Sugammadex, a gamma cyclodextrin discovered in 2007, provides a safe and effective alternative to drugs currently used in surgery by anesthesiologists. A problem in the current practice of anesthesia is the use of Succinylcholine, a neuromuscular blocking agent used for the cessation of the patient's skeletal muscle movement. Succinylcholine is used due to its unique fast onset and short duration, ideal for short procedures, difficult intubation scenarios, and rapid sequence intubation. However, it is used cautiously due to several risks such as causing myalgia, hyperkalemia, fasciculations, and increasing intracranial, intragastric, and intraocular pressure. Sugammadex provides a safer alternative to Succinylcholine because it allows immediate reversal of a neuromuscular blockade through a different mechanism, which does not lead to harmful adverse effects. Sugammadex works by encapsulating its target muscle relaxant, Rocuronium. Rocuronium is a relatively safer drug than Succinylcholine with a similar time of onset, but a very long duration of action. Since Sugammadex is able to immediately reverse the effects of Rocuronium, this combination of Rocuronium and Sugammadex provides the same desired effect as Succinylcholine but without the harmful side effects. The current most widely used reversal agent for muscle relaxation is Neostigmine. The problems with Neostigmine are that it can lead to residual paralysis and recurarisation if under dosed. It also produces unwanted cholinergic side effects that lead to cardiovascular instability. Due to this, the medical community is in need for a better reversal agent that can both quickly and completely reverse muscle paralysis without the need to manage unwanted side effects. Sugammadex is able to address both the problems of Succinylcholine and Neostigmine. Studies have shown Sugammadex to provide a faster, safer, and more predictable reversal of Rocuronium - induced neuromuscular blockade than Neostigmine. Sugammadex has shown to also achieve faster recovery from Rocuronium - induced muscle paralysis than the fast spontaneous recovery of Succinylcholine. With no serious adverse effects observed in these studies, the data supports the use of Sugammadex and its potential to replace the current standards of practice with Succinylcholine and Neostigmine. Furthermore, high dosage of Sugammadex has shown to be capable of immediately reversing profound neuromuscular blockades, an ability that no reversal drug currently in the market possesses. This enables the anesthesiologist to provide optimal muscle relaxation for the surgeon throughout the operation without the concern of being unable to reverse the patient in a timely manner. Studies on multiple patient population groups do not show any serious adverse effects are linked to using Sugammadex. There have been incidences of drug induced QTc prolongation in cardiac patients, but its cause was not determined to be related solely with Sugammadex. Sugammadex has shown to be the safer reversal agent compared to Neostigmine in cardiac, pulmonary, and renal patients. One problem that prevents the routine use of Sugammadex is its cost. The cost is significantly higher than Neostigmine. This cost is justified, however, due to staff costs saved from a faster patient recovery and shorter stay in the hospital. Therefore, while Sugammadex is definitely warranted over Succinylcholine due to its safety profile, its use over Neostigmine is dependent on each healthcare facility. While Sugammadex is currently under review by the Food and Drug Administration, it will evolve the practice of anesthesia if allowed into the United States market.

Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal.

京都大学 / 新制・課程博士 / 博士(医学) / 甲第23751号 / 医博第4797号 / 新制||医||1055(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 寺田 智祐, 教授 江藤 浩之, 教授 髙折 晃史 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

RATIONALE: The purpose of this study is to investigate the stored stability of dilutions of neuromuscular blocking agents (NMBAs), namely cisatracurium, rocuronium, and vecuronium, for skin prick/intradermal testing. METHODS: Concentrations of NMBAs were monitored by liquid chromatography-mass spectrometry (LC-MS/MS) for a period of 14 days. Dilutions of NMBAs were prepared in saline by factors of 10x, 100x, 1,000x, and 100,000x as sensitivity of the assay allowed. Diluted drug products were stored in a laboratory refrigerator until sampling. On sampling days, aliquots of each dilution were removed and compared to a freshly prepared set of reference dilutions. RESULTS: The results are measured as beyond use date (BUD) defined as recovery of drug versus the reference (90-110%). Based on the LC-MS/MS data, the BUD for cisatracurium diluted to 10x and 100x is 96 hours. Higher dilutions (1,000x to 100,000x) should be used immediately following preparation (within less than 24 hours). Vecuronium at 10x and 100x also has a BUD of 96 hours, and the 1,000x dilution is stable for 24 hours. The 10,000x dilution should be used immediately. Rocurium at 10x to 1,000x has a BUD of 48 hours, yet higher dilutions (10,000x and 100,000x) should be used immediately. CONCLUSIONS: With increasing dilution factors, the stability of these drugs in saline decreases, increasing deviation between samples and references. The most stable dilutions for each of the drugs tested were 10x and 100x. Stability of these drugs is likely compromised by hydrolysis of the ester bonds in the drug molecules.

Orientador: Newton Nunes / Banca: José Antonio Marques / Banca: Paulo Sérgio Patto dos Santos / Resumo: Avaliaram-se os efeitos do fornecimento de diferentes frações inspiradas de oxigênio em cães anestesiados com infusão contínua de propofol e rocurônio mantidos em ventilação mecânica controlada a pressão sobre os parâmetros respiratórios, hemogasométricos e hemodinâmicos. Foram utilizados 8 cães adultos, os quais foram submetidos a cinco anestesias com propofol (8,8 ± 3,3 mg/kg, seguido de infusão contínua de 0,7 mg/kg/min) e rocurônio (0,6 mg/kg bolus e infusão contínua 0,6 mg/kg/h), sendo que, cada procedimento anestésico foi diferenciado do outro pela FiO2 fornecida ao paciente, permitindo assim, a formação dos grupos: G100 (FiO2=1), G80 (FiO2=0,8), G60 (FiO2=0,6), G40 (FiO2=0,4) e G20 (FiO2=0,21). Os animais foram submetidos à ventilação mecânica no modo pressão controlada. Trinta minutos após a indução anestésica (M0) e a cada 15 minutos, durante um período de 60 minutos (M15, M30, M45 e M60) mensuraram-se os parâmetros. Os dados de cada grupo foram submetidos à Análise de Perfil (p<0,05). Os valores de PaO2, PvO2, SaO2 e SvO2 diminuíram quanto mais baixas foram as FiO2. Houve maiores médias na Rawi e WOB em G60, e de shunt e AaDO2 em G100, G80 e G60. Os cães mantiveram-se hemodinamicamente estáveis em todos os grupos. Concluiu-se que as diferentes FiO2 não alteram as variáveis hemodinâmicas e que o fornecimento de oxigênio a 60%, 80% e 100% deve ser evitado, pois proporciona altos valores de AaDO2 e shunt intrapulmonar. Além disso, verificou-se que FiO2 de 0,4 e 0,21 mantém melhor estabilidade dos parâmetros ventilatórios. / Abstract: The effects of several inspired oxygen fractions (FiO2) on the blood gases, respiratory and hemodynamic parameters in mechanical ventilation dogs anesthetized with continuous infusion of propofol and rocuronium were evaluated. Eight adult dogs were used. Each animal underwent five anesthesia with propofol (8,8 ± 3,3 mg/kg, followed by continuous infusion of 0,7 mg/kg/min) and rocuronium (0,6 mg/kg, followed by continuous infusion of 0,6 mg/kg/h). In each procedure the patient was allowed to breath a different FiO2, thereby resulting in five groups, namely: G100 (group FiO2 = 1), G80 (groupFiO2 = 0.8), G60 (group FiO2 =0.6), G40 (group FiO2 = 0.4), and G20 (group FiO2 = 0.21). The animals were submitted to pressure-controlled ventilation. The initial measurement (M0) was recorded thirty minutes after the infusion of propofol and rocuronium begun. Additional recordings were performed at 15 minute intervals for 60 minutes (M15, M30, M45 and M60). Numeric data was submitted to Profile Analysis (p<0.05). We recorded significantly lower values of PaO2, PvO2, SaO2 and SvO2 varied according to the higher changes in oxygen. Regarding Rawi and WOB the mean of G60 was greater than other groups. Qs/Qt and AaDO2 of G100, G80 e G60 was higher than other groups. We conclude that FiO2 does not impair hemodynamic parameters and 100%, 80% e 60% oxygen not be used because promote high values of AaDO2 and shunt intrapulmonary. FiO2=0,4 e FiO2=0,21 maintain stability of ventilatory parameters. / Mestre

Orientador: Norma Sueli Pinheiro Módolo / Resumo: Justificativa: O magnésio potencializa o efeito dos bloqueadores neuromusculares, atenua a resposta hemodinâmica à intubação e reduz o consumo de anestésico no intraoperatório. A inibição da liberação de acetilcolina mediada pelo cálcio nos terminais pré-sinápticos das junções neuromusculares, a redução da sensibilidade pós-sináptica à acetilcolina e os efeitos diretos no potencial de membrana dos miócitos parecem ser responsáveis pela ação relaxante muscular do magnésio. Além da ação do magnésio na placa motora e nos miócitos, esse íon pode interferir na farmacocinética dos bloqueadores neuromusculares por alteração do fluxo sanguíneo provocado pela vasodilatação e consequentemente aumento do aporte de bloqueador neuromuscular na placa motora. O objetivo do presente estudo é avaliar o efeito do magnésio sobre a latência de três doses diferentes do rocurônio. Avaliou-se ainda, a ação sobre a resposta hemodinâmica à intubação traqueal, as condições de intubação traqueal e a relação da variação do índice de perfusão com a latência do rocurônio. Métodos: 180 pacientes foram distribuídos em seis grupos de acordo com a administração ou não de magnésio (60 mg.kg-1) e pela dose de rocurônio (0,3, 0,6 ou 1,2 mg.kg-1) utilizada na indução anestésica. Determinando desse modo os seguintes grupos: ROC0.3, ROC0.6, ROC1.2, ROC0.3MG, ROC0.6MG e ROC1.2MG. A latência do rocurônio foi aferida por meio da aceleromiografia ... (Resumo completo, clicar acesso eletrônico abaixo) / Doutor

Submitted by CARLOS EDUARDO DAVID DE ALMEIDA null (cedalmeida@terra.com.br) on 2017-03-09T03:15:29Z No. of bitstreams: 1 Carlos Eduardo David de Almeida (Doutorado) após a defesa.pdf: 870499 bytes, checksum: 641d701ba65d5d16a6acd96d7d003702 (MD5) / Approved for entry into archive by LUIZA DE MENEZES ROMANETTO (luizamenezes@reitoria.unesp.br) on 2017-03-14T16:57:13Z (GMT) No. of bitstreams: 1 almeida_ced_dr_bot.pdf: 870499 bytes, checksum: 641d701ba65d5d16a6acd96d7d003702 (MD5) / Made available in DSpace on 2017-03-14T16:57:13Z (GMT). No. of bitstreams: 1 almeida_ced_dr_bot.pdf: 870499 bytes, checksum: 641d701ba65d5d16a6acd96d7d003702 (MD5) Previous issue date: 2017-02-17 / Justificativa: O magnésio potencializa o efeito dos bloqueadores neuromusculares, atenua a resposta hemodinâmica à intubação e reduz o consumo de anestésico no intraoperatório. A inibição da liberação de acetilcolina mediada pelo cálcio nos terminais pré-sinápticos das junções neuromusculares, a redução da sensibilidade pós-sináptica à acetilcolina e os efeitos diretos no potencial de membrana dos miócitos parecem ser responsáveis pela ação relaxante muscular do magnésio. Além da ação do magnésio na placa motora e nos miócitos, esse íon pode interferir na farmacocinética dos bloqueadores neuromusculares por alteração do fluxo sanguíneo provocado pela vasodilatação e consequentemente aumento do aporte de bloqueador neuromuscular na placa motora. O objetivo do presente estudo é avaliar o efeito do magnésio sobre a latência de três doses diferentes do rocurônio. Avaliou-se ainda, a ação sobre a resposta hemodinâmica à intubação traqueal, as condições de intubação traqueal e a relação da variação do índice de perfusão com a latência do rocurônio. Métodos: 180 pacientes foram distribuídos em seis grupos de acordo com a administração ou não de magnésio (60 mg.kg-1) e pela dose de rocurônio (0,3, 0,6 ou 1,2 mg.kg-1) utilizada na indução anestésica. Determinando desse modo os seguintes grupos: ROC0.3, ROC0.6, ROC1.2, ROC0.3MG, ROC0.6MG e ROC1.2MG. A latência do rocurônio foi aferida por meio da aceleromiografia do nervo ulnar (tempo entre o início da injeção do bloqueador neuromuscular até a redução da resposta motora a 5% da resposta inicial). A avaliação hemodinâmica foi feita imediatamente antes do início da infusão da solução estudada e um minuto após a intubação traqueal. As condições de intubação traqueal foram avaliadas pelo anestesiologista por meio das condições de laringoscopia, do posicionamento das cordas vocais e da resposta a inserção do tubo traqueal. Os níveis séricos de magnésio foram avaliados por coleta de 3 mL sangue do paciente antes e após a administração de magnésio. A aferição do índice de perfusão foi realizado com o objetivo de correlacionar a perfusão tecidual periférica com a alteração da latência do rocurônio. Resultados: Todos os pacientes tiveram condições excelentes ou boas de intubação traqueal. O MgSO4 reduziu a latência do rocurônio nas doses de 0,3 (de 88,5 s para 60 s) ou 0,6 mg.kg-1 (de 76 s para 44 s). Não ocorreu potencialização da dose de 1,2 mg.kg-1 de rocurônio. Os grupos que receberam MgSO4 apresentaram maiores variações do índice de perfusão comparativamente aos controles. Houve correlação entre redução da latência e aumento do índice de perfusão para as doses de 0,3 mg.kg-1 (p < 0,001 R= -0,50) e 0,6 mg.kg-1 (p < 0,001, R= -0,424) de rocurônio. Para a dose de 1,2 mg.kg-1 de rocurônio não existiu essa correlação. Entre os grupos que receberam MgSO4 e controles, não houve diferença estatística nos valores de pressão arterial, havendo um aumento discreto da frequência cardíaca nos pacientes do MgSO4. Conclusões: Neste estudo, o MgSO4 reduziu a latência do rocurônio nas doses de 0,3 e 0,6 mg.kg-1 . Não houve alteração da latência quando utilizado 1,2 mg.kg-1 de rocurônio. O aumento do índice de perfusão provocado pelo MgSO4 pode ter contribuído para a redução da latência. O sulfato de magnésio não alterou as condições de intubação entre os grupos que receberam a mesma dose de rocurônio. O sulfato de magnésio não promoveu alterações estatisticamente significante da pressão arterial, no entanto promoveu uma elevação da frequência cardíaca 1 min após a intubação traqueal. / Background: Magnesium potentiates the effect of neuromuscular blockers (NMBs), attenuates the hemodynamic response to intubation, and reduces intraoperative anesthetic consumption. Inhibition of calcium-mediated acetylcholine release at the presynaptic terminals of the neuromuscular junctions, the reduction of postsynaptic sensitivity to acetylcholine, and the direct effects on myocyte membrane potential appear to be responsible for the muscle relaxant action of magnesium. In addition to the action of magnesium on the motor plate and myocytes, this ion may interfere with the pharmacokinetics of NMB due to changes in the blood flow caused by vasodilation and consequently an increase in the NMB load in the motor plate. The aim of the present study is evaluate the effect of magnesium on the onset time of three different doses of rocuronium. We also evaluated action on the hemodynamic response to tracheal intubation, intubation conditions and the relationship between perfusion index variation and rocuronium onset time. Method: One hundred and eighty patients were randomised into six groups according to rocuronium dose received (0.3, 0.6, or 1.2 mg.kg-1) and the administration of saline or MgSO4 (60 mg. kg-1). The following groups were determined: ROC0.3, ROC0.6, ROC1.2, ROC0.3MG, ROC0.6MG e ROC1.2MG. Rocuronium onset time was measured by ulnar nerve acceleromyography (time between onset of NMB injection and reduction of motor response to 5% of initial response). The hemodynamic parameters were done immediately before the beginning of the infusion of the studied solution and one minute after the tracheal intubation. The conditions of tracheal intubation were evaluated by the anesthesiologist using the conditions of laryngoscopy, positioning of the vocal cords and response to the insertion of the tracheal tube. Serum magnesium levels were assessed by blood collection (3 mL) of the patient before and after administration of magnesium. The correlation between tissue perfusion and rocuronium onset time was determined by measuring variations in the perfusion index. Results: All patients had excellent or good conditions for tracheal intubation. Magnesium sulphate decreased onset time of rocuronium at doses of 0.3 and 0.6 mg.kg-1 (60 and 44 seconds, respectively; p < 0.05). Potentiation was not observed for rocuronium dosis of 1.2 mg.kg-1. Perfusion index variations in the groups that received MgSO4 were greater than in controls. A correlation between reduced onset time and increased perfusion index was observed for rocuronium doses of 0.3 mg.kg-1 (p < 0.001, R = -0.50) and 0.6 mg.kg-1 (p < 0.001, R = -0.424). However, this correlation was not observed for rocuronium doses of 1.2 mg.kg-1. There was no significant difference in blood pressure among the study groups; however, heart rate was increased slightly in patients who received MgSO4. Conclusions: In this study, MgSO4 reduced the rocuronium onset time at doses of 0.3 and 0.6 mg.kg-1, and onset time was not significantly affected for rocuronium dosis of 1.2 mg.kg-1. The increase in perfusion index may have contributed to the reduction in rocuronium onset time. Magnesium sulfate did not alter the intubation conditions between the groups receiving the same dose of rocuronium. Magnesium sulphate did not promote statistically significant changes in blood pressure, however, it promoted an increase in heart rate 1 min after tracheal intubation.

Made available in DSpace on 2014-06-11T19:23:43Z (GMT). No. of bitstreams: 0 Previous issue date: 2008-02-27Bitstream added on 2014-06-13T19:09:51Z : No. of bitstreams: 1 borges_pa_me_jabo.pdf: 511223 bytes, checksum: 0bc1cbed81a96c7f7bd4106271032631 (MD5) / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / Avaliaram-se os efeitos do fornecimento de diferentes frações inspiradas de oxigênio em cães anestesiados com infusão contínua de propofol e rocurônio mantidos em ventilação mecânica controlada a pressão sobre os parâmetros respiratórios, hemogasométricos e hemodinâmicos. Foram utilizados 8 cães adultos, os quais foram submetidos a cinco anestesias com propofol (8,8 ± 3,3 mg/kg, seguido de infusão contínua de 0,7 mg/kg/min) e rocurônio (0,6 mg/kg bolus e infusão contínua 0,6 mg/kg/h), sendo que, cada procedimento anestésico foi diferenciado do outro pela FiO2 fornecida ao paciente, permitindo assim, a formação dos grupos: G100 (FiO2=1), G80 (FiO2=0,8), G60 (FiO2=0,6), G40 (FiO2=0,4) e G20 (FiO2=0,21). Os animais foram submetidos à ventilação mecânica no modo pressão controlada. Trinta minutos após a indução anestésica (M0) e a cada 15 minutos, durante um período de 60 minutos (M15, M30, M45 e M60) mensuraram-se os parâmetros. Os dados de cada grupo foram submetidos à Análise de Perfil (p<0,05). Os valores de PaO2, PvO2, SaO2 e SvO2 diminuíram quanto mais baixas foram as FiO2. Houve maiores médias na Rawi e WOB em G60, e de shunt e AaDO2 em G100, G80 e G60. Os cães mantiveram-se hemodinamicamente estáveis em todos os grupos. Concluiu-se que as diferentes FiO2 não alteram as variáveis hemodinâmicas e que o fornecimento de oxigênio a 60%, 80% e 100% deve ser evitado, pois proporciona altos valores de AaDO2 e shunt intrapulmonar. Além disso, verificou-se que FiO2 de 0,4 e 0,21 mantém melhor estabilidade dos parâmetros ventilatórios. / The effects of several inspired oxygen fractions (FiO2) on the blood gases, respiratory and hemodynamic parameters in mechanical ventilation dogs anesthetized with continuous infusion of propofol and rocuronium were evaluated. Eight adult dogs were used. Each animal underwent five anesthesia with propofol (8,8 ± 3,3 mg/kg, followed by continuous infusion of 0,7 mg/kg/min) and rocuronium (0,6 mg/kg, followed by continuous infusion of 0,6 mg/kg/h). In each procedure the patient was allowed to breath a different FiO2, thereby resulting in five groups, namely: G100 (group FiO2 = 1), G80 (groupFiO2 = 0.8), G60 (group FiO2 =0.6), G40 (group FiO2 = 0.4), and G20 (group FiO2 = 0.21). The animals were submitted to pressure-controlled ventilation. The initial measurement (M0) was recorded thirty minutes after the infusion of propofol and rocuronium begun. Additional recordings were performed at 15 minute intervals for 60 minutes (M15, M30, M45 and M60). Numeric data was submitted to Profile Analysis (p<0.05). We recorded significantly lower values of PaO2, PvO2, SaO2 and SvO2 varied according to the higher changes in oxygen. Regarding Rawi and WOB the mean of G60 was greater than other groups. Qs/Qt and AaDO2 of G100, G80 e G60 was higher than other groups. We conclude that FiO2 does not impair hemodynamic parameters and 100%, 80% e 60% oxygen not be used because promote high values of AaDO2 and shunt intrapulmonary. FiO2=0,4 e FiO2=0,21 maintain stability of ventilatory parameters.

Orientadores: Lea Rodrigues Simioni, Yoko Oshima Franco / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas / Made available in DSpace on 2018-08-09T02:12:41Z (GMT). No. of bitstreams: 1 Barcelos_CarolineCoutinhode_M.pdf: 1481920 bytes, checksum: 51a5dae81283795439bd5ed51ac09f60 (MD5) Previous issue date: 2007 / Resumo: Atracúrio (ATC) e rocurônio (ROC) são bloqueadores neuromusculares de ação intermediária. Neste estudo, seus efeitos neuromusculares foram investigados in vitro e in vivo em ratos pré-tratados, via gavagem (7d), com os anticonvulsivantes (AC) carbamazepina (CBZ, 40 mg/kg) e fenobarbital (FB, 20 mg/kg) e sacrificados no 8º dia, sob anestesia com uretana. Os resultados foram comparados com a condição-controle (ratos não tratados com AC). A exposição crônica a AC pode determinar a indução de enzimas microssomais responsáveis pela metabolização (oxidação) de fármacos. Para o controle desse fenômeno farmacológico foram determinadas as concentrações enzimáticas de citocromo P450 e b5 redutase, em microssomos hepáticos de ratos tratados com AC, e comparados aos controles. As preparações in vitro e in vivo foram montadas de acordo com as técnicas de Bulbring e de Leeuwin e Wolters, respectivamente. As concentrações utilizadas dos bloqueadores nas preparações in vitro e in vivo foram, respectivamente, 20 µg/mL e 0,5 mg/kg para atracúrio (ATC); 4 µg/mL e 0,6 mg/kg para rocurônio (ROC). Cada protocolo teve um n=5 e as respostas foram observadas por 60 min. Os resultados tanto in vitro quanto in vivo mostraram que o pré-tratamento com a carbamazepina reduziu a resposta contrátil em cerca de 30%. Sob sua vigência, não houve alteração do bloqueio produzido pelo atracúrio e pelo rocurônio, possivelmente porque o tempo de tratamento com a carbamazepina não foi suficiente para causar indução enzimática. Em relação ao fenobarbital, os resultados in vitro e in vivo mostraram nenhuma alteração significativa sob a resposta contrátil. Sob sua vigência, diminuiu a sensibilidade do ATC em produzir o bloqueio neuromuscular in vitro. Contudo, in vivo potencializou o bloqueio neuromuscular de ambos os bloqueadores estudados. Essas alterações observadas em ambos os modelos experimentais podem ser devidas à indução ocorrida com o fenobarbital, conforme comprovado pela concentração de citocromo P450 (0,69 nmol/mg proteína) e b5 redutase (0,62 nmol/mg proteína) / Abstract: Atracurium (ATC) and rocuronium (ROC) are neuromuscular blockers of intermediate action. In this study, the neuromuscular effects had been investigated in vitro and in vivo in treated rats, by gavage (7d), with the anticonvulsantes (AC) carbamazepine (CBZ, 40 mg/kg) and phenobarbital (FB, 20 mg/kg) and sacrificed on the eight day, under anesthesia with urethane. The results had been compared with the control-condition (rats not treated AC). The chronic exposition the AC can determine the induction of microsomes enzyme for the responsible metabolization (oxidation) of drugs. For the control of this pharmacologic phenomenon the enzymatic concentrations of P450 and b5 cytochromes had been determined, in livers microsomes of rats treated with AC, and compared with the controls. The preparations in vitro and in vivo had been followed the Bulbring and Leeuwin and Wolters techniques, respectively. The in vitro and in vivo concentrations were 20 µg/ml and 0.5 mg/kg, respectively, for atracurium (ATC); and 4 µg/ml and 0.6 mg/kg for rocuronium (ROC). Each protocol presented n=5 and the answers were calculated during 60 minutes. The in vitro and in vivo results showed that treatment with carbamazepine reduced the extent of muscle response in about 30%. Under its validity, did not alter the extent of the muscle response block produced by atracurium and rocuronium possibly because the period of time of carbamazepine treatment was not enough to cause enzymatic induction. Regarding phenobarbital, the in vitro and in vivo results did not alter significant the extent of the muscle response block produced. Under its validity, reduced the ATC sensitivity the block neuromuscular in vitro produced. However, in vivo increased the neuromuscular block of both the blockers studied. These alterations observed in both the experimental models can have occured induction with the phenobarbital, as proven P450 (0,69 nmol/mg protein) and b5 (0,62 nmol/mg protein) of cytochrome concentration / Mestrado / Mestre em Farmacologia

Thesis (MMed)-- Stellenbosch University, 2013. / ENGLISH ABSTRACT: Introduction: Of the volatile anaesthetic agents, desflurane causes the greatest degree of potentiation of the neuromuscular blocking drugs (NMB). The purpose of this study was to determine whether desflurane prolongs the effects of 3xED95 doses of rocuronium and cisatracurium to the same degree. The two NMB represent potent and less potent classes respectively. Methods: Informed, written consent was obtained from 63 adult patients scheduled for routine surgery. They were randomly allocated to one of four groups to receive either desflurane-sufentanil (end-tidal partial pressure 4.0 kPa) or propofol-sufentanil anaesthesia and either rocuronium (0.9mg/kg) or cisatracurium (0.15mg/kg). All patients received a target-controlled sufentanil infusion (0.5 ng/ml). Neuromuscular blockade was recorded using accelerometry (TOFGUARD ®, Organon) while patients recovered spontaneously to a Train-of-Four ratio of 0.9 (TOFR0.9). Data were analysed using one- and two-way analysis of variance. The main effects were the types of anaesthetic and NMB on indices of recovery. Results: Compared with propofol-sufentanil anaesthesia, mean times to recovery to T125% and TOFR0.9, were prolonged by desflurane-sufentanil (p<0.01). There were no interactions. Mean prolongation of time to TOFR0.9 was 41 min (SD 36) for cisatracurium and 26.6 min (SD 39) for rocuronium. Discussion: Whereas previous studies did not reveal prolongation of the duration of action of rocuronium by desflurane, we demonstrated a statistically significant prolongation of the spontaneous recovery times of both rocuronium and cisatracurium by desflurane. From the data we could not conclude that there was a difference between the two NMB. A power study revealed that in order to detect a difference between times to recovery to TOF0.9, a sample size of 101 subjects per group would be required. Conclusion: Desflurane prolongs the mean time to spontaneous recovery from neuromuscular blockade after 3xED95 doses of both cisatracurium (a potent NMB) and rocuronium (a less potent NMB). There was wide inter-individual variation in times to spontaneous recovery. Any difference in the mean prolongations between the different types of NMB is unlikely to be of clinical importance. / AFRIKAANSE OPSOMMING: Inleiding Van al die vlugtige narkosemiddels veroorsaak desfluraan die grootste mate van potensiasie van die neuromuskulêre blokkeermiddels. Die doel van hierdie studie was om vas te stel of desfluraan wel die effek van driedubbel die ED95 dosis van rokuronium en cisatrakurium tot dieselfde mate sal verleng. Metodiek Geskrewe ingeligte toestemming is verkry van 63 pasiënte wat voorgedoen het vir roetiene chirurgiese prosedures. Pasiënte is lukraak in een van vier groepe ingedeel om of desfluraansufentaniel (eind-gety parsieële druk 4.0 kPa) of propofol-sufentaniel narkose en of rokuronium (0.9 mg/kg) of cisatrakurium (0.15 mg/kg) te ontvang. Alle pasiënte het 'n teiken-beheerde sufentaniel infusie (0.5 ng/ml). Neuromuskulêre blokkade is waargeneem met behulp van aksellerometrie (TOF-GUARD, Organon) terwyl pasiënte spontaan herstel het tot “reeks-van-vier” verhouding (Engels “Train-of-four” ratio) 0.9 (TOFR0.9). Data analise is gedoen met behulp van een- en tweerigting analise van variansie. Resultate Desfluraan-sufentaniel het die gemiddelde hersteltyd tot T125% en TOFR0.9 verleng in vergelyking met propofol-sufentaniel. Geen interaksies is waargeneem nie. Gemiddelde verlenging van TOFR0.9 vir cisatrakurium was 41 minute (standaardafwyking 36) en vir rokuronium 26.6 minute (standaardafwyking 39). Bespreking Vorige studies kon nie vasstel of desfluraan die werkingsduur van rokuronium verleng nie. Ons het in hierdie studie vasgestel dat desfluraan wel 'n statisties beduidende verlenging in die hersteltyd van beide rokuronium en cisatrakurium veroorsaak. Ons kon egter nie 'n verskil tussen die twee neuromuskulêre agente aandui nie. 'n onderskeidingsvermoëstudie het getoon dat ten minste 101 pasiënte per groep benodig sou word om 'n beduidende verskil tussen die hersteltye tot TOFR0.9 te verkry. Gevolgtrekking Desfluraan verleng die gemiddelde hersteltyd tot spontane herstel van neuromuskulêre blokkade na driedubbele ED95 dosisse van beide cisatrakurium en rokuronium. Daar was egter groot interindividuele variasie ten opsigte van spontane hersteltyd. Enige verskille in die gemiddelde verlenging is onwaarskynlik van kliniese belang.