Malgrat que hi ha molta química descrita al voltant dels borans i dels carborans, la falta de mètodes sintètics fa palesa la manca de clústers substituïts en els àtoms de bor. Concretament en el cas de l'o-carborà, la substitució en els bors no és tant comú com sobre els carbonis donada la menor acidesa dels hidrògens units a ells. Per poder funcionalitzar-los generalment es duu a terme una substitució electrofílica que tant sols és efectiva sobre els àtoms de bor més llunyans dels àtoms de carboni, restant les posicions directament connectades a ambdós àtoms de carboni, B3 i B6 sense substituïr. Així doncs, l'objectiu del present treball és l'estudi de la reactivitat sobre els àtoms de bor, centrant-se en la dels àtoms B3 i B6.Per assolir l'objectiu, s'ha dissenyat un mètode simple i ràpid per a la síntesi amb alt rendiment de borats halogenats de fórmula [B6X6]2- (X = Br, I). També s'han sintetitzat i caracteritzat carborans halogenats (iodats i bromats) en la posició 3 del clúster d'o-carborà. Per a aquests clústers s'han dut a terme càlculs teòrics dels desplaçaments químics de 11B-RMN i s'ha estudiat la seva reactivitat davant reactius de Grignard obtenint derivats alquílics i arílics a la posició 3 del clúster d'o-carborà. Per a un d'aquests compostos, el 3-Iodo-1,2-dicarba-closo-dodecaborà, s'ha estudiat la reactivitat de l'enllaç B-I front a la reacció amb metalls. En el cas del magnesi s'ha desenvolupat un nou mètode de reducció de l'o-carborà. A més a més, per difracció de raigs X s'ha resolt l'estructura crista·lina del 3-Iodo-1,2-dicarba-closo-dodecaborà en la que s'ha evidenciat l'existència d'interaccions intermoleculars. Per degradació parcial dels clústers halogenats closo, s'han sintetitzat nido-carborans halogenats en la posició 3 del clúster. També s'ha sintetitzat i caracteritzat el 3,6-I2-1,2-dicarba-closo-dodecaborà. Per a aquest clúster, la reacció amb derivats de Grignard ha permès obtenir carborans substituïts en les posicions 3 i 6 amb restes alquílics i arílics i s'ha demostrat com el desplaçament químic i en alguns casos l'acidesa dels àtoms d'hidrogen units als àtoms de carboni del clúster, depèn del tipus de substituent que es troba en aquestes posicions, essent un efecte additiu.També s'han sintetitzat i caracteritzat derivats de l'o-carborà nona i deca-B-iodats. Les síntesis s'han dut a terme en globalment dues etapes. La primera es basa en la combinació de les reaccions de degradació parcial i inserció que permet obtenir el clúster iodat en posició 3 o bé 3 i 6 i la segona en un atac electrofílic amb ICl sobre el clúster mono o diiodat que porta a l'obtenció del clúster nonaiodat o decaiodat respectivament. S'ha estudiat l'acidesa dels àtoms d'hidrogen units als àtoms de carboni del derivat per-B-iodat de l'o-carborà front la desprotonació amb diferents bases i la protonació de la seva base conjugada amb diferents àcids. S'han sintetitzat i caracteritzat nido-carborans octa i nona-halogenats.També s'ha sintetitzat el carborà nonametilat en dues etapes. La primera es basa en la combinació de les reaccions de degradació parcial, inserció i acoblament creuat que permet obtenir el 3-metil-o-carborà i la segona en un atac electrofílic amb MeI sobre el clúster monosubstituït que porta a l'obtenció del clúster nonametilat. Intents de sintetitzar el clúster per-B-metilat, han portat a un carborà octametilat. Aquest fet experimental s'ha atribuït a l'efecte dels grups metil sobre els àtoms de bor del clúster que ha estat quantificat mitjançant càlculs teòrics. Així, a mesura que augmenta el nombre de grups metil, augmenta la càrrega total positiva en el clúster, disminuint la susceptibilitat a l'atac electrofílic. Finalment s'ha estudiat l'aplicació de closo-carborans halogenats en el camp del radiomarcatge. / Although the chemistry of borates and carboranes is already quite well developed, the lack of synthesis methods makes plausible the need of new boron substituted carboranes. In the case of o-carborane, boron substitution is not so common as carbon substitution due to the lower acidity of the hydrogen atoms bonded to boron atoms. Functionalization of boron atoms in o-carborane is usually achieved by electrophilic substitution. This is only effective on the boron atoms remote to carbon atoms, leaving B3 and B6, adjacent to carbon atoms, unsubstituted. For this reason, the aim of this work is the study of the reactivity on boron atoms, concretely on B3 and B6.To achieve this aim, an easy and fast method to synthesise halogenated borates [B6X6]2- (X = Br, I) in high yield has been developed. B3-halogenated (iodinated and brominated) carboranes have also been synthesised. For these clusters, theoretical 11B-NMR chemical shifts has been calculated and through cross coupling with Grignard reagents alkyl and aryl B3-substituted carboranes have been obtained. For the 3-Iodo-1,2-dicarba-closo-dodecaborane, the reactivity of the B-I bond in front of different metals has been studied. In the case of magnesium, a new o-carborane reduction method has been developed. Furthermore, through X-Ray diffraction, the existence of intermolecular interactions in the crystal structure of 3-Iodo-1,2-dicarba-closo-dodecaborane has been evidenced. Through partial deboronation of halogenated closo clusters, halogenated nido-carborane has been obtained. The synthesis of 3,6-I2-1,2-dicarba-closo-dodecaborane has also been substituted. For this cluster, the cross coupling reaction with alkyl and aryl magnesium salts led to the obtaining of B3 and B6 disubstituted carboranes. The chemical shift, and in some cases the acidity of the hydrogen atoms bonded to cluster carbon atoms, depends on the type of substituent at B3 and B6, with additive effects.Nona and deca iodinated carboranes have been synthesised and characterized. In both cases the synthesis procedure has two main steps. One step is based on the combination of partial degradation and insertion of a new vertex that allows the obtaining of the iodinated cluster at B3 or B3 and B6. The second step consists in an electrophilic attack with ICl on the nona or decaiodinated clusters respectively. The acidity of the hydrogen atoms bonded to cluster carbon atoms of the per-B-iodinated carborane has been studied through the deprotonation with different bases and the protonation of its conjugated base with different acids. Octa and nona-halogenated nido carboranes have also been synthesised and characterized.A nonamethylated carborane has also been synthesised by two steps. One step is based on the combination of the partial degradation reaction, insertion and cross coupling reaction to obtain 3-methyl-o-carborane and the second step consists in an electrophilic attack with MeI on the monosubstituted cluster to lead the nonamethylated cluster. Attempts to synthesise the per-B-methylated cluster, led an octamethylated carborane. This experimental fact has been attributed to the methyl groups effect on the boron atoms. This effect has been quantified by theoretical calculations. The higher is the number of methyl groups, the higher the total cluster positive charge, decreasing thent the electrophilic attack susceptibility. Finally, the application of halogenated closo-carboranes in radiolabelling has been studied.

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Le scanner spectral à comptage photonique (SPCCT) associé à des agents de contraste spécifiques pourrait détecter certaines inflammations cardiovasculaires à un stade précoce. Les agents de contraste utilisés actuellement en imagerie à rayons X sont des petites molécules qui sont éliminées du système cardiovasculaire en quelques minutes. D’où la nécessité de développer des nanosystèmes présentant des nouvelles caractéristiques intéressantes (ciblage passif/actif, temps de circulation sanguine prolongé, etc.). Dans ce projet de recherche, des nanoparticules (NPs) de polymères iodés ont été produites à l’aide du procédé de nanoprécipitation. Dans un premier temps, les paramètres de procédé et de formulation ont été optimisés pour fournir un agent de contraste répondant à des spécifications physicochimiques précises. Des nanoparticules composées d’une matrice de polymère iodé enveloppée de PEG ont été formulées. Ces suspensions de NPs sont extrêmement stables (jusqu’à 8 mois dans l’eau et dans le sérum humain), monodisperses, avec un diamètre moyen de 150 nm. Une concentration en iode de 100 g(I). mL-1 obtenue après une étape de centrifugation / redispersion a fourni un agent de contraste avec une radiopacité dans la gamme appropriée pour l’imagerie du système cardiovasculaire et l’étude de la biodistribution. Les algorithmes de reconstructions implémentés dans le SPCCT (Décomposition de la matière et reconstruction K-edge), ont permis une quantification précise de l’iode, ainsi qu’une discrimination spécifique du gadolinium et de l’iode dans des phantoms contenant un mélange des deux éléments. La biodistribution a été évaluée après injection des NPs à des rats par voie intraveineuse. Les NPs permettent une visualisation détaillée du système cardio-vasculaire, accompagnée d’une accumulation progressive dans le foie et la rate. Ces deux organes étaient toujours visibles 15 jours après l’injection. Une étude de biodégradation des NPs a été menée sur des cellules de macrophages. Malgré la biodégradabilité potentielle des polymères, les NP intériorisées par les macrophages par phagocytose au cours d’une incubation de 5 heures restent intactes pendant 5 semaines, tandis que certaines cellules sont dégradées. Des NPs ciblant la tropoélastine ont également été synthétisées pour l’imagerie active de la plaque d’athérosclérose au niveau moléculaire. Un test Biacore a montré une affinité des NPs conjuguées avec le peptide de ciblage vis-à-vis de la molécule réceptrice / The Spectral Photon Counting Computed Tomography (SPCCT) technology associated with specific contrast agents could detect some cardiovascular inflammations at an early stage. Currently, contrast agents for CT are small molecules that are eliminated from the cardiovascular system within few minutes. Hence there is a need to develop nanosystems that present new interesting features (passive/active targeting, long blood circulation times, etc.). In this work, iodinated polymer nanoparticles (NPs) were produced using the nanoprecipitation process. First, the process and formulation parameters were optimized to provide a contrast agent that meets definite physicochemical specifications. Highly stable (up to 8 months in water and human serum), monodisperse suspensions of spherical NPs with an average diameter of 150 nm were obtained. The iodinated polymer matrix core is coated by a PEG shell. An iodine concentration of 100 g(I).mL-1 reached after a centrifugation/redispersion step provided radiopacity of the contrast agent in the right range for imaging cardiovascular system and studies of biodistribution. SPCCT material decomposition and K-edge reconstruction allowed accurate quantification of iodine, as well as specific discrimination of gadolinium and iodine in phantoms containing mixtures of both elements. Biodistribution was assessed after intravenous injection of iodinated polymer NPs to rats, revealing a clear visualization of the cardiovascular system, and progressive accumulation in liver and spleen. These organs were still visible up to 15 days post-injection. A biodegradation experiment was carried out on macrophages cell culture. Despite the potential biodegradability of the polymers, NPs internalized by the macrophages after a 5h incubation via the phagocytosis mecanism, remained intact during 5 weeks, while some cells were degraded. Tropoelastin targeting NPs were also developed for active imaging of the atherosclerosis plaque at the molecular level. A Biacore test showed specific affinity of the NPs conjugated with the targeting peptide towards tropoelastin

Made available in DSpace on 2014-06-11T19:23:07Z (GMT). No. of bitstreams: 0 Previous issue date: 2010-03-02Bitstream added on 2014-06-13T20:29:55Z : No. of bitstreams: 1 cremonini_ccr_me_botfm.pdf: 1144679 bytes, checksum: bf9c1e1e39c197477cae8519b0e360ce (MD5) / Fundação Pio Xii - Barretos / Avaliar a ocorrência e a gravidade das reações adversas agudas (RAA) com o uso do meio de contraste iodado iônico e não-iônico nos pacientes submetidos ao exame de tomografia computadorizada (TC) em hospital nacional terciário oncológico e avaliar neoplasia como possível risco para RAA. Secundariamente, avaliar o impacto do uso seletivo do meio de contraste iodado nos custos. Pacientes submetidos à TC com contraste iodado entre outubro de 2007 e agosto de 2008 foram avaliados quanto à ocorrência e à gravidade das reações adversas agudas aos meios de contrastes iônicos e nãoiônicos. As reações foram categorizadas em leve, moderada ou grave de acordo com o tipo dos sinais e sintomas e classificadas como agudas pelo tempo de ocorrência, desde o momento da injeção até 30 minutos após. Os testes do quiquadrado e exato de Fisher foram utilizados para análise estatística da ocorrência de RAA em relação às variáveis de gênero e idade. O estudo foi aprovado pelo Comitê de Ética local e o Termo de Consentimento Livre Esclarecido foi obtido. Houve 78 RAA ao contraste iodado iônico e 11 ao não-iônico, com uma ocorrência global de 3,3% (78/2.339) e 0,5% (11/2.216), respectivamente. A maioria das reações foi classificada como leve em ambos os grupos, representando 91% (71) no grupo iônico e 81,8% (9) no grupo não-iônico. As demais reações foram do tipo moderada não havendo nenhuma reação grave. Em relação ao início das RAA, 71% e 73% (iônico e não-iônico) ocorreram nos primeiros 5 minutos. A freqüência de RAA no grupo em que recebeu contraste iônico foi maior no sexo feminino (p < 0,001). No grupo não-iônico não houve diferença estatisticamente significativa entre os sexos (p = 1,0). Não houve associação entre a presença de reação aguda e as faixas... / To evaluate the occurrence and severity of acute adverse reactions (AAR) to iodinated ionic and non-ionic contrast media in patients undergoing computerized tomography (CT) at a national tertiary cancer hospital and to evaluate neoplasm as a possible risk for AAR. Secondly, to assess the impact of selective use of iodinated contrast agent costs. Patients who underwent contrast-enhanced CT between October 2007 and August 2008 were evaluated for the presence and severity of acute adverse reactions to ionic and non-ionic contrast media. The reactions were categorized as mild, moderate or severe according to the type of signs and symptoms and classified as acute by the time of occurrence, from the time of the injection up to 30 minutes afterwards. The chi-square and Fisher’s exact were used for statistical analysis of the occurrence of AAR for the variables of gender and age. The study was approved by the local Ethics Committee and informed consent was obtained. There were 78 AAR to ionic iodinated contrast and 11 to non-ionic, with an overall occurrence of 3.3% (78/2339) and 0.5% (11/2216), respectively. Most reactions were classified as mild in both groups, representing 91% (71) in the ionic group and 81.8% (9) in the non-ionic group. All other reactions were moderate and there were no severe reactions. Regarding onset of AAR, 71% and 73% (ionic and non-ionic group) occurred in the first five minutes. The occurrence of AAR in the group who received ionic contrast was higher in females (p <0.001). As for the non-ionic group, there was no significant statistical difference between genders (p = 1.0). There was no association between the presence of acute reaction and the age groups of the population in the ionic contrast group. For the non-ionic group, no statistical analysis was performed as the sample was deemed reduced. Among... (Complete abstract click electronic access below)

Orientador: Euclides Timótio da Rocha / Banca: Fabiano Rubião Lucchesi / Banca: Jorge Elias Junior / Resumo: Avaliar a ocorrência e a gravidade das reações adversas agudas (RAA) com o uso do meio de contraste iodado iônico e não-iônico nos pacientes submetidos ao exame de tomografia computadorizada (TC) em hospital nacional terciário oncológico e avaliar neoplasia como possível risco para RAA. Secundariamente, avaliar o impacto do uso seletivo do meio de contraste iodado nos custos. Pacientes submetidos à TC com contraste iodado entre outubro de 2007 e agosto de 2008 foram avaliados quanto à ocorrência e à gravidade das reações adversas agudas aos meios de contrastes iônicos e nãoiônicos. As reações foram categorizadas em leve, moderada ou grave de acordo com o tipo dos sinais e sintomas e classificadas como agudas pelo tempo de ocorrência, desde o momento da injeção até 30 minutos após. Os testes do quiquadrado e exato de Fisher foram utilizados para análise estatística da ocorrência de RAA em relação às variáveis de gênero e idade. O estudo foi aprovado pelo Comitê de Ética local e o Termo de Consentimento Livre Esclarecido foi obtido. Houve 78 RAA ao contraste iodado iônico e 11 ao não-iônico, com uma ocorrência global de 3,3% (78/2.339) e 0,5% (11/2.216), respectivamente. A maioria das reações foi classificada como leve em ambos os grupos, representando 91% (71) no grupo iônico e 81,8% (9) no grupo não-iônico. As demais reações foram do tipo moderada não havendo nenhuma reação grave. Em relação ao início das RAA, 71% e 73% (iônico e não-iônico) ocorreram nos primeiros 5 minutos. A freqüência de RAA no grupo em que recebeu contraste iônico foi maior no sexo feminino (p < 0,001). No grupo não-iônico não houve diferença estatisticamente significativa entre os sexos (p = 1,0). Não houve associação entre a presença de reação aguda e as faixas... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: To evaluate the occurrence and severity of acute adverse reactions (AAR) to iodinated ionic and non-ionic contrast media in patients undergoing computerized tomography (CT) at a national tertiary cancer hospital and to evaluate neoplasm as a possible risk for AAR. Secondly, to assess the impact of selective use of iodinated contrast agent costs. Patients who underwent contrast-enhanced CT between October 2007 and August 2008 were evaluated for the presence and severity of acute adverse reactions to ionic and non-ionic contrast media. The reactions were categorized as mild, moderate or severe according to the type of signs and symptoms and classified as acute by the time of occurrence, from the time of the injection up to 30 minutes afterwards. The chi-square and Fisher's exact were used for statistical analysis of the occurrence of AAR for the variables of gender and age. The study was approved by the local Ethics Committee and informed consent was obtained. There were 78 AAR to ionic iodinated contrast and 11 to non-ionic, with an overall occurrence of 3.3% (78/2339) and 0.5% (11/2216), respectively. Most reactions were classified as mild in both groups, representing 91% (71) in the ionic group and 81.8% (9) in the non-ionic group. All other reactions were moderate and there were no severe reactions. Regarding onset of AAR, 71% and 73% (ionic and non-ionic group) occurred in the first five minutes. The occurrence of AAR in the group who received ionic contrast was higher in females (p <0.001). As for the non-ionic group, there was no significant statistical difference between genders (p = 1.0). There was no association between the presence of acute reaction and the age groups of the population in the ionic contrast group. For the non-ionic group, no statistical analysis was performed as the sample was deemed reduced. Among... (Complete abstract click electronic access below) / Mestre

nÃo hà / Os meios de contraste iodado (MCI) sÃo imprescindÃveis na prÃtica mÃdica atual, durante as intervenÃÃes diagnÃsticas e terapÃuticas. A nefropatia induzida por meio de contraste (NIMC) à a terceira causa iatrogÃnica de insuficiÃncia renal aguda em pacientes hospitalizados. O objetivo deste trabalho foi estudar os efeitos renais dos meios de contraste ioxitalamato de meglumina e iobitridol, podendo contribuir para a descoberta de ferramentas farmacolÃgicas e/ou elucidar os mecanismos de nefrotoxicidade. Os efeitos dos meios de contraste ioado (MCI) foram avaliados em ratos Wistar mantidos em gaiolas metabÃlicas, a cada 24 horas, por um perÃodo de atà 72 horas apÃs a administraÃÃo do contraste por via intravenosa. No grupo controle foi administrado soluÃÃo salina, enquanto os grupos tratados receberam ioxitalamato de meglumina (alta osmolalidade) e iobitridol (baixa osmolalidade). Foram analisadas diariamente diurese, ingesta de Ãgua e alimento. A funÃÃo renal foi avaliada atravÃs da perfusÃo de rim isolado de ratos apÃs 72 horas da administraÃÃo do MCI, onde a perfusÃo foi realizada com soluÃÃo de Krebs Henseleit modificada com 6g% de albumina bovina. Os dados foram comparados atravÃs do teste Bonferroni e ANOVA, com significÃncia de p<0,05. A ingesta de Ãgua aumentou no grupo tratado com contraste de alta osmolalidade (26,00Â2,00) quando comparado ao grupo controle (19,00Â1,175) no tempo de 24 horas. A diurese do grupo tratado com contraste de alta osmolalidade (6,84Â0,767), no tempo de 24 horas, aumentou significativamente quando comparada ao grupo controle (3,57Â0,696). Em perfusÃo de rim isolado de rato, foi observado aumento da pressÃo de perfusÃo (PP) nos grupos que receberam contraste de alta (98,40Â2,467) e de baixa osmolalidade (126,8Â0,936) quando comparados ao grupo controle (89,13Â0,818), no tempo de 30 minutos. O ritmo de filtraÃÃo glomerular sofreu reduÃÃo nos grupos de alta osmolalidade (0,297Â0,039) e baixa osmolalidade (0,390Â0,053), quando comparado ao controle (0,741Â0,042), no tempo de 120 minutos. Em relaÃÃo ao transporte de eletrÃlitos, foi observado alteraÃÃo no transporte tubular de cloreto no grupo de baixa osmolalidade (72,41Â0,892) quando comparado aos grupos controle (83,68Â0,951) e de alta osmolalidade (79,72Â1,335), no tempo de 120 minutos; em relaÃÃo ao transporte tubular de potÃssio foi evidenciado uma reduÃÃo no grupo de alta osmolalidade (53,86Â5,847) quando comparado aos grupos controle (79,64Â1,710) e de baixa osmolalidade (69,34Â2,479), no tempo de 120 minutos. Na anÃlise histolÃgica, os rins que receberam contraste de alta e de baixa osmolalidade, no tempo de 72 horas, foi observado uma intensa deposiÃÃo cilÃndrica em todos os tÃbulos, tanto no cÃrtex quanto na medula. Os glomÃrulos nÃo apresentaram deposiÃÃo. Na cultura de cÃlulas MDCK foi evidenciado citoxocidade dos contrastes de alta e de baixa osmolalidade, com predomÃnio de apoptose atravÃs da avaliaÃÃo por citometria de fluxo. Estes resultados demonstram que os contrastes de alta e baixa osmolalidade induzem alteraÃÃes no metabolismo diÃrio dos ratos e nos parÃmetros vasculares e renais avaliados na perfusÃo de rim isolado e possui aÃÃo citotÃxica sobre as cÃlulas MDCK. / Iodinated contrast media (ICM) is important in current medical practice during diagnostic and therapeutic interventions. Nephropathy induced by contrast medium (CMIN) is the third iatrogenic cause of acute renal failure in hospitalized patients. The objective of this work was to study the renal effects of contrast media meglumine and ioxitalamato Iobitridol and may contribute to the discovery of pharmacological tools and / or elucidate the mechanisms of nephrotoxicity. The effects of contrast media ioado (MCI) were evaluated on male Wistar rats housed in metabolic cages, every 24 hours for a period of 72 hours after the administration of intravenous contrast. In the control group was administered saline, while groups received ioxitalamato meglumine (high osmolality) and Iobitridol (low osmolality). We analyzed daily urine output, water intake and food. Renal function was assessed by perfusion of isolated rat kidney after 72 hours of administration of the MCI , where perfusion was performed with Krebs Henseleit modified 6g% bovine albumin. Data were compared by ANOVA and Bonferroni test, with significance of p <0.05. The water intake increased in the group treated with high-osmolality contrast (mL/24hs 26.00  2.00) compared to the control group (19.00  1.175 mL/24hs) at the time of 24 hours. Diuresis contrast the group treated with high osmolality (6.84  0.767 mL/24hs), at 24 hours, increased significantly when compared to controls (3.57  0.696 mL/24hs). Perfused isolated rat kidney, we observed an increase in perfusion pressure (PP) in the groups receiving high contrast (98.40  2.467 mmHg *, p <0.05) and low osmolality (126.8  0.936 * mmHg, p <0.05) when compared to the control group (89.13  0.818 mmHg) at the time of 30 minutes. The glomerular filtration rate was reduced in the groups of high osmolality (0.297  0.039 mm.g-1.min-1 **, p <0.05) and low osmolality (0.390  0.053 mm.g-1.min-1 ** p <0.05) when compared with controls (0.741  0.042 mm.g-1.min-1) at time 120 minutes. Regarding the transport of electrolytes was observed for the percentage of tubular transport of chloride in the group of low osmolality (72.41  0.892% MCI-) compared with control groups (83.68  0.951% MCI-) and high osmolality (79.72  1.335%-TCL), in time of 120 minutes, in relation to the tubular transport of potassium was observed a reduction in high-osmolality group (53.86  5.847% TK +) compared to control groups (79 64  TK + 1.710%) and low osmolality (69.34%  2.479 TK +) at the time of 120 minutes. Histological analysis kidneys receiving high contrast and low osmolality in time of 72 hours, an intense deposition was observed in all cylindrical tubules both the cortex and spinal cord. The glomeruli showed no deposition. In MDCK cell culture cytotoxicity was evident contrasts of high and low osmolality, with a predominance of apoptosis by flow cytometric evaluation. The results demonstrate that the high contrast and low osmolality induce changes in the metabolism of rats daily and vascular parameters assessed in the kidney and kidney perfusion isolated and have cytotoxic activity on MDCK cells.

A hiperglicemia crônica favorece a ocorrência da nefropatia induzida por contraste iodado (NIC). Diabetes Mellitus (DM) e NIC compartilham mecanismos de lesão oxidativa e indução de enzimas de proteção e adaptação celular como a coenzima Q-10 (COQ-10). O objetivo deste estudo foi avaliar o papel da COQ-10 na função e hemodinâmica renal, perfil oxidativo e histologia renal em ratos diabéticos submetidos ao modelo de NIC. Métodos: Ratos Wistar, machos, 250 a 290 g, foram randomizados nos grupos: Citrato: animais que receberam tampão citrato 0,01M, (veículo da estreptozotocina), 0,4 ml intravenoso (i.v), 1 vez; Tween 80: animais que receberam Tween 80, 1%, (veículo da COQ-10), 0,5 ml, intraperitoneal (i.p.), 1 vez; DM: animais que receberam estreptozotocina (65 mg/kg), i.v., 1 vez, no 1º dia do protocolo; DM+CI: animais DM que no 26º dia de protocolo receberam contraste iodado (CI, 6 ml/kg), i.p., 1 vez; DM+CI+COQ-10: animais DM com pré-condicionamento com COQ-10 (10 mg/kg), 1 vez por 6 dias a partir do 22º dia de protocolo, e o tratamento com CI. O protocolo de todos os grupos teve duração de 4 semanas. Foram avaliados parâmetros fisiológicos (ingestão de ração e água, peso, glicemia, razão peso do rim e peso do animal), a função renal (clearance de inulina), a hemodinâmica renal (fluxo sanguíneo renal e resistência vascular renal), o perfil oxidativo (peróxidos, óxido nítrico e substâncias reativas ao ácido tiobarbitúrico na urina, tióis no tecido renal) e análise histológica renal. Resultados: Animais DM apresentaram hiperglicemia, polidipsia, poliúria, polifagia, perda de peso e aumento da relação peso rim/animal, com redução da função renal, além de redução do fluxo sanguíneo renal, elevação da resistência vascular renal, com aumento na excreção de metabólitos oxidativos e consumo de reserva antioxidante endógena. O grupo DM+CI demonstrou redução adicional na função, alterações na hemodinâmica renal e aumento nos parâmetros de estresse oxidativo. A administração de COQ-10 atenuou a redução da função renal, preveniu alterações hemodinâmicas renais e reduziu o estresse oxidativo no grupo DM+CI. As alterações histológicas no DM e DM+CI foram discretas e o tratamento com COQ-10 previniu a progressão de danos histológicos mais extensos nos animais que receberam CI. Conclusão: O tratamento com COQ-10 demonstrou efeito antioxidante na NIC em ratos diabéticos com melhora significativa da função e hemodinâmica renal. / Chronic hyperglycemia favors the occurrence of nephropathy induced by iodinated contrast (CIN). Diabetes Mellitus (DM) and CIN share oxidative damage mechanisms and induction of protective and cellular adaptation enzymes as coenzyme Q-10 (CoQ-10). The aim of this study was to investigate the role of COQ-10 in renal function and hemodynamics, oxidative profile and renal histology in diabetic rats submitted to the NIC model. Methods: Wistar rats, male, weighing 250-290 g, were randomized into two groups: Citrate: animals that received citrate buffer 0.01M (streptozotocin), 0.4 ml, intravenous (i.v.), once; Tween 80: animals that received Tween 80, 1% (CoQ-10 vehicle), 0.5 ml, intraperitoneal (i.p.), once; DM: animals given streptozotocin (65 mg/kg) i.v., once on the first day of the protocol; CI+DM: DM animals, on the 26º day protocol, tretated with iodinated contrast (CI, 6 ml/kg) i.p., once; DM+CI+COQ-10: DM animals preconditioned with COQ-10 (10 mg/kg), once a day, for 6 days from the 22º day and treated with CI. The protocol for all groups lasted 4 weeks. Physiological parameters evaluated were (food and water intake, corporal weight, blood glucose and right kidney weight), renal function (inulin clearance), renal hemodynamics (renal blood flow and renal vascular resistance), the oxidative profile (peroxides, nitric oxide and reactive substances to thiobarbituric acid in urine, thiols in renal tissue) and renal histological analysis. Results: DM animals showed hyperglycemia, polydipsia, polyuria, polyphagia, weight loss and increased weight kidney / animal relationship with reduced renal function, as well as a reduction on renal blood flow, increased renal vascular resistance and changes in oxidative profile with increased the excretion of metabolites and oxidative consumption of endogenous antioxidant reserve. DM+CI promoted further reduction in renal function, exacerbated hemodynamic changes and increase in oxidative stress parameters. COQ-10 administration preserved renal function, prevented hemodynamic changes and reduced oxidative stress in the DM + CI + COQ-10. Histological changes in DM and DM + CI were discrete and treatment with CoQ-10 prevented the progression of the histologic damage in the animals receiving CI. Conclusion: COQ-10 presented an antioxidant effect on the NIC in diabetic rats, by improving function and renal hemodynamics and reducing oxidative stress.

Introdução: A nefropatia induzida por contraste iodado (NIC) é um efeito adverso comum em pacientes com doença renal crônica (DRC). Caracteriza-se por uma síndrome de doença renal crônica agudizada. Resultado da vasoconstrição renal, hipóxia, ativação da cascata inflamatória, lesão celular oxidativa, a NIC deteriora a função renal, aumenta os dias de hospitalização, os custos hospitalares e a mortalidade do paciente portador de DRC. Objetivo: Avaliar o efeito renoprotetor do resveratrol, um polifenol com propriedades vasodilatadoras e anti-inflamatórias em ratos com doença renal crônica que receberam contraste iodado. Métodos: Ratos Wistar, machos, adultos randomizados em quatro grupos: SHAM: controle do modelo de doença renal crônica; Nx: ratos com nefrectomia 5/6 (modelo experimental de DRC); Nx+C: ratos Nx que receberam 6 ml/Kg de contraste iodado; Nx+C+R: animais Nx que foram pré-medicados com resveratrol 25 mg/Kg e 6 ml/Kg de contraste iodado. Foram avaliadas a função (clearance de inulina) e hemodinâmica renal (fluxo sanguíneo renal e resistência vascular renal), estresse oxidativo (peróxidos, óxido nítrico e substâncias reativas ao ácido tiobarbitúrico urinário e tióis no tecido renal) e análise histológica. Resultados: O uso de contraste resultou em deterioração da função renal, redução do fluxo sanguíneo renal, aumento da resistência vascular renal, lesão oxidativa e lesão túbulo intersticial dos ratos com DRC. O uso do resveratrol resultou na manutenção da taxa de filtração glomerular, do fluxo sanguíneo e resistência vascular renal, reduziu a lesão oxidativa e a lesão túbulo intersticial após a exposição ao contraste. Conclusões: O resveratrol apresentou efeito renoprotetor, hemodinâmico e antioxidante, na NIC em ratos com doença renal crônica. / Introduction: Contrast-Induced acute kidney injury (CI-AKI) is a common adverse effect in patients with chronic kidney disease (CKD). Result of renal vasoconstriction, hypoxia, activation of inflammatory cascade, oxidative cell damage, CI-AKI promote impaired renal function, increased length of hospitalization, hospital costs and mortality. Objective: This study evaluated the renoprotection of resveratrol, a polyphenol with vasodilating and anti-inflammatory properties in rats with chronic kidney disease receiving iodinated contrast media. Methods: Wistar, adult, male rats randomized into four groups; Sham: control of chronic renal injury model; Nx: rats with 5/6 nefrectomy (experimental model of CKD); Nx+IC: Nx rats that received 6 ml/kg of iodinated contrast; Nx+IC+R: Nx rats that received 6 ml/kg of iodinated contrast and resveratrol 25 mg/Kg. Renal function (inulin clearance), renal hemodynamics (renal blood flow and renal vascular resistance), oxidative profile (peroxides, urinary nitric oxide, reactive substances to thiobarbituric acid in urine, thiols in renal tissue) and histological analysis were evaluated. Results: Iodinated contrast led to impaired renal function, reduced renal blood flow, intensified renal vascular resistance, and promoted oxidative and tubular injury in CKD rats. Resveratrol maintained glomerular filtration rate, renal blood flow and vascular resistance, reduced oxidative and tubular injury after contrast exposition. Conclusion: Resveratrol showed a renoprotective effect, with antioxidant and hemodynamics impact, on CI-AKI in rats with CKD.

Thesis--Copenhagen. / Summary in Danish. Includes bibliographical references (p. 175-191).

Thesis--Copenhagen. / Summary in Danish. Bibliography: p. 175-191.