Submitted by Fabiana Gonçalves Pinto (benf@ndc.uff.br) on 2016-10-14T17:58:21Z No. of bitstreams: 1 Ana Luiza Soares Rodrigues.pdf: 1097029 bytes, checksum: 6d854fd13dfbf1dda2898d6f73d3ba62 (MD5) / Made available in DSpace on 2016-10-14T17:58:21Z (GMT). No. of bitstreams: 1 Ana Luiza Soares Rodrigues.pdf: 1097029 bytes, checksum: 6d854fd13dfbf1dda2898d6f73d3ba62 (MD5) Previous issue date: 2014 / Mestrado Acadêmico em Ciências do Cuidado em Saúde / O estudo teve como objetivos avaliar a efetividade do gel de papaína a 2% comparado ao gel de carboximetilcelulose a 2% no tratamento de pacientes com úlceras venosas crônicas e analisar as características sociodemográficas, econômicas e clínicas destes pacientes, atendidos no Ambulatório de Reparo de Feridas do Hospital Universitário Antonio Pedro/UFF. Método: Ensaio clínico controlado e randomizado (ECCR) com tempo de seguimento de 12 semanas. A amostra consecutiva foi composta por 18 voluntários e um total de 28 úlceras venosas. A coleta de dados ocorreu de abril de 2013 a janeiro de 2014. O desfecho primário do estudo foi a redução da área da lesão e os desfechos secundários foram a redução de tecidos desvitalizados no leito da úlcera e a redução da quantidade de exsudato. A pesquisa foi submetida ao Comitê de Ética em Pesquisa da Faculdade de Medicina, do Hospital Universitário Antonio Pedro/UFF e aprovada com o número 196/98, CAAE nº 0154.0.258.000-08. Resultados: Os grupos foram homogêneos quanto às características sociodemográficas, econômicas e clínicas. A idade dos voluntários variou de 45 a 85 anos, com média de 61,94 anos. A maioria dos participantes se declarou casado (55,6%), com escolaridade até o ensino fundamental (66,7%), residente de São Gonçalo (44,4%) e aposentado (66,7%). Todos os voluntários possuíam insuficiência venosa crônica, 61,1% apresentava hipertensão arterial sistêmica e 11,1% diabetes mellitus. A maioria das úlceras venosas lesões teve início há mais de dez anos (53,6%) e a localização mais acometida foi a região maleolar (53,6%). Quanto à evolução das úlceras ao longo de 12 semanas de tratamento, o grupo papaína apresentou redução significativa da área das lesões, especialmente no período entre a 5ª e a 12ª semanas de tratamento, com duas úlceras cicatrizadas e aumento expressivo da quantidade de tecido de epitelização no leito das lesões. Nos dois grupos de tratamento houve redução significativa da quantidade de tecido desvitalizado e aumento de tecido de granulação da 1ª semana para a 12ª semana (p-valor <0,05). Conclusão: o gel de papaína a 2% apresentou maior efetividade quanto à redução da área das lesões, entretanto se mostrou similar ao gel de carboximetilcelulose a 2% quanto à redução da quantidade de exsudato e de tecido desvitalizado. A partir dos resultados da pesquisa foram destacados os principais cuidados de enfermagem que podem auxiliar a assistência e o tratamento de pacientes com úlceras venosas crônicas. / The study aimed to evaluate the effectiveness of papain gel at 2% compared to the carboxymethylcellulose gel at 2% in the treatment of patients with chronic venous ulcers and analyze sociodemographic, economic and clinical characteristics of these patients, treated at the Outpatient Wound Repair at Antonio Pedro University Hospital/UFF. Method: Randomized Controlled Trial (RCT) with 12 weeks of follow-up. The consecutive sample consisted of 18 volunteers and a total of 28 venous ulcers. The data collection occurred from April 2013 to January 2014. The primary end point was the decrease of the lesion area and the secondary endpoints were devitalized tissue decrease in the ulcer bed and the reduction of the amount of exudate. The study was submitted to the Ethics Committee of the Faculty of Medicine, University Hospital Antonio Pedro/UFF and approved with the number 196/98, CAAE n. 0154.0.258.000-08. Results: The groups were homogenous regarding sociodemographic, economic and clinical characteristics. The volunteers ages ranged from 45 to 85 years old, with a mean of 61.94 years old. Most participants declared married (55.6%), with schooling up to elementary school (66.7%), resident of São Gonçalo (44.4%) and retired (66.7%). All volunteers had chronic venous insufficiency, 61.1% had hypertension and 11.1% diabetes mellitus. Most venous ulcers injuries began more than ten years ago (53.6%) and the most affected location was the malleolar area (53.6%). Regarding the ulcers evolution over the 12 weeks of treatment, the papain group showed a significant decrease in the lesions area, especially in the period between the 5th and the 12th weeks of treatment, with two healed ulcers and significant increase in the amount of epithelialization tissue. In both treatment groups, there was a significant decrease in the amount of devitalized tissue and an increase of the granulation tissue from 1st week to the 12th week (p <0.05). Conclusion: The papain gel at 2% was more effective in reducing of the lesions area, however it showed similar to the carboxymethylcellulose gel at 2% in reducing the amount of exudate and devitalized tissue. From the results of the research were highlighted the main nursing care that can help the assistance and treatment of patients with chronic venous ulcers.

Made available in DSpace on 2014-08-20T14:30:05Z (GMT). No. of bitstreams: 1 tese Rudimar_Antonio_Baldissera.pdf: 912046 bytes, checksum: 2e67255564e6053c35182672be9085fd (MD5) Previous issue date: 2012-09-14 / Composite restorations are daily performed in dental offices; however, few studies have reported the longevity of these restorations for long periods of observation. This study was conducted to evaluate the clinical performance of resin composite restorations placed in anterior and posterior teeth in the period between the years 1991 and 2001. From the files of a private dental clinic, 83 patients who received 375 restorations in posterior teeth and 61 patients with 237 restorations in anterior teeth with the composites Charisma (Heraeus Kulzer, Hanau, Germany), Herculite XR (Kerr, Orange, CA, USA) or Z100 (3M ESPE, St. Paul, MN, USA) participated in the study, being examined by two calibrated researchers. The restorations were evaluated according to the FDI criteria (World Dental Federation, HICKEL et al., 2007). After the fieldwork, data were double tabulated and subjected to statistical analysis using Stata version 11.0. Descriptive statistics were used to report the frequency of distribution of the restorations for the variables evaluated and for the causes of failures. The survival analyzes were performed using the Kaplan-Meier method, to obtain the survival curves for the variables of interest, followed by the Log-Rank test for comparison between groups (α=0.05). The analysis of factors associated with failure over time was performed using a model of multivariate analysis by Cox regression with shared fragility. Of the total of 612 restorations, 69 were considered unsatisfactory. The annual failure rate observed at the final of the period was 0.76 to anterior teeth and 1.16 to posterior teeth. The aesthetic factor was the major cause in the anterior teeth, while in posterior were the fractures. Regarding the material, the composite Herculite was significantly better than Z100 and this better than Charisma. Restorations with the largest number of surfaces involved had the worst performance. The result of this study showed a satisfactory clinical performance. In relation of the material, the composite Herculite was significantly better than the Z100 and this better than Charisma. The restorations with the highest number of surfaces involved had the worst performance / Restaurações de resina composta são confeccionadas diariamente nos consultórios odontológicos, porém poucos estudos reportam a longevidade destas restaurações por longos períodos de observação. Este estudo foi realizado para avaliar o desempenho clínico de restaurações de resina composta inseridas em dentes anteriores e posteriores no período de 1991 a 2001. A partir da verificação de prontuários do arquivo de uma clínica odontológica privada, 83 pacientes que receberam 375 restaurações em dentes posteriores e 61 pacientes com 237 restaurações em dentes anteriores com os compósitos Charisma (Heraeus Kulzer, Hanau, Alemanha), Herculite XR (Kerr, Orange, CA, EUA) ou Z100 (3M ESPE, St. Paul, MN, EUA) participaram do estudo e foram examinados por dois pesquisadores calibrados. As restaurações foram avaliadas de acordo com os critérios de avaliação clínica de restaurações propostos pela FDI (Federação Dentária Internacional) . Após o trabalho de campo, os dados foram tabulados por 2 digitalizadores e submetidos à análise estatística usando o Stata versão 11.0. Estatística descritiva foi usada para reportar a frequência de distribuição de restaurações para as variáveis avaliadas e para as causas de falhas. As análises de sobrevida foram realizadas pelo método de Kaplan Meier, para a obtenção das curvas de sobrevida para as variáveis de interesse, seguido do teste Log-Rank, para comparação entre grupos (α=0,05). A análise de fatores associados a falha ao longo do tempo foi realizada através de modelo de análise multivariável por regressão de Cox com fragilidade compartilhada. Do total das 612 restaurações, 69 foram consideradas insatisfatórias. A taxa de falha anual observada no final, foi de 0,76 para os dentes anteriores e de 1,16 para os posteriores. O fator estético foi a principal causa nos dentes anteriores enquanto que nos posteriores as fraturas., Em relação ao material a resina Herculite mostrou-se significantemente melhor que a Z100 e esta melhor que a Charisma. As restaurações com o maior número de faces envolvidas tiveram o pior desempenho. O resultado deste estudo mostrou que os compósitos apresentaram um bom desempenho clínico tanto em dentes posteriores quanto em anteriores, no acompanhamento a longo prazo

Made available in DSpace on 2014-08-20T14:30:13Z (GMT). No. of bitstreams: 1 Tese_Silvia_Terra_Fontes.pdf: 622962 bytes, checksum: 7bf1877d5a2267c9c8ee6f9619480978 (MD5) Previous issue date: 2011-12-16 / During restorative procedures, different isolation methods of the operative field can be used to promote moisture control and retraction of the gingival tissues. The aim of the present clinical trial was to evaluate the effects of two isolation techniques on the clinical performance of Class V restorations, as well on the periodontal conditions of restored sites. Patients presenting at least two noncarious cervical lesions (NCLs) were enrolled in this study. The NCLs were randomized into the following groups: (1) isolation performed with rubber dam and gingival retraction clamp and (2) isolation provided with cotton rolls and gingival retraction cord. Both techniques were used with a saliva suction device. All restorative procedures were performed using a selfetching adhesive system and a nanofilled composite resin according to the manufacturer s instructions. The clinical performance of restorations was recorded in terms of fracture and retention of restoration, marginal adaptation, marginal staining, postoperative hypersensitivity, and preservation of tooth vitality at 1 week and 6 months after placement.The periodontal condition of restored sites was evaluated based on the presence of supragingival plaque, gingival marginal bleeding, probing depth, and relative gingival recession. Thirty patients were enrolled in the study, yielding a total of 136 restorations (68 restorations per group). At the 6-month followup, one restoration from the rubber dam group and three restorations from the cotton roll group lost retention. In this period, the highest incidence of small marginal defects was observed in the group isolated with cotton rolls (p= 0.01). Both groups showed a statistically significant increase in supragingival plaque at six months after restoration placement (p< 0.05). However, no significant differences were detected among the two groups tested with respect to any of the criteria used to evaluate the restorations or the periodontal condition (p> 0.05). Within the limits of this study, it can be concluded that both isolation techniques resulted in equally clinically acceptable restorations without producing negative effects on periodontal tissues / Durante os procedimentos restauradores, diferentes métodos de isolamento do campo operatório podem ser utilizados a fim de promover controle de umidade e retração de tecidos gengivais. O objetivo do presente ensaio clinico foi avaliar os efeitos de duas técnicas de isolamento no desempenho clínico de restaurações Classe V, bem como na condição periodontal dos sítios restaurados. Pacientes apresentando, no mínimo, duas lesões cervicais não cariosas (LCNCs) foram selecionados para este estudo. As LCNCs foram randomizadas nos seguintes grupos: (1) isolamento com lençol de borracha e grampo retrator de gengiva e (2) isolamento com rolos de algodão e fio retrator de gengiva. Um sugador de saliva foi utilizado em ambas as técnicas. Todos os procedimentos restauradores foram executados com sistema adesivo autocondicionante e compósito restaurador nanoparticulado, seguindo as instruções dos fabricantes. O desempenho clinico das restaurações foi avaliado em termos de fratura e retenção da restauração, adaptação marginal, manchamento marginal, sensibilidade pós-operatória e preservação da vitalidade pulpar após 1 semana e 6 meses da inserção das restaurações.A condição periodontal dos sítios restaurados foi avaliada com base na presença de placa supragengival, sangramento gengival marginal, profundidade de sondagem e recessão gengival relativa. Trinta pacientes foram incluídos no estudo, resultando num total de 136 restaurações (68 restaurações por grupo). Após seis meses de acompanhamento, uma restauração do grupo isolado com lençol de borracha e três restaurações do grupo isolado com rolos de algodão perderam a retenção. Neste período, uma maior incidência de pequenos defeitos marginais foi observada no grupo que recebeu isolamento com rolos de algodão (p= 0.01). Ambos os grupos apresentaram um aumento significativo do acúmulo de placa supragengival após 6 meses da inserção das restaurações (p< 0.05). Porém, não foram detectadas diferenças estatisticamente significativas entre os dois grupos testados considerando os critérios utilizados para avaliação das restaurações e da condição periodontal (p> 0.05). Dentro das limitações deste estudo, foi possível concluir que ambas as técnicas de isolamento resultaram em restaurações clinicamente aceitáveis, sem produzir efeitos negativos nos tecidos periodontais

Les malformations artérioveineuses (MAV) cérébrales sont une pathologie rare et hétérogène dont l’imagerie est complexe du fait de leur caractère dynamique et la prise en charge controversée notamment du fait des risques liés aux traitements proposés.La première partie de cette thèse porte sur l’imagerie des MAVs, axée sur une nouvelle technique, l’angiographie en 4 dimensions. Initialement, nous avons étudié sa faisabilité et validé cette technique en la comparant à l’angiographie cérébrale conventionnelle. Puis nous l’avons comparé à une autre modalité dynamique, l’angiographie par résonance magnétique en 4 dimensions, dans l’analyse des caractéristiques angio-architecturales des MAVs. Enfin, nous avons utilisé cette technique comme aide au planning pré et peropératoire dans la chirurgie des micro-MAVs.La seconde partie de cette thèse porte sur la prise en charge des patients porteurs d’une MAV dans le cadre d’études cliniques. Face à l’absence de consensus et aux hétérogénéités des pratiques sur la prise en charge de cette pathologie, la réflexion de ce travail a été conduite en plusieurs temps : un état des lieux basé sur une revue systématique des critiques faites à un essai randomisé sur les MAVs non rompues ; puis la conception d’une nouvelle étude pragmatique en soins courant, randomisée et intégrant le jugement clinique du praticien et de l’équipe multidisciplinaire ; l’évaluation de l’applicabilité de cette conception aux différentes pratiques via l’interrogation des praticiens par questionnaires ; la mise en place de cette étude multicentrique internationale TOBAS (Treatment of Brain Arteriovenous Malformation) ; et enfin, l’analyse des résultats de la phase pilote montrant la faisabilité de l’étude. / Brain arteriovenous malformations (AVMs) are a rare and heterogeneous pathology. Imaging anAVM is complex because of their temporal dynamic feature. The management is controversial in particular due to the risks associated with the proposed treatments.The first part of this work is about imaging AVMs. We focused on a new technique, 4-Dimensional digital substraction angiography (4D DSA). Initially, we studied its feasibility and validated this technique in comparison with conventional cerebral angiography. Then we compared 4D DSA with another dynamic modality, 4-dimensional magnetic resonance angiography (4D MRA), in the analysis of angio-architectural characteristics of AVMs. Finally, we used this technique as a supplementary tool in the pre- and intraoperative planning of micro-AVM surgery.The second part deals with the management of AVMs patients in clinical studies. Given the lack of consensus, and the heterogeneity of practices in the management of this pathology, the conduct of this work was done in several stages: a systematic review and a critical analysis of a randomized trial recently published on unruptured brain AVMs; the design of a new pragmatic randomized trial incorporating the clinical judgment of the multidisciplinary team, the evaluation of the applicability of this design to the different practices using questionnaires; the implementation of this international multi-center study called TOBAS (Treatment of Brain Arteriovenous Malformation); and finally, the analysis of the pilot phase of the study.

In this thesis, we report the findings of designing data export functionality in Uppsala University Psychosocial Care Program (U-CARE) at Uppsala University. The aim of this thesis was to explore the design space for generic data export functionality in data centric clinical research applications for data analysis. This was attained by the construction and evaluation of a prototype for a data-centric clinical research application. For this purpose Action Design Research (ADR) was conducted, situated in the domain of clinical research. The results consist of a set of design principles expressing key aspects needed to address when designing data export functionality. The artifacts derived from the development and evaluation process each one constitutes an example of how to design for data export functionality of this kind.

La population néonatale est la population pédiatrique la plus vulnérable car immature et celle ayant probablement les besoins en médicaments les plus importants, compte tenu de la spécificité des pathologies néonatales. Pour autant, un grand nombre de médicaments sont prescrits en dehors des conditions de leur AMM, ne permettant pas leur utilisation optimale. Cela est lié notamment aux difficultés de la recherche clinique chez le nouveau-né. L’objectif de cette thèse est d’analyser les différentes étapes de l’évaluation des médicaments chez le nouveau-né et de discuter les méthodes permettant de les optimiser, en centrant la réflexion sur la classe des médicaments anti-infectieux. En effet, ces médicaments sont parmi les plus prescrits hors AMM chez le nouveau-né, prématuré et à terme, bien qu’ils soient commercialisés depuis de nombreuses années. Nos travaux ont porté sur les différentes étapes de leur évaluation, illustrées chacune par un exemple. 1) Analyse des spécificités de la population néonatale et des pratiques d’utilisation des médicaments, illustrées par l’enquête Européenne sur l’utilisation de la ciprofloxacine et du fluconazole dans les unités de soins intensifs néonatales. Cette enquête a mis en évidence la grande variabilité des pratiques entre les pays mais aussi entre les centres d’un même pays, 2) Recueil et analyse des données disponibles, illustrés par la revue exhaustive de la littérature sur l’utilisation de la ciprofloxacine pour le traitement d’infections néonatales à germes Gram négatif, 3) Détermination de la posologie adéquate. L’implémentation d’outils de modélisation et de simulation de données est particulièrement préconisée chez le nouveau-né. La validation de ces modèles est importante, illustrée ici par une étude d’évaluation externe des modèles pharmacocinétiques de population de la vancomycine chez le nouveau-né. 4) Conception et réalisation des essais cliniques illustrées par l’exemple du développement clinique de la ciprofloxacine en néonatologie. La revue de la littérature sur les essais contrôlés randomisés évaluant les antibiotiques chez le nouveau-né a montré que la qualité des résultats de ces essais était globalement faible. L’analyse des obstacles à leur réalisation a permis de discuter les alternatives méthodologiques afin de contourner les difficultés pratiques, cliniques et éthiques sous-jacentes. / Neonates represent the most vulnerable paediatric population and probably the one with the greatest needs in medicines with regard to the specificities of neonatal diseases. Nevertheless, the off-label prescribing of drugs with no marketing authorisation, consequentlywithout information for their proper use, is widespread in neonatology. This situation is related to the difficulties of clinical research encountered in this population. The objective of this thesis is to analyse the different steps of drug development in neonates and to discuss the possible methods to optimize drug evaluation. To illustrate this development, we expose examples from the evaluation of anti-infective agents in neonatology. These drugs are very often concerned by a use outside their product licence in term and preterm neonates, despite the fact that they have been marketed for many years. This thesis includes studies concerning the different steps of their development illustrated by examples. 1) Evaluation of the specificities of the neonatal population and of drug prescribing. This was demonstrated by the results of a European survey on the use of ciprofloxacin and fluconazole in neonatal intensive care units. The surveys’ results underline the considerable variability in drug prescribing observed between different countries but also between units in the same country. 2) Analysis of available data, illustrated by the systematic review of the literature on ciprofloxacin use for the treatment of Gram negative neonatal infections, 3) Definition of optimal dosing. Use of modelling and data simulation approaches should be particularly favoured in neonatal drug research. Correct validation of models should be performed as illustrated by the external validation of vancomycin population pharmacokinetic models. 4) Design and implementation of clinical trials. This step has been illustrated by the clinical development of ciprofloxacin in neonatology. The review of all randomised controlled trials evaluating the therapeutic and prophylactic use of antibiotics in neonates showed that these trials are poorly designed, conducted and reported. Different methods of evaluation should be considered and further developed to circumvent the difficulties in drug evaluation and ensure the efficient and safe use of antibiotics.

Neurodegeneration with Brain Iron Accumulation (NBIA) disorders, such as Phospholipase A2G6-Associated Neurodegeneration (PLAN) and Pantothenate Kinase-Associated Neurodegeneration (PKAN), are a group of rare early-onset, genetic disorders characterized by neurodegeneration and iron accumulation inside of the basal ganglia (BG), which is accompanied by progressive motor symptoms. In order to address the limitations in available models of NBIA, a B6.C3-Pla2g6m1J/CxRwb mouse model of PLAN was characterized. This model demonstrated key hallmarks of the disease presentation in NBIA, including a severe and early-onset motor deficit, neurodegeneration inside of the substantia nigra (SN) including a loss of dopaminergic function and the formation of abnormal spheroid inclusions as well as iron accumulation. The capture of these hallmarks of NBIA makes this an ideal animal research model for NBIA. Additionally, exploration of candidate systemic biomarkers of NBIA was performed in a case study of a patient with PLAN and in a cohort of 30 patients with PKAN. These investigations demonstrated reductions in transfer and slight, but not significant elevations in soluble transferrin receptor. No significant difference was seen in serum iron parameters. A systemic disease burden including chronic oxidative stress; elevated malondialdehyde, and inflammation; elevated C-reactive protein (CRP), IL-6 and TNFα was noted in both investigations. A number of candidate protein biomarkers including: fibrinogen, transthyretin, zinc alpha-2 glycoprotein and retinol binding protein were also identified. These markers correlated with measures of the severity of iron loading in the globus pallidus (GP); based on R2* magnetic resonance imaging (MRI) and the severity of motor symptoms (Barry-Albright Dystonia Rating Scale) making them potential candidates markers of dysfunction in NBIA. In the patient with PLAN, 37 weeks of therapy with the iron chelator deferiprone (DFP) as well as 20 months of therapy with the antioxidants alpha lipoic acid (ALA) and n-acetylcysteine (NAC) were efficacious in reducing the systemic oxidative and inflammatory disease burden, but it did not significantly alter the progression of the disease. In the antioxidant therapy, this efficacy was primarily due to ALA. When the cohort of patients with PKAN were treated with DFP for 18 months it was highly efficacious in lowering brain iron accumulation in the GP. No significant reduction in the speed of disease progression was seen in DFP treated patients compared to placebo based on initial analysis. Similar to the PLAN patient, DFP also mitigated the systemic disease burden in PKAN patients. In both cases DFP was well tolerated and had minimal impact on serum iron levels, TIBC and transferrin saturation. Collectively these investigations provide valuable insights into disease progression in NBIA. They also provide tools to aid further investigations in NBIA. These are provided in the form of a well-characterized B6.C3-Pla2g6m1J/CxRwb model of PLAN, which robustly captures the disease presentation seen in patients, as well as a panel of systemic blood-based markers of disease burden in NBIA and candidate markers of dysfunction in NBIA. These markers were used to assess two novel therapies in NBIA chelation with DFP and antioxidant therapy with ALA and NAC. / Graduate / 2019-04-19

Philosophiae Doctor - PhD / All research involving human subjects should be conducted in accordance to the general ethical principles of autonomy or respect for persons, beneficence and justice. Competent adults can exercise their autonomy and can choose to take on risk for the sake of others, therefore are able to protect their own interests while in the pediatric research the ‗best interests of the child‘ takes precedence over autonomy. In other words giving informed consent in the pediatric context, is not ‗who decides‟ but „what is the best decision for the child‟. Due to lack of consensus gold standard to guide researchers and assess the quality of parental informed consent in Botswana, the practical and ethical challenges posed in obtaining parental informed consent for child enrolment in pediatric HIV clinical trials were examined. The study aimed to determine the readability of the consent forms used in pediatric HIV clinical trials; assess communication methods, practices and perceptions of the trial staff regarding the informed consent process; assess the extent to which parents recall and understand the information disclosed to them and their satisfaction with the informed consent process as well as to identify and describe the reasons for parental approval to child enrolment into HIV clinical trial studies.

Depuis plusieurs années, la vectorisation de molécules est considérée comme la stratégie la plus prometteuse pour améliorer la pénétration cutanée des principes actifs et pour cibler et contrôler leur libération, augmentant ainsi l'efficacité thérapeutique des traitements tout en limitant leurs effets secondaires. Les nanoparticules polymériques ont fait l'objet de nombreuses études car elles possèdent une très grande stabilité et une capacité supérieure aux autres vecteurs à libérer les principes actifs de façon prolongée. Récemment, le laboratoire de Pharmacie Galénique de Besançon a montré, in vivo, que les nanoparticules polymériques de diamètre inférieure ou égale à 100 nm pénétraient spécifiquement dans la peau inflammée de la souris, alors qu'aucune pénétration n'était observée dans la peau saine. Le premier objectif de cette thèse était de confirmer ces hypothèses dans la peau inflammée d'un autre animal, le porc. Les résultats de notre étude in vivo confirment l'absence de pénétration des nanoparticules polymériques dans la peau saine du porc et montrent une pénétration taille dépendante dans la peau inflammée. Le second objectif poursuivi était de vérifier ces résultats chez l'Homme. Pour cela, une preuve de concept a été mise en place dans le service de Dermatologie du CHRU de Besançon. Les premiers résultats de cette étude clinique semblent confirmer l'absence de pénétration des nanoparticules polymérique de I 00 nm dans la peau des volontaires sains et dans la peau non lésée des patients souffrant de dermatite atopique. A l'inverse, une forte pénétration des nanoparticules est observée au niveau des plaques d'eczéma des patients. Si les résultats de l'étude clinique se confirment, nous prévoyons d'encapsuler un anti­inflammatoire ou un immunosuppresseur pour vérifier l'intérêt thérapeutique de ces vecteurs en médecine humaine dans le traitement de la dermatite atopique. Parallèlement, une évaluation pourrait être réalisée en médecine vétérinaire pour le traitement de cette pathologie fréquente chez le chien, et dont le traitement actuel repose sur l'administration per os de corticoïdes à l'origine de nombreux effets secondaires. / For several years now, nanocarriers have been considered as the most promising strategy to improve skin penetration of active ingredients. Moreover, these carriers are more efficient at targeting and controlling drug release into the skin, which leads to increased treatment efficiency and reduced side effects. Polymeric nanoparticles have been the object of an increasing number of studies due to their good physicochemical stability and prolonged release of active ingredients which is superior to any other carriers. Recently, the Laboratory of Pharmaceutical Engineering at Besançon proved in vivo, that polymeric nanoparticles with a diameter smaller or equivalent to I 00 nm specifically penetrated in inflamed skin of mice whilst no penetration was observed in healthy skin. The first aim ofthis thesis was to confirm this hypothesis on another animal's inflamed skin, in instance the pig. Our results confirm the poor penetration of polymeric nanoparticles in healthy skin ofpigs and show various degree ofpenetration depending on the size of the nanoparticles into the inflamed skin area. The second objective ofthis work was to evaluate the skin penetration of our polymeric nanoparticles in humans. A proof of concept has been developed in the Department of Dermatology at Besancon University Hospital. The first results ofthis clinical trial tend to confim1 the greater penetration ofour carrier, specifically in inflamed skin. In fact, no penetration of polymeric nanoparticles with a size close to 100 nm was observed in healthy skin ofvolunteers or in the non-inflamed skin of patients suffering from atopic dennatitis. Conversely, a high penetration ofthese carriers was observed in the skin lesions of patients with atopic dermatitis. If the results ofthis clinical trial are confirmed, we plan to load an anti-inflammatory or an immunosuppressive drug into the nanoparticles to evaluate the therapeutic value ofthese nanocarriers in human medicine in the treatment ofatopic dermatitis. Meanwhile, a similar study may be undertaken in veterinary medicine for the treatment of atopic dermatitis in dogs which is a common disease whose current treatment is based on the oral administration of corticosteroids and cause many undesirable side effects.

Chaque année, au moins 300 millions de personnes sont touchées par le paludisme et plus d’1 million d’entre elles en décèdent. Le neuropaludisme reste une complication mortelle, notamment chez les jeunes enfants d’Afrique. En dehors de la résistance aux antipaludiques, un défi de la lutte contre le paludisme est de définir la place des traitements protecteurs de l’hôte associés aux antipaludiques. En effet, le taux de mortalité résiduelle au cours du neuropaludisme est d’environ 20%, malgré un traitement adapté. Ce travail décrit les modèles expérimentaux de neuropaludisme, la place des neuroprotecteurs dans cette pathologie, puis, l’efficacité de deux neuroprotecteurs, l’érythropoïétine recombinante et les statines, au cours d’un neuropaludisme expérimental. Enfin, la pertinence de la neuroprotection sera documentée par une étude de preuve de concept chez l’Homme en zone d’endémie. / There are at least 300 million cases of malaria each year, resulting in more than a million deaths. Cerebral malaria is the most severe complication of malaria especially in young African children. Besides drug resistance, another challenge in the fight against malaria is the protective treatment of the host combined to the conventional antimalarial treatment. This opportunity came with the consideration of cerebral malaria residual case fatality rate of about 20%, despite a timely adequate antimalarial treatment. This work describes the available experimental model of cerebral malaria, the place of neuroprotective therapies in this disease and the efficacy of two neuroprotective drugs, recombinant erythropoietin and statins, during experimental cerebral malaria. Last, a proof-of-concept study documented the relevance of neuroprotection during human cerebral malaria in endemic area