentiators (inhibitors of the DPP4, which is the enzyme responsible for the very short half-life of GLP-1), and the incretinomimetics (synthetic agonists of the GLP-1 receptor). Recently, this last class has also been approved to treat obesity. This demonstrates the interest of this signaling pathway in the treatment of metabolic disorders. Hence, GLP-1 secretagogue compounds may prove to be an interesting approach, and could complement the two other classes.The aim of this work was then to obtain potent, selective and original agonists of the TGR5 receptor. In order to decrease the risk of on-target and off-target effects, we decided to take advantage of the intestinal localization of our target by designing compounds that would only expose the gastro-intestinal tract, by limiting their absorption. Thus, we wanted to obtain non systemic GLP-1 secretagogue compounds.Our strategy was to develop chimeric compounds consisting of a pharmacophore part, which would be a potent and selective agonist of TGR5, linked to a kinetophore part, which would decrease membrane permeability. After having optimized the pharmacophore part and having identified a position where we could link various kinetophore moieties with only weak impact on the activity, we obtained several potent TGR5 agonists with very low membrane permeability. In vivo evaluations of these compounds have validated both their GLP-1 secretagogue activity and their low systemic exposure. In the end, evaluation of our lead compound on mouse model of diabetes was recently started.

O objetivo deste estudo foi investigar o potencial inibidor de desgaste dentário ocasionado por erosão e abrasão de um novo produto, o verniz ClinPro XT Varnish, em comparação com vernizes fluoretados convencionais à base de TiF4 e NaF. Sessenta amostras de esmalte bovino (n=15/grupo) com microdureza superficial entre 300-380KHN foram selecionadas e aleatoriamente tratadas com: verniz de NaF (Duraphat®, 2,26% F-), verniz de TiF4 (2,45% F-), ClinPro XT varnish (fluoraluminiosilicato e glicerofosfato de cálcio) e controle (sem tratamento). Após receberem os respectivos tratamentos, as amostras foram submetidas a 3 dias de desafios erosivos de 4x5 min/dia (Sprite® Zero) e a abrasão 2x15s/dia, utilizando uma máquina de escovação. Entre os ciclos de erosão e abrasão, as amostras permaneceram em saliva artificial. A perda de esmalte foi medida com perfilômetro óptico. Os dados foram submetidos ao teste Kruskal-Wallis seguido pelo Dunn (p<0,05) .Ambos vernizes de NaF (-5,84m [-12,06; 1,64]b) (mediana ± 95%IC) e TiF4 (-3,60m [-8,72; -0,45]b) foram eficazes em reduzir o desgaste do esmalte quando comparados ao grupo controle (-16,60m [-19,92; -10,04]a). O ClinPro XT varnish permaneceu na superfície do esmalte (106,21m [30,67; 126,22]c), impedindo completamente o desgaste. Assim foi possível concluir que o ClinPro XT teve um efeito superior aos outros vernizes, impedindo completamente a erosão e abrasão do esmalte por 3 dias in vitro. / The purpose of this study was to investigate the erosion and abrasion inhibiting effect of a newly released product, Vanish XT varnish, and compare it to conventional TiF4 and NaF varnishes. Sixty bovine enamel blocks (300-380 KHN) were selected and randomly allocated into 4 treatment groups (n=15/group): NaF varnish (Duraphat®, 2.26% F-), TiF4 varnish (2.45% F-), Vanish XT varnish (fluoroaluminosilicate and calcium glycerophosphate), and control (no treatment). The samples received their respective treatments one single time at the beginning of the experiment. During a total of 3 days, erosive challenges were done 4x5min/day (Sprite Zero®) and abrasion 2x15s/day using a brushing machine. In between the erosive and abrasive challenges and overnight the samples remained immersed in artificial saliva. Enamel loss was measured using a non-contact profilometer. The data were subjected to Kruskal-Wallis and Dunn tests (p<0.05). Both NaF (-5.84m [-12.06; 1.64]b) (median ± 95%CI) and TiF4 (-3.60m [-8.72; -0.45]b) varnishes were able to reduce enamel wear when compared to the control group (-16.60m [-19.92; -10.04]a). Vanish XT varnish remained on the enamel surface (106.21m [30.67; 126.22]c), completely preventing enamel wear. Therefore, we concluded that Vanish XT presented a superior effect when compared to conventional varnishes, completely preventing enamel erosion and abrasion for 3 days in vitro.

Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2008.