Pneumonia is one of the main causes of death worldwide, specially of the elderly and the children under 5 years old. The traditional antibiotic-based therapy faces a crisis due to the increase in resistance and a lack of new molecules approved. Recently, our research group demonstrated the photodynamic inactivation of streptococcal pneumonia in vivo, a technique to which the development of resistance is described to be unlikely. This study proposed to investigate the applicability of nebulization as a delivery method for photosensitizers, in the hope to advance the research of the photodynamic inactivation of bacterial pneumonia. First, the critical attributes for nebulization (droplet size and delivery rate), the extent of nebulization, and the stability of three photosensitizers were stablished, and they were all found to be compatible with the technique. Then, the delivery was validated in an animal model using the most promising compound. It was possible to activate it using extracorporeal infrared light without causing acute lung or liver damage. In conclusion, nebulization presented itself as a promising tool for the delivery of photosensitizers to the respiratory tract. / A pneumonia é uma das principais causas de morte no mundo, sobretudo de idosos e crianças menores de cinco anos. A terapia tradicional, baseada em antibióticos, enfrenta uma crise diante do aumento da resistência e do número reduzido de novas moléculas que são aprovadas. Recentemente, este grupo de pesquisa demonstrou a inativação fotodinâmica da pneumonia pneumocócica in vivo, uma técnica para a qual o surgimento de resistência é descrito como pouco provável. Este estudo se propôs a investigar a aplicabilidade da nebulização como método de entrega de fotossensibilizadores, na esperança de avançar a pesquisa da inativação fotodinâmica da pneumonia bacteriana. Inicialmente, os atributos críticos da nebulização (tamanho de gotícula e taxa de entrega), a extensão da dose nebulizada, e a estabilidade de três fotossensibilizadores foram estabelecidas. Todos eles se mostraram compatíveis com a técnica. Então, a entrega foi validada em um modelo animal, utilizando o composto mais promissor. Foi possível ativá-lo usando luz infravermelha extracorpórea sem que houvesse dano agudo pulmonar ou hepático. Em conclusão, a nebulização se mostrou uma ferramenta promissora na entrega de fotossensibilizadores ao trato respiratório.

A circulação extracorpórea (CEC) pode alterar a concentração plasmática prevista para fármacos administrados durante a anestesia. Os objetivos deste estudo foram avaliar os efeitos da CEC sobre a farmacocinética, farmacodinâmica e as concentrações plasmáticas do propofol em pacientes submetidos à cirurgia de revascularização miocárdica (RM) com ou sem utilização de CEC, correlacionando-se às concentrações plasmáticas obtidas com as previstas por infusão contínua alvo-controlada. Dez pacientes submetidos à RM com CEC (Grupo CEC) e dez sem CEC (Grupo sem CEC) foram comparados em relação à concentração plasmática obtida, utilizando-se cromatografia líquida de alta eficiência e aquela prevista por infusão alvo-controlada, em relação à farmacocinética (t1/2ß, volume de distribuição e clearance plasmático), ao grau de hipnose (índice bispectral) e aos parâmetros hemodinâmicos (pressão arterial média e freqüência cardíaca), avaliados nos períodos intra-operatório e pós-operatório imediato. Os dados foram avaliados pela análise de variância para medidas repetidas, considerando-se significativo p<0,05. A concentração obtida de propofol foi maior no grupo sem CEC nos momentos 120 min (3,32±1,76 no grupo sem CEC e 2,48±1,12 no grupo CEC, p=0,005) e 240 min (3,24±2,71 no grupo sem CEC e 2,23±2,48 no grupo CEC, p=0,0212) após o início da cirurgia. A concentração medida de propofol foi maior que a prevista nos 2 grupos, com valores superiores no grupo sem CEC (p=0,02). O t1/2 ß foi maior no grupo sem CEC (3,67±1,15 grupo sem CEC e 1,82±0,5 no grupo CEC, p=0,0005) e o clearance plasmático maior no grupo CEC (28,36±11,40 no grupo CEC e 18,29±7,67 no grupo sem CEC, p=0,03). O grau de hipnose foi superior no grupo CEC. Os grupos não diferiram quanto à análise hemodinâmica. Conclui-se que a CEC promove alterações na farmacocinética e nas concentrações plasmáticas de propofol, com conseqüente diferença no grau de hipnose em relação aos pacientes submetidos à revascularização do miocárdio sem utilização de CEC / Cardiopulmonary bypass (CPB) can alter predicted plasmatic concentration of drugs administered during anesthesia. The aim of this study was evaluate the effects of cardiopulmonary bypass under pharmacokinetics, pharmacodynamics and plasmatic concentration of propofol in patients undergoing coronary artery bypass grafting surgery (CABG) with or without CPB, comparing measured plasmatic concentration with predicted concentration administered by target-controlled infusion. Ten patients undergoing coronary artery bypass grafting surgery with CPB (CPB Group, n=10) and ten without CPB (off-pump Group, n=10) were compared in relaction to measured plasmatic concentration using high performance liquid chromatography (HPLC) and predicted concentration administered by target-controlled infusion, pharmacokinetics (t1/2 ß, volume of distribution and total clearance), hypnosis degree (bispectral index) and hemodynamics parameters (mean arterial pressure and heart rate) during and after surgery. Statistical analysis was done using analysis of variance for repeated measures (*p<0,05). Measured plasmatic concentration was higher in off-pump group in the moments 120 min (3,32±1,76 in off-pump group and 2,48±1,12 in CPB group, p=0,005) and 240 min (3,24±2,71 in off-pump group and 2,23±2,48 in CPB group, p=0,0212) after the beginning of surgery. Measured plasmatic concentration was higher than predicted in two groups, with superior values in off-pump group (p=0,02). T1/2 ß was greater in off-pump group (3,67±1,15 in off-pump group and 1,82±0,5 in CPB group, p=0,0005) and total clearance was higher in CPB group (28,36±11,40 in CPB group and 18,29±7,67 in off-pump group, p=0,03). Hypnosis degree was greater in CPB group. Hemodynamics parameters did not differ between the groups. In conclusion, CPB causes alterations on pharmacokinetics and under propofol plasmatic concentration with higher hypnosis degree when compared with patients undergoing coronary artery bypass grafting surgery without CPB (off-pump group)

A circulação extracorpórea (CEC) pode alterar a concentração plasmática prevista para fármacos administrados durante a anestesia. Os objetivos deste estudo foram avaliar os efeitos da CEC sobre a farmacocinética, farmacodinâmica e as concentrações plasmáticas do propofol em pacientes submetidos à cirurgia de revascularização miocárdica (RM) com ou sem utilização de CEC, correlacionando-se às concentrações plasmáticas obtidas com as previstas por infusão contínua alvo-controlada. Dez pacientes submetidos à RM com CEC (Grupo CEC) e dez sem CEC (Grupo sem CEC) foram comparados em relação à concentração plasmática obtida, utilizando-se cromatografia líquida de alta eficiência e aquela prevista por infusão alvo-controlada, em relação à farmacocinética (t1/2ß, volume de distribuição e clearance plasmático), ao grau de hipnose (índice bispectral) e aos parâmetros hemodinâmicos (pressão arterial média e freqüência cardíaca), avaliados nos períodos intra-operatório e pós-operatório imediato. Os dados foram avaliados pela análise de variância para medidas repetidas, considerando-se significativo p < 0,05. A concentração obtida de propofol foi maior no grupo sem CEC nos momentos 120 min (3,32±1,76 no grupo sem CEC e 2,48±1,12 no grupo CEC, p=0,005) e 240 min (3,24±2,71 no grupo sem CEC e 2,23±2,48 no grupo CEC, p=0,0212) após o início da cirurgia. A concentração medida de propofol foi maior que a prevista nos 2 grupos, com valores superiores no grupo sem CEC (p=0,02). O t1/2 ß foi maior no grupo sem CEC (3,67±1,15 grupo sem CEC e 1,82±0,5 no grupo CEC, p=0,0005) e o clearance plasmático maior no grupo CEC (28,36±11,40 no grupo CEC e 18,29±7,67 no grupo sem CEC, p=0,03). O grau de hipnose foi superior no grupo CEC. Os grupos não diferiram quanto à análise hemodinâmica. Conclui-se que a CEC promove alterações na farmacocinética e nas concentrações plasmáticas de propofol, com conseqüente diferença no grau de hipnose em relação aos pacientes submetidos à revascularização do miocárdio sem utilização de CEC / Cardiopulmonary bypass (CPB) can alter predicted plasmatic concentration of drugs administered during anesthesia. The aim of this study was evaluate the effects of cardiopulmonary bypass under pharmacokinetics, pharmacodynamics and plasmatic concentration of propofol in patients undergoing coronary artery bypass grafting surgery (CABG) with or without CPB, comparing measured plasmatic concentration with predicted concentration administered by target-controlled infusion. Ten patients undergoing coronary artery bypass grafting surgery with CPB (CPB Group, n=10) and ten without CPB (off-pump Group, n=10) were compared in relaction to measured plasmatic concentration using high performance liquid chromatography (HPLC) and predicted concentration administered by target-controlled infusion, pharmacokinetics (t1/2 ß, volume of distribution and total clearance), hypnosis degree (bispectral index) and hemodynamics parameters (mean arterial pressure and heart rate) during and after surgery. Statistical analysis was done using analysis of variance for repeated measures (*p < 0,05). Measured plasmatic concentration was higher in off-pump group in the moments 120 min (3,32±1,76 in off-pump group and 2,48±1,12 in CPB group, p=0,005) and 240 min (3,24±2,71 in off-pump group and 2,23±2,48 in CPB group, p=0,0212) after the beginning of surgery. Measured plasmatic concentration was higher than predicted in two groups, with superior values in off-pump group (p=0,02). T1/2 ß was greater in off-pump group (3,67±1,15 in off-pump group and 1,82±0,5 in CPB group, p=0,0005) and total clearance was higher in CPB group (28,36±11,40 in CPB group and 18,29±7,67 in off-pump group, p=0,03). Hypnosis degree was greater in CPB group. Hemodynamics parameters did not differ between the groups. In conclusion, CPB causes alterations on pharmacokinetics and under propofol plasmatic concentration with higher hypnosis degree when compared with patients undergoing coronary artery bypass grafting surgery without CPB (off-pump group)

In cell culture, the cellular responses on Day 6 and Day 18, and matrix mineralization (Day 35) of human periosteal cells after stimulated by ESW, LIPUS and ESW+LIPUS treatments were studied. Our results showed that LIPUS only exerted transiently beneficial effects on Day 6, but no effect was observed on Day 18. In contrast, ESW inhibited the differentiation on Day 6, and then exerted a time-delayed stimulation effect on cellular response and matrix mineralization. Data of the ESW+LIPUS showed that it was mainly under ESW effects, but LIPUS might impact the beneficial effect of ESW on Day 18, leading to reduced ALP and matrix mineralization. The potentials of the osteocytes to function as mechanosensors and signal relay were also investigated with untreated periosteal cells that separately received conditioned medium from MLO-Y4 osteocyte-like cells, which received the ESW LIPUS and ESW+LIPUS treatments. The periosteal cells showed stimulated proliferation in the ESW+LIPUS and ESW groups, indicating that the stimulus of ESW was transferred in the conditioned medium. / In conclusion, although our in vivo and in vitro findings did not support our hypothesis of the beneficial effects of combined treatment, but ESW had been shown to improve BMD and bone microarchitecture in osteoporotic bone, by stimulation of osteogenic activities in osseous cells. ESW might potentially be developed as treatment for osteoporosis. Our study also indicated that stimulation of osteogenic activities may be the direct interaction of ESW on osteoblast/periosteal cells, or indirectly through biochemical signals relayed by the osteocytes which acted as mechanosensors. / Osteoporosis is a bone disorder with decreased bone mass and deteriorated microarchitecture, leading to increased fracture risk. By using non-invasive biophysical interventions that stimulate osteogenesis, i.e. extracorporeal shockwave (ESW) and low-intensity pulsed ultrasound (LIPUS), may reduce bone loss effectively. We hypothesized that the combined treatment of ESW and LIPUS might produce synergistic effects on osteoporotic bone. The aim of this study was to investigate the efficacy of using ESW treatment alone and combined treatment of ESW and LIPUS to increase bone mineral acquisition on intact osteoporotic bone in vivo, and to investigate their underlying mechanisms in vitro. / Ten osteoporotic goats were used and divided into ESW and ESW+LIPUS groups (n=5). The ESW group received shockwave at calcaneus, distal radius, and femoral condyle on the left limbs once per month. The ESW+LIPUS group also received ESW treatment monthly and LIPUS for 6 day/week. The opposite limbs served as contralateral control. After nine months, percentage BMD changes, mineral apposition rate, trabecular thickness in treatment sites were found higher than that of controls in both groups. Cumulatively increase of serum bone-specific alkaline phosphatase indicated that the improvements were due to the increased osteogenic activities in bone. Of all parameter, no significant difference was found between the ESW+LIPUS and ESW groups. / by Tam Kam Fai. / "August 2006." / Adviser: Kwok Sui Leung. / Source: Dissertation Abstracts International, Volume: 68-03, Section: B, page: 1550. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2006. / Includes bibliographical references (p. 156-184). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstracts in English and Chinese. / School code: 1307.

Introdução: O monitoramento plasmático e a avaliação farmacocinética são importantes ferramentas empregadas no controle terapêutico. O sufentanil é responsável pela estabilização hemodinâmica do paciente com melhor supressão da resposta neuroendócrina comparado ao seu análogo o fentanil. Este fármaco tem sido largamente utilizado em cirurgias cardíacas devido também, a sua menor meia vida plasmática em relação ao fentanil o que permite uma rápida recuperação cirúrgica de pacientes submetidos a tais procedimentos. Objetivo: Realizar o monitoramento plasmático do sufentanil em pacientes submetidos à cirurgia cardíaca com e sem circulação extracorpórea (CEC) e posteriormente avaliar a farmacocinética do mesmo. Casuística: Investigaram-se 42 pacientes de ambos os sexos, portadores de insuficiência coronária crônica e candidatos à cirurgia eletiva de revascularização do miocárdio com ou sem circulação extracorpórea, internados na enfermaria clínica do Instituto do Coração do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo. Métodos - Etapa Clínica: Os pacientes inclusos neste estudo foram preparados para a realização do procedimento cirúrgico. Na indução da anestesia administrou-se 0,5 &#181;g/Kg de sufentanil através de bolus, seguido de infusão de manutenção de 0,5 &#181;g/Kg-h. Coletaram-se amostras seriadas de sangue no intra-operatório pós-indução e no pós operatório até 36 h após administração do sufentanil. A infusão de sufentanil foi suspensa no momento do término da sutura da pele. O plasma foi separado e transferido para tubos de polietileno devidamente identificados e armazenados em temperatura - 20 ºC até a realização da análise. Métodos - Etapa Analítica: As concentrações plasmáticas foram determinadas através do método desenvolvido e validado por cromatografia líquida acoplada a espectrometria de Massas (LC-MS/MS). As amostras biológicas foram extraídas através de extração líquido-líquido em meio alcalino as quais foi adicionado fentanil como padrão interno. A separação cromatográfica foi obtida através de uma coluna C18 e fase móvel constituída por acetonitrila:acetato de amônio 5 mM + ácido fórmico 0,25% (70:30 v/v). O espectrômetro triplo quadro pólo, eletrospray positivo, monitorou as transições de massa entre 387,0>238,0, 285,7>165,1 e 337,0>188,0, para sufentanil, morfina e fentanil respectivamente. Métodos - Etapa Estatística: A modelagem farmacocinética foi realizada através da aplicação do software NonCompartmental Analysis, PK Solutions 2.0. O índice de significância empregado foi de 5% (p<0,05). Utilizou-se o teste Qui-quadrado para avaliação da distribuição do gênero e o teste t-student para os parâmetros idade, peso, altura e IMC. Para os dados de concentração plasmática foi utilizado o teste não paramétrico de Friedman seguido do teste post-hoc de Dunn\'s para comparação dos momentos da cirurgia do grupo que foi submetido a CEC. Para comparação dos momentos entre os grupos (submetido a CEC versus sem CEC) aplicou-se o teste de Wilcoxon. Resultados: Os pacientes cirúrgicos incluídos no protocolo eram adultos de ambos os sexos 9F/33M, com média de idade de 62,48 anos, 68,66 kg e IMC de 25,52 kg/m2. Destes, 30 pacientes referem-se ao Grupo com CEC e 12 são do grupo sem CEC. As doses totais médias de sufentanil administradas ao grupo com CEC e ao grupo sem CEC foram semelhantes, 3,23 ±0,67&#181;g/kg e 3,53 ±0,90&#181;g/kg respectivamente. O método analítico proposto apresentou-se linear no intervalo entre 0,05 - 500 ng/mL para o sufentanil e 10 - 1000 ng/mL para a morfina. Os dados obtidos na validação do método apresentaram especificidade, linearidade, robustez, precisão e exatidão. As concentrações plasmáticas obtidas forma estatisticamente diferentes entre os grupos com CEC e sem CEC. Durante o procedimento de circulação extra-corpórea foi observada intensa flutuação das concentrações plasmáticas de sufentanil. Foi aplicado o modelo tri-compartimental na avaliação cinética do sufentanil. Foram determinados os seguintes parâmetros farmacocinéticos: meia-vida de eliminação (t1/2), alfa (&#945;), beta (&#946;) e gama (&#947;), área sob a curva (ASC), volume de distribuição (VD) e a depuração plasmática total (Cl). Destes, apenas T1/2 (&#947;) apresentou diferença significativa entre os grupos. Conclusões: O método proposto foi empregado satisfatoriamente na avaliação cinética do sufentanil. O protocolo realizado e os limites de quantificação do método analítico desenvolvido oportunizaram o emprego do modelo farmacocinético tricompartimental para o fármaco estudado. As concentrações plasmáticas de sufentanil foram afetadas pela CEC o que implicou na diferença significativa entre as meia-vida de eliminação &#947; calculadas para os grupos com CEC e sem CEC. / Introduction: The plasma monitoring and the pharmacokinetic assessment are important tools employed in therapeutic control. Sufentanil is responsible for the hemodynamic stabilization of the patient with a better suppression of the neuroendocrine response compared to its analogue fentanyl. This pharmaco has been widely used in cardiac surgery also due to its shorter plasma half-life in relation to fentanyl, which allows a fast surgical recovery of patients who have undergone such procedures. Objectives: Perform the plasma monitoring of sufentanil in patients undergoing cardiac surgery with or without extracorporeal circulation and afterwards assess the pharmacokinetics of it. Study design: 42 patients of both genders with chronic coronary disease and candidates to elective surgery of myocardial revascularization with or without extracorporeal circulation were investigated. They were hospitalized in the clinical ward of the Heart Institute Hospital of the Medicine Faculty Clinic of the University of São Paulo. Methods- Clinical phase: the patients included in this study were prepared for the performance of the surgical procedure. In the anesthesia induction 0,5 &#181;g/Kg was administered through bolus, followed by maintenance infusion 0,5 &#181;g/Kg-h. Serial blood samples were collected in the intra-operatory after induction and in the pos-toperatory after 36 h of administration of sufentanil. Sufentanil infusion was suspended just as the skin suture was finished. The plasma was separated and transferred to the identified polyethylene test-tube and stored in a temperature -20ºC until the analyses. Methods - Analytical phase: The plasma concentrations were determined through the developed method and validated by liquid chromatography mass spectrometry (LC-MS/MS). The biological samples were extracted through liquid-liquid extraction in alkaline mean, to which fentanyl was added as an internal pattern. The chromatographic separation was obtained through a C18 column and the mobile phase constituted by acetonitrile: 5 mM ammonia acetate + 0,25% formic acid (70:30 v/v). The triple-quad pole spectrometry, positive electrospray, monitored the mass transitions among 387.0>238.0, 285.7>165.1 and 337.0>188.0, for sufentanil, morphine and fentanyl , respectively. Methods - Statistical phase: The pharmacokinetic modeling was performed through the application of the software NonCompartmental Analysis, PK Solutions 2.0. The significance index employed was 5% (p<0,05). The qui-square test was used for the assessment of gender distribution and the t-student test for the age, weight, height and IMC parameters. The nonparametric test of Friedman was used for the plasma concentration, followed by Dunn´s post-hoc test for the comparison of the surgery moments of the group that was submitted to extracorporeal circulation. The test Wilcoxon was applied for the comparison of the moments between the groups (submitted to extracorporeal circulation versus without extracorporeal circulation). Results: The surgical patients included in the protocol were adults of both genders 9F/33M, with an average age of 62.48 years old, 68.66 kg and IMC of 25.52 kg/m2. 30 patients are from the group with extracorporeal circulation and 12 are from the group without extracorporeal circulation. The average total doses of sufentanil administered to the group with extracorporeal circulation and to the group without extracorporeal circulation were similar, 3.23 ±0.67&#181;g/kg and 3.53 ±0.90&#181;g/kg respectively. The analytical method proposed proved linear in the interval between 0.05 - 500 ng/mL for sufentanil and 10 - 1000 ng/mL for morphine. The data obtained in the validation proved specificity, linearity, robustness, precision and accuracy. The plasma concentrations obtained were statistically different between the groups with extracorporeal circulation and without extracorporeal circulation. During the extracorporeal circulation procedure an intense fluctuation was observed in the plasma concentration of sufentanil. The tri-compartmental model was applied in the kinetic assessment of sufentanil. The following pharmacokinetic parameters were determined: half-life elimination (t1/2), alpha (&#945;), beta (&#946;) and gamma (&#947;), area under the curve, distribution volume and the total plasma depuration. Only T1/2 (&#947;) presented a significant difference between the groups. Conclusions: The proposed method was satisfactorily employed in the kinetic assessment of sufentanil. The protocol carried out and the quantification limits of the analytical method developed opportunized the employment of the tri-compartmental pharmacokinetic model for the pharmaco studied. The plasma concentrations of sufentanil were affected by the extracorporeal circulation, which implied in the meaningful difference between the elimination half-life &#947; calculated for the groups with extracorporeal circulation and without extracorporeal circulation.

Conclusion This series of investigations demonstrated how we can apply our knowledge to improve the treatment outcome of ESWL. Based on clinical information, such as age, suitable candidates for ESWL can be identified, and hence better application of ESWL can be achieved. With an understanding of the benefits and limitations of imaging (NCCT and intravenous urography), treatment success can be predicted, and better treatment plans for patients can be formulated. A policy of more liberal use of analgesia during ESWL can also help to improve the treatment outcomes of patients. Finally, with the use of different assessment methods, the true impact of various new technologies or treatment protocols can be assessed, and the results can lead to better understanding of ESWL and also improvement in the treatment outcomes. / Materials and Methods In a retrospective review of treatment information of 2192 patients, the effect of age on stone-free rates after ESWL was assessed. Next, in a prospective study, the role of stone parameter, measured using non-contrast computerized tomography (NCCT), in predicting the treatment outcomes of upper ureteric stones was examined. The general applicability of caliceal pelvic height (CPH) in determining the treatment outcomes for lower caliceal stones for three different lithotriptors was assessed in the third study. In another retrospective comparative study, the effect on treatment outcomes of additional usage of intravenous analgesic during ESWL, as compared to oral analgesic premedication alone, was analyzed. Finally, the feasibility of the use of two statistical methods, logistic regression and matched-pair analysis, in comparing the treatment results of different lithotriptors was investigated. / Objectives Despite the initial success of extracorporeal shock wave lithotripsy (ESWL), the performance of the contemporary machines has never been as good as that of the first-generation machine. Therefore, a series of studies was conducted to advance the current knowledge of ESWL and investigate possible ways to further optimize the treatment outcomes. / Results We found that the stone-free rate after ESWL for older patients with renal stones, but not for those with ureteric stones, was significantly lower than that of younger patients. Stone parameters measured using NCCT, namely, mean stone density, stone volume, and skin-to-stone distance, were significant predictive factors for successful ESWL for upper ureteric stones. However, caliceal pelvic height, measured by intravenous urography, was a significant predictor of treatment outcomes of lower caliceal stones for only the Piezolith 2300 lithotriptor, and not the other two types of lithotriptors. The additional usage of intravenous analgesic improved the effectiveness quotient and hence treatment outcomes of ESWL. Finally, both logistic regression and matched-pair analysis were found to be feasible approaches for the comparison of the performance of different lithotriptors. / Chi-Fai Ng. / Source: Dissertation Abstracts International, Volume: 73-02, Section: B, page: . / Thesis (M.D.)--Chinese University of Hong Kong, 2010. / Includes bibliographical references (leaves 224-243). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [201-] System requirements: Adobe Acrobat Reader. Available via World Wide Web.

Made available in DSpace on 2014-06-11T19:31:06Z (GMT). No. of bitstreams: 0 Previous issue date: 2010-02-22Bitstream added on 2014-06-13T19:40:58Z : No. of bitstreams: 1 francischetti_i_dr_botfm.pdf: 3036523 bytes, checksum: 16d5951b642a829416e73e1b1c9c6644 (MD5) / O uso da circulação extracorpórea desencadeia uma resposta inflamatória sistêmica, que somada às reações em cadeia relacionadas à isquemia-reperfusão de coração e pulmões pode levar a lesões celulares e até falência de órgãos no pós-operatório de cirurgia cardíaca. Vários estudos foram feitos visando melhor entendimento desses processos inflamatórios associados à circulação extracorpórea. Assim, esta revisão abordará os mecanismos de isquemia-reperfusão cardiopulmonar a ativação da cascata inflamatória por esse processo e o papel dos leucócitos na fisiopatologia destas lesões. Serão consideradas as interações de proteínas imunomoduladoras na resposta leucocitária e o bloqueio das mesmas por meio de filtros biológicos, do uso de anticorpos monoclonais e do estímulo à apoptose. / The use of extracorporeal circulation starts a whole body inflammatory response that when added with a chain reactions related to heart and lung ischemia-reperfusion may cause cellular injuries and organ failures in the cardiac surgery pos-operative period. Many studies were made to achieve better comprehension of the inflammatory process that occur with use of extracorporeal circulation. So, this review discusses the ischemia- reperfusion events, their large activated inflammatory cascade as well as the leukocytes role on the pathophysiology of their associated injuries. The interactions of immunomodulatory proteins with the leukocitary response and their blockade through leukocytes filters, the monoclonal antibody use and the apoptosis stimuli will be approached too.

Made available in DSpace on 2014-06-11T19:31:06Z (GMT). No. of bitstreams: 0 Previous issue date: 2009-05-27Bitstream added on 2014-06-13T21:02:10Z : No. of bitstreams: 1 pyles_md_dr_botfmvz.pdf: 1285768 bytes, checksum: c7e043fd85c25b169c8a9bb3a6e24772 (MD5) / Universidade Estadual Paulista (UNESP) / O objetivo deste estudo foi avaliar os efeitos da aplicação de ondas de choque extracorpóreas no osso terceiro metacarpiano de equinos hígidos através da determinação da elasticidade óssea. Para tanto, foram utilizados 20 equinos da raça Puro Sangue Inglês, machos e fêmeas, com dois anos de idade, clinicamente sadios e em início de treinamento, sendo selecionados quanto ao estado de higidez com especial atenção quanto à integridade do aparelho locomotor. No D0, dia zero do experimento, todos os animais foram submetidos à avaliação da elasticidade óssea realizada no osso terceiro metacarpiano. Os animais foram divididos aleatoriamente em dois grupos de dez animais em cada (Grupo Controle e Grupo Tratamento). A aplicação da terapia com ondas de choque extracorpóreas (ESWT) foi realizada no membro torácico direito dos animais do Grupo Tratamento, na região coincidente à da avaliação da elasticidade óssea e para tanto foi utilizado aparelho para terapia de ondas extracorpóreas com densidade de fluxo de energia de 0,15 mJ/mm2 e 2000 pulsos com sonda E6R20, com a característica do foco da onda de choque de 20mm. As aplicações da ESWT foram repetidas a cada 21 dias totalizando três sessões (D0, D21 e D42). A análise da determinação da elasticidade óssea, além do D0, foi realizada no 21o dia após a primeira aplicação, no 21o dia após a segunda aplicação e no 30o dia após a terceira aplicação de ESWT (D21, D42 e D72). A média da velocidade ultrassonográfica (SOS) diferiu entre os grupos no D21, D42 e D72, sendo que os animais do Grupo Tratamento apresentaram menor densidade mineral óssea após as aplicações da ESWT. Houve diferença também à análise da massa óssea (Z-Score) entre os grupos no D21 e D42, quando... / The purpose of this study was to evaluate the effects of extracorporeal shock waves in third metacarpus bone from healthy horses by determination of bone elasticity. It were used 20 Thoroughbred horses, male and female, with two years old, clinically healthy and on top of training, selected as healthy state and special attention on the integrity of the locomotor system. At D0, day zero of the experiment, all animals were submitted to evaluation of bone elasticity held in the third metacarpus bone. The animals were randomly divided into two groups of ten animals (Control Group and Treatment Group). The application of extracorporeal shock wave therapy (ESWT) was performed on the right forelimb of the animals in the Treatment group in the same location evaluated for bone elasticity and extracorporeal therapy of waves was applied with 0.15mJ/mm2 energy flux density and 2000 pulses with E6R20 probe, with focus feature of the shock wave of 20mm. The applications of ESWT were repeated every 21 days, a total of three sessions (D0, D21 and D42). The analysis of bone elasticity determination was realized at D21, D42 and D72. The average speed ultrasound (SOS) differed between groups at D21, D42 and D72, and the animals from treatment group had lower bone mineral density after applications of ESWT. There was also difference in the analysis of bone mass (Z-Score) between the groups at D21 and D42, where animals from treatment group showed a significant decrease in bone mass. The risk of fracture were higher in animals from treatment group at D21. It was concluded that ESWT is able to promote change in bone mineral density.

Orientador: Winston Bonetti Yoshida / Banca: Carlos Eli Piccinato / Banca: Marcone Lima Sobreira / Banca: Ana Terezinha Guilaumon / Banca: Valter Castelli / Resumo: O uso da circulação extracorpórea desencadeia uma resposta inflamatória sistêmica, que somada às reações em cadeia relacionadas à isquemia-reperfusão de coração e pulmões pode levar a lesões celulares e até falência de órgãos no pós-operatório de cirurgia cardíaca. Vários estudos foram feitos visando melhor entendimento desses processos inflamatórios associados à circulação extracorpórea. Assim, esta revisão abordará os mecanismos de isquemia-reperfusão cardiopulmonar a ativação da cascata inflamatória por esse processo e o papel dos leucócitos na fisiopatologia destas lesões. Serão consideradas as interações de proteínas imunomoduladoras na resposta leucocitária e o bloqueio das mesmas por meio de filtros biológicos, do uso de anticorpos monoclonais e do estímulo à apoptose. / Abstract: The use of extracorporeal circulation starts a whole body inflammatory response that when added with a chain reactions related to heart and lung ischemia-reperfusion may cause cellular injuries and organ failures in the cardiac surgery pos-operative period. Many studies were made to achieve better comprehension of the inflammatory process that occur with use of extracorporeal circulation. So, this review discusses the ischemia- reperfusion events, their large activated inflammatory cascade as well as the leukocytes role on the pathophysiology of their associated injuries. The interactions of immunomodulatory proteins with the leukocitary response and their blockade through leukocytes filters, the monoclonal antibody use and the apoptosis stimuli will be approached too. / Doutor

Introdução: O monitoramento plasmático e a avaliação farmacocinética são importantes ferramentas empregadas no controle terapêutico. O sufentanil é responsável pela estabilização hemodinâmica do paciente com melhor supressão da resposta neuroendócrina comparado ao seu análogo o fentanil. Este fármaco tem sido largamente utilizado em cirurgias cardíacas devido também, a sua menor meia vida plasmática em relação ao fentanil o que permite uma rápida recuperação cirúrgica de pacientes submetidos a tais procedimentos. Objetivo: Realizar o monitoramento plasmático do sufentanil em pacientes submetidos à cirurgia cardíaca com e sem circulação extracorpórea (CEC) e posteriormente avaliar a farmacocinética do mesmo. Casuística: Investigaram-se 42 pacientes de ambos os sexos, portadores de insuficiência coronária crônica e candidatos à cirurgia eletiva de revascularização do miocárdio com ou sem circulação extracorpórea, internados na enfermaria clínica do Instituto do Coração do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo. Métodos - Etapa Clínica: Os pacientes inclusos neste estudo foram preparados para a realização do procedimento cirúrgico. Na indução da anestesia administrou-se 0,5 &#181;g/Kg de sufentanil através de bolus, seguido de infusão de manutenção de 0,5 &#181;g/Kg-h. Coletaram-se amostras seriadas de sangue no intra-operatório pós-indução e no pós operatório até 36 h após administração do sufentanil. A infusão de sufentanil foi suspensa no momento do término da sutura da pele. O plasma foi separado e transferido para tubos de polietileno devidamente identificados e armazenados em temperatura - 20 ºC até a realização da análise. Métodos - Etapa Analítica: As concentrações plasmáticas foram determinadas através do método desenvolvido e validado por cromatografia líquida acoplada a espectrometria de Massas (LC-MS/MS). As amostras biológicas foram extraídas através de extração líquido-líquido em meio alcalino as quais foi adicionado fentanil como padrão interno. A separação cromatográfica foi obtida através de uma coluna C18 e fase móvel constituída por acetonitrila:acetato de amônio 5 mM + ácido fórmico 0,25% (70:30 v/v). O espectrômetro triplo quadro pólo, eletrospray positivo, monitorou as transições de massa entre 387,0>238,0, 285,7>165,1 e 337,0>188,0, para sufentanil, morfina e fentanil respectivamente. Métodos - Etapa Estatística: A modelagem farmacocinética foi realizada através da aplicação do software NonCompartmental Analysis, PK Solutions 2.0. O índice de significância empregado foi de 5% (p<0,05). Utilizou-se o teste Qui-quadrado para avaliação da distribuição do gênero e o teste t-student para os parâmetros idade, peso, altura e IMC. Para os dados de concentração plasmática foi utilizado o teste não paramétrico de Friedman seguido do teste post-hoc de Dunn\'s para comparação dos momentos da cirurgia do grupo que foi submetido a CEC. Para comparação dos momentos entre os grupos (submetido a CEC versus sem CEC) aplicou-se o teste de Wilcoxon. Resultados: Os pacientes cirúrgicos incluídos no protocolo eram adultos de ambos os sexos 9F/33M, com média de idade de 62,48 anos, 68,66 kg e IMC de 25,52 kg/m2. Destes, 30 pacientes referem-se ao Grupo com CEC e 12 são do grupo sem CEC. As doses totais médias de sufentanil administradas ao grupo com CEC e ao grupo sem CEC foram semelhantes, 3,23 ±0,67&#181;g/kg e 3,53 ±0,90&#181;g/kg respectivamente. O método analítico proposto apresentou-se linear no intervalo entre 0,05 - 500 ng/mL para o sufentanil e 10 - 1000 ng/mL para a morfina. Os dados obtidos na validação do método apresentaram especificidade, linearidade, robustez, precisão e exatidão. As concentrações plasmáticas obtidas forma estatisticamente diferentes entre os grupos com CEC e sem CEC. Durante o procedimento de circulação extra-corpórea foi observada intensa flutuação das concentrações plasmáticas de sufentanil. Foi aplicado o modelo tri-compartimental na avaliação cinética do sufentanil. Foram determinados os seguintes parâmetros farmacocinéticos: meia-vida de eliminação (t1/2), alfa (&#945;), beta (&#946;) e gama (&#947;), área sob a curva (ASC), volume de distribuição (VD) e a depuração plasmática total (Cl). Destes, apenas T1/2 (&#947;) apresentou diferença significativa entre os grupos. Conclusões: O método proposto foi empregado satisfatoriamente na avaliação cinética do sufentanil. O protocolo realizado e os limites de quantificação do método analítico desenvolvido oportunizaram o emprego do modelo farmacocinético tricompartimental para o fármaco estudado. As concentrações plasmáticas de sufentanil foram afetadas pela CEC o que implicou na diferença significativa entre as meia-vida de eliminação &#947; calculadas para os grupos com CEC e sem CEC. / Introduction: The plasma monitoring and the pharmacokinetic assessment are important tools employed in therapeutic control. Sufentanil is responsible for the hemodynamic stabilization of the patient with a better suppression of the neuroendocrine response compared to its analogue fentanyl. This pharmaco has been widely used in cardiac surgery also due to its shorter plasma half-life in relation to fentanyl, which allows a fast surgical recovery of patients who have undergone such procedures. Objectives: Perform the plasma monitoring of sufentanil in patients undergoing cardiac surgery with or without extracorporeal circulation and afterwards assess the pharmacokinetics of it. Study design: 42 patients of both genders with chronic coronary disease and candidates to elective surgery of myocardial revascularization with or without extracorporeal circulation were investigated. They were hospitalized in the clinical ward of the Heart Institute Hospital of the Medicine Faculty Clinic of the University of São Paulo. Methods- Clinical phase: the patients included in this study were prepared for the performance of the surgical procedure. In the anesthesia induction 0,5 &#181;g/Kg was administered through bolus, followed by maintenance infusion 0,5 &#181;g/Kg-h. Serial blood samples were collected in the intra-operatory after induction and in the pos-toperatory after 36 h of administration of sufentanil. Sufentanil infusion was suspended just as the skin suture was finished. The plasma was separated and transferred to the identified polyethylene test-tube and stored in a temperature -20ºC until the analyses. Methods - Analytical phase: The plasma concentrations were determined through the developed method and validated by liquid chromatography mass spectrometry (LC-MS/MS). The biological samples were extracted through liquid-liquid extraction in alkaline mean, to which fentanyl was added as an internal pattern. The chromatographic separation was obtained through a C18 column and the mobile phase constituted by acetonitrile: 5 mM ammonia acetate + 0,25% formic acid (70:30 v/v). The triple-quad pole spectrometry, positive electrospray, monitored the mass transitions among 387.0>238.0, 285.7>165.1 and 337.0>188.0, for sufentanil, morphine and fentanyl , respectively. Methods - Statistical phase: The pharmacokinetic modeling was performed through the application of the software NonCompartmental Analysis, PK Solutions 2.0. The significance index employed was 5% (p<0,05). The qui-square test was used for the assessment of gender distribution and the t-student test for the age, weight, height and IMC parameters. The nonparametric test of Friedman was used for the plasma concentration, followed by Dunn´s post-hoc test for the comparison of the surgery moments of the group that was submitted to extracorporeal circulation. The test Wilcoxon was applied for the comparison of the moments between the groups (submitted to extracorporeal circulation versus without extracorporeal circulation). Results: The surgical patients included in the protocol were adults of both genders 9F/33M, with an average age of 62.48 years old, 68.66 kg and IMC of 25.52 kg/m2. 30 patients are from the group with extracorporeal circulation and 12 are from the group without extracorporeal circulation. The average total doses of sufentanil administered to the group with extracorporeal circulation and to the group without extracorporeal circulation were similar, 3.23 ±0.67&#181;g/kg and 3.53 ±0.90&#181;g/kg respectively. The analytical method proposed proved linear in the interval between 0.05 - 500 ng/mL for sufentanil and 10 - 1000 ng/mL for morphine. The data obtained in the validation proved specificity, linearity, robustness, precision and accuracy. The plasma concentrations obtained were statistically different between the groups with extracorporeal circulation and without extracorporeal circulation. During the extracorporeal circulation procedure an intense fluctuation was observed in the plasma concentration of sufentanil. The tri-compartmental model was applied in the kinetic assessment of sufentanil. The following pharmacokinetic parameters were determined: half-life elimination (t1/2), alpha (&#945;), beta (&#946;) and gamma (&#947;), area under the curve, distribution volume and the total plasma depuration. Only T1/2 (&#947;) presented a significant difference between the groups. Conclusions: The proposed method was satisfactorily employed in the kinetic assessment of sufentanil. The protocol carried out and the quantification limits of the analytical method developed opportunized the employment of the tri-compartmental pharmacokinetic model for the pharmaco studied. The plasma concentrations of sufentanil were affected by the extracorporeal circulation, which implied in the meaningful difference between the elimination half-life &#947; calculated for the groups with extracorporeal circulation and without extracorporeal circulation.