Thesis (M.S.)--University of Michigan, 1972.

Thesis (M.S.)--University of Michigan, 1972.

A research report submitted to the Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, in partial fulfilment of the requirements for the degree of Master of Medicine in the branch of Anaesthesiology Johannesburg, 2013 / Background: Microbial contamination of multi-dose vials is one of the mechanisms by which transmission of pathogens to patients can occur in anaesthesia. Common practice at Chris Hani Baragwanath Academic Hospital (CHBAH) is to use boluses of a self-prepared, multi-dose phenylephrine solution (referred to as the solutions) to treat hypotension, due to the vasodilatory effects of a spinal anaesthetic, in stable patients undergoing a caesarean section. Aims: The aims of this study were to determine if there was microbial contamination of the solutions used at CHBAH and to evaluate if appropriate labelling and aspiration practices were adhered to with regard to the solutions A sample was collected and the labelling data was documented from the solutions found in the obsteric theatres at CHBAH over a period of three months. The samples were sent to a laboratory for microbial investigation. Microbial contamination was identified in seven of 110 (6.36%) samples collected from the solutions. The name of the solution was indicated on all 110 (100%) containers and the concentration of the solution was indicated on 106 (96.36%) containers. The date the solution was prepared was indicated on 82 (74.55%) containers and the time the solution was prepared was indicated on 63 (57.27%) containers. Only nine (8.18%) of the healthcare workers that prepared the solutions confirmed it by placing a signature on the container. Labelling data was written directly on all 110 (100%) containers and a spike device was used in 71 (64.54%) containers. This study demonstrated microbial contamination of the solutions and that safe injection practices were not adhered to when intravenous medications were prepared and administered. This is important at CHBAH since a large proportion of South African patients are immunocompromised and susceptible to opportunistic infections. Inappropriate labelling of medications is a cause of medication administration errors and this may have serious legal implications for the anaesthetist.

Thesis (Ph. D.)--University of California, San Diego and San Diego State University, 2007. / Title from first page of PDF file (viewed May 29, 2007). Available via ProQuest Digital Dissertations. Vita. Includes bibliographical references (p. 57-65).

Phenylephrine (PE) is the most commonly used over-the-counter nasal decongestant. The problem associated with phenylephrine is that it undergoes extensive first pass metabolism in the intestinal gut wall leading to its poor and variable oral bioavailability. This research project aims at developing strategies in order to increase the oral bioavailability of PE by co-administration of GRAS compounds. A HILIC assay method was developed to detect the parent drug, phenylephrine (PE) and its sulfate metabolite (PES).The enzyme kinetic studies were done with phenolic dietary or GRAS compounds using LS180 human intestinal cell model, recombinant SULT enzymes and human intestinal cytosol (HIC). From the screening studies done, one inhibitor was selected in order to study the mechanism of inhibition. In conclusion the studies done in vitro provided a basis in order to predict in vivo intrinsic clearance through the sulfation pathway.

CoordenaÃÃo de AperfeiÃoamento de Pessoal de NÃvel Superior / Um estudo prospectivo, randomizado, duplo-cego, com grupos em paralelo e controle ativo foi conduzido para comparar os efeitos cardiovasculares da soluÃÃo aquosa de fenilefrina a 2,5% versus a 10% em pacientes diabÃticos do tipo 2, submetidos a angiografia fluoresceÃnica, e tambÃm para comparar a eficÃcia dessas soluÃÃes na dilataÃÃo pupilar. Os voluntÃrios foram atendidos no Hospital Santo InÃcio, em Juazeiro do Norte, CearÃ, e randomicamente alocados em dois grupos. Os pacientes no grupo A receberam uma gota de proximetacaÃna a 0,5%, de tropicamida a 1% e de fenilefrina a 2,5% em ambos os olhos, enquanto os do grupo B receberam proximetacaÃna a 0,5%, tropicamida a 1% e fenilefrina a 10%. A pressÃo arterial e a freqÃÃncia cardÃaca foram mensuradas cinco minutos antes e em vÃrios instantes apÃs a instilaÃÃo de fenilefrina no fÃrnice conjuntival ao longo de um perÃodo de trÃs horas. As alteraÃÃes no ritmo cardÃaco foram gravadas por uma unidade de Holter em todos os pacientes. A Ãrea pupilar foi calculada antes e sessenta minutos apÃs a instilaÃÃo de fenilefrina. Dos quarenta e trÃs pacientes envolvidos, 22 foram alocados no grupo A e 21, no grupo B. NÃo houve diferenÃa estatisticamente significante entre os grupos na mÃdia da pressÃo arterial sistÃlica apÃs a instilaÃÃo de fenilefrina. Essa observaÃÃo tambÃm foi vÃlida para todos os instantes em relaÃÃo à mÃdia da pressÃo diastÃlica, menos em um (150 minutos), onde o grupo da fenilefrina a 10% registrou valor mais alto (P = 0,0460). Um aumento significativo na mÃdia da pressÃo arterial (sistÃlica e diastÃlica - P < 0,001) foi igualmente verificado no momento da injeÃÃo endovenosa de fluoresceÃna nos dois grupos. NÃo se observou diferenÃa estatisticamente significante entre os grupos na mÃdia da freqÃÃncia cardÃaca. As mudanÃas no ritmo cardÃaco nÃo se relacionaram com o uso da fenilefrina em qualquer dos grupos. A magnitude da dilataÃÃo pupilar sessenta minutos apÃs o uso da fenilefrina nÃo foi diferente entre os grupos. Diante destes resultados, pÃde-se concluir que, apÃs uma Ãnica instilaÃÃo, a fenilefrina a 2,5% comparada à fenilefrina a 10% foi igualmente capaz de induzir e de manter adequada midrÃase em pacientes diabÃticos do tipo 2, submetidos a angiografia fluoresceÃnica. O aumento na pressÃo arterial que seguiu a injeÃÃo de fluoresceÃna, principal mudanÃa nos parÃmetros cardiovasculares analisados, provavelmente nÃo se relacionou diretamente com qualquer das concentraÃÃes de fenilefrina usadas / A prospective, randomized, double-blind study with groups in parallel and active control was conducted to compare the cardiovascular effects of aqueous solution of phenylephrine 2.5% versus 10% in diabetic type 2 patients undergoing fluorescein angiography, and also to compare their efficacy on pupillary dilation. The volunteers at the Santo InÃcio Hospital, in Juazeiro do Norte, Cearà were randomized into two groups. Patients in group A received one drop of 0.5% proxymetacaine, 1% tropicamide, and 2.5% phenylephrine in both eyes, whereas those in group B received 0.5% proxymetacaine, 1% tropicamide, and 10% phenylephrine. Blood pressure and heart rate were measured five minutes before and several times after phenylephrine eyedrop instillation for a period of three hours. Alterations in cardiac rhythm were recorded by Holter in all patients. Pupil surface was measured before and sixty minutes after phenylephrine instillation. Forty three patients were allocated into 22 patients (group A) and 21 patients (group B). There was no significant difference in the mean systolic blood pressure after phenylephrine instillation between the two groups. This observation was also valid for all but one instant where the mean diastolic blood pressure (150 minutes) was significantly higher in 10% phenylephrine group (P = 0.0460). A significant raise in mean systolic and diastolic blood pressure was registered at the moment of intravenous fluorescein injection in both groups (P < 0.001). No statistically significant difference was detected in the mean heart rate. Changes in cardiac rhythm could not be attributed to phenylephrine in either group. The amount of pupillary dilation at sixty minutes did not differ between the groups. In conclusion, after a single dose instillation, 2.5% phenylephrine compared to 10% phenylephrine was equally able to induce and keep adequate pupil dilation in diabetic type 2 patients undergoing fluorescein angiography. The raise in blood pressure following fluorescein injection was the main change observed in the cardiovascular parameters analyzed and probably did not relate to the use of any phenylephrine concentration

O uso de vasoconstritores associados a soluções anestésicas locais em pacientes que fazem uso de antidepressivos tricíclicos gera controvérsias por seu possível efeito sobre o sistema cardiovascular. Este estudo teve por objetivo avaliar alterações na pressão arterial e frequência cardíaca de ratos tratados ou não com antidepressivos tricíclicos, após a infiltração em fundo de sulco vestibular e injeção intravenosa de adrenalina, felipressina e fenilefrina, em doses equivalentes (DE) às quantidades presentes em 2, 8 e 32 tubetes de anestésico local. Foram utilizados 42 ratos Wistar machos pesando de 300 a 500 gramas, tratados por gavagem durante sete dias com cloridato de amitriptilina (0,3mg/Kg). No oitavo dia, após anestesia do animal, um cateter foi implantado na artéria carótida, a cânula arterial foi conectada a um transdutor de pressão acoplado ao sistema PowerLab 4/30 de registro invasivo de pressão arterial, utilizando software adequado. Após a infiltração e injeção intravenosa, um intervalo de 30 minutos foi respeitado entre as doses para evitar efeito cumulativo. Para a análise dos resultados foi utilizada análise de variância de medidas repetidas a um ou dois critérios de classificação, seguido do teste de Holm-Sidak. Observou-se que o tratamento com amitriptilina provocou elevação significativa na frequência cardíaca no grupo tratado em relação ao controle (n=21) (258,252 ± 6,32 e 221,790 ± 7,22, respectivamente, p<0,001) e queda significativa na pressão arterial do grupo tratado comparado ao grupo controle (101,80 ± 2,52 e 110,12 ± 2,91, respectivamente, p<0,05). A adrenalina mesmo utilizada em via infiltrativa apresentou efeito cronotrópico positivo em todas as doses (2 DE 197.15 ± 3,74 e 240.67 ± 8,14, 8 DE 212.44 ± 6,72 e 238.17 ± 10,05, e 32 DE 246.45 ± 11,13 e 251.32 ± 10,46 bpm, para controle e tratado, respectivamente, p>0,05). Na injeção intravenosa, mesmo com o nítido aumento de pressão e da frequência cardíaca, não houve diferença significativa entre o grupo controle e tratado. O tratamento com amitriptilina potencializa ligeiramente a resposta hipertensora após infiltração de adrenalina. A felipressina promove menores alterações de pressão arterial e a fenilefrina mostrou-se o vasoconstritor mais potente dos três estudados, produzindo alterações importantes de pressão arterial e de frequência cardíaca, mesmo por via infiltrativa, em doses superiores a 8 tubetes. / The use of vasoconstrictors associated with local anesthetic solutions in patients taking tricyclic antidepressants generates controversies because of its possible effect on the cardiovascular system. The aim of this study was to evaluate changes in blood pressure and heart rate of rats treated or not with tricyclic antidepressants after infiltration in buccal groove and intravenous injection of epinephrine, felypressin and phenylephrine in equivalent doses (ED) to the amounts present in 2, 8 and 32 local anesthetic tubes. We used 42 male Wistar rats weighing 300 to 500 grams, treated by gavage for seven days with amitriptyline hydrochloride (0.3mg / kg). On the eighth day, after anesthesia of the animal, a catheter was implanted in the carotid artery, the arterial cannula was connected to a pressure transducer coupled to invasive blood pressure recording PowerLab 4/30 system using appropriate software. After infiltration and intravenous injection, a 30-minute interval was observed between doses to avoid cumulative effect. For the analysis of the results we used Repeated measures analysis of variance to one or two classification criteria, followed by the Holm-Sidak test. It was observed that treatment with amitriptyline caused a significant increase in heart rate in the treated group in relation to the control (n = 21) (258,252 ± 6.32 and 221,790 ± 7,22, respectively, p <0.001) and a significant decrease in blood pressure of the treated group compared to the control group (101.80 ± 2.52 and 110.12 ± 2.91, respectively, p <0.05). The epinephrine used in the infiltrative route showed a positive chronotropic effect at all doses (2 ED 197.15 ± 3,74 and 240.67 ± 8,14, 8 ED 212.44 ± 6,72 and 238.17 ± 10,05, and 32 ED 246.45 ± 11,13 and 251.32 ± 10,46 bpm, for control and treated, respectively, p <0.05). In intravenous injection, even with the clear increase in blood pressure and heart rate, there was no statistically significant difference between the control and treated groups. Treatment with amitriptyline slightly potentiates the hypertensive response after infiltration of epinephrine. Felypressin promotes lower blood pressure changes and phenylephrine proved to be the most potent vasoconstrictor of the three studied, producing important changes in blood pressure and heart rate, even through infiltration, in doses greater than 8 tubes.

Made available in DSpace on 2015-07-22T20:49:57Z (GMT). No. of bitstreams: 0 Previous issue date: 2010-05-26 / A redução da massa de anestésico local é utilizada para minimizar os efeitos da hipotensão arterial, relacionados com raquianestesia para cesariana, diminuindo a incidência de eventos adversos maternos e preservando o bem-estar fetal. Esta estratégia tem o risco de resultar em anestesia insuficiente. Por outro lado, a hipotensão associada às maiores massas de anestésico local no espaço subaracnóideo pode ser controlada com infusão contínua profilática de fenilefrina.! Objetivo: Avaliar os efeitos da infusão contínua e profilática de fenilefrina para controle pressórico sobre os eventos adversos maternos e conceptuais em cesarianas com diferentes doses de bupivacaína na raquianestesia. Métodos: Foi realizado um estudo clínico prospectivo, não-aleatório, com 60 gestantes a termo, admitidas para cesariana eletiva. Todas as pacientes receberam raquianestesia com bupivacaína hiperbárica, acrescida de 5 mcg de sufentanil e 100 mcg de morfina. Foram alocadas em dois grupos, G12 e G8, na dependência da dose de bupivacaína hiperbárica administrada, 12 ou 8 mg, respectivamente. Foi realizada hidratação com 10 ml/Kg de solução de Ringer Lactato, 10 a 15 minutos antes da realização do bloqueio. Logo após, iniciou-se infusão contínua de 100 mcg/min de fenilefrina, com o objetivo de manter a pressão arterial dentro de limites estritos. Foram avaliados níveis sensitivos de bloqueio anestésico, consumo de vasopressores, incidência de eventos adversos maternos e condições do recém-nascido. Resultados: Os dados maternos mostraram que os dois grupos foram semelhantes, quanto ao nível de bloqueio anestésico, consumo de fenilefrina por unidade de tempo e incidências de hipotensão e hipertensão arterial, bradicardia, náuseas, vômitos, dispnéia, dor e tremores. Os dados conceptuais evidenciaram que os grupos foram semelhantes quanto à gasometria de artéria e veia umbilicais e lactato arterial e venoso. Todos os RN apresentaram pH > 7,2 e apenas 1 obteve pontuação < 7 no Apgar do primeiro minuto. Conclusões: Quando a pressão arterial é mantida dentro de controle rígido, por meio da infusão profilática contínua de fenilefrina, a incidência de eventos adversos maternos e conceptuais não difere quando a raquianestesia é realizada com 12 mg ou 8 mg de bupivacaína hiperbárica. / Background: Reduced local anesthetic dose is used for minimizing hypotension changes related with spinal anesthesia for cesarean section, optimizing both maternal and fetal outcomes. This strategy can result in neuroaxial block failure. On the other hand, the higher doses associated with hypotension can be controlled with continuous prophylactic infusion of phenylephrine. The present study assessed the effects of continuous infusion of phenylephrine under strict blood pressure control and the maternal-fetal outcomes in patients under spinal anesthesia for elective cesarean section with two anesthetic solution. Methods: The number of 60 patients, scheduled for elective cesarean section, was allocated into 2 non-randomized groups (30 individuals each) for this prospective clinical study identified as Group 12 (G12), who were administered 12 mg hyperbaric bupivacaine and; Group 8 (G8), who were injected with 8 mg hyperbaric bupivacaine. In both groups, the anesthetic solution was added to sufentanyl 5 !g and morphine 100 !g. Pre-hydration with Ringer Lactate solution – 10 ml/Kg. Continuous phenylephrine infusion started at the end of the spinal block, with a infusion rate of 100 !g/min under strict blood pressure control. Comparatively, sensitive anesthetic block level, vasopressor consumption, adverse maternal and neonate outcomes were evaluated. Results: The incidence of maternal adverse effects such as nausea, vomiting, dispnea, pain, tremor, and bradicardy, necessity of atropine, hypotension and hypertension showed no significant difference between groups. In addition, other parameters were evaluated in neonates, pH, pCO2, BE and lactate of umbilical vases and the consumption of phenylephrine per time unit. All neonates showed pH higher than 7.20, as well as the Apgar score higher than 7 at 5`; only one neonate of G12 showed the Apgar score lower than 7 at 1`. Conclusion: Strict arterial blood pressure performed with prophylactic continuous infusion of phenylephrine, doesn’t change the maternal and fetal outcomes in patients scheduled for elective cesarean section under spinal anesthesia. / TEDE / BV UNIFESP: Teses e dissertações

The present study was undertaken to investigate the origin of cocaine- and amphetamine-regulated transcript (CART) peptide immunoreactive (irCART) fibers observed in the nucleus of the solitary tract (NTS) and assess the role of CART peptide on phenylephrine (PE)-induced baroreflex. Immunohistochemical and retrograde tract-tracing studies showed that some of the irCART fibers observed in the NTS may have their cell bodies in the nodose ganglia. In urethane-anesthetized rats, intracisternal or bilateral intra-NTS microinjection of the CART peptide fragment 55-102 (0.1-3 nmol), referred to herein as CARTp, consistently and dose dependently attenuated PE-induced bradycardia. CARTp, in the doses used here, caused no significant changes of resting blood pressure or heart rate. Bilateral intra-NTS injections of CART antibody (1:500) potentiated PE-induced bradycardia. Injections of saline, normal rabbit serum, or concomitant injection of CARTp and CART antiserum into the NTS caused no significant changes of PE-induced baroreflex. The result suggests that endogenously released CARTp from primary afferents or exogenously administered CARTp modulates PE-induced baroreflex.

R-(-)-Phenylephrine (PE) is the most commonly used nonprescription oral nasal decongestant in the United States. It is a selective α1-adrenergic receptor agonist and has many years of safe usage. However, the efficacy of PE is controversial, due to its extensive pre-systemic metabolism, which leads to low and variable oral bioavailability (38 ± 9%, mean ± SD). Sulfation plays a very important role in pre-systemic metabolism of PE. The sulfation of PE occurs at its phenolic group, which is the preferred structural feature of many sulfotransferase (SULT) substrates. Compounds with phenolic groups have similar structures to PE, which may share the same SULT isoforms with PE and have the potential to inhibit PE sulfation. Co-administration of the phenolic compounds from the Food and Drug Administration’s (FDA) “Generally Recognized as Safe” (GRAS) list, Everything Added to Food in the United States (EAFUS), or dietary supplements along with PE could be an effective strategy to inhibit the pre-systemic sulfation of PE. The primary side effect of PE is hypertension. Since monoamine oxidase (MAO) inhibitors may increase the risk of hypertension, they should not be taken with PE. In order to increase the oral bioavailability and eventually improve the efficacy of PE, this research project aimed to investigate the feasibility of inhibiting the pre-systemic sulfation of PE with phenolic dietary compounds. Considering the safety issue, this research project also aimed to investigate whether these phenolic dietary compounds have inhibitory effects on MAO-A/B. A human colon adenocarcinoma epithelial cell line (LS180), which shows sulfation activity, was used as a model to test the effect of these phenolic compounds on the sulfation of PE. The extent of disappearance of PE was significantly (p < 0.05) decreased to the following (mean ± SEM, as % of control) when incubated with phenolic dietary compounds in LS180 cells for 14 - 19 hrs: curcumin 24.5 ± 14.0%, guaiacol 51.3 ± 8.0%, isoeugenol 73.9 ± 4.3%, pterostilbene 70.6 ± 4.2%, resveratrol 14.2 ± 28.0%, zingerone 52.4 ± 14.6%, and the combinations eugenol + propylparaben 42.6 ± 8.4%, vanillin + propylparaben 37.0 ± 11.2%, eugenol + propylparaben + vanillin + ascorbic acid 31.1 ± 10.9%, eugenol + vanillin 57.5 ± 20.6%, and pterostilbene + zingerone 36.5 ± 7.0%. The combinations of curcumin + resveratrol and curcumin + pterostilbene + resveratrol + zingerone almost completely inhibited PE disappearance. PE sulfate formation was inhibited 67.0 ± 4.2% (mean ± SEM, as % of control) by guaiacol and 71.7 ± 2.6% by pterostilbene + zingerone. The combinations of curcumin + resveratrol and curcumin + pterostilbene + resveratrol + zingerone inhibited ≥ 99% of PE sulfate formation. These results were consistent with those from analysis of the disappearance of PE in LS180 cells. These phenolic inhibitors for sulfation were also tested to see whether they have any inhibitory effects on MAO-A or B. Significant inhibition was found with curcumin, guaiacol, isoeugenol, pterostilbene, resveratrol, and zingerone on both MAO-A and B. Further kinetic studies were conducted to investigate the concentration of an inhibitor at which the enzyme activity is reduced by half (IC50) (mean ± SEM) of these inhibitors. The most potent inhibitor for MAO-A was resveratrol (0.313 ± 0.008 μM) followed by isoeugenol (3.72 ± 0.20 μM), curcumin (12.9 ± 1.3 μM), pterostilbene (13.4 ± 1.5 μM), zingerone (16.3 ± 1.1 μM), and guaiacol (131 ± 6 μM). The most potent inhibitor for MAO-B was pterostilbene (0.138 ± 0.013 μM), followed by curcumin (6.30 ± 0.11 μM), resveratrol (15.8 ± 1.3 μM), isoeugenol (102 ± 5 μM), and guaiacol (322 ± 27 μM). Since these phenolic compounds all have relatively low oral bioavailability, any MAO inhibition which could occur systemically is expected to be limited. Most inhibitory effects on MAO-A and B if any would be limited to the GI tract and liver. In conclusion, several compounds and combinations showed inhibition on PE sulfation in LS180 cell model, which may have potential to inhibit the pre-systemic sulfation of PE to improve its oral bioavailability. These compounds also showed the unexpected inhibition on human MAO-A and B with different potency, which could guide the selection of phenolic dietary compounds for further studies, along with the sulfation inhibition results and their pharmacokinetic (PK) properties such as bioavailability.