Made available in DSpace on 2015-07-22T20:50:23Z (GMT). No. of bitstreams: 0 Previous issue date: 2009-05-27 / Associação Fundo de Incentivo à Psicofarmacologia (AFIP) / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / O chá de ayahuasca (AYA) é uma bebida com propriedades psicoativas preparada a partir do cozimento de duas plantas: o cipó Banisteriopsis caapi (Spruce ex Griseb.) C.V. Morton (Malpighiaceae) e as folhas de Psychotria viridis (Ruiz & Pav.) (Rubiaceae). A DMT, presente nas folhas da P. viridis, é o principal componente alucinógeno do chá, mas quando ingerida é rapidamente inativada pela MAO-A presente nos intestinos, o que é evitado com a associação das ß-carbolinas inibidoras da MAO que estão presentes na B. caapi. Apesar do aumento do número de usuários deste chá, ainda existem poucos estudos a respeito das possíveis interações de seus princípios ativos com outras drogas, o que torna cada vez mais importante conhecer as possíveis interações entre o chá e fármacos empregados na clínica. No presente trabalho foi avaliada a possível interação do chá de ayahuasca com dois agentes de muita importância em anestesia: propofol e morfina. As doses utilizadas no estudo foram obtidas a partir da dose média consumida pelo ser humano nos rituais (equivalente a 120 mg/kg, encontrada em 70 mL do chá), definidas como 1 vez (1X) até 20 vezes (20X) ou 2400 mg/kg. No teste do “screening” farmacológico (SF) os animais apresentaram alguns sinais de toxicidade, quando administrado por via ip (diminuição da atividade motora, hipersensibilidade a estímulos e tremor intenso). A administração oral do chá (1X e 10X) não provocou alterações no teste do rotarod, mas no teste da atividade motora, os animais que receberam AYA 10X apresentaram efeito bifásico (diminuição inicial da ambulação até 30 min, seguida de aumento entre 2h e 4h). A dose de 10X aumentou o tempo de sono induzido pelo hexabarbital e diminuiu o tempo de “grooming”, em experimento onde este parâmetro foi quantificado. Em relação à associação chá de ayahuasca com morfina, no teste do SF observou-se que os animais apresentaram cauda de “Straub” mais intensa e duradoura quando comparado com o grupo morfina; ataxia e tremores quando comparados com o grupo AYA. No teste da atividade motora, o grupo que recebeu AYA 1X + morfina apresentou menor atividade locomotora do que o grupo que recebeu apenas a morfina, porém após 2h houve aumento da locomoção em relação a todos os outros. Os resultados obtidos no teste da placa quente demonstram uma potencialização dos efeitos da morfina, embora estes resultados não sejam confirmados pelo teste de contorções abdominais (CA) e formalina. Também não foi demonstrada qualquer interação no grupo administrado com a associação de chá e morfina no teste do trânsito intestinal. O chá isoladamente não apresentou efeito antinociceptivo no teste da placa quente, mas apresentou efeito antinociceptivo central e periférico nos testes de CA e formalina. Ao se avaliar qualitativamente o efeito da associação AYA e propofol, no teste do SF observou-se uma potencialização dos tremores induzidos pelo chá, que se manifestaram mais intensos e prolongados. No teste do rota-rod foi observado uma tendência de prejuízo no grupo que recebeu o chá e em seguida o anestésico. Já no teste do tempo de sono, AYA 1X diminuiu este parâmetro, portanto, interferindo com os efeitos do propofol. Em síntese, o conjunto de resultados indica alguma interação no que se refere à associação do chá de ayahuasca com a morfina e o propofol. Essas interações foram discretas e necessitariam de experimentação clínica apropriada para verificar sua ocorrência no ser humano. / Ayahuasca tea (AYA) is a beverage with psychoactive properties, prepared by the cooking of two plants: Banisteriopsis caapi (Spruce ex Griseb.) C.V. Morton (Malpighiaceae) (stem bark) and the leaves of Psychotria viridis (Ruiz & Pav.) (Rubiaceae). The major hallucinogenic compound present in P. viridis is DMT, but when it is ingested by oral route it is quickly inactivated by MAO-A present in the bowel, which is avoided by the combination of â- carbolines IMAO, present in B. caapi. Despite the constantly increasing use of AYA, there are few studies about the possible interactions produced by this tea in association with other drugs. The aim of this study was to evaluate the possible interactions between AYA and two other drugs used in anesthesia procedures: morphine and propofol; with doses established from the amount ingested by people in the rituals (equivalent of 120 mg/kg). The doses tested varied from 120 mg/kg (1X or 1 dose), to 2400 mg/kg (20X or 20 doses). Concerning pharmacological screening test (PST), AYA showed some signs of toxicity when administered by ip route (decreased of motor activity, hypersensitivity about stimulus and intense tremor). The oral route was better tolerated than ip. Administration of AYA (1X and 10X) did not interfered with motor coordination in the rota-rod test, but AYA 10X showed a biphasic effect on the motor activity test, because it decreased the initial ambulation (until 30 min), followed by an increase between 2h and 4h. AYA 10X increased the sleeping time induced by hexobarbital, however when AYA was administered 24h before hexobarbital did not occurred any interference in the sleeping time. Concerning grooming, the groups treated with AYA 10X showed a decrease of this signs. Results of association of AYA + morphine on the PST, mice showed Straub tail more intense and durable when compared with morphine group and ataxia and tremor when compared with AYA group. In the test of motor coordination, the group treated with the association of drugs, showed a lower motor activity when compared with the morphine group followed by an increase after 2h when compared to the other groups. The results obtained in hot plate test showed a potencialization of the morphine effects; however these results are not confirmed by abdominal contortions and formalin test. Intestinal transit test did not show any results about interaction. To qualitatively evaluate the effect of the association AYA + propofol in the PST, the data showed a potencialization of tremors induced by AYA more intense and durable. In the rota-rod test was observed a diminishing tendency in the AYA + propofol group. On the sleeping time test, AYA 1X decreased the sleeping time induced by propofol. Therefore, AYA interfered with the propofol effects. In summary, the whole results indicate some association interaction among AYA and morphine and propofol. These interactions were subtle and need proper clinical experimentation to verify its occurrence in humans. / TEDE / BV UNIFESP: Teses e dissertações

Made available in DSpace on 2015-07-22T20:50:40Z (GMT). No. of bitstreams: 0 Previous issue date: 2012-02-22. Added 1 bitstream(s) on 2015-08-11T03:26:01Z : No. of bitstreams: 1 Publico-12449.pdf: 2083853 bytes, checksum: fc7929ee968e83049b55729492ddf124 (MD5) / Introdução: Pacientes cirróticos frequentemente são submetidos a procedimentos de endoscopia digestiva alta diagnóstica ou terapêutica. A cirrose hepática pode prejudicar o metabolismo das drogas utilizadas para sedação devido às alterações de função hepática, com possíveis consequências para a eficácia e a segurança durante os procedimentos. Idealizamos um estudo comparando dois esquemas para sedação durante endoscopia digestiva neste grupo de pacientes: propofol associado a fentanil e midazolam associado a fentanil. Objetivos: comparar os dois esquemas de sedação propostos quanto à eficácia (proporção de exames completos realizados com o esquema inicialmente proposto), segurança (ocorrência de complicações relacionadas à sedação) e tempo de recuperação (definido como tempo entre o término do exame endoscópico e a alta ambulatorial). Pacientes e método: realizamos estudo prospectivo aleatorizado no período de fevereiro de 2008 a fevereiro de 2009. Foram incluídos para análise 210 pacientes cirróticos ambulatoriais, distribuídos em dois grupos: Grupo Midazolam (110 pacientes) e Grupo Propofol (100 pacientes). A dose inicialmente proposta de sedação foi, para o grupo Midazolam, 0,05 mg/kg associado a fentanil, 50 μg, por via intravenosa; e para o grupo Propofol, 0,5mg/kg associado a fentanil, 50 μg, por via intravenosa. Resultados: Não houve diferença entre os grupos quando comparados em relação à idade, sexo, peso, etiologia da cirrose, classificação de Child-Pugh ou ASA, bem como em relação ao tipo de procedimento endoscópico realizado (exame diagnóstico, ligadura elástica ou escleroterapia de varizes). A sedação com propofol e fentanil mostrou-se mais eficaz (100% vs. 88.2% - p <0,001) e com menor tempo de recuperação que a sedação com midazolam associado a fentanil (16,23 DP 6,84 min vs. 27,40 DP 17,19 min, respectivamente - p < 0,001). A ocorrência de complicações foi semelhante nos dois grupos (14% vs. 7,3% - p = 0,172). Conclusão: Ambos os esquemas mostraram-se seguros. A sedação com propofol e fentanil foi mais eficaz e apresentou tempo de recuperação mais curto quando comparado ao midazolam associado ao fentanil. Propofol deve ser considerado como alternativa para sedação durante endoscopia digestiva alta em pacientes cirróticos ambulatoriais. / Background: Cirrhotic patients often undergo diagnostic or therapeutic upper gastrointestinal endoscopy. The liver cirrhosis might impair the metabolism of drugs used to sedation due to changes in liver function, with possible consequences for the efficacy and safety during procedures. We designed a study to compare two regimens for sedation during endoscopy in this group of patients: propofol with fentanyl and midazolam with fentanyl. Objectives: To compare the two schemes proposed regarding the sedation efficacy (proportion of complete procedures using the initial proposed scheme), safety (occurrence of sedation-related complications) and recovery time (defined as time between the end of the procedure and ambulatory discharge). Patients and methods: We performed a prospective randomized controlled trial conducted between February 2008 to February 2009. Two hundred and ten cirrhotic outpatients were included and randomized in two groups: Midazolam Group (110 patients, 0.05 mg / kg associated with fentanyl, 50 mg intravenously) and Propofol Group (100 patients, 0.5 mg / kg combined with fentanyl, 50 mg intravenously). Results: There were no differences between groups regarding age, sex, weight, etiology of cirrhosis, classification Child-Pugh or ASA classification, as well as to the type of procedure exam was performed (diagnostic test, band ligation or sclerotherapy for esophageal varices). Sedation with propofol and fentanyl was more efficacious (100% vs. 88.2% - p <0.001) and had a shorter recovery time than sedation with midazolam to fentanyl (16.23 ± 6.84min vs. 27.40 ± 17.19 min, respectively - p <0.001). Complications rate were similar in both groups (14% vs. 7.3% - p = 0.172). Conclusion: Both sedation regimens were safe in this setting. Sedation with propofol and fentanyl was more efficacious and had shorter recovery time when compared to midazolam plus fentanyl. Propofol should be considered as an alternative to sedation during upper GI endoscopy in cirrhotic outpatients. / TEDE / BV UNIFESP: Teses e dissertações

Made available in DSpace on 2014-06-11T19:32:51Z (GMT). No. of bitstreams: 0 Previous issue date: 2006-12-01Bitstream added on 2014-06-13T19:43:38Z : No. of bitstreams: 1 duque_ctn_dr_jabo.pdf: 940048 bytes, checksum: 7cf59ce6ead86a57d64eaccbc29434ce (MD5) / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / A anestesia total intravenosa tem sido bastante empregada na neuroanestesia em humanos, geralmente para evitar o efeito vasodilatador do óxido nitroso (N20) e outros agentes voláteis. Dessa forma, este estudo determinou, em cães, os efeitos da anestesia com infusão contínua de propofol em diferentes doses, associada ou não ao N20, sobre variáveis intracranianas, cardiovasculares e índice biespectral (BIS). Foram utilizados 32 cães adultos distribuídos em quatro grupos de oito animais, denominados grupo propofol decrescente + N20 (GPDO, n=8), grupo propofol decrescente (GPD, n=8), grupo propofol crescente + N20 (GPCO, n=8) e grupo propofol crescente (GPC, n=8). Os animais foram induzidos à anestesia pela administração intravenosa de propofol (10mg/kg). Após intubação orotraqueal, o GPDO recebeu N20 a 70% e 02 a 30%. Em seguida, iniciou-se a infusão contínua de propofol na dose de 0,8mg/kg/min. A dose do anestésico foi reduzida para 0,6mg/kg/min e então para O,4mg/kg/min, respeitando um intervalo de 50 minutos entre cada uma. O mesmo protocolo foi adotado para o GPD, substituindo-se o fluxo diluente por 02 a 100%. Para GPCO e GPC, iniciou-se a infusão de propofol na dose de O,4mg/kg/min. A dose do anestésico foi acrescida para O,6mg/kg/min e depois para 0,8mg/kg/min, respeitando um intervalo de 50 minutos entre cada uma, sendo que o fluxo diluente no GPCO foi de N20 a 70% e 02 a 30%, e o GPC recebeu 02 a 100%. Os dados foram submetidos à análise de variância de uma via seguida pelo teste de Tukey (p<0,05) para detectar diferenças entre os grupos. Para comparação dos momentos ao longo do tempo utilizou-se a análise de variância de uma via para medições repetidas seguida pelo teste de Tukey (p<O,05)... / Total intravenous anesthesia has been used in neuroanesthesia as a method to avoid the cerebral vasodilating effects of nitrous oxide (N20) and volatile agents. The aim of this study was to evaluate intracranial and cardiovascular variables, and also bispectral index (BIS) in dogs submitted to continuous infusion rates of propofol combined with nitrous oxide (N20). Thirty two adult dogs were assigned into four groups composed by eight animais: group propofol decreasing + N20 (GPDO, n=8); group propofol decreasing (GPD, n=8); group propofol increasing + N20 (GPCO, n=8); and group propofol increasing (GPC, n=8). Anesthesia was induced with propofol administered intravenously (10mg/kg). After orotracheal intubation, GPDO received 70% N20 and 30% 02. Subsequently, continuous infusion of propofol was begun using a primary dose of 0.8mg/kg/min. The anesthetic dose was decreased to 0.6mg/kg/min, and then to O.4mg/kg/min, respecting an interval of 50 minutes between them. The GPD was submitted to the same protocol; however, the diluent flow was substituted by 100% 02. For GPCO and GPC, continuous infusion of propofol was begun using a primary dose of 0.4mg/kg/min. The anesthetic dose was increased to 0.6mg/kg/min, and then to 0.8mg/kg/min, respecting an interval of 50 minutes between them. The GPCO received 70% N20 and 30% O2 and GPC 100% O2. The data were submitted to One way Anova following Tukey test (p<0.05) to detect differences between groups. For comparisons between moments, one way RM Anova followed by Tukey test (p<0.05) was used. Cerebral perfusion pressure (CPP), BIS, heart rate (HR), systolic (SAP) diastolic (DAP), and mean arterial (MAP) pressures, systemic vascular resistance (SVR) and index (ISVR) diminished with the highest infusion rate in ali groups. Cardiac output (C O) and index (CI) increased using 0.6mg/kg/min dose of propofol in GPDO and GPD groups, with the highest ...(Complete abstract, click electronic access below)

Made available in DSpace on 2014-06-11T19:27:56Z (GMT). No. of bitstreams: 0 Previous issue date: 2010-02-25Bitstream added on 2014-06-13T19:56:56Z : No. of bitstreams: 1 mazoti_ma_me_botfm.pdf: 303335 bytes, checksum: 4f4fd9740f381b988fb0ea70236c2a7c (MD5) / Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / Introdução. Cirurgia gera no paciente uma resposta inflamatória conhecida como stress. Não está esclarecido o papel dos anestésicos voláteis e venosos na modulação do perfil de citocinas inflamatórias em pacientes saudáveis submetidos a cirurgias eletivas pouco invasivas. Assim, o objetivo deste trabalho foi estudar o perfil das citocinas IL-1 , IL- 6, IL-8, IL-10, IL-12 e TNF- frente à anestesia inalatória com isoflurano e intravenosa com propofol, em pacientes saudáveis submetidos a cirurgias eletivas pouco invasivas. Métodos. Quarenta pacientes ASA I, submetidos à cirurgia de otorrinolaringologia, foram alocados ao acaso para receber anestesia com isoflurano 1 CAM (concentração alveolar mínima) (n = 20) ou com propofol 2 a 4 μg mL-1 (n = 20). Também foram administrados fentanil 5 mg kg-1 e brometo de rocurônio 0,6 mg kg-1 a todos os pacientes. Foram coletados 10 mL de sangue venoso de cada paciente em cada um dos seguintes momentos: antes do início da cirurgia e anestesia (M1), 2 h após o início da cirurgia (M2) e no dia posterior ao ato anestésico-cirúrgico (M3). As concentrações plasmáticas das interleucinas IL-1β, IL-6, IL-8, IL-10 e IL-12 e do fator de necrose tumoral TNF-α foram mensuradas em cada amostra pela técnica de citometria de fluxo, utilizando o método Cytometric Bead Array (CBA). Amostras de sangue venoso de quinze voluntários não submetidos a stress também foram coletadas como controle, dosando nessas amostras as mesmas citocinas. Resultados. A comparação das concentrações plasmáticas de citocinas entre os grupos de anestésicos (M1) e o grupo de voluntários mostrou aumento de IL-8 nos grupos propofol e isoflurano. Os pacientes dos grupos isoflurano e propofol apresentaram baixas concentrações plasmáticas das citocinas pró-inflamatórias IL-1 , IL-12 e TNF- e da anti-inflamatória... / Introduction. A surgery causes in the patient an inflammatory response known as stress. The role of volatile and venous anesthetics on the modulation of inflammatory cytokine profile in healthy patients subjected to minimally invasive elective surgeries is not elucidated. Thus, the aim of this paper was to study the profile of cytokines IL-1 , IL-6, IL-8, IL-10, IL-12 and TNF- under inhalation anesthesia with isoflurane and intravenous anesthesia with propofol in healthy patients subjected to minimally invasive elective surgeries. Methods. Forty ASA-I patients, subjected to otorhinolaryngology surgery, were randomly allocated to receive anesthesia with isoflurane 1 MAC (minimum alveolar concentration) (n = 20) or propofol 2 to 4 μg mL-1 (n = 20). Fentanyl 5 mg kg-1 and rocuronium bromide 0.6 mg kg-1 were also administered to all patients. Venous blood (10 mL) was collected from each patient at each of the following times: before the beginning of surgery and anesthesia (T1), 2 h after the beginning of surgery (T2), and on the day after the anesthetic-surgical procedure (T3). Plasma concentrations of interleukins IL-1β, IL-6, IL-8, IL-10 and IL-12 and tumor necrosis factor (TNF-α) were measured in each sample through flow cytometry technique by using the method Cytometric Bead Array (CBA). Venous blood samples from fifteen volunteers not subjected to stress were also collected as control, and the same cytokines were measured. Results. Plasma concentrations of IL-8 increased in Propofol and Isoflurane groups (T1), compared to the group of volunteers. Patients of Isoflurane and Propofol groups had low plasma concentrations of proinflammatory cytokines IL-1 , IL-12 and TNF- and anti-inflammatory cytokine IL-10 throughout the study period. On the other hand, plasma concentration of IL-6 significantly increased at T2 and T3 in the group of patients... (Complete abstract click electronic access below)

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

Submitted by (edna.saturno@ufrpe.br) on 2016-08-12T12:21:41Z No. of bitstreams: 1 Charles Nunes e Silva.pdf: 865500 bytes, checksum: 3df986a247dedbfd019fc1390f69fb24 (MD5) / Made available in DSpace on 2016-08-12T12:21:41Z (GMT). No. of bitstreams: 1 Charles Nunes e Silva.pdf: 865500 bytes, checksum: 3df986a247dedbfd019fc1390f69fb24 (MD5) Previous issue date: 2008-02-12 / In this work the propofol and ketamine chemical restraint 30 pretreated goats with acepromazine, through clinical and laboratory aspects. The animals were divided into three groups and received acepromazine and ketamine associations group - AQ (n = 10); acepromazine and propofol group - AP (n = 10); and control - C (n = 10) who received no medication. We evaluated the decubitus time (DT), ruminal movements (MR), heart rate (HR) and rectal temperature (RT); and measurement of blood urea levels, creatinine and aspartate aminotransferase (AST), and leukocyte count. We used the nonparametric Kruskal-Wallis test for comparison between groups, adopting a 5% significance level. There was a significant difference (p <0.05) for MR, HR and TD compared between groups. Laboratory tests showed significant changes (p <0.05) in urea values, AST and leukocytes. From the results obtained it can be concluded that the studied drugs have characteristics suitable for chemical containment for short procedures. The association acepromazine and propofol was more appropriate to allow faster recovery, as prolonged recumbent is harmful goats. / Neste trabalho avaliou-se o propofol e a quetamina na contenção química de 30 cabras pré-tratadas com acepromazina, através de aspectos clínicos e laboratoriais. Os animais foram divididos em três grupos, que receberam associações de acepromazina e quetamina, Grupo – AQ (n = 10); acepromazina e propofol, Grupo – AP (n = 10); e Controle – C (n = 10), que não recebeu nenhuma medicação. Foram avaliados o tempo de decúbito (TD), movimentos ruminais (MR), freqüência cardíaca (FC) e temperatura retal (TR); e mensuração das dosagens sangüíneas de uréia, creatinina e aspartato aminotransferase (AST), e contagem de leucócitos. Utilizou-se o teste não paramétrico de Kruskal-Wallis para comparação entre os grupos, adotando-se 5% de significância. Houve diferença significativa (p<0,05) para MR, FC e TD na comparação entre os grupos. Os exames laboratoriais apresentaram alterações significativas (p<0,05) nos valores de uréia, AST e leucócitos. A partir dos resultados obtidos pode-se concluir que os fármacos estudados apresentam características adequadas para contenção química em procedimentos de curta duração. A associação acepromazina e propofol se mostrou mais adequada por permitir recuperação mais rápida, uma vez que o decúbito prolongado é nocivo aos caprinos.

Abstract Cessation of the blood circulation for some time during surgery of the aortic arch and repair of congenital heart defects is normally required to allow a bloodless operation field. Hypothermia is the most important mechanism for end-organ protection, particularly the brain, during such operations. Cardiopulmonary bypass is used for core cooling before total hypothermic circulatory arrest (HCA) or selective cerebral perfusion (SCP) are initiated. During hypothermic cardiopulmonary bypass, pH can be managed according to either pH- or alpha-stat principles. In the present work, the optimal pH management strategy for operations requiring HCA or SCP was explored. An experimental porcine model was used. Firstly, outcome was evaluated in a HCA model using either the α- or pH-stat perfusion strategy (I). Secondly, we sought to determine which acid-base management is more effective in attenuating ischemic brain injury during combined HCA and embolization conditions (II). In the third study, the impact of propofol anesthesia and α-stat perfusion strategy on outcome was explored (III). Finally, the acute effects of perfusion strategies in a SCP porcine were compared (IV). Hemodynamics, temperature, EEG (I-III), brain microdialysis, intracranial pressure (I-III), brain tissue oxygen partial pressure (I-III), and intravital microscopy (IV) were monitored intraoperatively. In the chronic studies, survival, postoperative neurologic recovery and brain histopathologic examination were evaluated (I-III). pH-stat strategy was associated with superior outcome compared to the α-stat strategy during a 75-minute period of deep HCA (I). In addition, despite the pH-stat strategy-related cerebral vasodilatation, this method provided better neuroprotection in a setting of cerebral particle embolization prior to a 25-minute period of deep HCA (II). Propofol anesthesia combined with α-stat perfusion strategy was observed to deteriorate the brain injury during HCA evaluated by key brain microdialysis parameters (III). Finally, when employing moderately hypothermic SCP, the differences between pH- and α-stat strategies in cerebral metabolism and microcirculation were minimal. These findings are clinically relevant since α-stat perfusion strategy is still the most commonly used acid-base perfusion strategy during hypothermic cardiopulmonary bypass in adults, and propofol one of the most used anesthetics in clinical practice. It is also noteworthy that the pH-stat strategy is not currently used in adults because of the perceived increased risk of atherosclerotic embolization. However, the advantage of pH-stat strategy over α-stat strategy could not be observed when employing SCP.

Philosophiae Doctor - PhD / Conscious sedation or moderate sedation and analgesia is an effective and popular alternative option for procedures outside the operating theater. If conscious sedation is a viable alternative to general anaesthesia then we as sedation practitioners must use safe sedation techniques in facilities that meet all the requirements for safe practice. Three studies were done to determine the safety and efficacy of conscious sedation outside the operating theatre. In the first study post sedation satisfaction in one hundred children aged 3-9 years was evaluated. It was extremely important to determine whether the combination of midazolam, ketamine and propofol, called an advanced sedation technique (SASA, 2015), can be safely used for paediatric sedation outside the operating theatre. The incidence of side-effects after conscious sedation using multiple drugs were documented. It is clear that intravenous sedation with midazolam, ketamine and propofol is safe and effective to use. There may be side effects but they are not long lasting and usually not life-threatening. In the second study intravenous sedation was administered to 447 adults (aged 18 years and older) using fentanyl (sublimazeR), ketamine (ketalar), midazolam (dormicum) and propofol (Diprivan) (FKMP) called an advanced sedation technique. Post sedation satisfaction, post sedation recovery on arrival home, and the relationship between side effects and different dental procedures were evaluated. The results of the study show that side effects are possible, and can be expected, when we use sedative and analgesic drugs for sedation. However, we report a low incidence of side effects when we compare it with other studies in literature as mentioned. It is known that the use of combinations of drugs may cause unforeseen synergistic pharmacological effects which can be lifethreatening. Our results show that the drugs used can be safely used for advanced sedation techniques. In trying to demonstrate the safety of sedative and analgesic agents used during sedation we looked at the haemodynamic parameters, duration of sedation, pulse rate and systolic blood pressure, in the third study. The sedation records of 335 patients for dental surgery were assessed for the period 2010 – 2011. Our results show the mean Duration of sedation is substantially and statistically significantly greater with combination FKMP than with the other combinations. The mean duration of sedation is not significantly different between ketamine and propofol (KP) and fentanyl, ketamine and propofol (FKP) (Figure 10). The use of polypharmacy regarding the combination of drugs, specifically FKMP, will cause a longer duration of sedation. This has implications for safety, as well as the side effect profile during and after sedation. When we use combinations of drugs patients were more comfortable which shows that we do not yet have a single drug that has all the characteristics of an ideal drug for sedation. Different combinations of drugs are used by other practitioners with a higher incidence of side effects. It is difficult to explain the higher values of blood pressures when all four drugs were used. It may have been a ketamine effect, although one would not expect this when using propofol with ketamine. In clinical terms the higher blood pressures are no reason for concern as all our patients were classified as ASA I and II. Our research study support the view that ketamine can be used safely outside the operating theatre with exciting possibilities for Third World countries for procedures outside the operating theatre. Sedation can be considered a reasonable alternative to general anaesthesia for certain surgical procedures in the Third World. Sedation will be an attractive option not only as far as costs are involved but also the availability of sedation providers. The important lesson from all the results is that sedation providers must be trained in procedural sedation as defined by all international sedation guidelines. We proved in this research study that sedation can be done safely, however we need to make a contribution to train sedation providers. Sedation will become an attractive alternative to general anaesthesia because of the low side-effect profile and high patient satisfaction. It is interesting that few studies are available that looked at this aspect of sedation. It is clear that a high side-effect profile can contribute to an unsafe sedation technique. Severe nausea and vomiting can cause numerous haemodynamic disturbances and dehydration. Our research study support the findings of the study by Lapere et al., (2015) that there is a high rate of patient satisfaction, and a low side-effect profile during and after sedation. This is an extremely important research study and the results are crucial as far as an option for healthcare in developing countries. Sub-Saharan Africa is a densely populated and resource poor subcontinent that provides unique challenges in patient care. These challenges include a lack of facilities and staff for the performance of operative as well as non-operative procedures. In conclusion, we feel that we are part of Sub-Saharan Africa with all the problems mentioned as far as provision of healthcare is concerned. This research study can make a crucial contribution to safe and cost-effective management of healthcare in Africa for procedures outside the operating theatre.

Propofol is one of the most commonly used general anesthetics in the world, and yet precisely how it enables loss of consciousness still eludes us. It exhibits rich spectral characteristics on electroencephalogram (EEG) recordings from human patients, including alpha oscillations (8-14 Hz) and Slow Wave Oscillations (SWO, 0.5-2.0 Hz). Additionally, these two oscillations are phase-amplitude coupled (PAC) in a dose-dependent manner: low doses cause “trough-max” coupling where alpha power is maximal during the trough of the SWO cycle, while high doses cause “peak-max” coupling where alpha power is maximal during the peak of the SWO cycle. These propofol rhythms occur at the same frequencies as sleep spindles and sleep SWO, and likely use the same well-studied thalamocortical circuitry. The study of anesthesia therefore represents a safe method for investigating both how our brains sleep and the much-debated components of consciousness. In this dissertation, I use Hodgkin-Huxley-style computational models of both the thalamus and cortex to explain how the direct and indirect effects of propofol can generate such spectral phenomena. In the first part of this dissertation, I discuss results from a thalamic model. I illustrate how GABAA potentiation by propofol can create sustained alpha oscillations in the hyperpolarized thalamus by utilizing the same mechanisms used by sleep spindles. I then show how the thalamus, under artificial SWO conditions, can output trough-max or peak-max PAC depending on background excitation, GABAA potentiation, and H-current conductance. In the second part of this dissertation, I discuss results from a thalamocortical model. My analysis reveals how, in a simulated EEG signal, trough-max PAC can arise from competition between thalamocortical and intracortical synaptic currents, while peak-max PAC can arise from their cooperation. Furthermore, the coherence of cortical SWO rhythms can directly control whether the system expresses trough-max or peak-max PAC, while the indirect effects of propofol on acetylcholine are required for both PAC states. This culmination of years of work reveals just how complex the inner workings of anesthesia can be in enabling its profound effects.