La douleur neuropathique centrale post accident vasculaire cérébral est une condition débilitante dont le traitement s’avère souvent délicat et infructueux. Le but de ce projet était de reproduire cette condition chez le rat en injectant par stéréotaxie une solution de collagènase produisant une hémorragie localisée dans le noyau ventropostérolatéral du thalamus. Des tests comportementaux évaluant la coordination motrice, la sensibilité mécanique, au chaud et au froid étaient réalisés régulièrement afin d’établir la présence de douleur neuropathique puis les effets de l’administration de kétamine, d’amitriptyline, de gabapentine, et de carbamazepine étaient évalués. L’induction d’une hémorragie intrathalamique conduit à l’apparition d’allodynie mécanique bilatérale persistante ainsi que d’allodynie au froid transitoire chez certains sujets et ce sans modification de la coordination motrice. L’administration de kétamine à forte dose renverse l’allodynie mécanique mais est associée à une altération de la motricité. L’administration de gabapentine renverse également cette allodynie mécanique sans effet notable sur la coordination motrice. Les autres médicaments n’ont pas démontré d’effet significatif. L’évaluation histopathologique des cerveaux montre une lésion bien localisée dans la zone d’intérêt. Ces résultats montrent que l’injection intrathalamique de collagénase peut être utilisée comme un modèle fiable de douleur neuropathique centrale. Si la kétamine semble capable de soulager ce type de douleur, elle est associée à des effets indésirables. En revanche, la gabapentine serait une molécule prometteuse pour le traitement de cette condition. Le rôle des récepteurs NMDA et des canaux calciques voltage dépendants, cibles respectives de la kétamine et de la gabapentine dans le maintien de cette douleur mérite d’être précisé. / Central post stroke pain is a debilitating condition for which treatment is often difficult and unsuccessful. The goal of this project was to reproduce an animal model of this condition by performing a stereotaxic injection of collagenase solution inducing a localized hemorrhage within the ventroposterolateral thalamic nuclei of rats. Behavioral tests to evaluate motor coordination, sentivity to mechanical, hot and cold stimuli were performed regurlarly to establish if neuropathic pain was present. Then, the effects of ketamine, amitriptyline, gabapentin and carbamazepine on such pain were evaluated. Induction of an intrathalamic hemorrhage produced bilateral persistent mechanical allodynia as well as transient cold allodynia in some animals without notable changes in motor coordination. High doses of ketamine did reverse mechanical allodynia but with significant impairment in motor coordination. Similarly gabapentin also reversed mechanical allodynia without undesirable effect on coordination. The others two drugs failed to show any significant effect. Histopathological evaluation of the brain revealed a well localized lesion in the area of interest. These results show that an intrathalamic collagenase injection produced a reliable model of central neuropathic pain. Ketamine was able to reverse mechanical allodynia but with significant side effects. Gabapentin appeared to be a promising drug for the treatment of this condition. The role of NMDA receptors and voltage dependant calcium channels, that target ketamine and gabapentin respectively in the maintenance of this pain, needs to be further defined.

No description available.

Les co-cristaux représentent une classe de composés offrant de grandes opportunités pour l'industrie pharmaceutique. La plupart des études présentées dans la littérature porte sur le diagramme thermodynamique et sur l'ingénierie cristalline. Ce travail y ajoute l'aspect cinétique qui est essentiel à prendre en compte pour la mise en place d'un procédé de cristallisation à l'échelle industrielle. Différentes techniques d'analyse en ligne ont été mises en oeuvre pour suivre le procédé de co-cristallisation. Le système modèle carbamazépine / nicotinamide a été sélectionné. Dans un premier temps, l'utilisation d'une sonde de visualisation in-situ a permis la construction d'un diagramme de phase pour le système modèle étudié. Par la suite, les chemins cinétiques du procédé de co-cristallisation ont été mesurés en solution grâce au suivi des concentrations en soluté par spectroscopie InfraRouge à Transformée de Fourier. Enfin, la transition entre les phases solides (carbamazépine et cocristaux) a été suivie in-situ par spectroscopie IR et en couplant la sonde de visualisation avec la sonde Lasentec FBRM. Les essais ont permis de vérifier qu'une dérive de procédé conduisant à une autre phase cristalline que les co-cristaux peut être corrigée pour obtenir au final uniquement des co-cristaux / Co-crystals represent a class of compounds, which offers huge opportunities for the pharmaceutical industry. Most studies presented in the literature deals with the thermodynamic diagram and crystal engineering. This work adds the kinetic aspect that must imperatively be taken into account in the establishment of a crystallization process at an industrial case. Different in-line process analytical techniques were carried out to monitor the co-crystallization process. The model system carbamazepine / nicotinamide was selected. The use of an in-situ visualization probe allowed us to build the phase diagram of the model system studied. Afterwards, the kinetic pathways of the co-crystallization process were highlighted thanks to the following of the solute concentrations by Fourier Transform InfraRed spectroscopy. Finally, the phase transition between carbamazepine and co-crystals was monitored by IR spectroscopy, and by using simultaneously the visualization probe with the Lasentec FBRM probe. In order to finally obtain the only co-crystal phase, we subsequently verified that it was possible to correct a situation of process deviation, for which another crystalline phase remained in suspension

The main aim of this study was to investigate the efficiency of wastewater treatment plant (WWTP) in České Budějovice for the elimination of selected pharmaceuticals (carbamazepine, diclofenac, atenolol, metoprolol, sotalol, bisoprolol, valsartan, verapamil and tramadol) over a long time period (March 2011 - February 2012). Time-proportional 24 hours pooled samples of wastewater from influent and effluent of the WWTP were used to assess the efficiency of WWTP. The concentrations of target compounds were determined by using in line SPE/LC-MS/MS analysis. The average annual concentrations in the effluent of WTP were in the range of 0,019 microgram/l (verapamil) to 1,00 microgram/l (atenolol). Average annual efficiencies of pharmaceutical elimination in WWTP based on pooled samples were found in the case of carbamazepine (-22 %), tramadol (-15 %), sotalol (-1 %), diclofenac (15 %), metoprolol (16 %), verapamil (43 %), bisoprolol (48 %) and valsartan (85 %). The statistical analysis of daily results in the winter and in the summer period showed significantly higher efficiency of the WWTP in the summer for 5 target compounds (diclofenac, atenolol, valsartan, sotalol and bisoprolol). Removal efficiency for the rest of pharmaceuticals did not show significant differences. Elevated temperature and longer irradiation period in summer can positively affect biodegradation or increased photolysis respectively.

O fígado desempenha um papel central na disposição metabólica de vários agentes químicos endógenos e exógenos, incluindo quase todos os fármacos. Neste processo de biotransformação pode ocorrer a formação de metabólitos intermediários altamente reativos que se não forem convenientemente eliminados podem interagir com macromoléculas celulares lesando o órgão. A hepatotoxicidade idiossincrática associada ao uso de antiepilépticos aromáticos (AEA) é bem conhecida e tem sido atribuída ao acúmulo de intermediários tóxicos (areno-óxidos) formados durante a bioativação hepática. Embora a participação de processos imunológicos no mecanismo de ação tóxica dos AEA tenha sido demonstrada, existe a possibilidade de mecanismos adjuvantes envolvendo a toxicidade mitocondrial, evento ainda não explorado na literatura científica. Neste estudo avaliou-se, in vitro, o efeito dos AEA: carbamazepina, fenitoína e fenobarbital, bem como dos seus respectivos metabólitos na função mitocondrial e na indução do estresse oxidativo em mitocôndrias de fígado de rato, como possível mecanismo de ação hepatotóxica desses fármacos. Sistema microssomal hepático de rato foi utilizado para bioativação dos fármacos e produção dos respectivos metabólitos in vitro. Sem a bioativação, somente o fenobarbital (em concentrações elevadas) apresentou efeitos inibidores sobre o estado 3 da respiração, síntese de ATP e potencial de membrana, sem, contudo induzir o estresse oxidativo. Quando bioativados, todos os fármacos apresentaram efeitos sobre a função mitocondrial através de processo mediado por estresse oxidativo. Todos os fármacos bioativados afetaram a respiração mitocondrial, causando diminuição do consumo de oxigênio no estado 3, diminuição do RCR e aumento do consumo de oxigênio no estado 4. Foram também evidenciadas alterações na captação/liberação de cálcio, inibição da síntese de ATP, diminuição do potencial de membrana e inibição do intumescimento mitocondrial induzido pelo cálcio. A oxidação de proteínas e lipídeos mitocondriais foi demonstrada pela formação de proteínas carboniladas, diminuição de proteínas com grupamentos sulfidrila, aumento de malondialdeído (MDA) e pela oxidação da cardiolipina. O sistema de defesa antioxidante mitocondrial também foi afetado, como evidenciado pela diminuição da relação GSH/GSSG (glutationa reduzida/glutationa oxidada). Os resultados sugerem fortemente a participação do dano mitocondrial, mediado pelo estresse oxidativo causado pelos metabólitos dos AEA, no desenvolvimento da hepatotoxicidade idiossincrática induzida por esses fármacos. / The liver plays a central role in the metabolic disposition of various endogenous and exogenous chemicals, including almost all drugs. During the biotransformation process, highly reactive metabolites can be produced, and if they are not detoxified, they can interact with cellular macromolecules and cause organ injury. Idiosyncratic hepatotoxicity is a well-known complication associated with aromatic antiepileptic drugs (AAED), and it has been suggested to occur due to the accumulation of toxic arene oxide metabolites. Although the participation of an immune process in the toxic action mechanism of AAED has been demonstrated, adjuvant mechanisms involving mitochondrial toxicity is also possible and such event has not been studied yet. Therefore, we investigated, in vitro, the effects of carbamazepine (CB), phenytoin (PT), phenobarbital (PB) and their respective metabolites on the hepatic mitochondrial function as well as their ability to induce oxidative stress in rat liver mitochondria, as a possible hepatotoxic action mechanism. The murine hepatic microsomal system was used to bioactivate the drugs and to produce the anticonvulsant metabolites in vitro. As an unaltered drug, only phenobarbital (in high concentrations) presented inhibitory effects on state 3 respiration, ATP synthesis, and membrane potential; however, it did not induce oxidative stress. All the bioactivated drugs affected mitochondrial function through an oxidative stress-mediated process. All the bioactivated drugs affected mitochondrial function causing decrease in state 3 respiration, decrease in RCR and increase in state 4 respiration. They also caused impairment of Ca+2 uptake /release, decrease in ATP synthesis, decrease in membrane potential and inhibition of calcium-induced swelling. Oxidation of proteins and lipids was evidenced by carbonil proteins formation, decrease in thiol proteins, increase in malonaldehyde (MDA) and cardiolipin oxidation. The mitochondrial antioxidant defense system was also affected, as evidenced by the decreased GSH/GSSG ratio (reduced glutathione/oxidized glutathione). Results strongly suggest the involvement of mitochondrial damage, which is mediated by the oxidative stress caused by the AAED metabolites, in the development of AAED-induced idiosyncratic hepatotoxicity.

Carbamazepina (Carba) é um anticonvulsivante, uma droga psicotrópica muito utilizada no tratamento de pacientes com distúrbios intelectuais. Esta droga foi utilizada para diminuir o volume urinário no Diabetes Insípido (DI), pois possui um efeito antidiurético, mas a incidência de hiponatremia é uma ocorrência comum. O lítio é uma das drogas mais importantes para o tratamento do distúrbio bipolar. No entanto, ele tem uma grande capacidade de induzir DI dificultando o seu uso em pacientes debilitados psicologicamente. Atualmente, a associação destas drogas é frequentemente utilizada para o tratamento de pacientes com distúrbios psiquiátricos e neurológicos. O objetivo deste trabalho foi investigar o efeito da Carba no ducto coletor medular interno (DCMI) de ratos normais e elucidar a sua ação no DI induzido pelo lítio: 1) Estudos in vitro- A) Estudos com microperfusão de segmentos isolados do néfron onde a permeabilidade à água (Pf, m/sec) foi determinada em DCMI perfundidos de ratos normais (n=20) na presença de Carba à 10-5 M, e na ausência de HAD. B) estudos com a técnica de Imunoblotting para avaliar a expressão da proteína Aquaporina 2 (AQP2) em suspensão de túbulos de DCMI de ratos normais incubados com 10-5 M de Carba por 30 minutos. 2) Estudos in vivo A) quatro grupos foram formados: a) Controle (n=5); b) Li (40 mmol/Kg/dieta por 3 semanas; n=4); c) Li+Carba (40 mmol Li/Kg/dieta + 400 mg carba/Kg/dia por 3 semanas; n=5); d) Carba (400 mg /Kg/dia por 3 semanas; n=5); - B) estudo da expressão da AQP2 no DCMI destes quatro grupos pela técnica de Western Blot. Resultados: 1) Estudos in vitro A) nos estudos de microperfusão a carba adicionada ao banho aumentou a Pf dos DCMI, na ausência de HAD (n=6) Controle12,3+ 3,6, Carba-62,6+14,8 (p<0,01), Recuperação (Rec)-17,4+5,5 (p<0,01). Com o intuito de estudar o mecanismo pelo qual a Carba ativa a cascata do HAD, foi utilizado o inibidor do receptor V2 do HAD (AV2; n=10): Controle-23,5+5,2, Carba-37,4±4,4 (p<0,01), Carba+AV2-19,6±5,0 (p<0,05), Rec-21,4+5,5; e Controle-18,6+7,0, AV2-27,3+7,2, AV2+Carba-25,3+5,7, Rec-32,6+6,4. O inibidor da PKA (H8; n=4) também foi utilizado: Controle-15,0+9,0, Carba-106,1+12,3 (p<0,01), Carba+H8-60,3+16,4 (p<0,01), Rec- 44,5+13,2. B) a análise densitométrica mostrou um aumento de 38,8% na expressão da AQP2 (Controle-100,0+8,3 vs. Carba-138,8+12,12, p<0,05); 1) Estudos in vivo Volume urinário (UV, mL/24h) Controle-10,7+3,0, Li-62,6+6,0 (p<0,001), Li+Carba-28,5+4,9 (p<0,001), Carba-23,3+3,0 (<0,001). Osmolalidade urinária (mOsm/Kg/H2O) Controle-819,6+175,7, Li-149,4+18,0 (p<0,01), Li+Carba-251,5+39,7 (p<0,05), Carba-396,2+75,5 (p<0,01). FENa+ (%) - Controle-0,15+0,01, Li-0,10+0,02, Li+Carba-0,12+0,02, Carba-0,11+0,02. Expressão da AQP2 (%) Controle-100,0+6,7, Li-55,8+5,4 (p<0,01), Li+Carba-75,8+9,6 (p<0,01), Carba- 99,7+4,7 (p<0,05). Não houve diferenças significantes no Na+, K+ e Osmolalidade plasmáticas. Em resumo, nossos dados revelaram que a Carba diminui o UV, aumenta a osmolalidade urinária e a expressão da AQP2 no DI induzido pelo lítio, e aumenta a permeabilidade à água, provavelmente agindo diretamente no receptor da vasopressina (V2). Estes resultados enfatizam que a hiponatremia encontrada nos pacientes que fazem uso da Carba pode ser explicada, pelo menos em parte, pelo aumento da permeabilidade osmótica no DCMI e que a poliúria do DI ocasionado pelo uso do lítio pode ser diminuída com a associação da Carba. / Carbamazepine (Carba) is an anticonvulsant and a psychotropic medication commonly used in the treatment of patients with intellectual disability (ID). This drug has been used to try to decrease the urinary volume in Diabetes Insipidus (DI) because Carba presents an antidiuretic effect, but the incidence of the hyponatremia in neurological patients is a common ocurrence. Lithium (Li) is one of the most important drugs used to treat bipolar mood disorders. However, Li has the undesirable capacity to induce DI complicating its usage in patients psychologically weakened. Nowadays, the association of these drugs is used in the treatment of patients with psychiatric and neurological problems. Our objective was to investigate the effect of Carba in the Inner Medullary Collecting Duct (IMCD) and elucidate its effect in the lithium-induced DI: 1) In vitro study: A) Microperfusion studies the water permeability (Pf, m/sec) was determined in normal rats IMCD isolated and perfused by the standard methods. Carba 10-5M was added to the bath fluid. B) Immunoblotting studies for AQP2 protein expression in IMCD tubule suspension from normal rats incubated with Carba 10-5M for 30 minutes. 2) In vivo study A) four groups of normal rats were done - a) Control (C, n=5); b) Li (40 mmol/kg/food/3 weeks n=4) c) Li+Carba (40 mmol Li/kg/food/3 weeks and 400 mg Carba/kg/bw/2 last weeks, n=5); and Carba (400 mg Carba/kg/bw/3weeks, n=5); - B) AQP2 expression in IMCD from the four groups, by Western Blot. Results: 1) In vitro study A) in microperfusion, Carba added to the bath in Vasopressin (Vp) absence (n=6) increased Pf Control-12.3+3.6, Carba-62.6+14.8 (p<0.01), Recuperation (Rec)-17.4+5.5 (p<0.01). In order to study the mechanism by which Carba activates the Vp cascade, the antagonist of the Vp receptor 2 (AV2; n=10) was used: Control-23.5+5.2, Carba-37.4±4.4 (p<0.01), Carba+AV2-19.6±5.0 (p<0.05), Rec-21.4+5.5; and Control-18.6+7.0, AV2- 27.3+7.2, AV2+Carba-25.3+5.7, Rec-32.6+6.4. The PKA inhibitor (H8; n=4) was also used: Control-15.0+9.0, Carba-106.1+12.3 (p<0,01), Carba+H8-60.3+16.4 (p<0.01), Rec-44.5+13.2. B) the densitometric analysis showed an increased of 38.8% in AQP2 expression (Control- 100.0+8.3 vs. Carba-138.8+12.12, p<0.05); B) In vivo study Urinary volume (UV, mL/24h) Control-10.7+3.0, Li-62.6+6.0 (p<0.001), Li+Carba-28.5+4.9 (p<0.001), Carba-23.3+3.0 (p<0.001). Urinary Osmolality (mOsm/Kg/H2O) Control-819.6+175.7, Li-149.4+18.0 (p<0.01), Li+Carba-251.5+39.7 (p<0.05), Carba-396.2+75.5 (p<0.01). FENa+ (%) - Control- 0.15+0.01, Li-0.10+0.03, Li+Carba-0.12+0.02, Carba-0.11+0.02. AQP2 expression (%) Control-100.0+6.7, Li-55.8+5,4 (p<0.01), Li+Carba-75.8+9.6 (p<0.01), Carba-99.7+4.7 (p<0.05). There were no significant differences in Na+, K+ and plasma osmolality. In summary, our data showed that Carba decreased the UV, increased the UOsm and the AQP2 expression in Li-induced DI, increased the water permeability, probably acting directly in the Vp V2 receptor-Protein G complex, since its action was blocked by the specific Vp V2 receptor antagonist. These results emphazise that the hyponatremia found in patients using Carba could be explained, at least in part, by increased osmotic permeability of IMCD. In addition, poliuria observed in lithium-induced DI can be decreased with Carba-treatment.

Endocrine-disrupting compounds (EDCs) interfere with the physiology of hormone systems. Traditionally, steroidogenic pharmaceuticals have been studied as EDCs however there has been growing evidence that non-steroidogenic pharmaceuticals can alter sex steroid levels and impair reproductive functions in fish. This is of concern as pharmaceuticals are detected in surface waters at the ng L-1 to µg L-1 range. Zebrafish (Danio rerio) were exposed to 10 µg L-1 of the pharmaceuticals carbamazepine and gemfibrozil for 6 weeks. Male-biased sex ratios were observed in the sexually mature offspring after paternal exposure, suggesting that sexual differentiation may be impacted in juveniles. Currently, the ability of pharmaceuticals to interfere with sexual differentiation of parentally exposed offspring is unknown. This thesis examined the gonad histology of juvenile zebrafish to understand how sexual differentiation was affected in the offspring of exposed parents. Paternal, but not maternal, exposure to carbamazepine resulted in a significantly faster sexual differentiation of the gonads and led to a male-biased sex ratio; these effects were not observed when both parents were exposed. Combined paternal and maternal exposure to gemfibrozil resulted in significantly faster sexual differentiation and paternal, but not maternal, exposure to gemfibrozil led to male-biased sex ratios. Interestingly, sex ratios observed in the juveniles did not always reflect those found in the same lineage at sexual maturity, suggesting a sex reversal, including a male to female transition, occurred past the juvenile sexual differentiation period in some fish. This thesis demonstrates that pharmaceuticals have the ability to disrupt sexual differentiation in the F1 offspring of exposed parents and that paternal exposure is most relevant for offspring effects. / Thesis / Master of Science (MSc) / Parental exposure to the environmentally-relevant pharmaceuticals carbamazepine or gemfibrozil led to male-biased sex ratios in adult offspring of zebrafish (Danio rerio), a common model organism. The development of the gonads in juveniles was investigated to determine how this process was impacted. Predominately, paternal exposure was found to result in a faster development of the testes and male-biased sex ratios. Interestingly, sex ratios in juveniles did not always reflect those in adults, suggesting a sex reversal may have occurred in adulthood. This study demonstrates the ability of pharmaceuticals to alter gonad development in offspring of exposed parents.

No / The surface energetic parameters of carbamazepine and paracetamol have been studied using inverse gas chromatography modified to produce dry and ambient conditions within the column. The values of the dispersive component of the surface free energy (¿DS) do not change significantly at the increased relative humidity. In contrast the specific component of the free energy of adsorption (-¿GSPA) as measured by polar probes, can either remain constant or decrease by up to 10%, depending on the material and the probe. This indicates that an increase in the relative humidity causes a decrease in the surface energetics of the powder surface. It is proposed that where the water molecules are adsorbing to the same sites as the polar probes, the interaction of these probes with the surface is decreased. To identify these sites, the preferential interaction of each probe, including water, with the drug molecule has been modelled.

La carbamazépine (CBZ) est un antiépileptique largement consommé, peu dégradé dans les stations de traitement des eaux usées et donc rejeté dans les eaux de surface. Cette thèse vise à étudier le devenir de CBZ et de deux métabolites, l'oxcarbazépine (OxCBZ) et l'acide 9-carboxylique acridine (9-CAA), sous irradiation par la lumière solaire dans des eaux naturelles douces et salées. Les suivis cinétiques ont permis de mettre en évidence des comportements différents en fonction des composés mais aussi des types d’eaux et impliquant des mécanismes de phototransformation directe et induite mais aussi des réactions d’atténuation naturelle. Pour approfondir ces résultats, la spectrophotométrie d’absorption résolue en temps et l’utilisation d’une sonde chimique ont souligné la formation d’espèces réactives (radicaux hydroxyles, carbonates et halogénés) et des réactions de compétition ont permis de mesurer leur réactivité avec les composés étudiés.La formation de dérivés issus de processus d’hydroxylation, d’oxydation, de perte de la fonction latérale, d’ouverture et/ou contraction de cycle aromatique (etc.) et de sous-produits halogénés dans les eaux salées ont été identifiés lors de la photodégradation de CBZ, OxCBZ et 9-CAA. Enfin, l’écotoxicité aiguë et chronique de CBZ, OxCBZ et 9-CAA a été évaluée individuellement et en mélange à dose environnementales sur 3 espèces vivantes de différents niveaux trophiques en mesurant les paramètres suivants : luminescence sur la bactérie Vibrio fischeri, phytométabolites sur la lentille d'eau Lemna minor et altération aux niveaux population, cellulaire et moléculaire sur le cnidaire Hydra circumcincta. / Carbamazepine (CBZ) is a widely consumed anti-epileptic pharmaceutical drug, inefficiently removed in activated sludge secondary treatment process. Consequently, it is almost completely rejected in its original form into surface waters. Hence, this thesis aimed to study the fate of CBZ and two of its known bio-metabolites, i.e. oxcarbazepine (OxCBZ) and 9-carboxylic acridine acid (9-CAA), under solar light irradiation in fresh and salty waters. Kinetic monitoring revealed different behaviours both compounds and water types dependent implying photolysis, induced photodegradation but also natural attenuation reactions. To deeper understand these results, laser flash photolysis experiments and the use of a chemical probe highlighted the formation of reactive species (hydroxyl, carbonate and halogenated radicals). By implementing competition reactions, the rate constants of each compound with each chemical radical species were determined.The formation of derivatives from hydroxylation, oxidation, ring contraction, loss of side function, aromatic ring opening (etc.) and also halogenated by-products in salty waters were identified throughout CBZ, OxCBZ and 9-CAA phototransformations.Finally, acute and chronic ecotoxicity of CBZ, OxCBZ and 9-CAA individually and in mixture at environmental concentration levels were investigated on 3 living species from different trophic levels. The following endpoints were monitored: luminescence on the bacteria Vibrio fischeri, growth and development and phytometabolites on the duckweed Lemna minor and alterations at the population, cellular and molecular levels on the cnidarian Hydra circumcincta.

Ziele dieser Dissertation sind die Aufklärung der Strömungsverhältnisse und Untersuchungen zum Verhalten von Arzneimittelrückständen im Tegeler See, die Entwicklung eines Simulationsmodells für Szenarioberechnungen sowie die Ableitung neuer Bewirtschaftungskonzepte unter Zuhilfenahme der gewonnenen Erkenntnisse und Modellergebnisse. Das zweidimensionale Strömungsmodell 2D-POM kann die Mischungsverhältnisse der beiden Zuflüsse zum Tegeler See, insbesondere den Einstrom der Oberhavel, ausreichend genau abbilden. Der Oberhaveleinstrom ist sowohl windinduziert als auch vom Abfluss der Oberhavel abhängig. Der Wind wirkt je nach Windrichtung verstärkend oder abschwächend auf den Oberhaveleinstrom. Der Tegeler See weist im Vergleich zu anderen Oberflächengewässern, die als Trinkwasserressource dienen, die höchsten bisher berichteten Gehalte an Arzneimittelrückständen auf. Die räumliche Verteilung von Carbamazepin (CBZ) und Sulfamethoxazol (SMX) wird hauptsächlich durch die Verdünnung mit Oberhavelwasser bestimmt. Nur ein geringer Teil des CBZ (40%) wird im Tegeler See eliminiert. Für SMX konnte keine Elimination festgestellt werden. Im Gegensatz dazu wird Diclofenac (DCF) im Oberflächenwasser photolytisch abgebaut (50% in den Wintermonaten, mehr als 95% im Sommer). Die Konzentrationen von DCF im Tegeler See zeigen deshalb eine hohe saisonale Variabilität. Durch Simulation von sieben Bewirtschaftungsszenarien wurde untersucht, ob mithilfe der existierenden Seeleitung und Phosphateliminierungsanlage die Konzentrationen der Arzneimittelrückstände im Tegeler See verringert werden können, ohne die erfolgreiche Seerestaurierung zu gefährden. In keinem Szenario konnten die Gehalte an Arzneimittelrückständen und Phosphor gleichzeitig auf einem akzeptablen Niveau gehalten werden. Aus diesem Grund sind ergänzende Maßnahmen notwendig, z.B. eine zusätzliche Spurenstoffentfernung im Zulauf des Sees oder eine weitere Phosphorreduzierung in der Oberhavel. / This cumulative thesis aims at (i) understanding the hydrodynamic characteristics of Lake Tegel, (ii) examining the occurrence and fate of pharmaceutical micro-pollutants in the lake, (iii) developing a modeling tool for scenario prediction, and (iv) utilizing the above findings and applying the above modeling tool to create new management strategies for Lake Tegel. The free-surface two-dimensional circulation model 2D-POM serves as an adequate tool for representing the intrusion of River Havel and the mixing intensity of both inflows, as validated by measured data. The calculations indicated that the intrusion of River Havel into Lake Tegel fluctuates with river discharge and wind, both of which can amplify or neutralize the other. Compared to other surface waters also used as drinking water resources, Lake Tegel seams to feature the highest ever reported pharmaceutical concentrations worldwide. The spatial distribution of carbamazepine (CBZ) and sulfamethoxazole (SMX) in the lake was shown to be primarily affected by dilution with water from River Havel rather than by degradation within the lake. By contrast, concentrations of diclofenac (DCL) are affected by both dilution and photodegradation. DCF showed the strongest elimination of all three pharmaceuticals and revealed significant seasonality with 50% elimination in winter and more than 95% in summer. Elimination of CBZ was 40%, while SMX did not degrade at determinable rates. Seven different management scenarios were tested to answer the question of whether the existing lake pipeline could be used to reduce the amount of pharmaceuticals in Lake Tegel without deteriorating the current phosphorus level. No scenario provided a strategy optimal for both pharmaceuticals and phosphorus. Consequently, additional efforts need to be made, such as supplementary pharmaceutical treatment of the inflow originating from the wastewater treatment plant, or phosphorus reduction in the River Havel catchment.