In risk analysis, Benchmark dose (BMD)methodology is used to quantify the risk associated with exposure to stressors such as environmental chemicals. It consists of fitting a mathematical model to the exposure data and the BMD is the dose expected to result in a pre-specified response or benchmark response (BMR). Most available exposure data are from single chemical exposure, but living objects are exposed to multiple sources of hazards. Furthermore, in some studies, researchers may observe multiple endpoints on one subject. Statistical approaches to address multiple endpoints problem can be partitioned into a dimension reduction group and a dimension preservative group. Composite scores using desirability function is used, as a dimension reduction method, to evaluate neurotoxicity effects of a mixture of five organophosphate pesticides (OP) at a fixed mixing ratio ray, and five endpoints were observed. Then, a Bayesian hierarchical model approach, as a single unifying dimension preservative method is introduced to evaluate the risk associated with the exposure to mixtures chemicals. At a pre-specied vector of BMR of interest, the method estimates a tolerable area referred to as benchmark dose tolerable area (BMDTA) in multidimensional Euclidean plan. Endpoints defining the BMDTA are determined and model uncertainty and model selection problems are addressed by using the Bayesian Model Averaging (BMA) method.

Pour analyser les images en tomodensitométrie, une méthode stœchiométrique est gé- néralement utilisée. Une courbe relie les unités Hounsfield d’une image à la densité électronique du milieu. La tomodensitométrie à double énergie permet d’obtenir des informations supplémentaires sur ces images. Une méthode stœchiométrique a été dé- veloppée pour permettre de déterminer les valeurs de densité électronique et de numéro atomique effectif à partir d’une paire d’images d’un tomodensitomètre à double énergie. Le but de cette recherche est de développer une nouvelle méthode d’identification de tissus en utilisant ces paramètres extraits en tomodensitométrie à double énergie. Cette nouvelle méthode est comparée avec la méthode standard de tomodensitométrie à simple énergie. Par ailleurs, l’impact dosimétrique de bien identifier un tissu est déterminé. Des simulations Monte Carlo permettent d’utiliser des fantômes numériques dont tous les paramètres sont connus. Les différents fantômes utilisés permettent d’étalonner les méthodes stœchiométriques, de comparer la polyvalence et la robustesse des méthodes d’identification de tissus double énergie et simple énergie, ainsi que de comparer les distributions de dose dans des fantômes uniformes de mêmes densités, mais de compo- sitions différentes. La méthode utilisant la tomodensitométrie à double énergie fournit des valeurs de densi- tés électroniques plus exactes, quelles que soient les conditions étudiées. Cette méthode s’avère également plus robuste aux variations de densité des tissus. L’impact dosimé- trique d’une bonne identification de tissus devient important pour des traitements aux énergies plus faibles, donc aux énergies d’imagerie et de curiethérapie. / A stoichiometric method is usually used to analyze computed tomography images. A curve links the Hounsfield units on the images to the electron density in a given me- dium. Dual-energy computed tomography gives additional information on a scan. A stoi- chiometric method was developed to acquire both electron density and effective atomic number from a pair of images. The aim of this research is to develop a new method to identify tissues using the parame- ters extracted from dual-energy computed tomography. This new method is compared to the standard single-energy computed tomography segmentation method. Furthermore, the effect of correctly assigning tissues on dose distribution is studied. Monte Carlo simulations allow the use of perfectly known numerical phantoms. Dif- ferent phantoms allowed the calibration of the stoichiometric methods, the comparison of the versatility and the robustness of the dual-energy and the single-energy methods, and the comparison of dose distribution in phantoms of same densities, but of different compositions. The dual-energy identification method gives more accurate values of electron density in any studied condition. This method is also more robust to tissues of variable density. The dosimetric impact of an accurate identification becomes more important for treatments using lower energy photons, such as imaging energies and brachytherapy.

Le cancer pulmonaire est la principale cause de décès parmi tous les cancers au Canada. Le pronostic est généralement faible, de l'ordre de 15% de taux de survie après 5 ans. Les déplacements internes des structures anatomiques apportent une incertitude sur la précision des traitements en radio-oncologie, ce qui diminue leur efficacité. Dans cette optique, certaines techniques comme la radio-chirurgie et la radiothérapie par modulation de l'intensité (IMRT) visent à améliorer les résultats cliniques en ciblant davantage la tumeur. Ceci permet d'augmenter la dose reçue par les tissus cancéreux et de réduire celle administrée aux tissus sains avoisinants. Ce projet vise à mieux évaluer la dose réelle reçue pendant un traitement considérant une anatomie en mouvement. Pour ce faire, des plans de CyberKnife et d'IMRT sont recalculés en utilisant un algorithme Monte Carlo 4D de transport de particules qui permet d'effectuer de l'accumulation de dose dans une géométrie déformable. Un environnement de simulation a été développé afin de modéliser ces deux modalités pour comparer les distributions de doses standard et 4D. Les déformations dans le patient sont obtenues en utilisant un algorithme de recalage déformable d'image (DIR) entre les différentes phases respiratoire générées par le scan CT 4D. Ceci permet de conserver une correspondance de voxels à voxels entre la géométrie de référence et celles déformées. La DIR est calculée en utilisant la suite ANTs («Advanced Normalization Tools») et est basée sur des difféomorphismes. Une version modifiée de DOSXYZnrc de la suite EGSnrc, defDOSXYZnrc, est utilisée pour le transport de particule en 4D. Les résultats sont comparés à une planification standard afin de valider le modèle actuel qui constitue une approximation par rapport à une vraie accumulation de dose en 4D. / Pulmonary cancer is the main cause of death amongst all cancers in Canada with a prognosis of about 15% survival rate in 5 years. The efficiency of radiotherapy treatments is lower when high displacements of the tumors are observed, mostly caused by intrafraction respiratory motion. Advanced techniques such as radiosurgery and intensity-modulated radiotherapy treatments (IMRT) are expected to provide better clinical results by delivering higher radiation doses to the tumor while sparing the surrounding healthy lung tissues. The goal of this project is to perform 4D Monte Carlo dose recalculations to assess the dosimetric impact of moving tumors in CyberKnife and IMRT treatments using dose accumulation in deforming anatomies. Scripts developed in-house were used to model both situations and to compare the Monte Carlo dose distributions with those obtained with standard clinical plans. Displacement vectors fields are obtained from a 4D CT data set and a deformable image registration (DIR) algorithm which allows a voxel-to-voxel correspondence between each respiratory phase. The DIR is computed by the Advanced Normalization Tools (ANTs) software and is mostly based on diffeormophisms. A modified version of DOSXYZnrc from EGSnrc software, defDOSXYZnrc, is used to transport radiation through non-linear geometries. These results are then compared to a typical 3D plan to determine whether or not the current planification is a good approximation of the true 4D dose calculation.

L'application d'ultrasons sur une tumeur, où des liposomes se sont accumulés, permet potentiellement de libérer le médicament mais aussi d'en favoriser l'absorption dans les cellules. La cavitation inertielle ultrasonore est le phénomène pressenti pour la libération sous ultrasons de médicament encapsulé dans de petits liposomes solides. Elle est très dépendante des conditions expérimentales et peut-être intense et imprévisible. L'objectif principal du travail réalisé dans le cadre de cette thèse est de contrôler et quantifier la cavitation inertielle, pour induire le largage de médicaments encapsulés dans des liposomes. Dans cette optique, une dose de cavitation inertielle (DC), basée sur le filtrage du bruit large bande émis lors de ce régime de cavitation, est mise au point in vitro pour suivre le largage de médicament encapsulé. Sous divers régimes d'ultrasons pulsés, la DC a été validée en dosant chimiquement les radicaux hydroxyles générés lors de l'implosion des bulles. Les tests menés sur diverses formulations de liposomes contenant de la doxorubicine (dox) ont montrés une haute corrélation entre le taux de largage de dox et la DC permettant de conclure que la cavitation inertielle est impliquée dans ce largage. Le rôle de la température sur la production de radicaux hydroxyles et la libération de dox a également été exploré. Les expériences réalisées ont permis de sélectionner les formulations les plus sensibles aux ultrasons pour les tester sur des rats implantés avec des tumeurs prostatiques. Après plusieurs expériences in vivo menées avec différents dispositifs ultrasonores et formulations de liposomes, le bénéfice du traitement combiné a pu être démontré. / The sonication of a tumor, where liposomes have been accumulated, allows potentially to release encapsulated drug and to promote its absorption in cells. Ultrasonic inertial cavitation is supposed to be implicated in the release of drug encapsulated in small solid liposomes under ultrasonic exposure. Inertial cavitation is strongly dependent on experimental conditions and can be very intense and unpredictable. The main objective of this thesis was to control and quantify inertial cavitation in order to induce drug release from liposomes. In this purpose, an inertial cavitation dose (CD), based on broadband noise emission associated with inertial cavitation, was defined to monitor in vitro encapsulated drug release. The CD was chemically validated with the dosing of hydroxyl radicals generated by bubbles collapses under various pulsed ultrasound exposures. A high correlation between doxorubicin (dox) release rate from liposomes and CD was de monstrated for all liposomes formulations tested and under different pulsed ultrasound exposures. The role of temperature on hydroxyl radical production and dox release was also investigated. The performed experiments allowed selecting the liposomes formulations that are the most sensible to ultrasound in order to test them on rats implanted with prostatic tumors. After several campaigns of in vivo experiments performed with various ultrasonic setups and liposomes formulations, the benefit of the combined treatment was demonstrated.

Ce travail de thèse porte sur la quantification et la prise en compte des variations anatomiques en cours de radiothérapie guidée par l'image pour le cancer de la prostate. Nous proposons tout d'abord une approche basée population pour quantifier et analyser les incertitudes géométriques, notamment à travers des matrices de probabilité de présence de la cible en cours de traitement. Nous proposons ensuite une méthode d'optimisation des marges suivant des critères de couverture géométrique de la cible tumorale. Cette méthode permet d'obtenir des marges objectives associées aux différents types d'incertitudes géométriques et aux différentes modalités de repositionnement du patient. Dans un second temps, nous proposons une méthode d'estimation de la dose cumulée reçue localement par les tissus pendant un traitement de radiothérapie de la prostate. Cette méthode repose notamment sur une étape de recalage d'images de façon à estimer les déformations des organes entre les séances de traitement et la planification. Différentes méthodes de recalage sont proposées, suivant les informations disponibles (délinéations ou points homologues) pour contraindre la déformation estimée. De façon à évaluer les méthodes proposées au regard de l'objectif de cumul de dose, nous proposons ensuite la génération et l'utilisation d'un fantôme numérique reposant sur un modèle biomécanique des organes considérés. Les résultats de l'approche sont présentés sur ce fantôme numérique et sur données réelles. Nous montrons ainsi que l'apport de contraintes géométriques permet d'améliorer significativement la précision du cumul et que la méthode reposant sur la sélection de contraintes ponctuelles présente un bon compromis entre niveau d'interaction et précision du résultat. Enfin, nous abordons la question de l'analyse de données de populations de patients dans le but de mieux comprendre les relations entre dose délivrée localement et effets cliniques. Grâce au recalage déformable d'une population de patients sur une référence anatomique, les régions dont la dose est significativement liée aux événements de récidive sont identifiées. Il s'agit d'une étude exploratoire visant à terme à mieux exploiter l'information portée par l'intégralité de la distribution de dose, et ce en fonction du profil du cancer. / This work deals with the quantification and the compensation of anatomical deformations during image-guided radiotherapy of prostate cancer. Firstly, we propose a population-based approach to quantify the geometrical uncertainties by means of coverage probability matrices of the target tumor during the treatment. We then propose a margins optimization method based on geometrical coverage criteria of the tumor target. This method provides rationnal margins models associated to the different geometrical uncertainties and patient repositioning protocols. Secondly, we propose a method to estimate the locally accumulated dose during the treatment. This method relies on a deformable image registration process in order to estimate the organ deformations between each treatment fraction and the planning. Different registration methods are proposed, using different level of user interactions (landmarks specification or delineations) to constrain the deformation estimation. In order to evaluate the performance of the proposed methods, we then describe the generation of a numerical phantom based on a biomechanical model. The results are presented for the numerical phantom and real clinical cases. We show that the benefit brought by the manual placement of some landmarks to constrain the registration represents a good compromise between the required interaction level and the dose estimation accuracy. Finally, we address the issue of the analysis of population data in order to better understand the relationship between the locally delivered dose and clinical effects. With deformable image registration of a population of patients on an anatomical template, regions whose dose is significantly associated with recurrence events are identified. This last part is an exploratory study aiming to better use the information carried by the entire distribution dose, and according to the cancer profile.

En radiothérapie externe, l'imagerie par rayons X (CT-scan et CBCT) est l'imagerie de référence pour la planification et la délivrance du traitement. Le CT-scan permet l'accès aux densités électroniques des tissus, requises pour le calcul de dose. Le CBCT permet le positionnement du patient, le tracking et le gating de la tumeur. Cependant, l'imagerie par rayons X présente un faible contraste entre les tissus mous et est irradiante. Grâce à un meilleur contraste, l'IRM pourrait améliorer le positionnement du patient, la délinéation des volumes d'intérêt, et le ciblage de la dose. L'IRM présente ainsi un intérêt majeur pour la planification de radiothérapie. L'objectif de cette thèse a été premièrement d'optimiser un protocole d'acquisition d'images IRM de la sphère ORL, avec patient en position de traitement. Le second objectif a été de réaliser une dosimétrie à partir de l'IRM. Cependant, à contrario du CT-scan, l'IRM ne fournit pas la densité électronique des tissus. Pour palier cela, une méthode patch-based (PBM) et une méthode de deep learning (DLM) ont été utilisées pour générer des pseudo-CT, et calculer la dose. La DLM fut un réseau antagoniste génératif et la PBM fut développée en utilisant une recherche de patchs similaires avec des descripteurs d'images. Ces méthodes ont été évaluées et comparées à une méthode atlas (ABM) et une méthode d'assignation de densité (BDM) à partir de critères de jugement images et dosimétriques. La DLM et la PBM apparurent comme les méthodes les plus précises. La DLM fut la méthode la plus rapide et robuste aux variations anatomiques. / In external beam radiotherapy, X-ray imaging (CT-scan and CBCT) is the main imaging modality for treatment planning and dose delivery. CT-scan provides the electron density information required for dose calculation. CBCT allows fast imaging for patient positioning, tracking and gating of the tumor. However, X-ray imaging has a poor soft tissue contrast, and it is an ionizing imaging, in contrast of MRI. Thanks to this better soft tissue contrast, MRI could improve patient positioning, tumor and organs at risk delineation, and dose targeting. The introduction of MRI in the radiotherapy workflow is therefore a topical issue. This thesis firstly aims to optimize an MRI protocol with patient in head-and-neck radiotherapy treatment position. This protocol was endorsed by our clinical center. The second aim of this thesis was to conducted dose calculation from MRI. However, this imaging, unlike CT, lacks the electron density information required for dose calculation. To address this issue, an original non-local-mean patch-based method (PBM) and a deep learning method (DLM) were used to generate pseudo-CTs from MRIs, and compute the dose. The DLM was a generative adversarial network, and the PBM was performed by using an approximate nearest neighbor search with MR feature images. These both methods were evaluated and compared to an atlas-based method (ABM) and a bulk density method (BDM). This comparison was performed by using image and dosimetric endpoints. The DLM and PBM appeared the most accurate methods. The DLM was faster and more robust to anatomical variations than the PBM.

Neste trabalho foi avaliada a dose efetiva recebida pelos trabalhadores da Gerência de Rejeitos Radioativos do IPEN devido à inalação de 222Rn nos galpões de armazenamento de rejeitos radioativos tratados e não tratados. As concentrações de 222Rn no interior dos galpões foram determinadas por meio da técnica de detecção passiva com detectores de traços nucleares do estado sólido (SSNTD). O detector utilizado foi o CR-39 inserido em uma câmara de difusão do tipo NRPB. Foram monitorados um total de 12 pontos internos e 1 ponto externo no galpão de rejeitos radioativos tratados G4 e 13 pontos no galpão de rejeitos radioativos não tratados G3, durante um período de 11 meses, entre junho de 2012 e maio de 2013. As concentrações variaram de 0,73 ± 0,08 e 4,55 ± 0,16 kBqm-3 entre os períodos de monitoramento no galpão G4 e entre 0,61 ± 0,07 e 2,94 ± 0,12 kBqm-3 no galpão G3. A dose efetiva devido à inalação de 222Rn no interior dos galpões de rejeitos radioativos foi calculada de acordo com os procedimentos da Comissão Internacional de Proteção Radiológica (ICRP) a partir de um fator de conversão de dose, da concentração média do 222Rn no ar e do tempo de exposição dos indivíduos. Os valores de doses apresentados são uma média das concentrações entre os períodos de monitoramento que variam 15,70 mSva-1 no G4 e de 9,27 mSva-1 no G3, sendo que em um dos períodos obteve-se valores superiores ao estabelecidos pelo órgão regulador (CNEN) e recomendados pela Comissão Internacional de Proteção Radiológica (ICRP) de 20 mSva-1 para indivíduos ocupacionalmente expostos, indicando a necessidade de medidas mitigadoras. Cabe, contudo, informar que foi considerada uma hipótese bastante conservativa de 2000 horas de trabalho no local. / Some radionuclides that make up the radioactive series are noted for their contribution to the total exposure to which individuals are subjected, an important example is known as radon 222Rn and their descendants, responsible for more than half of the radiation dose received by the population due to natural sources. In this work the effective dose received by the workers of the Management of Radioactive Waste in IPEN due to inhalation of 222Rn in storage sheds from treated and untreated radioactive waste was evaluated. Concentrations of 222Rn inside the sheds of treated and untreated radioactive waste G3 and G4 were determined by the technique of passive detection with solid state nuclear track (SSNTD) detectors. The detector used was CR-39 inserted in a diffusion chamber type NRPB. A total of 12 internal points and 1 external point were monitored in the shed radioactive waste treated G4 and 13 points in the shed radioactive waste untreated G3, for a period of 11 months between June 2012 and May 2013. Concentrations ranged 0.73 ± 0.08 to 4.55 ± 0.16 kBqm-3 among the monitoring periods in the shed G4 and between 0.61 ± 0.07 and 2.94 ± 0.12 kBqm-3 in the shed G3. The effective dose due to inhalation of 222Rn inside the sheds radioactive waste was calculated according to the procedures of the International Commission on Radiological Protection (ICRP) from a conversion factor of dose, the mean concentration of 222Rn in the air and time of exposure of individuals. The dose values for G4 and G3 are 15.70 and 9.27 mSva-1 respectively, this being greater than the value established by the National Nuclear Energy Commission (CNEN) and recommended by the International Commission on Radiological Protection (ICRP) 20 mSv / a for occupationally exposed individuals, thus indicating the need for mitigation measures. It should, however, report that was considered a very conservative assumption of 2,000 hours of work on site.

A pesquisa teve como objetivo verificar o fluxo de emergência das plantas daninhas e determinar o banco de sementes em condições de semeadura direta e convencional e verificar a eficácia do glyphosate em plantas daninhas de difícil controle. Para tanto, foi realizado no período de 2001 e 2002, um experimento de campo, onde de 15 em 15 dias, foi feito o levantamento de plantas daninhas para determinação do fluxo de emergência. O delineamento experimental foi o de blocos casualizados, com parcelas subdivididas. As doses de glyphosate foram de 0, 540, 720, 900, 1080, 1260 e 1440 g.i.a / ha. O banco de sementes foi avaliado através da retirada de 20 sub-amostras de solo, em cada parcela, nas profundidades de 0,0-2,5; 2,5-5,0; 5,0-10,0; 10,0-15,0 e 15,0-20,0 cm. Também foram realizados dois experimentos em câmara de crescimento com o objetivo de avaliar o controle e curvas dose - resposta das espécies de plantas daninhas Bidens pilosa L., Commelina benghalensis L., Digitaria insularis L. (Feed), Tridax procumbens L. e Ipomoea grandifolia Dammer e Spermacoce latifolia Abul. ao herbicida glyphosate. Para avaliar o controle, foram aplicadas as seguintes doses de glyphosate: 0, 720, 960; 1200, 1440, 1680, 1920 g.i.a/ha, após 25 dias da emergência das plantas daninhas. Na determinação das curvas-dose resposta as aplicações das doses de glyphosate foram de 0,0; 11,3; 22,5; 45; 90; 180; 360; 720 e 1440 g.i.a. / ha. A elaboração da curva dose - resposta foi feita através do ajuste da biomassa verde utilizando modelo matemático log-logístico: Y = C+D-C / 1 + Exp(b(log(x)-log(GR50))), calculado por modelo não linear dos dados. Nas análises estatísticas foram utilizados os programas estatísticos SAS e SANEST para analisar a variância dos dados. Nas condições locais de campo em que foi realizado o experimento podemos concluir que o herbicida glyphosate mostrou-se ser eficaz no controle de plantas daninhas existentes na área a partir da dose de 540 g.i.a/ha. No ano de 2001 ocorreram fluxos das espécies Leucas martinicensis Jacq. e Richardia brasilensis Gomes de uma forma mais diferenciada no direto do que no convencional. Também as espécies Cenchrus echinatus L. e Digitaria insularis (Feed) L. apresentaram maior emergência no sistema direto do que no convencional. No ano de 2002 essas diferenças dos fluxos das espécies não foram tão expressivas como em 2001. As sementes concentraram-se nos 2,5-5,0 cm superficiais do solo, no sistema direto, enquanto que o preparo convencional distribuiu as sementes em maiores profundidades. Os resultados obtidos em câmara de crescimento indicaram que o herbicida glyphosate controlou Bidens pilosa e Digitaria insularis. Commelina benghalensis foi considerada de difícil controle. A dose de glyphosate necessária para atingir índices de controle acima de 91% foi de 1680 g.i.a/ha para Commelina benghalensis, 960 g.i.a/ha na espécie Tridax procumbens e 1440 g.i.a/ha aos 21 DAA para Ipomoea grandifolia. Após a determinação da curva dose - resposta concluiu-se que a espécie Bidens pilosa foi considerada a planta daninha mais suscetível ao herbicida glyphosate, pois foi a espécie que obteve menor GR50 (31,86 g.i.a/ha). As espécies Tridax procumbens, Digitaria insularis, Spermacoce latifolia, Ipomoea grandifolia, Commelina benghalensis obtiveram GR50 de 58,40; 128,50; 250,44; 615,49 e >1440,00 g.i.a/ha, respectivamente. / The research had the objective of determining the emergence periodicity, seeds bank for the no tillage and convencional tillage systems, and verify the efficacy of glyphosate on weeds of difficult control. During 2001 and 2002, a field experiment was conducted where after applications of glyphosate in the no tillage and convencional tillage systems was made every 15 days the emergence periodicity and seeds bank determination. The experimental design was the randomized blocks with subdivide plots. The applied glyphosate rates were 0, 540, 720, 900, 1080, 1260 and 1440 g.i.a.ha -1 . The bank of seeds was evaluated through the retreatment of 20 soil sub-samples, in each plot, in the depths of 0.0-2.5; 2.5-5.0; 5.0- 10.0; 10.0-15.0 and 15.0-20.0 cm. Experiments were also led in a completely randomized black growth chamber with the objective of evaluating the susceptibility and dose-response curves of the species of weeds Bidens pilosa L., Commelina benghalensis L., Digitaria insularis L. (Feed), Ipomoea grandiofolia L., Tridax procumbens L. and Spermacoce latifolia Abul. to the herbicide glyphosate. To evaluate the control the following glyphosate doses: 0, 720, 960; 1200, 1440, 1680, 1920 g.i.a.ha -1 . The applications of glyphosate were doses of 0, 11.3, 22.5, 45, 90,180, 360, 720, and 1440 and g.i.a.ha -1 . The elaboration of the curves dose - response was made through the adjustment of the green biomass it dries using the following mathematical model log - logistic: Y = C+D-C / 1 + Exp(b(log(x)-log( GR50))), using the statistical procedure of non linear analyses. The SANEST program was used to the statistical analyses and SAS program to analyze the variance of the data. In field conditions of field were experiment was carried out, glyphosate was effective to control of weeds starting from dose of 540 g.i.a.ha -1 . In the year of 2001, emergence periodicity of the species dicotiledons Leucas martinensis Jacq. and Richardia brasilensis Gomes in a more different way in the no tillage than in the convencional tillage; also, the species monocotiledons Cenchrus echinatus L. and Digitaria insularis L. (Feed) presented a larger emergence in the no tillage than in the convencional tillage systems. In the year of 2002, that differences of the flows of the species were not as expressive as in 2001. The seeds concentrated on the 2.5-5.0 cm superficial of the soil, in the no tillage system, while the convencional tillage distributed the seeds in the soil. The results in the chamber showed that glyphosate controlled Bidens pilosa and Digitaria insularis. Commelina benghalensis was considered a specie of difficult control. The glyphosate rate to reach control indexes above 91% was of 1680 g.i.a.ha -1 of glyphosate for Commelina benghalensis, 960 g.i.a.ha -1 in the Tridax procumbens and 1440 g.i.a.ha -1 of glyphosate for Ipomoea grandifolia in 21 DAA. After the curves dose - response determination it was ended that Bidens pilosa was considered the more susceptible weed to glyphosate, because it was the species of smaller GR50 (31.86 g.i.a.ha -1 ). On the other hard species Tridax procumbens, Digitaria insularis, Spermacoce latifolia, Ipomoea grandifolia, Commelina benghalensis obtained GR50 equal to 58.40, 128.50, 250.44, 615.49 and >1440,00 g.i.a.ha -1 , respectively.

Introdução: A sepse é a maior causa de morbidade e mortalidade em pacientes queimados, uma vez que profundas alterações ocorrem na farmacocinética de agentes antimicrobianos prescritos para o controle das infecções. Além disso, pacientes queimados podem apresentar quadro de infecção por germes da comunidade, numa fase precoce de internação na UTI, e devem receber antimicrobianos que diferem daqueles indicados na sepse. Na vigência de infecção fúngica, o quadro se torna ainda mais grave para os pacientes queimados de prolongada internação e imunocomprometidos. Objetivo: Realizar o monitoramento plasmático de oito antimicrobianos largamente prescritos na UTI, a investigação da farmacocinética e a modelagem PK-PD para o ajuste do regime de dose e controle das infecções em pacientes queimados. Casuística: Investigaram-se 32 pacientes queimados internados na UTI/Unidade de Queimados - Divisão de Cirurgia Plástica do HC FMUSP, portadores de infecção recebendo pela via sistêmica sete antimicrobianos e um antifúngico. Métodos- Etapa Clinica: Os pacientes receberam os antimicrobianos geralmente em associação para o controle das infecções seguindo as recomendações da CCIH do hospital relativas ao regime de dose empírica inicial do controle de infecção na UTI de Queimados, na fase precoce e tardia da internação. Realizou-se o monitoramento plasmático do fluconazol, para a infecção fúngica, e dos sete antimicrobianos mais prescritos na UTI para os germes da comunidade e hospitalares (cefepime, ciprofloxacino, imipenem, oxacilina, piperacilina, sulfametoxazol e vancomicina) através das coletas de amostras sanguíneas de pico (termino da infusão) e vale (imediatamente antes da dose subseqüente). Complementarmente, a critério Clínico, foram colhidas amostras seriadas de sangue (pico, 1ª, 2ª, 4ª, 6ª e vale), totalizando seis coletas, para investigação da farmacocinética do agente que requereu ajuste de dose e individualização de terapia no paciente queimado. As coletas de sangue foram realizadas através de cateter venoso (2mL/coleta em tubos contendo EDTA sódico) pelo médico intensivista de plantão na UTI; o plasma foi obtido pela centrifugação para análise do fármaco de interesse ou então armazenado no congelador (-80o C) até o ensaio. Métodos - Etapa Analítica: Previamente à realização da Etapa Clínica, foi realizado no Laboratório o desenvolvimento, validação e otimização de método bioanalítico para quantificação dos oito antimicrobianos no plasma. Preferencialmente, as análises foram realizadas no dia da coleta de sangue do paciente, e o \"Laudo de Exame\" contendo os resultados foi expedido no mesmo dia ou na manhã do dia subseqüente possibilitando a intervenção precoce da Equipe Clínica e se necessária a substituição do regime empírico pela terapia individualizada dose ajustada. Métodos- Etapa estatística: A estatística propriamente dita foi realizada pelo tratamento estatístico com utilização do software GraphPad Instat 4.0., GraphPad Prism 4.0, pela utilização de testes paramétricos e não paramétricos. A modelagem farmacocinética foi realizada através da aplicação do software NonCompartmental Analysis, PK Solutions 2.0, aos pares de dados (C vs T) para cada antimicrobiano. Adicionalmente, aplicou-se o software GraphPad Prism 4.0 para a modelagem PK-PD, ferramenta importante na tomada de decisão relativa à alteração do regime empírico dos antimicrobianos. Resultados: Os pacientes queimados incluídos no protocolo eram adultos de ambos os sexos 23F/9M, 39,6 anos, 69,5 kg, 33,9% SCQ, e os agentes da queimadura foram para 27 pacientes/ térmico-fogo e para três pacientes/trauma elétrico; a lesão inalatória foi registrada em 11/32 pacientes. Foram realizados 303 seguimentos farmacoterapêuticos com a emissão de laudos de exame para os antimicrobianos prescritos aos pacientes nas fases precoce e tardia da internação. O ajuste de dose foi requerido para a vancomicina em 88% das solicitações de exame, cefepime (65%), sulfametozaxol (52%), fluconazol (74%) e imipenem (19%). Registrou-se alta variabilidade na farmacocinética para todos os antimicrobianos investigados. Adicionalmente, registrou-se alteração significativa dos parâmetros farmacocinéticos do imipenem, fluconazol, sulfametoxazol e vancomicina nos seguimentos de pacientes queimados com disfunção renal dialítica relativamente aqueles em que se registrou função renal preservada. A modelagem PK-PD para os diversos antimicrobianos se baseou nos parâmetros de predição de eficácia recomendados tais como o intervalo de tempo em que a concentração plasmática permaneceu acima da concentração inibitória mínima (%Δ T> CIM) para o cefepime, imipenem, oxacilina e piperacilina, ASCss0-24/CIM + Cssmax/CIM para o ciprofloxacino, ASCss0-24/CIM para o fluconazol e para a vancomicina e ASCss0-24/CIM +%Δ T> CIM para a sulfametoxazol. Conclusões: Registrou-se alta variabilidade na farmacocinética dos agentes investigados e a modelagem PK-PD justificou plenamente a substituição da terapia empírica inicial pela dose ajustada para a cobertura dos germes sensíveis, daqueles apresentando sensibilidade dose dependente ao antimicrobiano, além daqueles com alto CIM, pouco sensíveis as doses usuais. Finalmente, a modelagem PK-PD mostrou-se definitiva e ferramenta indispensável na manutenção desses agentes no arsenal terapêutico, garantindo terapia eficaz ao paciente queimado, evitando a emergência bacteriana e o desenvolvimento de resistência. / Introduction: Sepsis is a main cause of morbidity and mortality in burn patients, once pharmacokinetics of antimicrobials prescribed for the control of infections are significantly altered in those patients. In addition, burn patients in the ICU, initially can present infections by community microbial and must receive different antimicrobials than those prescribed for sepsis. On the other hand, burn immunocompromized patients with prolonged staying in the ICU, re-incidence of sepsis and fungal infection requires an effective antifungal agent that must be associated to the antimicrobials prescription. Objective: Therapeutic plasma monitoring of eight antimicrobials largely prescribed to burn patients from the ICU, Pharmacokinetic and PK-PD modeling for dose adjustment and for the control of infections. Study design: Thirty two burn inpatients with infections from the ICU Burns- Division of Plastic Surgery of Clinics Hospital Medical School University of Sao Paulo received systemically antimicrobials/ antifungal agents. Methods - Clinical Procedures: In general burn patients received several antimicrobial agents as recommended by the Control of Hospital Infection Committee as empirical dose at the beginning of therapy and also afterwards in the ICU. The control of infections by community microbials or yet by hospital microbials, and also for fungal infection, was performed by drug plasma monitoring of cefepime, ciprofloxacin, imipenem, oxacillin, piperacillin, sulphamethoxazole, vancomycin and fluconazole after blood sample collection at the peak and at the trough. Complementary, usually by clinical criteria, six blood sample collections were performed at time dose interval (end of drug infusion, 1st, 2nd, 4th, 6th and at the trough) for pharmacokinetic purposes, dose adjustment and individualization of drug therapy for burn patients. Blood sample collection was done by the physician from the ICU by venous catheter (2mL/each into blood collection tubes sodium EDTA); plasma obtained by centrifugation of blood tubes were analyzed in the same day or in a deep freezer to storage (-80o C) until assay. Methods - Analytical Procedures: Previously to the clinical study, in the Laboratory School of Pharmaceutical Sciences was performed the development, validation and optimization of bioanalytical methods for drug plasma monitoring of eight antimicrobial/antifungal agents by HPLC-UV. Drug measurements were performed on the day of blood collection and data were preferentially informed to the physician at the same day or at the early morning of the following day to facilitate the therapeutic intervention and changes on the morning prescription to guarantee drug efficacy. Methods Statistics Procedures: Descriptive statistics was performed by applying the software GraphPad Instat v 4.0., GraphPad Prism v.4.0 by parametric and non parametric tests. Pharmacokinetics was estimated by applying the software NonCompartmental Analysis, PK Solutions 2.0, to data (C vs T) for each antimicrobial agent. Additionally, the software GraphPad Prism v 4.0 was applied to PK-PD modeling, an important tool related to dilemma decision about changes on empirical dose of an antimicrobial agent and obviously helps the physician in the rationalization of drug therapy in severe burns. Results: Burn patients included in the protocol were of both genders 23F/9M, 39.6 yrs, 69.5 kg, 33.9% TBSA; agents of the accident were fire/ alcohol for 27 patients and electrical trauma for three patients; inhalation injury were described for 11/32 patients. Approximately 1500 drug plasma measurements for all antimicrobials prescribed to burn patients for the control of infection in the ICU were performed totalizing 303 follow up for pharmacokinetic purposes during the period in the ICU for 32 burn patients. Dose adjustment was required in 88% of vancomycin prescription, 65% for cefepime, 52% for sulphamethoxazole, 74% for fluconazole e 19% for imipenem. High pharmacokinetic variability was registered for all agents investigated. In addition, significant changes on pharmacokinetic parameters were described for imipenem, fluconazole, sulphamethoxazole and vancomycin for burn patients with dialytic renal dysfunction compared to those with renal function preserved. PK-PD modeling applied to antimicrobials investigated in the present study was based on predictive parameters recommended like time interval to maintain drug plasma concentration higher than the minimum effective concentration (%Δ T> MIC) for cefepime and also for imipenem, oxacillin and piperacillin; AUCss0-24/MIC plus Cssmax/MIC for ciprofloxacin, AUCss0-24/MIC for fluconazole and vancomycin, and finally, AUCss0-24/MIC plus %Δ T> MIC for sulphamethoxazole. Conclusions: High pharmacokinetic variability was obtained for all investigated agents. PK-PD modeling applied could justify definitively the antimicrobial therapy dose adjustment instead the empirical dose regimen. Then, drug efficacy was guaranteed against susceptible microbial, spreading to susceptible to antimicrobial dose dependent and also those presenting high value for MIC related to microbial resistance to empiric dose regimen. In conclusion, it was demonstrated that PK-PD modeling of antimicrobials with basis on predictive drug efficacy parameter is definitively an important tool to preserve and safeguard these agents for the control of severe infection in burn patients, to avoid the bacterial emergency and microbial resistance.

O consumo de tabaco é uma das principais causas de doenças e morte prematuras no mundo; é a segunda droga mais consumida entre os adolescentes brasileiros, sendo considerado uma importante porta de entrada para o uso de drogas ilícitas. O Brasil é o segundo produtor mundial de tabaco e desde de 1993 destaca-se como o maior exportador. Os radionuclídeos naturais das séries do 232Th e 238U são encontrados no tabaco em baixas concentrações absorvidos diretamente do solo ou por deposição foliar. No ato de fumar ocorre a transferência desses radionuclídeos através da queima do tabaco para os tecidos e órgãos humanos podendo gerar lesões cancerígenas, sendo o mais relevante o câncer de pulmão. Existem poucos dados sobre a caracterização radiológica e elementar dos derivados do tabaco brasileiros, o que torna relevante o presente estudo que teve como objetivos a determinação da radioatividade natural e da concentração de elementos maiores e traços em derivados de tabaco produzidos e comercializados no Brasil. As técnicas analíticas empregadas foram alfa e beta total após separação radioquímica para os radionuclídeos 226Ra, 228Ra e 210Pb com determinação em detector proporcional de fluxo gasoso e baixa radiação de fundo, espectrometria alfa após separação radioquímica para o radionuclídeo 210Po, análise por ativação com nêutrons instrumental (INAA) e fluorescência por dispersão de raios X (EDXRF) para determinação de 238U, 232Th, elementos maiores e traços. Foram analisados produtos derivados da Nicotina tabacum L. de diferentes marcas adquiridas em tabacarias: cigarro não aromatizados, cigarro aromatizado, charuto, rapé, cigarro de palha e fumo de corda. Pela técnica de INAA foi possível determinar a concentração de 19 elementos e pela técnica de EDXRF de 31 elementos o que possibilitou uma ampla caracterização multielementar e as técnicas analíticas empregadas se mostraram complementares. Os elementos que apresentaram maiores valores de concentração foram o Ca e o K entre todas as amostras amostragem e entre todos os radionuclídeos naturais determinados o 228Ra apresentou maiores valores de concentração de atividade. A partir da concentração de atividade determinada foram calculadas a dose anual estimada e a dose anual efetiva para os radionuclídeos 210Pb e 210Po, levando-se em consideração um consumo anual de 3,65 kg de tabaco por ano. A dose anual efetiva variou de 69,5 μSv ano-1 à 121 μSv ano-1. Os produtos que apresentaram maiores valores de concentração e consequentemente maiores valores de dose anual efetiva, para a maioria dos radionuclídeos analisados, foram os cigarros de palha e fumos de corda. / Tobacco use is one of the leading causes of premature illness and death in the world; is the second most consumed drug among Brazilian adolescents, being considered an important gateway to the use of illicit drugs. Brazil is the second largest tobacco producer in the world and since 1993 it has been the largest exporter. The natural radionuclides from the 232Th and 238U series are found in tobacco at low concentrations absorbed directly from the soil or by foliar deposition. In the act of smoking occurs the transference of these radionuclides through the burning of the tobacco to the human tissues and organs and they can generate carcinogenic lesions, being the lung cancer the most relevant. There are few data on the elemental and radiological characterization of Brazilian tobacco products, which makes relevant the present study that had as objectives the determination of the natural radioactivity and the concentration of major and trace elements in tobacco products produced and marketed in Brazil. The analytical techniques employed were gross alpha and beta, after radiochemical separation for the radionuclides 226Ra, 228Ra and 210Pb with determination in a gaseous flow proportional detector of low background radiation, alpha spectrometry after radiochemical separation for the radionuclide 210Po, instrumental neutron activation analysis (INAA) and X-ray scattering fluorescence (EDXRF) for determination of 238U, 232Th, major and trace elements. Nicotine tabacum L. products from different brands acquired in cigar stores were analyzed: non-flavored cigarettes, flavored cigarettes, cigar, snuff, straw cigarettes and rope smoke. Using the INAA technique, it was possible to determine the concentration of 19 elements and with the EDXRF technique 31 elements, which enabled a wide multielementar characterization; the analytical techniques employed were complementary. The elements that presented the highest concentration values were Ca and K among all the samples and among all the natural radionuclides determined the 228Ra presented higher values of activity concentration. The estimated annual dose and annual effective dose for the 210Pb and 210Po radionuclides were calculated from the determined activity concentration, taking into account an annual consumption of 3.65 kg of tobacco per year. The effective annual dose ranged from 69.5 μSv y-1 to 121 μSv y-1. The products with the highest concentration values and hence the highest annual effective dose for the majority of the radionuclides analyzed were straw cigarettes and rope smoke.