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In this thesis I examined molecular mechanisms involved in acute and chronic liver injury, and also studied basic pathways mediating tumour promotion. Acute hepatic failure secondary to paracetamol poisoning is associated with high mortality. C-jun (NH2) terminal kinase (JNK) is a member of the mitogen activated protein kinase family and is a key intracellular signaling molecule involved in the control of cell fate. Paracetamol induced hepatic JNK activation in both human and murine paracetamol hepatotoxicity, and in a murine model preceded the onset of hepatocyte death. JNK inhibition in vivo (using two JNK inhibitors with different mechanisms of action) markedly reduced mortality in murine paracetamol hepatotoxicity. In addition, delayed administration of JNK inhibitor was more effective than N-acetylcysteine following paracetamol poisoning in mice. JNK inhibition was not protective in acute carbon tetrachloride or anti-Fas antibody mediated hepatic injury, suggesting specificity for the role of JNK in paracetamol hepatotoxicity. Furthermore, disruption of the JNK1 or JNK2 genes did not protect against paracetamol-induced hepatic damage. Pharmacological JNK inhibition had no effect on paracetamol metabolism, but markedly inhibited hepatic TNF-alpha production following paracetamol poisoning. These data demonstrate a central role for JNK in the pathogenesis of paracetamol induced liver failure, thereby identifying JNK as an important therapeutic target in the treatment of paracetamol hepatotoxicity. Liver fibrosis with loss of tissue architecture and subsequent hepatic failure represents a massive healthcare burden worldwide. Expression of Galectin-3 (a beta-galactoside binding animal lectin) is upregulated in established human fibrotic liver disease, during the development of experimental liver fibrosis and is temporally and spatially related to the induction and resolution of experimental hepatic fibrosis. Disruption of the gene encoding Galectin-3 blocks transdifferentiation of precursors to myofibroblasts in vitro and in vivo, markedly attenuating hepatic scarring in a murine model of liver fibrosis. Inhibition of Galectin-3 expression by siRNA in primary murine and human hepatic stellate cells significantly reduced myofibroblast activation and procollagen(I) expression. The reduction in hepatic fibrosis observed in the Galectin-3-/- mouse occurred despite equivalent liver injury and inflammation, and similar tissue expression of TGF-beta. TGF-beta failed to transactivate Galectin-3-/- hepatic stellate cells, in contrast with wild type hepatic stellate cells. However TGF-beta stimulated signaling via Smad-2 and 3 was equivalent in both Galectin-3-/- and wild type hepatic stellate cells indicating that Galectin-3 is required for TGF-beta mediated myofibroblast activation and matrix production. This supports a novel and important mechanistic role for Galectin-3 in the regulation of myofibroblast activation and consequent liver fibrosis. Finally, in vivo siRNA knockdown of Galectin-3 inhibited myofibroblast activation following hepatic injury and may therefore provide a novel therapeutic approach to the prevention and treatment of liver fibrosis. CD98hc (a ligand for Galectin-3) constitutively and specifically associates with beta1 integrins and is highly expressed on the surface of human tumour cells irrespective of the tissue of origin. CD98hc promotes both anchorage- and serum-independent growth. Using chimeras of CD98hc and the type II membrane protein CD69 demonstrated that the transmembrane domain of CD98hc is necessary and sufficient for integrin association in cells. Furthermore, CD98hc/β1 integrin association is required for focal adhesion kinase-dependent phosphoinositol 3-hydroxykinase activation and cellular transformation. Amino acids 82-87 in the putative cytoplasmic/transmembrane region appear to be critical for the oncogenic potential of CD98hc and provide a novel mechanism for tumour promotion by integrins.

El presente trabajo tuvo como objetivo evaluar el impacto del uso de tecnología automatizada sobre la productividad y mejora del proceso de manufactura, en operaciones unitarias de fabricación de Paracetamol 500 mg + Diclofenaco sódico 50 mg tabletas recubiertas, mediante la transferencia tecnológica en las etapas de granulación, compresión y recubierta de las tabletas. La metodología consistió en desarrollar las etapas del proceso para la obtención de tabletas recubiertas, se utilizó el granulador de lecho fluido, amasador de alta velocidad, tableteadora rotativa y recubridora de bombo cerrado, en reemplazo de equipos de tecnología convencional. En el diseño del proceso para el cambio a esta nueva tecnología se tomó en cuenta las características de los productos, tamaño de diseño, características de los equipos y los controles a realizar durante el proceso. Los resultados físicos, fisicoquímicos y microbiológicos obtenidos del producto bajo el nuevo diseño de proceso en los nuevos equipos, fueron conformes a las especificaciones de calidad establecidas para las tabletas recubiertas de Paracetamol 500mg + Diclofenaco sódico 50 mg. La investigación se realizó en dos lotes industriales, un lote ingresó a estudio de estabilidad mostrando resultados conformes. Del trabajo se concluye que el empleo de tecnología automatizada y el incremento de tamaño de lote, bajo el diseño propuesto, fue satisfactorio, asimismo se identificaron los parámetros críticos de proceso en estas etapas y los atributos de calidad de estos productos fueron conformes, se reporta un ahorro significativo de 40% por lote y un ahorro anual de 400% aproximadamente (Horas-Hombre y Horas-Maquina) en tiempos, lo que permite incrementar la operatividad para la planta farmacéutica.

Zugl.: Dortmund, Techn. Univ., Diss., 2009

Made available in DSpace on 2014-06-12T18:01:36Z (GMT). No. of bitstreams: 2 arquivo116_1.pdf: 1394719 bytes, checksum: 139c388c8b366e90a503d871c7e50d00 (MD5) license.txt: 1748 bytes, checksum: 8a4605be74aa9ea9d79846c1fba20a33 (MD5) Previous issue date: 2011 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / O interesse da comunidade científica no estudo de micropoluentes é muito recente e tem aumentado a cada dia, uma vez que estas substâncias vêm causando alterações importantes no meio ambiente, interferindo no sistema endócrino de animais e de seres humanos. Logo, foi necessário classificar essas substâncias que receberam o nome de contaminantes emergentes, dentre os quais estão os fármacos de diferentes classes como: analgésicos, antiinflamatórios, drogas psiquiátricas, antilipêmicos, antibióticos além de outras substâncias largamente utilizadas no consumo doméstico. Pesquisadores do mundo todo buscam verificar a presença desses compostos em matrizes ambientais, como estações de tratamento de efluentes e rios, e propor tratamento para os mesmos. O uso de processos oxidativos avançados (POA) surge nesse cenário como uma tecnologia capaz de remover estes micropoluentes dos meios contaminados. O presente trabalho tem por objetivo avaliar, quantificar e tratar soluções aquosas com os contaminantes emergentes (CE): Ácido Acetilsalicílico (AAS), Diclofenaco e Paracetamol. Planejamento Fatorial 23 com ponto central foi utilizado para determinar a melhor condição de operacionalização. Soluções sintéticas foram preparadas com o princípio ativo dos três fármacos em estudo, quantificadas antes e após a aplicação do POA, através de análise por LC/MS IT-TOF. Para que fossem obtidos resultados consistentes, a metodologia utilizada para quantificação dos fármacos por análise cromatográfica acoplada a espectrometria de massas foi validada utilizando normas exigidas pelos órgãos competentes (ANVISA E INMETRO). Análise de Carbono Orgânico Total foi também realizada, contribuindo na determinação da cinética apresentada no processo de degradação. O Processo de Fotólise e os Processos Foto-Fenton e UV/H2O2 foram utilizados e comparados os seus resultados. O processo de Fotólise não apresentou um percentual de degradação significativa para os fármacos estudados, enquanto que o Processo Foto-Fenton conseguiu degradar de modo eficiente todos os fármacos alcançando percentuais de degradação superiores a 90,00%. Após submissão das amostras aos POA, foi realizada análise da concentração de peróxido residual não detectando presença de peróxido. A análise da conversão de carbono orgânico total apresentou melhor resultado (84,84%) para o processo UV/H2O2, o qual também conseguiu obter 100,00% de degradação dos compostos estudados. Portanto, a modelagem cinética foi elaborada para o processo UV/H2O2, que se comportou de modo eficiente tanto para a remoção dos compostos estudados, bem como para a conversão de carbono orgânico total. O modelo cinético agrupado em dois grupos de compostos, refratários e não refratários, foi adotado para descrever o perfil da concentração de COT residual, conseguindo representar de modo satisfatório o perfil da fração residual dos compostos orgânicos analisados

Bakgrund: Barn nyttjar paracetamol på ett sätt som medför risker för barnets hälsa En del barn är inte medvetna om varför de har ont, utan självmedicinerar med paracetamolpreparat. Syfte: Att belysa skolsköterskors uppfattning om användande av substansen paracetamol bland elever i grundskola. Metod: Studien genomfördes med en kvalitativ metod med en fenemenografisk analys, genom e-post intervjuer med skolsköterskor i årskurs förskoleklass till 9. Resultat: Studiens resultat visar att skolsköterskor som arbetar i grundskola uppfattar att elever, främst i högstadieskola, självmedicinerar somatiska och psykosomatiska symtom med paracetamol. Det framkommer ur resultatet att skolsköterskorna uppfattar att elevers inställning speglar föräldrars inställning till paracetamol och detta påverkar användningen av paracetamol bland elever i grundskola. Konklusion: Skolsköterskor är en viktig källa till att lokalisera elever som mår dåligt och självmedicinerar med paracetamol. Genom exempelvis hälsofrämjande samtal kan skolsköterskor stödja de elever som självmedicinerar med paracetamol. Skolsköterskor har en stödjande roll i att försöka få elever att förstå och förändra sin livsstil för att främja hälsa.

The concept of sequential injection analysis (SIA), introduced as a simple and convenient principle, has established itself as a well defined analytical technique suitable for routine laboratory analysis. This technique is fully computerized and reliable with a reasonable sample frequency, low sample and reagent consumption and low frequency of maintenance. In pharmaceutical based analysis SIA can be used at each step through the entire production process, from raw material to the final consumer product. With its substantial advantages, an SIA system can replace sophisticated instrumentation facilities, which are unlikely to be used for manufacturing environments. The aim of this study was to investigate the application of the sequential injection analysis technique in the determination of selected substances of biological importance from the pharmaceutical industry (zinc, paracetamol and boron). It is important to control the level of zinc and boron in human, animals and plants. Overdose of paracetamol is a problem in our body. That is why the uniformity tests of paracetamol must be very accurate and precise. The aim was successfully achieved. The results obtained for all substances proved the high reliability of the SIA technique. / Dissertation (MSc (Chemistry))--University of Pretoria, 2006. / Chemistry / unrestricted

Background: Managing pain is challenging, especially in neonates. Uncontrolled pain and opioid exposure are associated with short- and long-term adverse events. Adequately controlling pain while reducing opioid exposure is paramount in the neonatal population. This thesis presents three studies, all aiming to determine if IV acetaminophen is an appropriate adjunct to current opioid-based postoperative pain regimens. The population of interest is neonates admitted to the neonatal intensive care unit (NICU) treated with major abdominal and thoracic surgery. Chapter 1 provides the scientific framework underpinning this work and the rationale for performing the included studies. Chapter 2 presents the results of a systematic review and meta-analysis assessing the effect of IV acetaminophen on postoperative pain in pediatric patients. This chapter further expands on gaps and opportunities for future research. Chapter 3 reports the results of a national survey in which pediatric surgeons, anesthesiologists, and neonatologists reported their postoperative pain prescribing practices in the NICU and their perspectives on the use of IV acetaminophen. Chapter 4 describes the protocol for a pilot randomized controlled trial (RCT). This study will assess the feasibility of a multicenter RCT to evaluate the effectiveness of IV acetaminophen for postoperative pain in neonates recovering from major abdominal and thoracic surgery. Chapter 5 summarizes the results of the studies in context and details how the results of each study informed the others. It also discusses areas of future research. / Thesis / Master of Science (MSc) / All patients experience some amount pain after major surgery. Babies who are born too early (i.e., preterm) may experience more pain than babies those who are born close to their due date. Opioid drugs such as Fentanyl are commonly used to manage pain after surgery, but they have side effects, such as slowing down breathing and causing problems with gut function. Using non-opioid drugs (such as acetaminophen) and opioid drugs together may reduce the amount of opioids needed. This combination may also help with pain control. We want to know if using intravenous (IV) acetaminophen will reduce the rate of side effects, decrease the amount of opioids given, and still control pain well. To answer this question, we completed three studies. The first study reviewed all the published data on IV acetaminophen in children who need surgery. In the second study, we surveyed pediatric surgeons, anesthesiologists, and neonatologists to see how they manage pain after surgery and what they thought about IV acetaminophen. The last study is the plan for our pilot trial, where we will see if giving IV acetaminophen and opioids together is better than opioids alone.

No description available.

Made available in DSpace on 2016-08-10T10:29:24Z (GMT). No. of bitstreams: 1 Alexandre Garcia Marques.pdf: 763762 bytes, checksum: e8e667113a357b13ba2b50e4a42421e8 (MD5) Previous issue date: 2010-06-22 / The research presents a critical analysis on the absence of ostensive spreading of the potential risk of what is submitted to the Pharmacy consumer based on paracetamol and the legal consequences caused in the in the area of civil responsibility to the different segments, departments and medical and pharmaceutical professional areas. For this identification a brief analysis on paracetamol drug and its hepatotoxicity were done. In wide context, the approach to the need of uniting and furnishing of the information to the consumer, by written means of audiovisual means, specially directed to the final consumer. In a concomitant way, the analyzing with thematic is dealt with by the European Union and the adapted conducts by means of the legislation with the will to provide security and minimize the risks occurred from the use of the medication being studied. In the way, Brazil wide, the deficiency of information in the commercializing of the paracetamol in blister is pointed out by the fact of not furnishing the consumers, in an ostensive way, enough orientation on the risk caused by the product. A Critical analysis of the RDC #47/Anvisa/09 and the RDC #071/Anvisa/2009 resolutions were accomplished , before the art. 9th of the Law #8,078/90 that got the Consumer Defense Code CDC. In a legal approach, the extension of consequences of the conduct omission to the risk and paracetamol hepatotoxicity in relation to industry, commerce, health professional, dentist surgeon, and pharmaceutics, through a national legislation approach. The current research has intends to subsidies the ones who deal with the paracetamol and its consumers, on the respect of the furnishing duty and precise information gotten as to the risk of the product, in an ostensive way, assuring the human health and effectively of the regulations of the security principal. It is expected, therefore, that the State adopts by means of specific regulations, means of controlling the use of the acetaminophen, such as it occurs in Europe or in the USA, by educating intervention, forcing the industry and commerce of the pharmaceutical area to unite condition equality, in the advertisement of the product being studied, clearly waning the ostensive on the risk, as well as providing on the primary and secondary packaging of the paracetamol, in high and bold letters, warning such as: AFTER THE CONSUMPTION OF ALCOHOL THERE IS RISK OF FULMINANT HEPATITIS, making it a requirement to offer the written warnings, in sufficient quantity, even when the medicine is sold in blister form. / O estudo apresenta uma análise crítica sobre a ausência de divulgação ostensiva do risco potencial a que está submetido o consumidor de fármaco à base de paracetamol e as conseqüências jurídicas decorrentes na área da responsabilidade civil para os diversos segmentos, setores e profissionais da área médica e farmacêutica. Para esta identificação faz-se breve análise sobre o fármaco paracetamol e sua hepatotoxidade. Em amplo contexto, aborda-se a necessidade de veiculação e fornecimento de informações ao consumidor, via bula e por meio da comunicação audiovisual, voltada especialmente ao consumidor final. De forma concomitante, analisa-se como a temática é tratada pela União Européia e as condutas adotadas por meio da legislação com o intuito de propiciar segurança e minimizar os riscos decorrentes do uso do fármaco sob estudo. Nesse sentido, em nível de Brasil, a deficiência de informações na comercialização do paracetamol em blister é apontada pelo fato de não se fornecer aos consumidores, de forma ostensiva, orientações suficientes sobre o risco decorrente do produto. Realiza-se análise crítica das Resoluções RDC nº47/Anvisa/09 e RDC nº071/Anvisa/2009, frente ao disposto no art. 9º da Lei nº 8.078/90 que institui o Código de Defesa ao Consumidor - CDC. Em uma abordagem jurídica, é delineada a extensão das consequências da conduta omissiva quanto ao risco e hepatotoxidade do paracetamol em relação à indústria, comércio, profissional médico, cirurgião-dentista e farmacêutico, através de uma abordagem da legislação nacional. O presente estudo visa subsidiar os que lidam com o paracetamol e os consumidores deste, sobre a respeito da obrigação de fornecimento e obtenção de informação precisa quanto ao risco do produto, de forma ostensiva, na garantia da saúde humana e efetividade da norma regulamentadora do princípio da segurança. Espera-se por fim, que sejam adotadas pelo Estado, por meio de regulamentação específica, medidas de contenção do uso e consumo do acetaminofeno, tal qual ocorre na Europa e EUA, mediante intervenção educativa, obrigando a indústria e comércio do ramo farmacêutico a veicular em igualdade de condições, nas propagandas do produto sob estudo, advertência clara e ostentiva sobre o risco, bem como que passe a constar nas embalagens secundárias e primárias do paracetamol, em caixa alta e em negrito, advertência do tipo: APÓS O CONSUMO DE ÁLCOOL HÁ RISCO DE HEPATITE FULMINANTE, tornando por fim obrigatório a oferta de bula avulsa, em número suficiente, mesmo quando o fármaco for vendido na forma de blister