Ketoprofen is a potent non-steroidal anti-inflammatory drug which is used for the treatment of rheumatoid arthritis. The oral administration of ketoprofen can cause gastric irritation and adverse renal effects. Transdermal delivery of the drug can bypass gastrointestinal disturbances and provide relatively consistent drug concentrations at the site of administration. The release of ketoprofen from proprietary gel products from three different countries was evaluated by comparing the in vitro release profiles. Twenty extemporaneously prepared ketoprofen gel formulations using Carbopol® polymers were manufactured. The effect of polymer, drug concentration, pH and solvent systems on the in vitro release of ketoprofen from these formulations were investigated. The gels were evaluated for drug content and pH. The release of the drug from all the formulations obeyed the Higuchi principle. Two static FDA approved diffusion cells, namely the modified Franz diffusion cell and the European Pharmacopoeia diffusion cell, were compared by measuring the in vitro release rate of ketoprofen from all the gel formulations through a synthetic silicone membrane. High-performance liquid chromatography and ultraviolet spectrophotometric analytical techniques were both used for the analysis of ketoprofen. The validated methods were employed for the determination of ketoprofen in the sample solutions taken from the receptor fluid. Two of the three proprietary products registered under the same manufacturing license exhibited similar results whereas the third product differed significantly. Among the variables investigated, the vehicle pH and solvent composition were found have the most significant effect on the in vitro release of ketoprofen from Carbopol® polymers. The different grades of Carbopol® polymers showed statistically significantly different release kinetics with respect to lag time. When evaluating the proprietary products, both the modified Franz diffusion cell and the European Pharmacopoeia diffusion cell were deemed adequate although higher profiles were generally obtained from the European Pharmacopoeia diffusion cells. Smoother diffusion profiles were obtained from samples analysed by high-performance liquid chromatography than by ultraviolet spectrophotometry in both diffusion cells. Sample solutions taken from Franz diffusion cells and analysed by ultraviolet spectrophotometry also produced smooth diffusion profiles. Erratic and higher diffusion profiles were observed with samples taken from the European Pharmacopoeia diffusion cell and analysed by ultraviolet spectrophotometry. The choice of diffusion cells and analytical procedure in product development must be weighed against the relatively poor reproducibility as observed with the European Pharmacopoeia diffusion cell.

Submitted in fulfillment for the Degree of Master of Applied Sciences in Biotechnology, Durban University of Technology, Durban, South Africa, 2017. / South Africa has a wide range of medicinal plants that are used traditionally by black Zulu South Africans for the treatment of a range of illnesses, including inflammatory ailments; disease conditions caused by oxidative stress and wound healing. It has been indicated that bioactive compounds isolated from plants contribute to their anti-inflammatory, antioxidant and wound healing properties; hence, herbal remedies have been widely used traditionally in many countries in the management and treatment of wounds. Inflammation is the main condition that relates to a variety of diseases affecting most of the world’s population. It is the body’s immune response to infection and injury and is induced by the release of pro-inflammatory mediator’s —prostaglandins and leukotrienes—following wound occurrence. Wounds result in disruption of living tissue caused by oxidative stress. Anti-inflammatory agents, antioxidants, and antimicrobials play an important role in the wound healing process and they prevent aggravated wound conditions.Controlling inflammation during wound repair is important to minimize any additional complications that may result; hence, chemical agents such as non-steroidal anti-inflammatory drugs (NSAIDS), synthetic antioxidantsand steroids are frequently used. These drugs block the enzymes that are responsible for prostaglandin synthesis in inflammation, react with free radicals thereby interfering with oxidation process as a result affect one or more phases of wound healing. The use of these drugs, however, has been limited as they can cause detrimental side effects when used over long periods of time.There is, consequently, a need to find alternative natural therapeutic drugs. Studies on medicinal plants confirmed that herbal drugs exhibit fewer side effects in comparison with chemical agents and are more cost-effective.Thus the aim of this study was to investigate South African medicinal plants, for anti-inflammatory, antioxidant and wound healing properties. Dissolved extracts of thirty-eight medicinal plants were evaluated for theiranti-inflammatory activity using the 5-lipoxygenase assay as well as free radical scavenging activity using the 1; 1-diphenyl-2-picrylhydrazyl (DPPH) assay.Their safety was evaluated using brine shrimp lethality assay. Proliferation and viability of fibroblast cells was determined by the3-(4, 5-dimethylthiazolyl)-2, 5-diphenyltetrazolium bromide(MTT) assay furthermore a scratch wound assay was used to study the properties of wound healing in vitro and to confirm the anti-inflammatory activities of the dissolved extracts. Migration rate was evaluated quantitatively by an image analyzer. Methanol was chosen for extraction because it completely dissolves extracts. Anova was used for statistical analysis. Almost all aqueous extracts were found to be effective in inhibiting lipoxygenase enzyme when compared to nordihydroguaiaretic acid (NDGA). Aqueous extracts exhibited remarkably high percentage inhibition of lipoxygenase with most above 100% when compared to methanolic extracts. Amaranthus dubius and Portulaca oleracea were found to have good biological activities in the inhibition of 5-lipoxygenase enzymes when compared to the other plants. However, Galinsoga parviflora and Syzygium cordatumwere least effective in inhibiting enzyme activity with percentages as low as -2% and 34% respectively. Percentage inhibitions for methanolic extracts were lower than that of aqueous extracts. Amaranthus spinosus had the highest percentage inhibition among all the methanolic extracts andGalinsoga parviflorahad the lowest. The methanolic plant extracts were found to be more effective in scavenging DPPH free radicals than the corresponding aqueous extracts. All the methanolic extracts exhibited free radical scavenging ability in the range of 60%–104%. Asystasia gangetica, Ficus sur, Heteropyxis natalensis, Hibiscus sabdariffa, Pelargonium sp. showed notably higher scavenging abilities, ranging from 101%–104% compared to Rutin. Methanolic extracts of Heteropyxis natalensis and Hibiscus sabdariffa exhibited scavenging ability even at the lowest concentration of 10μg/ml. Furthermore, aqueous extracts displayed remarkably lower activities than methanolic extracts with thirty-one extracts having a scavenging capacity ranging from 22%—59%. None of the extracts were found to be detrimental to brine shrimp. Almost all the extracts were shown to stimulate the growth of fibroblast cells except the methanolic extract of Solanum nodiflorum, which was shown to be killing the cells at high concentrations with a percentage viability of 46%.As the concentration decreased, however, the viability of cells with this extract increased to 143%. An increase in the number of fibroblast cells was observed in the scratched area of the treated cells and a significant migration rate was also noted with some of the extracts. Aqueous extracts of Sonchus oleraceus (86%), Justicia flava (85%) and Dichrostachys cinerea (85%) and methanolic extracts of Senna occidentalis and Hibiscus sabdariffa were found to have the highest migration rate compared to untreated cells that served as a control. No cell migration was observed with methanolic extract of Solanum nodiflorum.Instead, the extract was found to be toxic to the cells. Some of the plants evaluated in this study have been studied for either anti-inflammatory, antioxidantand wound healing properties in vivo, however, no work has been conducted to demonstrate a correlation between anti-inflammatory, antioxidant and wound healing properties of plant species in vitro. The current study was, therefore, conducted to review medicinal herbs considered as anti-inflammatory, antioxidants and wound healing agents as well as collecting evidence for their effectiveness and pharmacological mechanisms in modern science. In the plant species investigated Amaranthus dubius, Asystasia gangetica, Bidens pilosa, Buddleja saligna, Carpobrotus dimidiatus, Chenopodium album, Dichrostachys cinerea, Emex australis, Ficus sur, Guilleminea densa, Hibiscus sabdariffa, Physalis viscose, Syzygium cordatum, Taraxacum officinale and Tulbaghia violacea demonstrated good anti-inflammatory and wound healing properties.In conclusion the results from this study demonstrated promising anti-inflammatory and antioxidantactivities as well as wound healing properties,furthermoreit was aslo shown that the plant extracts were not toxic to the cells hencethis suggested that the plants investigated, can be used as substitutes or to formulate wound healing agents that are safe to use in primary healthcare. / M

Formation of lipid-laden macrophage foam cells and inflammation are the central components in the initiation and progression of atherosclerosis. ABCA1 is well established as an anti-atherogenic factor that facilitates cellular cholesterol and phospholipid efflux, promotes reverse cholesterol transport, and suppresses pro-inflammatory cytokine secretion. Through these functions, ABCA1 is capable of reducing the lipid burden in atherosclerotic plaque. PKA signaling is an integral factor in promoting many anti-atherogenic functions of ABCA1; however, mechanistic aspects of PKA signaling associated with ABCA1 remain poorly defined. Thus, the first part of this study investigates the involvement of spatially regulated PKA signaling in ABCA1 activities through the use of st-Ht31, a PKA de-anchoring peptide. It appears that de-anchoring PKA robustly increases ABCA1-mediated microparticle release, one of the cholesterol efflux pathways of ABCA1, and reverses macrophage foam cell formation. These results highlight the significance of subcellular compartmentalization of PKA signaling in ABCA1 functions and present PKA de-anchoring as a potential therapeutic strategy for atherosclerotic lesion regression. The second part of this study provides evidence that ABCA1 activates PKA and promotes the secretion of anti-inflammatory IL-10, a cytokine crucial for inflammation resolution. Furthermore, we provide evidence that this elevated PKA activity is the underlying mechanism in which macrophage ABCA1 promotes M2-like inflammatory response. Our results also suggest that ABCA1 activates PKA by regulating cholesterol, which poises macrophages towards an anti-inflammatory or M2-activated phenotype. Collectively, we demonstrate that PKA signaling plays a crucial multifactorial role in anti-atherogenic functions of ABCA1.

Le travail décrit dans cette thèse a commencé avec la découverte d’effets anti-inflammatoires chez certaines souches de L. delbrueckii. Il avait été montré que l’effet anti-inflammatoire est souche-dépendant, et implique l’action de protéines exposées à la surface de la bactérie. Dans le but d’identifier l’effecteur bactérien à l’origine de l’effet immuno-modulateur, 8 souches de L. delbrueckii ont été sélectionnées. Deux de ces souches sont à fort effet anti-inflammatoires, et les 6 restantes sont à effet faible ou intermédiaire. Pour l’identification des protéines potentiellement responsables pour l’effet anti-inflammatoire, des études de génomique et transcriptomique comparatives des 8 souches de L.delbrueckii ont été entreprises, ainsi qu’une étude comparative du protéome de surface bactérienne.La première partie de cette thèse décrit les résultats de finition du génome d’une des deux souches hautement anti-inflammatoires. Cette étape a révélé que la partie manquante de la séquence génomique était principalement composée de séquences répétées de type séquences d’insertions (IS), dont le nombre s’avère particulièrement élevé.La deuxième partie de la thèse décrit une étape de valorisation des données génomiques à travers une étude comparative entre souches de la ssp. lactis et souches de la ssp. bulgaricus. Cette étude révèle que les deux ssp. de L. delbrueckii évoluent en adaptation au milieu lait. Toutefois, la ssp. bulgaricus semble avoir atteint un stade d’adaptation plus avancé que celui de la ssp. lactis. L’adaptation des deux ssp. à leur environnement se fait principalement par un phénomène de perte spontanée de gènes devenus superflus.Une étude plus avancée de la structure génomique des deux ssp. révèle deux nouveaux aspects des différences de structure génomique. Tout d’abord, au sein du core génome des deux sous-espèces, les évènements d’échange génétique et recombinaison ont contribué plus à la diversité au sein de la ssp. lactis qu’à la diversité chez la ssp. bulgaricus. Ensuite, une structure inversée répétée de grande taille, rarement observée dans les génomes bactériens, s’avère caractéristique de la ssp. bulgaricus. La troisième partie de thèse décrit les trois approches comparatives menées dans le but d’identifier les protéines bactériennes à l’origine de l’effet anti-inflammatoire. Au bout de ces études, nous avons sélectionné 56 gènes candidats, dont 41 ont été clonés dans un système d’expression hétérologue. Pour l’instant, 17 clones d’expression ont été testés in vitro pour leur potentiel immuno-modulateur. Les résultats préliminaires ont permis l’identification d’une protéine à effet anti-inflammatoire. / The work described in this thesis began with the discovery of anti -inflammatory effects in certain strains of L. delbrueckii. The anti- inflammatory effect had been shown to be strain - dependent, and implicate the action of bacterial surface exposed proteins.In order to identify the bacterial effector responsible for the immunomodulatory effect, eight strains of L. delbrueckii were selected. Two of these strains have a strong anti -inflammatory effect, whereas the remaining strains have a weak to intermediary effect. To identify proteins that may be responsible for the anti- inflammatory effect, comparative genomic and transcriptomic studies of the 8 L.delbrueckii strains were conducted, as well as a comparative study of the bacterial surface proteome.The first part of this thesis describes the genome finishing of one of the highly anti- inflammatory strains. This step revealed that the missing part of the genome sequence was mainly composed of repeated sequences such as insertions sequences (IS), that were present in a particularly high number.The second part of the thesis describes the valorisation of genomic data through a comparative study between ssp. lactis strains and ssp. bulgaricus strains. This study reveals that both L. delbrueckii ssp. are evolving in adaptation to the milk environment. However, the ssp. bulgaricus appears to have reached a more advanced stage of adaptation than the ssp. lactis. The adaptation of both ssp. to their environment is primarily a phenomenon of spontaneous loss of genes that have become superfluous. A more detailed study of the genome structure of the two ssp. reveals two important differences. Firstly, within the L. delbrueckii core genome, genetic exchange and recombination contributed much more to the ssp. lactis diversity than to the ssp. bulgaricus diversity. Furthermore, a large inverted repeat structure, rarely observed in bacterial genomes, appears to be characteristic of the ssp. bulgaricus.The third part of the thesis describes the three comparative approaches used to identify bacterial proteins responsible for the anti- inflammatory effect.We selected 56 candidate genes, of which 41 were cloned in a heterologous expression system. So far, 17 expression clones were tested in vitro for their immunomodulatory potential. The preliminary results allowed the identification of one protein with anti-inflammatory effects.

Third molar surgery may be associated with a number of complications the most common of which are postoperative pain, swelling and trismus, and dry socket formation. The appearance of these post-operative sequelae is intimately related to the manifestations of inflammation in response to tissue injury. There is significant post-operative morbidity associated with these complications and it was thus the objective of this study to - investigate the effect of a combined antibiotic/anti-inflammatory intrasocket medication on post-operative pain, swelling and dry socket formation. The medication chosen for the study was Covomycin D®. Covomycin D® is a commercially prepared opthalmological preparation - each 1 millilitre contains 2 mg chloramphenicol, 5 mg neomycin sulphate and 0,5 mg dexamethasone. Nineteen subjects were included in the study after fullfilling certain criteria. All subjects were operated under general anaesthesia by the same surgeon. The patients were blinded to the side of the medication and were asked to complete a pain visual analogue scale and note the side of the worst swelling in the post¬operative period. All patients were followed up in the first week following surgery by an independent oral and maxillofacial surgeon who was also blinded to the side on which the medication was placed. The results showed a significant difference (p<0.6) in the pain experienced on the non-medicated compared to the medicated side on day one in eleven of the nineteen patients (57.9%). When the data was analysed over the six day postoperative period sixteen of the nineteen patients (84.2%) had significantly less pain on the medicated side compared to the non-medicated side (p<0.6). The swelling was reported as being worse on the non-medicated side in fourteen out of the nineteen patients (73.7%). Dry socket occurred in three out of nineteen patients or three out of thirty eight surgical extraction sites; an overall incidence of 7.9% or an incidence of 0% for the medicated side and an incidence of 15.8% on the non-medicated side i.e. all the dry sockets occurred on the non-medicated side. In conclusion, this double-blinded prospectve study, showed that the use of a combined antibiotic/anti-inflammatory intrasocket medication favourably influences the common adverse post-operative sequelae following the removal of lower third molars. / Dissertation (MChD (Chir Max-Fac Med))--University of Pretoria, 2007. / Maxillo-Facial and Oral Surgery / unrestricted

Please read the abstract in the section 00front of this document / Thesis (PhD (Geneeskundige Immunologie))--University of Pretoria, 2005. / Pharmacology / unrestricted

Made available in DSpace on 2016-05-02T13:54:45Z (GMT). No. of bitstreams: 1 Patricia Costa.pdf: 508722 bytes, checksum: a02bd42feee52e02068566c6c8bdfd6e (MD5) Previous issue date: 2010-04-16 / The treatment of several affections of the musculoskeletal system with anti-inflammatory drugs is very frequent. However, the effects of such drugs on boné neoformation and osseointegration after fractures or bone surgeriesare not well understood yet. This study aimed at evaluating the effect of ketoprofen (NSAID) and dexamethasone (SAID) on osteogenesis around a dense hydroxiapatite (DHA) implant in the left tibia and left parietal bone, and on the femur bone resistance. Fifteen fifty-day-old Wistar rats (Rattus norvegicus albinus) weighing on average 250±30 g were used. The animals were separated into three groups (n=5): control (CT); non-steroidal anti-inflammatoryl (NSAID); and steroidal anti-inflammatory (SAID). After anesthesia with IM ketamine/xylazine, a 3 mm cavity was made in the left parietal bone and in the proximal epiphysis of the left tibia. A DHA bioceramic was implanted in the tibia. The periosteum and the skin were repositioned by suturing their borders. The animals were treated subcutaneously during 30 days as follows: NSAID group: ketoprofen at the dose of 12/Kg/day; SAID group: dexamethasone, 0,10 mg/kg/day. The CT group received saline through the same route. All the animals received the same solid diet and water ad libitum. The daily water and ration consumption were calculated to evaluate the animals nutritional conditions. After 30 days of experiment, the animals wereeuthanized, and their femurs collected for the mechanical test, while their tibia and parietal sites were prepared for the histomorphometrical analysis. The daily consumption of water and ration was satisfactory, showing neither dehydration nor protein undernourishment. Microscopically, the SAID and NSAID groups showed a lower volume of neoformed bone. In addition, the NSAID and SAID group femurs required lower maximum force for complete rupture when compared with the CT group. It was concluded that ketoprofen and dexamethasone interfered with osteogenesis and decreased bone resistance by altering the bone tissue metabolism, mainly by inhibiting the COX-2 and decreasing prostaglandins. Therefore, the use of ketoprofen and dexamethasone after boné surgeries can compromise the stability and maintenance of implants. / O tratamento de diversas afecções do sistema musculoesquelético com anti-inflamatórios é muito freqüente. Entretanto, os efeitos da utilização dessas drogas na neoformação óssea e osseointegração após fraturas ou cirurgias ósseas permanecem pouco esclarecidos. O objetivo deste estudo foi avaliar o efeito do cetoprofeno (AINES) e da dexametasona (AIES) na osteogênese ao redor de implante de hidroxiapatita densa (HAD) na tíbia esquerda, no osso parietal esquerdo, e na resistência óssea do fêmur. Utilizaram-se 15 ratos (Rattus norvegicus albinus, Wistar), pesando em média 250±30 g, com 50 dias de idade. Os animais foram divididos aleatoriamente em três grupos (n=5): controle (CT), anti-inflamatório não esteroidal (AINES) e anti-inflamatório esteroidal (AIES). Após a anestesia com quetamina/xilazina IM, foi produzido no osso parietal esquerdo e na epífise proximal da tíbia esquerda uma cavidade de 3 mm. Na cavidade da tíbia foi implantada a biocerâmica hidroxiapatita densa. O periósteo e a pele foram reposicionados através da sutura de suas bordas. Os animais do grupo AINES foram submetidos ao tratamento com cetoprofeno na dose de 12 mg/Kg/dia, e os do grupo AIES receberam doses de 0,10 mg/kg/dia de dexametasona por via subcutânea durante 30 dias. Os animais do grupo CT receberam solução salina pela mesma via de administração. Todos os animais receberam a mesma dieta sólida e água ad libitum. Foram calculados os consumos diários de água e ração para avaliar o estado nutricional dos animais. Após 30 dias de experimento os animais sofreram eutanásia, os fêmures coletados, para teste mecânico, e os locais do implante das tíbias e o osso parietal, para análise histomorfométrica. O consumo diário de água e de ração foi satisfatório entre os grupos, mostrando não haver desnutrição protéica e desidratação. Microscopicamente observamos menor volume de osso neoformado nos animais dos grupos AINES e AIES. Além disso, os animais dos grupos AINES e AIES necessitam de menor força máxima para a ruptura completa dos fêmures quando comparados com o grupo CT. Concluímos que o cetoprofeno e a dexametasona interferiram na osteogênese e ao redor do implante de HAD e no osso parietal, e diminuiu a resistência óssea por alterar o metabolismo do tecido ósseo, principalmente pela inibição da COX2 e diminuição das prostaglandinas. Assim,o uso do cetoprofeno e da dexametasona pós-cirurgias ósseas pode comprometer a estabilidade e manutenção do implante.

Visando a produção de um alimento que possua elevados teores de compostos bioativos, a piramidação de genes é uma técnica capaz de estimular o acúmulo e a expressão de novas classes de flavonoides em tecidos vegetais, como por exemplo, o tomate roxo, rico em antocianinas. As antocianinas podem atenuar o processo inflamatório através da modulação da cascata de sinalização e da expressão de enzimas, sendo este um dos possíveis mecanismos de ação que leva a promoção da saúde, atribuído a esta classe de compostos. Assim, o objetivo deste trabalho foi avaliar a ação anti-inflamatória do extrato de tomate roxo, obtido por piramidação dos genes Anthocyanin Fruit (Aft), Aubergine (Abg) e atroviolaceum (atv), em camundongos submetidos ao modelo de peritonite induzida por lipopolissacarídeo (LPS). O fruto tomate vermelho - Micro Tom (MT) e o transformado foram caracterizados quanto ao seu perfil de compostos fenólicos. A casca do tomate roxo, rica em antocianinas, apresentou conteúdo de fenólicos totais dez vezes maior quando comparado à casca do MT, apresentando também maiores quantidades de ácido ascórbico e capacidade antioxidante avaliado nos métodos DPPH e ORAC; em relação à polpa e casca do tomate vermelho e a polpa do tomate roxo. Os principais flavonoides identificados na casca do tomate roxo, por CLAE-DAD, foram: as antocianidinas petunidina (86,5 mg/100 g b.u.), delfinidina (6,85 mg/100 g b.u.), principalmente na forma acilada, e o flavonol rutina (106,26 mg/100 g b.u.). A propriedade anti-inflamatória dos compostos fenólicos foi avaliada através de um modelo de peritonite, em camundongos, induzida por LPS. O extrato aquoso do tomate roxo, rico em antocianinas (2 e 4 mg petunidina eq./100 g peso corpóreo) foi administrado, por via oral, 30 minutos antes do estímulo inflamatório. No exsudato peritoneal, coletado após 3h do estímulo, foi observada, no grupo que recebeu 4 mg quando comparado ao grupo estimulado com LPS, uma redução significativa (p<0,05) de cerca de 37% no número de leucócitos totais e de 64% na expressão gênica de mRNA de COX-2 e na produção de citocinas pró-inflamatórias (TNF-&#945;, IL-1&#946;, IL-2, IL-6 e MCP-1), assim como um aumento significativo da citocina anti-inflamatória IL-10. Em estudo de absorção, os metabólitos: delfinidina aglicona (m/z 303) e malvidina aglicona (m/z 331) foram detectados, por cromatografia líquida ESI-MS/MS, nas amostras de fígado dos animais eutanasiados após 30 minutos de administração do extrato do tomate roxo. Portanto, os resultados demonstram que as antocianinas presentes no tomate roxo, por meio dos metabólitos encontrados no fígado dos animais, apresentam atividade anti-inflamatória através do controle do influxo leucocitário, da modulação da expressão gênica de COX-2 e da produção citocinas. / Aiming to produce a food having high contents of bioactive compounds, the gene pyramiding is a technique capable of stimulating the expression and accumulation of new classes of flavonoids in plant tissues, such as purple tomato, rich in anthocyanins. Anthocyanins may attenuate the inflammatory process by modulating the signaling cascade and expression of enzymes, which is one of the possible mechanisms of action that leads to health promotion, assigned to this class of compounds. The objective of this study was to evaluate the anti-inflammatory action of the purple tomato paste, obtained by pyramiding of genes Fruit Anthocyanin (Aft), Aubergine (Abg) and atroviolaceum (atv) in mice submitted to peritonitis model induced by lipopolysaccharide (LPS). The tomato fruit - Micro Tom (MT) and the transformed were characterized according to their profile of phenolic compounds. The purple tomato peel, rich in anthocyanins, phenolics content presented ten times higher compared to the shell of the MT, and also provides increased amounts of ascorbic acid and antioxidant activity in the DPPH rated and the ORAC methods; than the pulp and peel the tomato pulp and purple tomatoes. The main flavonoids identified in tomato peel purple, by HPLC-DAD were: petunidin the anthocyanidins (86.5 mg / 100 g wb), delphinidin (6.85 mg / 100 g wb), especially in the acylated form, and flavonol rutin (106.26 mg / 100 g bu). The anti-inflammatory properties of the phenolic compounds was evaluated through a model of peritonitis in mice induced by LPS. The extract of purple tomato, rich in anthocyanins (2 and 4 petunidin mg eq. / 100 g body weight) was administered orally 30 minutes before the inflammatory stimulus. In the peritoneal exudate collected after 3 h of stimulation was observed in the group receiving 4 mg as compared to the LPS stimulated group, a significant reduction (p <0.05) of about 37% in the number of total leukocytes and 64 % mRNA gene expression of COX-2 and production of proinflammatory cytokines (TNF-&#945;, IL-1&#946;, IL-2, IL-6 and MCP-1), as well as a significant increase of the anti-inflammatory cytokine IL-10. In a study of absorption, the metabolites: aglycone delphinidin (m / z 303) and malvidin aglycone (m / z 331) were detected by HPLC - ESI-MS / MS, in liver samples from animals euthanized 30 minutes after administration the purple tomato extract. Therefore, the results show that anthocyanins present in the purple tomato, through the metabolites found in animal liver, exhibit anti-inflammatory activity by controlling the leukocyte influx, the modulation of gene expression of COX-2 and production cytokines.

La fièvre est la première cause de consultation et d’exposition médicamenteuse chez l’enfant. Les principales molécules utilisées dans cette indication sont le paracétamol et un anti-inflammatoire non stéroïdien (AINS), l’ibuprofène. L’objectif général de cette thèse était de produire des connaissances nouvelles sur les pratiques des parents et des professionnels de santé pour la prise en charge symptomatique, notamment médicamenteuse, de la fièvre chez l’enfant. Les données étaient issues d’une étude transversale nationale menée entre 2007 et 2008, où 1534 médecins généralistes, pédiatres et pharmaciens (taux de participation 13%) ont inclus 6596 enfants avec une fièvre < 48h. Les analyses ont notamment utilisé des modèles multi-niveau multivariés. Les connaissances et les pratiques des parents et des professionnels étaient fréquemment discordantes par rapport aux recommandations, notamment pour la mise en œuvre des mesures antipyrétiques. Les principaux déterminants de pratiques non concordantes aux recommandations étaient un faible niveau d’études des parents, un âge élevé de l’enfant et la formation initiale de généraliste du professionnel consulté. Pour les enfants ayant reçu du paracétamol, un recours important aux suppositoires a été observé, y compris chez les enfants âgés et sans vomissement. Les parents utilisaient beaucoup plus d’AINS que les professionnels de santé et ce gradient augmentait dans des situations potentiellement à risque d’effet indésirable. Nos résultats montrent la nécessité d’actions d’éducation à la santé et de formation médicale continue pour la prise en charge de la fièvre de l’enfant et permettent de cerner les messages prioritaires. / Fever is the first reason for consultation and drug treatment in children in primary care. Main drugs used in this indication are acetaminophen and a non-steroidal anti-inflammatory drugs (NSAIDs), ibuprofen. The objective of this thesis was to produce new knowledge on parents’ and healthcare professionals' (HPs) practices for the symptomatic treatment of fever in children with a focus on drug treatments. We used data from an observational, cross-sectional, national study performed from October 2007 to June 2008, where 1,534 general practitioners, primary care pediatricians, and pharmacists (participation rate 13%) included 6,596 children with fever < 48 hr. Analyses used notably multivariate multilevel models.Knowledge and practices of parents and HPs were frequently discordant with recommendations, notably for antipyretic measures. The main determinants of discordant practices were a low parental educational level, an older child’s age and the healthcare professional being a general practitioner. Among children who received acetaminophen, a large use of suppositories has been observed, including for non-vomiting and/or older children. Parents used more NSAIDs than HPs, and this gradient increased in clinical conditions potentially at risk of adverse effect. Our results highlight the need for health education interventions and continuing medical training on fever management in children, and enable to identify priority messages.

Autism spectrum disorder (ASD) is associated with functional abnormalities of the anterior cingulate cortex (ACC), a brain area that mediates social behavior. Given evidence of a role of inflammation in ASD, markers of pro-inflammatory and anti-inflammatory microglia were studied using postmortem ACC tissues from ASD and age-matched typically developed control donors. Gene expression levels of pro-inflammatory (CD68, HLA-DRA, IL1B, NOS2, PTGS2) and anti-inflammatory (ARG1, IGF1, MRC1, PPARG) microglial genes were measured using quantitative real-time PCR. Additionally, brain sections were immunohistochemically stained for a microglial marker. Expression levels of IGF1 were modestly higher, while the expression of MRC1 was modestly lower in ASD donors when compared to control donors. No other differences in gene expression levels between the two groups of donors were observed. Statistical significance for changes in expression levels IGF1 and MRC1 did not survive correction for multiple comparisons. Further research on anti-inflammatory microglial involvement in ASD is warranted.