Thesis (M.S.)--University of Wisconsin--Madison. / Typescript. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references (leaves 17-18).

Hepatic ischaemia-reperfusion injury occurs when patients undergoing liver operations such as liver transplantation, tumour resection and shock. Intravenous and intrathecal administration of morphine can be used to provide analgesia prior or after liver surgery. It has been reported that systemically administered morphine conferred protective effect on numerous organs, including heart, brain and kidney. The focus of my research is to investigate the effect of intravenous and intrathecal morphine preconditioning on normal and cirrhotic livers. Further, PI3K/Akt, STAT3 and HO-1/iNOS pathways had been shown to ameliorate hepatic ischemia-reperfusion injury. Hence, we aim to investigate these possible signaling pathways associated with morphine mediated hepato-protection. A partial hepatic ischaemia reperfusion injury model in rats was used. The experiments were divided into two series: one involved in normal livers and the other one involved in cirrhotic livers. For the normal livers, morphine at different doses were administrated intravenously or intrathecally prior the onset of ischaemia, and the experiments were repeated with previous intravenous administration of naloxone methiodide (opioid receptor antagonist), or wortmannin (Akt inhibitor), respectively. For the cirrhotic livers, morphine at optimal doses were injected intravenously or intrathecally prior the onset of ischaemia. Those rats with only induced hepatic ischaemia-reperfusion injury only were marked as control groups. The effect of morphine preconditioning on hepatic architecture, apoptosis and liver function were evaluated respectively by hematoxylin-eosin (H&E) staining, Terminal deoxynucleotide transferase-mediated dUTP nick end labeling (TUNEL) staining, the expression of cleaved Caspase-3, and serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Meanwhile, the expression of phosphorylated Akt, phosphorylated JAK2, phosphorylated STAT3, HO-1 and iNOS were detected by Western Blot to determine the signaling pathways involved by intravenous and intrathecal morphine preconditioning. The normal livers series presented intravenous and intrathecal morphine preconditioning at the 100μg/kg, 10μg/kg, respectively, better persevered hepatic architecture when compared with control groups. The degree of liver cell apoptosis and expression of cleaved caspase-3 were also reduced by intravenous and intrathecal morphine preconditioning. In additional, intravenous and intrathecal morphine preconditioning ameliorated hepatocellular damage by reducing ALT&AST release. Moreover, the expressions of phosphorylated Akt and its downstream protein STAT3 were significantly increased by intravenous and intrathecal morphine preconditioning, compared with their respective control groups. The hepato-protective effect of intravenous and intrathecal morphine preconditioning was reversed by naloxone methiodide or wortmannin pretreatment. The similar pattern of protection was observed in cirrhotic livers. Both intravenous and intrathecal morphine preconditioning protected hepatic architecture much better than control groups. They also attenuated hepatic apoptosis degree and hepatocellular enzyme release. Furthermore, the expression of HO-1 was up-regulated, whereas the expression of iNOS was down-regulated by intravenous and intrathecal morphine preconditioning. In summary, this study provided evidence that intravenous and intrathecal morphine preconditioning could attenuate hepatic ischaemia-reperfusion injury in normal and cirrhotic livers. The involvement of opioid receptors, Akt/STAT3 pathway and HO-1 pathway might be the underlying mechanisms of morphine hepato-protection. Finally, the protective effect of morphine preconditioning might provide a potential therapeutic approach for clinical usage. / published_or_final_version / Anaesthesiology / Master / Master of Philosophy

Tez (Tıpta Uzmanlık) - Süleyman Demirel Üniversitesi, Tıp Fakültesi, Anesteziyoloji ve Reanimasyon Anabilim Dalı, 2006. / Bibliyografya var.

Made available in DSpace on 2014-06-11T19:29:05Z (GMT). No. of bitstreams: 0 Previous issue date: 2009-12-18Bitstream added on 2014-06-13T20:18:51Z : No. of bitstreams: 1 simoni_rf_me_botfm.pdf: 286447 bytes, checksum: 285c09bd4daeaa3c8d21ed54be946f3b (MD5) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / A constante de equilíbrio entre o plasma e o sítio efetor (ke0) é utilizada pelos modelos farmacocinéticos para prever a concentração do fármaco em seu local de ação (Ce). Seria interessante que a Ce de propofol fosse semelhante na perda e na recuperação da consciência. O objetivo desse estudo foi avaliar o desempenho clínico de duas diferentes ke0 (rápida = 1,21 min-1 e lenta = 0,26 min-1) com relação à concentração de propofol prevista em seu local de ação durante a perda e a recuperação da consciência usando o modelo farmacocinético de Marsh. Material e Método – Participaram desse estudo 20 voluntários adultos, sadios e do sexo masculino. Em todos os voluntários foi administrado propofol em regime de infusão alvo-controlada modelo farmacocinético de Marsh ke0 rápida e em outra oportunidade foi usado, o mesmo modelo farmacocinético com a ke0 lenta. Inicialmente, o propofol foi infundido em concentração-alvo plasmática de 3,0 μg.mL-1. A perda da consciência e recuperação da consciência foi baseada na resposta ao estímulo verbal. A concentração de propofol prevista em seu local de ação foi anotada no momento da perda e recuperação da consciência. Resultados - Na perda e recuperação da consciência, a concentração média de propofol prevista em seu local de ação pela ke0 rápida foi diferente (3,64 ± 0,78 e 1,47 ± 0,29 μg.mL-1, respectivamente, p < 0,0001), enquanto que com a ke0 lenta a concentração média de propofol prevista em seu local de ação foi semelhante (2,20 ± 0,70 e 2,13 ± 0,43 μg.mL-1, respectivamente, p = 0,5425). Conclusão - Do ponto de vista clínico, a ke0 lenta (0,26 min-1) incorporada ao modelo farmacocinético de Marsh apresentou melhor desempenho que a ke0 rápida (1,21 min-1), uma vez que a concentração de propofol prevista em seu local de ação na perda e recuperação da consciência foi... / The ke0 can be defined as the proportional variation of the gradient of concentration between the plasma and the effect-site in relation to the unit of time. Theoretically, the higher the value of the ke0, the faster the drug enters the effectsite. Therefore, drugs with short T½ke0 have high ke0s and fast onset of action. The aim of this study was to assess the clinical performance of two different ke0s (fast and slow) in terms of propofol effect-site concentration (Ce) during the loss and recovery of consciousness, using Marsh's pharmacokinetic model. Method: Twenty healthy male adult volunteers participated in this study. Propofol was first administered to the individual volunteer using Marsh's pharmacokinetic targetcontrolled infusion model with ke0 of 1.21 min-1 and, on another opportunity, with the same pharmacokinetic model but ke0 of 0.26 min-1. Propofol was infused in plasma target-concentration of 3.0 μg.mL-1. Loss and recovery of consciousness was defined as response of the volunteer to verbal stimulus. The Ce was registered at the moments of loss and recovery of consciousness. Results: At loss and recovery of consciousness, propofol Ce means predicted by the fast ke0 were different (3.64 ± 0.78 and 1.47 ± 0.29 μg.mL-1, respectively, p < 0.0001), whereas with the slow ke0 the predicted Ce means were similar (2.20 ± 0.70 and 2.13 ± 0.43 μg.mL-1, respectively, p = 0.5425). Conclusion: It can be concluded that slow ke0 (0.26 min-1) incorporated into Marsh's pharmacokinetic model showed better clinical performance than fast ke0 (1.21 min-1), since the predicted effect-site concentrations of propofol at loss and recovery of consciousness were similar. Key words: Intravenous anesthesia: propofol, pharmacokinetic model; Monitoring: bispectral index.

Orientador: Pedro Thadeu Galvão Vianna / Banca: Eliana Marisa Ganem / Banca: Gilberto Denucci / Resumo: A constante de equilíbrio entre o plasma e o sítio efetor (ke0) é utilizada pelos modelos farmacocinéticos para prever a concentração do fármaco em seu local de ação (Ce). Seria interessante que a Ce de propofol fosse semelhante na perda e na recuperação da consciência. O objetivo desse estudo foi avaliar o desempenho clínico de duas diferentes ke0 (rápida = 1,21 min-1 e lenta = 0,26 min-1) com relação à concentração de propofol prevista em seu local de ação durante a perda e a recuperação da consciência usando o modelo farmacocinético de Marsh. Material e Método - Participaram desse estudo 20 voluntários adultos, sadios e do sexo masculino. Em todos os voluntários foi administrado propofol em regime de infusão alvo-controlada modelo farmacocinético de Marsh ke0 rápida e em outra oportunidade foi usado, o mesmo modelo farmacocinético com a ke0 lenta. Inicialmente, o propofol foi infundido em concentração-alvo plasmática de 3,0 μg.mL-1. A perda da consciência e recuperação da consciência foi baseada na resposta ao estímulo verbal. A concentração de propofol prevista em seu local de ação foi anotada no momento da perda e recuperação da consciência. Resultados - Na perda e recuperação da consciência, a concentração média de propofol prevista em seu local de ação pela ke0 rápida foi diferente (3,64 ± 0,78 e 1,47 ± 0,29 μg.mL-1, respectivamente, p < 0,0001), enquanto que com a ke0 lenta a concentração média de propofol prevista em seu local de ação foi semelhante (2,20 ± 0,70 e 2,13 ± 0,43 μg.mL-1, respectivamente, p = 0,5425). Conclusão - Do ponto de vista clínico, a ke0 lenta (0,26 min-1) incorporada ao modelo farmacocinético de Marsh apresentou melhor desempenho que a ke0 rápida (1,21 min-1), uma vez que a concentração de propofol prevista em seu local de ação na perda e recuperação da consciência foi... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: The ke0 can be defined as the proportional variation of the gradient of concentration between the plasma and the effect-site in relation to the unit of time. Theoretically, the higher the value of the ke0, the faster the drug enters the effectsite. Therefore, drugs with short T½ke0 have high ke0s and fast onset of action. The aim of this study was to assess the clinical performance of two different ke0s (fast and slow) in terms of propofol effect-site concentration (Ce) during the loss and recovery of consciousness, using Marsh's pharmacokinetic model. Method: Twenty healthy male adult volunteers participated in this study. Propofol was first administered to the individual volunteer using Marsh's pharmacokinetic targetcontrolled infusion model with ke0 of 1.21 min-1 and, on another opportunity, with the same pharmacokinetic model but ke0 of 0.26 min-1. Propofol was infused in plasma target-concentration of 3.0 μg.mL-1. Loss and recovery of consciousness was defined as response of the volunteer to verbal stimulus. The Ce was registered at the moments of loss and recovery of consciousness. Results: At loss and recovery of consciousness, propofol Ce means predicted by the fast ke0 were different (3.64 ± 0.78 and 1.47 ± 0.29 μg.mL-1, respectively, p < 0.0001), whereas with the slow ke0 the predicted Ce means were similar (2.20 ± 0.70 and 2.13 ± 0.43 μg.mL-1, respectively, p = 0.5425). Conclusion: It can be concluded that slow ke0 (0.26 min-1) incorporated into Marsh's pharmacokinetic model showed better clinical performance than fast ke0 (1.21 min-1), since the predicted effect-site concentrations of propofol at loss and recovery of consciousness were similar. Key words: Intravenous anesthesia: propofol, pharmacokinetic model; Monitoring: bispectral index. / Mestre

Made available in DSpace on 2014-06-11T19:22:21Z (GMT). No. of bitstreams: 0 Previous issue date: 2002Bitstream added on 2014-06-13T19:27:34Z : No. of bitstreams: 1 mannarino_r_me_botfm.pdf: 1143230 bytes, checksum: e78de0e8beeaacc11674b6664d6aa357 (MD5) / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / A vantagem da anestesia injetável é a facilidade de produzir os componentes da anestesia (inconsciência, analgesia, relaxamento muscular e proteção neurovegetativa) com doses definidas dos diversos fármacos. Existem controvérsias sobre as doses de propofol necessárias para prover analgesia para realização de cirurgias. Objetivaram-se definir as taxas mínimas de infusão do propofol isoladamente e em associação com a lidocaína para anestesia intravenosa em cães, e a possível potencialização analgésica da lidocaína, avaliando-se os efeitos cardiovasculares e grau de hipnose. As DE50 do propofol e propofol associado a lidocaína foram calculadas em 10 cães (12,85 l 1,22 kg), sem raça definida, anestesiados 2 vezes com intervalo de 15 dias. G1: indução anestésica com propofol (6 mg/kg/iv) e manutenção inicial na velocidade de 0,7 mg/kg/min. G2: indução anestésica com propofol (6 mg/kg) e lidocaína (1,5 mg/kg) e manutenção inicial com propofol (0,7 mg/kg/min) e lidocaína em velocidade constante (0,25 mg/kg/min). A analgesia foi avaliada através do pinçamento de membrana interdigital dos membros posteriores e da ponta da cauda por 15 (quinze) segundos. De acordo com a resposta, a velocidade foi aumentada ou diminuída em 0,05 mg/kg/min, verificando-se a analgesia 10 (dez) minutos após até a determinação da velocidade na qual não havia respostas aos dois estímulos. Esta velocidade foi mantida por mais 2 (duas) mensurações. Em não havendo resposta era considerada a DE50. A média entre as velocidades (com e sem resposta) foi utilizada na determinação da taxa de infusão mínima de cada grupo. Esta DE50 foi utilizada na 2o etapa. Doze cães (12,28 l 1,37 kg) foram divididos em 2 grupos de seis. G3: indução anestésica com 6 mg/kg de propofol e manutenção... / There is a controversy on the doses of propofol to produce sufficient surgical analgesia. This study aimed to define the minimum infusion rate of propofol and propofol combined to lidocaine for IV anesthesia in dogs. The ED50 of propofol and propofol combined with lidocaine was calculated in 10 dogs, weighing 12.85 l 1.22 kg, anesthetized twice with a interval of 15 days. Anesthesia was induced (6 mg/kg/iv) and maintained with propofol (0.7 mg/kg/min.) (G1) and induced with propofol (6 mg/kg) and lidocaine (1.5 mg/kg) and maintained with propofol (0.7 mg/kg/min) and lidocaine (0.25 mg/kg/min) (G2). Analgesia was investigated by tail clamping and podal reflex. The infusion rate was increased or reduced in 0.05 mg/kg/min, until no painful response was observed. The infusion rate was maintained for more 2 (two) evaluations, with a 10 minutes interval and this rate was considered the DE50 of propofol. The mean infusion rate between no pain response and positive response was considered the mean minimal infusion rate and was used in the second part of the study. Other 12 dogs (12.28 l 1.37 kg) were divided in 2 groups of 6 animals. G3 was treated with the same protocol as G1 and G4 as G2, with the propofol infusion rates previously calculated. Anesthesia was maintained for 2 hours. Hemodynamic and respiratory variables as well as BIS and temperature were measured during anesthesia. There was a smaller cardiovascular depression and greater vascular resistance and acidosis in animals treated with propofol and lidocaine. The BIS was maintained between 40 and 60 in both groups. Lidocaine potentiated in 21% the analgesia produced by propofol. The minimum infusion rate of propofol was 1.25 mg/kg/min when used alone and 0.985 mg/kg/min when combined to lidocaine. Lidocaine potentiated hypnosis and analgesia produced by propofol and minimized the cardiovascular depression, increasing recovery.

Orientador: Stelio Pacca Loureiro Luna / Resumo: A vantagem da anestesia injetável é a facilidade de produzir os componentes da anestesia (inconsciência, analgesia, relaxamento muscular e proteção neurovegetativa) com doses definidas dos diversos fármacos. Existem controvérsias sobre as doses de propofol necessárias para prover analgesia para realização de cirurgias. Objetivaram-se definir as taxas mínimas de infusão do propofol isoladamente e em associação com a lidocaína para anestesia intravenosa em cães, e a possível potencialização analgésica da lidocaína, avaliando-se os efeitos cardiovasculares e grau de hipnose. As DE50 do propofol e propofol associado a lidocaína foram calculadas em 10 cães (12,85 l 1,22 kg), sem raça definida, anestesiados 2 vezes com intervalo de 15 dias. G1: indução anestésica com propofol (6 mg/kg/iv) e manutenção inicial na velocidade de 0,7 mg/kg/min. G2: indução anestésica com propofol (6 mg/kg) e lidocaína (1,5 mg/kg) e manutenção inicial com propofol (0,7 mg/kg/min) e lidocaína em velocidade constante (0,25 mg/kg/min). A analgesia foi avaliada através do pinçamento de membrana interdigital dos membros posteriores e da ponta da cauda por 15 (quinze) segundos. De acordo com a resposta, a velocidade foi aumentada ou diminuída em 0,05 mg/kg/min, verificando-se a analgesia 10 (dez) minutos após até a determinação da velocidade na qual não havia respostas aos dois estímulos. Esta velocidade foi mantida por mais 2 (duas) mensurações. Em não havendo resposta era considerada a DE50. A média entre as velocidades (com e sem resposta) foi utilizada na determinação da taxa de infusão mínima de cada grupo. Esta DE50 foi utilizada na 2o etapa. Doze cães (12,28 l 1,37 kg) foram divididos em 2 grupos de seis. G3: indução anestésica com 6 mg/kg de propofol e manutenção... (Resumo completo clicar acesso eletrônico abaixo) / Abstract: There is a controversy on the doses of propofol to produce sufficient surgical analgesia. This study aimed to define the minimum infusion rate of propofol and propofol combined to lidocaine for IV anesthesia in dogs. The ED50 of propofol and propofol combined with lidocaine was calculated in 10 dogs, weighing 12.85 l 1.22 kg, anesthetized twice with a interval of 15 days. Anesthesia was induced (6 mg/kg/iv) and maintained with propofol (0.7 mg/kg/min.) (G1) and induced with propofol (6 mg/kg) and lidocaine (1.5 mg/kg) and maintained with propofol (0.7 mg/kg/min) and lidocaine (0.25 mg/kg/min) (G2). Analgesia was investigated by tail clamping and podal reflex. The infusion rate was increased or reduced in 0.05 mg/kg/min, until no painful response was observed. The infusion rate was maintained for more 2 (two) evaluations, with a 10 minutes interval and this rate was considered the DE50 of propofol. The mean infusion rate between no pain response and positive response was considered the mean minimal infusion rate and was used in the second part of the study. Other 12 dogs (12.28 l 1.37 kg) were divided in 2 groups of 6 animals. G3 was treated with the same protocol as G1 and G4 as G2, with the propofol infusion rates previously calculated. Anesthesia was maintained for 2 hours. Hemodynamic and respiratory variables as well as BIS and temperature were measured during anesthesia. There was a smaller cardiovascular depression and greater vascular resistance and acidosis in animals treated with propofol and lidocaine. The BIS was maintained between 40 and 60 in both groups. Lidocaine potentiated in 21% the analgesia produced by propofol. The minimum infusion rate of propofol was 1.25 mg/kg/min when used alone and 0.985 mg/kg/min when combined to lidocaine. Lidocaine potentiated hypnosis and analgesia produced by propofol and minimized the cardiovascular depression, increasing recovery. / Mestre

published_or_final_version / Pharmacology and Pharmacy / Doctoral / Doctor of Philosophy

Tez (Yüksek Lisans) - Süleyman Demirel Üniversitesi, Sağlık Bilimleri Enstitüsü, Histoloji ve Embriyoloji Anabilim Dalı, 2005. / Bibliyografya var.

Diss. (sammanfattning) Stockholm : Karol. inst., 2003. / Härtill 5 uppsatser.