In der vorliegenden prospektiven Studie wurde der postoperative Krankheitsverlauf von 93 Hündinnen mit Mammatumoren untersucht. Ziel der Studie war es, eine präoperative Einschätzung der Dignität der Tumoren und der Prognose für die Hündin anhand der Relaxin-Plasmakonzentration zu gewinnen. In einer humanmedizinischen Studie konnte gezeigt werden, dass an Brustkrebs erkrankte Frauen mit einer hohen Relaxin-Plasmakonzentration häufiger an einem malignen Tumor erkrankt sind, der Tumor häufiger bereits metastasiert hatte und die Frauen früher starben. Der Kastrationsstatus (p = 0,132), eine hormonelle Läufigkeitsunterdrückung (p = 0,960), vorausgegangene Graviditäten (p = 0,780) und das Auftreten von Pseudograviditäten (p = 0,138) bei den an Mammatumoren erkrankten Hündinnen hatten keinen Einfluss auf die präoperativ bestimmte Relaxin-Plasmakonzentration. An Mammatumoren erkrankte Hündinnen und gesunde Kontrolltiere hatten keine unterschiedlichen Relaxin-Plasmakonzentrationen (p = 0,813). Die Relaxin-Plasma-konzentrationen von Hündinnen mit einer Herzerkrankung aus der Patientengruppe waren identisch mit denen der herzgesunden Hündinnen aus der Kontrollgruppe (p = 0,328). Innerhalb der Patientengruppe war es hinsichtlich der gemessenen Relaxin-Plasmakonzentration unerheblich, ob die Hündinnen einerseits an einem solitären oder an multiplen Mammatumoren erkrankt waren (p = 0,470), oder ob andererseits bei ihnen einseitig oder beidseitig Mammatumoren feststellbar waren (p = 0,371). Weder die Tumorgröße (p = 0,518) noch eine Ulzeration (p = 0,746) wirkten sich auf die Relaxin-Plasmakonzentration aus. Das Vorliegen von Nahmetastasen (p = 0,131) oder eines malignen Mammatumors (p = 0,240) führte zu keiner erhöhten Relaxin-Plasmakonzentration. Entsprechend war auch das Stadium der Erkrankung ohne Einfluss auf das gemessene Relaxin (p = 0,829). Im Rahmen der Verlaufsuntersuchung gab es keinen Unterschied zwischen den präoperativ und den sechs Monate postoperativ bestimmten Relaxin-Plasmakonzentrationen (p = 0,983). Weder eine Rezidivierung des Mammatumors (p = 0,084) noch eine Metastasierung des Tumors in die Lunge sechs Monate postoperativ (p = 0,200) waren anhand der präoperativ bestimmten Relaxin-Plasmakonzentrationen vorhersehbar. Auch lieferte Relaxin keinen Hinweis auf einen Tod infolge der Mammatumoren (p = 0,205). In dieser Arbeit konnte nach Auswertung der vorliegenden Daten kein Hinweis auf die Verwendbarkeit der Relaxin-Plasmakonzentration als prognostischer Marker für an Mammatumoren erkrankte Hündinnen gefunden werden. Es konnte, wie in vorherigen Studien, bestätigt werden, dass Hündinnen mit Tumoren kleiner 3 cm (p = 0,001) und Hündinnen im Stadium I der Erkrankung (p = 0,009, p = 0,022) eine signifikant niedrigere Wahrscheinlichkeit haben innerhalb des ersten Jahres postoperativ an den Folgen des Mammatumors zu versterben als Hündinnen mit größeren Tumoren oder in einem höheren Stadium der Erkrankung. Hündinnen, die an einem ulzerierenden Mammatumor erkrankt waren (p = 0,002) oder bei denen histopathologisch nachweisbare Metastasen in den regionären Lymphknoten vorlagen (p = 0,001), hatten eine signifikant niedrigere Wahrscheinlichkeit das erste postoperative Jahr zu überleben. Die Tiere, bei denen sechs Monate postoperativ Metastasen in der Lunge festgestellt werden konnten (p = 0,001) oder bei denen es zu einer Rezidivierung des Mammatumors kam (p = 0,001), hatten eine sehr hohe Wahrscheinlichkeit innerhalb des ersten postoperativen Jahres zu versterben.

Elevated plasma concentrations of asymmetric dimethylarginine (ADMA) are associated with an increased risk of mortality and adverse cardiovascular outcomes. ADMA can be metabolized by dimethylarginine dimethylaminohydrolases (DDAHs) and by alanine-glyoxylate aminotransferase 2 (AGXT2). Deletion of DDAH1 in mice leads to elevation of ADMA in plasma and increase in blood pressure, while overexpression of human DDAH1 is associated with a lower plasma ADMA concentration and protective cardiovascular effects. The possible role of alternative metabolism of ADMA by AGXT2 remains to be elucidated. The goal of the current study was to test the hypothesis that transgenic overexpression of AGXT2 leads to lowering of plasma levels of ADMA and protection from vascular damage in the setting of DDAH1 deficiency. We generated transgenic mice (TG) with ubiquitous overexpression of AGXT2. qPCR and Western Blot confirmed the expression of the transgene. Systemic ADMA levels were decreased by 15% in TG mice. In comparison with wild type animals plasma levels of asymmetric dimethylguanidino valeric acid (ADGV), the AGXT2 associated metabolite of ADMA, were six times higher. We crossed AGXT2 TG mice with DDAH1 knockout mice and observed that upregulation of AGXT2 lowers plasma ADMA and pulse pressure and protects the mice from endothelial dysfunction and adverse aortic remodeling. Upregulation of AGXT2 led to lowering of ADMA levels and protection from ADMA-induced vascular damage in the setting of DDAH1 deficiency. This is especially important, because all the efforts to develop pharmacological ADMA-lowering interventions by means of upregulation of DDAHs have been unsuccessful.

Pacientes submetidos à revascularização do miocárdio (RM), frequentemente utilizam beta-bloqueadores no pré-operatório para o controle da angina pectoris, e continuam o tratamento após a cirurgia, para a redução de mortalidade e complicações cardiovasculares perioperatórias. Entretanto, a circulação extracorpórea (CEC), empregada na maioria das cirurgias cardíacas, pode alterar as concentrações plasmáticas e a disposição cinética de muitos fármacos, e consequentemente seus efeitos terapêuticos. O atenolol é um beta-bloqueador altamente hidrossolúvel, de absorção incompleta e eliminação renal-dependente. O objetivo deste estudo foi o de investigar a influência da CEC sobre as concentrações plasmáticas do atenolol no intra-operatório de cirurgia cardíaca, além de comparar a sua farmacocinética no pré e pós-operatório de RM com CEC, em pacientes com insuficiência coronariana. Investigou-se ainda, a variabilidade das concentrações plasmáticas do atenolol no período que antecede a cirurgia cardíaca. Na primeira etapa, avaliaram-se 19 pacientes coronarianos, em terapia crônica com atenolol PO, submetidos à cirurgia cardíaca com ou sem CEC. Na segunda parte, investigaram-se os períodos pré e pós-cirúrgico de 7 pacientes submetidos à RM com CEC e tratados com atenolol PO em regime de doses múltiplas. Todos os pacientes investigados apresentavam função renal dentro da normalidade ou leve disfunção renal, decorrente da idade e da insuficiência coronariana. O monitoramento do atenolol plasmático no intra-operatório de RM e o estudo farmacocinético realizado antes e após a revascularização, exigiram coletas de amostras sangüíneas seriadas. A quantificação do atenolol em plasma foi realizada através da cromatografia líquida de alta eficiência com detector de fluorescência e consistiu num procedimento analítico rápido, simples e de baixo custo. Apenas 200 L de plasma foram utilizados em cada análise cromatográfica. O estudo de validação demonstrou que o método desenvolvido apresenta alta linearidade, sensibilidade e seletividade adequadas, alta recuperação, boa precisão e exatidão, além de estabilidade e robustez. Conclui-se que a circulação extracorpórea altera as concentrações do atenolol no intra-operatório de RM, visto que o decaimento das concentrações plasmáticas mostrou-se mais pronunciado na ausência da CEC. Entretanto, apesar das maiores concentrações obtidas ao final da cirurgia com CEC, o atenolol mostra-se seguro, em virtude do baixo acúmulo do fármaco administrado em regime de doses múltiplas. Além disso, a disposição cinética do atenolol permaneceu inalterada, quando os períodos pré e pós-operatórios foram comparados; entretanto, registrou-se uma tendência à normalização do volume de distribuição e da depuração plasmática do atenolol após a revascularização. Adicionalmente, a ausência de correlação entre meia-vida biológica e volume aparente de distribuição sugere que, tanto no pré quanto no pós-operatório, as concentrações do atenolol dependem apenas da sua depuração plasmática. Finalmente, verificou-se que o atenolol apresenta baixa variabilidade inter-pacientes nos regimes posológicos empregados no tratamento da insuficiência coronariana. / Patients submitted to coronary artery bypass grafting (CABG) surgery frequently are using beta-blockers agents for the control of angina pectoris, and continue the treatment after the surgery to reduce the mortality and cardiovascular events. However, the technique of cardiopulmonary bypass (CPB), used in most cardiac surgeries with cardioplegia, causes important changes in the plasma concentrations and pharmacokinetics of many drugs and may also alter their therapeutic effects. Atenolol is a hydrophilic beta-blocker characterized by incomplete absorption, a relatively small volume of distribution and a renal function-dependent elimination. The objective of this study was to investigate the effects of CPB on the plasma concentrations of atenolol during the intra-operative period of cardiac surgery, as well as, to compare the pharmacokinetics of atenolol in the pre and post-operative periods of revascularization with CPB, in patients with coronary insufficiency. In addition, it was investigated the variability of plasma atenolol concentrations before the cardiac surgery. In the first part of the study, it was investigated 19 coronary patients, under chronic therapy with atenolol and submitted to cardiac surgery performed with and without CPB. At the second part, it was evaluated the pre and post-operative periods from 7 patients submitted to the CABG surgery with CPB, who were chronically treated with atenolol in a multiple regimen. All enrolled patients presented normal or slightly reduced renal function as a result of age and underlying disease. A serial blood samples collection was required for monitoring of plasma atenolol concentrations at the intra-operative period and also for pharmacokinetic study at the pre and post-CABG. The quantification of plasma atenolol was performed using high-performance liquid chromatography with fluorescence detection and consisted of a relatively rapid, simple and low-cost analytical procedure. Only 200 µL of plasma was used for each chromatographic analysis. Validation of this analytical method showed high linearity, adequate sensitivity and selectivity, high recovery, good accuracy and precision, in addition to stability and a guarantee of robustness. It was concluded that the CPB changes plasma atenolol concentrations in the intra-operative period, since a marked decrease in plasma atenolol concentrations was observed in patients undergoing cardiac surgery without CPB. Thus, despite the lower decline in plasma levels observed in patients submitted to CPB, atenolol can be used safely, due to the low accumulation of the drug administrated at multiple dose regimens. In addition, pharmacokinetics of atenolol remained unaltered when pre and post-operative periods were compared; although it was observed a tendency of normalization of volume of distribution and plasma clearance of atenolol after the revascularization. Moreover, the lack of correlation between biological half-life and apparent volume of distribution suggests that, in both periods, plasma atenolol concentration only depends on its plasma clearance. Finally, it was verified a small inter-patient variability of atenolol in the dose regimens used for the control of coronary insufficiency.

Pacientes submetidos à revascularização do miocárdio (RM), frequentemente utilizam beta-bloqueadores no pré-operatório para o controle da angina pectoris, e continuam o tratamento após a cirurgia, para a redução de mortalidade e complicações cardiovasculares perioperatórias. Entretanto, a circulação extracorpórea (CEC), empregada na maioria das cirurgias cardíacas, pode alterar as concentrações plasmáticas e a disposição cinética de muitos fármacos, e consequentemente seus efeitos terapêuticos. O atenolol é um beta-bloqueador altamente hidrossolúvel, de absorção incompleta e eliminação renal-dependente. O objetivo deste estudo foi o de investigar a influência da CEC sobre as concentrações plasmáticas do atenolol no intra-operatório de cirurgia cardíaca, além de comparar a sua farmacocinética no pré e pós-operatório de RM com CEC, em pacientes com insuficiência coronariana. Investigou-se ainda, a variabilidade das concentrações plasmáticas do atenolol no período que antecede a cirurgia cardíaca. Na primeira etapa, avaliaram-se 19 pacientes coronarianos, em terapia crônica com atenolol PO, submetidos à cirurgia cardíaca com ou sem CEC. Na segunda parte, investigaram-se os períodos pré e pós-cirúrgico de 7 pacientes submetidos à RM com CEC e tratados com atenolol PO em regime de doses múltiplas. Todos os pacientes investigados apresentavam função renal dentro da normalidade ou leve disfunção renal, decorrente da idade e da insuficiência coronariana. O monitoramento do atenolol plasmático no intra-operatório de RM e o estudo farmacocinético realizado antes e após a revascularização, exigiram coletas de amostras sangüíneas seriadas. A quantificação do atenolol em plasma foi realizada através da cromatografia líquida de alta eficiência com detector de fluorescência e consistiu num procedimento analítico rápido, simples e de baixo custo. Apenas 200 L de plasma foram utilizados em cada análise cromatográfica. O estudo de validação demonstrou que o método desenvolvido apresenta alta linearidade, sensibilidade e seletividade adequadas, alta recuperação, boa precisão e exatidão, além de estabilidade e robustez. Conclui-se que a circulação extracorpórea altera as concentrações do atenolol no intra-operatório de RM, visto que o decaimento das concentrações plasmáticas mostrou-se mais pronunciado na ausência da CEC. Entretanto, apesar das maiores concentrações obtidas ao final da cirurgia com CEC, o atenolol mostra-se seguro, em virtude do baixo acúmulo do fármaco administrado em regime de doses múltiplas. Além disso, a disposição cinética do atenolol permaneceu inalterada, quando os períodos pré e pós-operatórios foram comparados; entretanto, registrou-se uma tendência à normalização do volume de distribuição e da depuração plasmática do atenolol após a revascularização. Adicionalmente, a ausência de correlação entre meia-vida biológica e volume aparente de distribuição sugere que, tanto no pré quanto no pós-operatório, as concentrações do atenolol dependem apenas da sua depuração plasmática. Finalmente, verificou-se que o atenolol apresenta baixa variabilidade inter-pacientes nos regimes posológicos empregados no tratamento da insuficiência coronariana. / Patients submitted to coronary artery bypass grafting (CABG) surgery frequently are using beta-blockers agents for the control of angina pectoris, and continue the treatment after the surgery to reduce the mortality and cardiovascular events. However, the technique of cardiopulmonary bypass (CPB), used in most cardiac surgeries with cardioplegia, causes important changes in the plasma concentrations and pharmacokinetics of many drugs and may also alter their therapeutic effects. Atenolol is a hydrophilic beta-blocker characterized by incomplete absorption, a relatively small volume of distribution and a renal function-dependent elimination. The objective of this study was to investigate the effects of CPB on the plasma concentrations of atenolol during the intra-operative period of cardiac surgery, as well as, to compare the pharmacokinetics of atenolol in the pre and post-operative periods of revascularization with CPB, in patients with coronary insufficiency. In addition, it was investigated the variability of plasma atenolol concentrations before the cardiac surgery. In the first part of the study, it was investigated 19 coronary patients, under chronic therapy with atenolol and submitted to cardiac surgery performed with and without CPB. At the second part, it was evaluated the pre and post-operative periods from 7 patients submitted to the CABG surgery with CPB, who were chronically treated with atenolol in a multiple regimen. All enrolled patients presented normal or slightly reduced renal function as a result of age and underlying disease. A serial blood samples collection was required for monitoring of plasma atenolol concentrations at the intra-operative period and also for pharmacokinetic study at the pre and post-CABG. The quantification of plasma atenolol was performed using high-performance liquid chromatography with fluorescence detection and consisted of a relatively rapid, simple and low-cost analytical procedure. Only 200 µL of plasma was used for each chromatographic analysis. Validation of this analytical method showed high linearity, adequate sensitivity and selectivity, high recovery, good accuracy and precision, in addition to stability and a guarantee of robustness. It was concluded that the CPB changes plasma atenolol concentrations in the intra-operative period, since a marked decrease in plasma atenolol concentrations was observed in patients undergoing cardiac surgery without CPB. Thus, despite the lower decline in plasma levels observed in patients submitted to CPB, atenolol can be used safely, due to the low accumulation of the drug administrated at multiple dose regimens. In addition, pharmacokinetics of atenolol remained unaltered when pre and post-operative periods were compared; although it was observed a tendency of normalization of volume of distribution and plasma clearance of atenolol after the revascularization. Moreover, the lack of correlation between biological half-life and apparent volume of distribution suggests that, in both periods, plasma atenolol concentration only depends on its plasma clearance. Finally, it was verified a small inter-patient variability of atenolol in the dose regimens used for the control of coronary insufficiency.

Magister Pharmaceuticae - MPharm / Many studies have investigated the pharmacokinetics of anti-tuberculosis drugs in patients infected with tuberculosis. However, little is known about the pharmacokinetics of the drugs that are used in the treatment of multi-drug resistant tuberculosis (MDRTB).Therefore, the objective of the present study was to investigate the steady state concentrations and the pharmacokinetics of ofloxacin, one of the drugs used in the treatment of MDR-TB in patients infected with MDR-TB and patients with MDR-TB co-infected with HIV Plasma samples were drawn at different times over 24 hours after ofloxacin oral administration. For the determination of ofloxacin plasma concentrations, the liquid chromatography coupled with mass spectrometry analysis method was used.The method was validated over a concentration range of 0.1-10 μg/ml. The lower limit of ofloxacin detection was 0.05μg/ml, while the lower limit of quantification was 0.1μg/ml. The response was linear over the range used with a mean recovery of 97.6%. Ofloxacin peak was well separated at a retention time of 9.6 minutes.The pharmacokinetic parameters obtained were presented as mean ± standard deviation(SD). The peak concentration of ofloxacin (Cmax) was 4.71± 2.27 μg/ml occurred at Tmax 3±1.29 hours after ofloxacin oral administration. The mean (±SD) for the area under the concentration-time curve (AUC0-24) and the area under the concentration-time curve(AUC0-∞) were 68.8±42.61 μg/ml.hr and 91.93±76.86 μg/ml.hr, respectively. Ofloxacin distributed widely with a mean (±SD) volume of distribution (Vd) 2.77±1.16 L/kg and it was eliminated with a mean (±SD) total clearance rate of 0.27±0.25 L/hr/kg. Ofloxacin mean (±SD) half-life was 9.55± 4.69 hours and mean (±SD) of the mean residence time (MRT) was 1512± 6.59 hours.In summary, compared with the previous findings in the literature, ofloxacin pharmacokinetic was altered in MDR-TB patients with or without HIV co-infection.The AUC and Cmax were reduced, while the half-life and the time to reach the peak concentration were prolonged. This suggests that, both the rate and the extent of ofloxacin absorption were decreased. Furthermore, ofloxacin was highly eliminated in patients, which may be related to the altered liver function in this group of patients.Further studies investigating the effect of HIV, liver and kidney dysfunctions on ofloxacin pharmacokinetics are recommended in large number of patients infected with MDR-TB.in addition to the therapeutic drug monitoring to maintain the desired concentration of ofloxacin in the patients.