BACKGROUND: Current guidelines give class I recommendations for uninterrupted use of dabigatran rivaroxaban as an alternative to vitamin K antagonist (VKA) in patients of atrial fibrillation (AF) who are undergoing catheter ablation. The recent randomized controlled trials have shown similar efficacy of novel oral anticoagulants when compared to VKA in these patients. We sought to perform a meta-analysis with a focus on subgroup analysis of novel oral anticoagulants. METHODS: We searched PubMed, Clinical trials registry and the Cochrane Center Register of Controlled Trials were searched through August 2020. Six RCTs studies (n = 2260) comparing the use of NOACs versus VKA in patients with AF undergoing catheter ablation were included. The odds ratio (OR) with 95% confidence interval was computed and P < 0.05 was considered as a level of significance. Major adverse cardiac events (MACE) were considered as a primary endpoint. RESULTS: Our results showed a significant difference in MACE between NOACs and VKA [OR 0.57 (0.37-0.88); P = 0.01] and in major bleeding events [OR 0.55 (0.35-0.86); P = 0.009], which is mainly derived from the use of dabigatran. No significant difference in MACE or major bleeding events was found on the subgroup analysis of rivaroxaban and apixaban over VKA therapy. CONCLUSION: Uninterrupted use of NOACs is safe and effective alternative for the prevention of cerebral thromboembolism and reducing the risk of major bleeding in patients undergoing catheter ablation of AF. However, the individual subgroup analysis showed that only dabigatran is superior to VKA in terms of reducing MACE through a reduction in major bleeding. The rivaroxaban, apixaban and edoxaban are non-inferior to VKA therapy based on these results. Further studies are needed to generalize these recommendations in morbidly obese patients.

The efficacy and safety of oral nadolol in supraventricular tachycardia were evaluated prospectively in 27 children (median age 5.5 years). Fifteen patients had an unsuccessful trial of digoxin therapy. Intravenous nadolol was given to seven patients during electrophysiologic study; five of these had an excellent response and two had a partial response (25% decrease in tachycardia rate). Six of these patients had a similar response to oral nadolol. Twelve patients received both propranolol and nadolol. Among six patients, intravenous propranolol was successful in four and unsuccessful in two; all six had a similar response to oral nadolol. With oral propranolol, tachycardia was well controlled in four patients and persistent in two; five of five patients had a similar response to oral nadolol. Twenty-six patients were treated with oral nadolol; the arrhythmia was well controlled in 23, 2 had recurrent tachycardia and 1 patient had tachycardia at a 25% slower rate. The effective dose of nadolol ranged between 0.5 and 2.5 mg/kg body weight once daily (median dose 1 mg/kg per day). During follow-up (3 to 36 months), compliance and tolerance were excellent; excluding 2 patients with reactive airway disease who developed wheezing, only 3 (12%) of 24 had side effects necessitating a change in drug therapy. Once a day nadolol is a safe and effective agent in the management of supraventricular tachycardia in children. Its long-term efficacy can be predicted by the short-term response to intravenous nadolol or propranolol during programmed electrophysiologic study.

Thesis (MScMedSc)--Stellenbosch University, 2012. / Includes bibliography / ENGLISH ABSTRACT: In this thesis, research results are reported on the role of dipalmitoyl phosphatidyl choline (DPPC) and DPPC-liposomes on the in vitro permeability characteristics of various antimycobacterial drugs across porcine bronchial tissue. The permeability flux values of the different compounds (isoniazid, ofloxacin and moxifloxacin) and their relevant DPPC formulations were determined using a continuous flow through perfusion system. Mean steady state flux values were compared statistically by means of a t-test at a significance level of 5% as well as an F-test using whole curve comparisons. The results indicated that the different formulations of drug and their DPPC combinations retard the permeation of drug through bronchial tissue. However, moxifloxacin permeation was significantly enhanced when in a DPPC-liposomal formulation. These results demonstrate the important role that molecular weight, electrostatic charge, partitioning of the molecules in DPPC and DPPC-liposomes play in transmembrane diffusion. In addition, the effect of individual drugs and their DPPC combinations on the surface tension lowering property of DPPC was evaluated. The results obtained showed minimal decreases in the surface tension lowering capability of DPPC; however, the minimal increases in surface tension do not alter the integrity of DPPC to a large extent. Drug susceptibility testing of Mycobacterium tuberculosis cultures against the individual antitubercular drugs and their DPPC combinations was done by using the Radiometric BACTEC 460TB™ system. Drug-entrapped DPPC liposomes were tested at concentrations comparable to their relative minimum inhibitory concentrations (MIC). The results for the BACTEC assay indicated that the mycobacteria were susceptible to the developed drug entrapped liposomes; of which their encapsulation efficiencies for the relevant drugs were approximately ± 50%. It was concluded that drug-entrapped DPPC liposomes could fulfill the dual role of pulmonary drug delivery and alveolar stabilization due to antiatelectatic effect of DPPC which can improve the distribution of anti-tubercular drugs in the lung / AFRIKAANSE OPSOMMING: Hierdie tesis doen verslag oor navorsingsresultate met betrekking tot die rol van dipalmitoïel-fosfatidiel-cholien (DPPC) en DPPC-liposome in die in vitro-permeasiekenmerke van verskeie antimikobakteriese middels oor vark- brongiale weefsel. Die permeasievloedwaardes van die verskillende verbindings (isoniasied, ofloksasien en moksifloksasien) en hul betrokke DPPC-formules is met behulp van ’n deurlopende-deurvloei-perfusiestelsel bepaal. Gemiddelde vloedwaardes in ’n bestendige staat is statisties vergelyk met behulp van ’n t-toets op ’n beduidendheidsvlak van 5%, sowel as ’n F-toets met behulp van heelkurwevergelykings. Die resultate dui daarop dat die verskillende middelformules en hul DPPC-kombinasies middelpermeasie oor brongiale weefsel vertraag. Tog is die permeasie van moksifloksasien aansienlik versterk in ’n DPPC-liposomale formule. Hierdie resultate bevestig die belangrike rol van molekulêre gewig, elektrostatiese lading, die verdeling van molekules in DPPC sowel as DPPC-liposome in transmembraandiffusie. Daarbenewens is die uitwerking van individuele middels en hul DPPC-kombinasies op die oppervlakspanningsverligtingsvermoë van DPPC beoordeel. Die resultate toon minimale afnames in die oppervlakspanningsverligtingsvermoë van DPPC. Die minimale toenames in oppervlakspanning het egter meestal geen noemenswaardige effek op die integriteit van DPPC gehad nie. Voorts is die vatbaarheid van Mycobacterium tuberculosis-kwekings vir die individuele anti-tuberkulêre middels en hul DPPC-kombinasies met behulp van die radiometriese BACTEC 460TB™-stelsel getoets. Middel-ingeslote DPPC-liposome is getoets in konsentrasies wat met hul relatiewe minimum inhibisiekonsentrasies (MIK) vergelyk kan word. Die resultate van die BACTEC-toets toon dat die mikobakterieë vatbaar was vir die ontwikkelde middel-ingeslote liposome, met ’n enkapsuleringsdoeltreffendheid van ongeveer 50% vir die betrokke middels. Die studie kom tot die gevolgtrekking dat middel-ingeslote DPPC-liposome die dubbele rol van pulmonêre middel-lewering en alveolêre stabilisering kan vervul weens die anti-atelektatiese werking van DPPC, wat die verspreiding van anti-tuberkulêre middels in die long kan verbeter.

INTRODUÇÃO: As neoplasias do sistema nervoso central são frequentes nafaixa etária pediátrica e o tratamento antineoplásico pode resultar em efeitos adversos agudos ou tardios na cavidade oral. As anormalidades dentárias de forma, tamanho e número de dentes podem ocorrer se o tratamento por radioterapia de crânio e coluna, quimioterapia ou ambas forem coincidentes com a época de formação dentária em pacientes pediátricos. A gravidade das alterações depende do tipo de tratamento e da idade do paciente ao diagnóstico. OBJETIVOS: Avaliar a frequência de anormalidades dentárias em pacientes tratados para neoplasias do sistema nervoso central. MÉTODOS: Neste estudo transversal foram avaliados 31 pacientes com diagnóstico de neoplasia do sistema nervoso central que estavam fora de terapia há pelo menos um ano, comparativamente com um grupo controle composto por 31 pacientes saudáveis, pareados por idade com o grupo de estudo. As anormalidades dentárias foram avaliadas por meio de radiografias panorâmicas. RESULTADOS: A idade média ao diagnóstico dos pacientes do grupo de estudo foi de 7,3 ± 3,9 anos e as neoplasias mais frequentemente observadas foram meduloblastoma (58,1%), astrocitoma (25,8%) e ependimoma (3,2%). Não se observou diferença na frequência de anormalidades dentárias entre os grupos. As anormalidades mais frequentemente observadas nos pacientes do grupo de estudo foram microdontia (9,7%) e encurtamento radicular grau III (16,1%). Microdontia foi mais frequente em crianças que tiveram o diagnóstico antes dos 5 anos de idade, com diferença significante. Encurtamento radicular grau III foi observado em pacientes com mais de 10 anos de idade no momento do exame radiográfico, também com diferença significante. Pacientes tratados por radioterapia associada à quimioterapia apresentaram maior frequência de anormalidades dentárias, comparativamente com pacientes tratados somente por radioterapia ou quimioterapia isoladamente. Microdontia apresentou alta correlação com os dentes segundos premolares e segundos molares em pacientes tratados para neoplasias do sistema nervoso central. CONCLUSÕES: Pacientes tratados para neoplasias do sistema nervoso central apresentam alta frequência de anormalidades dentárias, porém neste estudo não houve diferença entre os grupos de estudo e controle. Microdontia foi a anormalidade dentária mais frequente em pacientes submetidos ao tratamento antineoplásico antes dos 5 anos de idade, com significância estatística. Encurtamento radicular grau III foi observado nos pacientes com mais de 10 anos de idade no momento do exame radiográfico, com diferença estatisticamente significante. Pacientes submetidos à radioterapia associada à quimioterapia apresentaram maior frequência de anormalidades dentárias / INTRODUCTION: Central nervous system neoplasms are frequent in pediatric patients and antineoplastic treatment may result in acute or late adverse effects in the oral cavity. Tooth abnormalities of shape, size and number of teeth can occur if craniospinal irradiation, drug therapy or both are coincident with the time of tooth development. Severity of these alterations depends on the type of treatment and the patient´s age at diagnosis. OBJECTIVES: To evaluate the frequency of tooth abnormalities in pediatric patients treated for central nervous system neoplasms. METHODS: This cross-sectional study assessed 31 patients with central nervous system neoplasms, who were off therapy for at least one year, comparatively with a control group of 31 healthy patients matched for age with the study group. Tooth abnormalities were evaluated by panoramic radiographs. RESULTS: Study group´s mean age at diagnosis was 7.3 ± 3.9 years and the most frequent neoplasms were medulloblastoma (58.1%), astrocytoma (25.8%) and ependyoma (3.2%). There was no difference in the frequency of tooth abnormalities between groups. The most frequently tooth abnormalities observed in the study group were microdontia (9.7%) and root shortening grade III (16.1%). Microdontia was the most common abnormality in children who were diagnosed before 5 years of age, with a significant difference. Root shortening grade III was observed in patients over 10 years of age at the time of radiographic examination, also with a significant difference. Patients treated with craniospinal irradiation combined with drug therapy presented more frequency of tooth abnormalities compared with patients treated only by craniospinal irradiation or drug therapy alone. Microdontia was highly correlated with the teeth second premolars and second molars. CONCLUSIONS: Patients treated for central nervous system neoplasms present high frequency of tooth abnormalities; however in this study there was no difference between study and control groups. Microdontia was the most frequent tooth abnormality in patients submitted to antineoplastic treatment before 5 years of age, with statistical significance. Root shortening grade III was observed in patients over 10 years of age at the time of radiographic examination, with statistically significant difference. Patients undergoing craniospinal irradiation combined with drug therapy showed high frequency of tooth abnormalities

Estudo descritivo, quantitativo que teve como objetivo comparar a Capacidade Funcional de mulheres com câncer de mama, que realizaram tratamento oncológico (G1), com a de mulheres que nunca apresentaram diagnóstico de câncer (G2), e identificar se a qualidade de vida de mulheres com neoplasia mamária correlaciona-se com a capacidade funcional. O G1 foi composto por 42 mulheres submetidas ao tratamento para o câncer de mama, até um ano do período da coleta de dados, e que frequentavam um núcleo de reabilitação. O G2 foi composto por 42 mulheres, pareadas com o G1, por idade e nível sócio-econômico. A coleta de dados se deu no período de janeiro a julho de 2009. Os instrumentos utilizados para a comparação da Capacidade Funcional foram Índice de Katz e Índice de Lawton, e para a Qualidade de Vida, o EORTC QLQ-C30 e EORCT QLQ-BR23. Os resultados mostraram que o G1 apresentou leve comprometimento nas condições físicas, como fadiga, imagem corporal, função sexual, função física e sintomas na mama e no braço, e moderadas alterações psicossociais na função emocional e nas atividades de lazer e de participação social, comprometendo, assim, sua QV. A comparação entre G1 e G2 mostrou que o tratamento oncológico prejudicou muito a realização das AIVDs das integrantes do G1, porém não interferiu nas ABVD. Acredita-se que os resultados referentes às ABVDs se devam ao fato de elas frequentarem um núcleo de reabilitação e receberem orientações para continuar realizando as ABVDs, mesmo no período pós-operatório. Além disso, participar do núcleo pode ter contribuído para a manutenção do autocuidado e ser também uma importante estratégia para o melhor enfrentamento das limitações físicas e emocionais impostas pelo câncer de mama. O período de realização da coleta dos dados, ao término dos tratamentos, também pode ter favorecido a indicação, pelas componentes do G1, de um menor comprometimento de alguns eventos adversos ao tratamento e alterações psicossociais. No entanto, evidenciou-se ainda, com os resultados relativos às AIVDs, a importância de um maior investimento no cuidado à mulher com câncer de mama, em relação à sua QV e CF, no que se refere às funções física, emocional e social. Sugere-se a realização de estudos de abordagem qualitativa que façam uma avaliação subjetiva dos comprometimentos dos eventos adversos dos tratamentos, das alterações psicossociais para as mulheres com câncer de mama e das estratégias de que elas se utilizam para vivenciá-los. Outras investigações poderão abordar ainda aspectos individuais no DO, como as AIVDs e atividades de lazer; avaliar a eficácia de serviços de reabilitação no manejo dos sintomas, como dor, fadiga, insônia, perda de apetite, aderência cicatricial e outros, além do papel frente às alterações psicossociais; e avaliar as demais categorias que integram o DO de mulheres com câncer de mama, para compreender a influência desta doença sobre aspectos como os de repouso e sono, educação, trabalho e participação social, a fim de possibilitar uma melhor intervenção multidisciplinar junto a esta população. / This descriptive study aimed to compare the functional capacity of women with breast cancer who underwent treatment (G1), with women who never had cancer (G2), and identify if the quality of life of women with breast cancer correlates with functional capacity.G1 was composed of 42 women undergoing treatment for breast cancer, up to a year of data collection, and who attended a rehabilitation center. The G2 is the G1 paired by age and socioeconomic status. Data collection took place from January to July 2009. The instruments used for comparison were the Functional Capacity Index Katz and Lawton Index, and Quality of Life, EORTC QLQ-C30 and QLQ-BR23 EORCT. The results showed that G1 showed mild impairments in physical conditions such as fatigue, body image, sexual function, physical function and symptoms in breast and arm, and moderate changes in the psychosocial and emotional function in leisure activities and social participation, compromising thus their QOL. The comparison between G1 and G2 showed that cancer treatment was very damaging to the performance of IADL members of G1, but did not interfere with ABVD. It is believed that the results concerning the ABVD be attributed to the fact that they attend a rehabilitation unit and received guidance to continue performing the ADL, even in the postoperative period. Moreover, the core part may have contributed to the maintenance of self-care. Thus, attending a rehabilitation service can be an important strategy to better cope with the emotional and physical limitations imposed by breast cancer. The timing of data collection at the end of treatments, may also have favored the statement, the components of the G1, a lower commitment of some adverse events related to treatment and psychosocial changes. However, there was still, with the results for the AIVD, the importance of increased investment in care for women with breast cancer in relation to their QOL and CF, with regard to the functions physically, emotionally and socially. It is suggested for studies of a qualitative approach to make a subjective evaluation of the commitments of the adverse events of treatment, the psychosocial changes for women with breast cancer and strategies that they use to experience them. Further investigation will also address individual aspects of the DO, as the IADL and leisure activities, evaluate the effectiveness of rehabilitation services in the management of symptoms such as pain, fatigue, insomnia, appetite loss, scar tissue and others, besides the paper front psychosocial changes, and evaluate the other categories that comprise the OD of women with breast cancer, to understand the influence of this disease on aspects such as rest and sleep, education, employment and social participation, to enable a better multidisciplinary intervention with this population.

Para investigar clinicamente aspectos da personalidade de 30 pacientes provenientes do Ambulatório do Serviço de Cirurgia de Cólon, Reto e Ânus da Divisão de Clínica Cirúrgica II do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo submetidos à radioquimioterapia como primeira abordagem ao tratamento de câncer de reto distal, utilizou-se técnica psicológica de bases psicodinâmicas. Alguns doentes não foram operados, outros submetidos à intervenção cirúrgica com ou sem colostomia definitiva, sendo continuamente tratados há pelo menos três anos. Verificou-se que os três subgrupos apresentam-se em condições emocionais semelhantes embora os pacientes do gênero masculino tenham revelado melhores condições de elaboração do luto pelas perdas causadas pela doença / In order to investigate personality clinical aspects from 30 patients, proceeding from Colon, Rectum and Anus Surgery Service Ambulatory of Surgical II Clinical Division from the Medicine School Hospital of University of Sao Paulo, Brazil, submitted to radio chemotherapy as the first approach to low rectum cancer treatment, psychological technique on psychodynamic base was utilized. Some patients were not operated, others were submitted to operation requiring or not a permanent colostomy, all of them clinically assisted along three years at least. It was found the three subgroups reveal themselves in analogous emotional conditions nevertheless men probe better than women, to elaborate mournfulness for losses succeeded by the illness

Avaliou-se o uso do laser de baixa intensidade e do Light-Emitting Diode (LED) no comportamento de fibroblastos e na redução da incidência da mucosite bucal em crianças sob tratamento quimioterápico. Para tanto, o estudo foi executado em dois períodos experimentais distintos. No primeiro período, foi realizada a análise da viabilidade de fibroblastos Balb/c 3T3 cultivados sob déficit nutricional irradiados com laser vermelho (660nm, 40mW), laser infravermelho (780nm, 50mW) e LED vermelho (637 ± 15nm, 40mW) por 4 e 8 segundos através dos ensaios de redução do MTT e captação do vermelho neutro. No segundo período experimental realizouse ensaio clínico randomizado duplo-cego para avaliar a eficácia do laser vermelho (660nm, 40mW) e do LED vermelho (637 ± 15nm, 40mW) na redução da incidência e da severidade da mucosite bucal e da dor relacionada em crianças portadoras de câncer submetidas a quimioterapia utilizando-se o sistema de graduação da mucosite bucal da Organização Mundial de Saúde e a Escala de Dor de Faces Revisada associada à escala analógica visual. A análise estatística foi realizada utilizando-se o teste não paramétrico de Kruskal-Wallis e analise de variância do modelo linear geral com nível de significância de 5% (p = 0,05). Observou-se com a redução do MTT uma tendência de aumento da proliferação celular relacionado diretamente com o tempo de irradiação, no entanto, não significante estatisticamente. Após 72 horas, os grupos que apresentaram maior proliferação celular foram: grupo irradiado com laser infravermelho, grupo irradiado com LED, grupo irradiado com laser vermelho, grupo controle positivo e grupo controle negativo. Já através da captação do vermelho neutro, após 72 horas o grupo que apresentou maior proliferação celular foi o grupo controle positivo (cultivado sob condições nutricionais ideais) seguido pelo grupo irradiado com laser infravermelho, grupo controle negativo e grupos irradiados com LED e laser vermelho. Através da análise dos resultados obtidos e considerando os parâmetros e protocolo de fototerapia utilizados, pode-se concluir que a fototerapia com laser de baixa intensidade e diodo emissor de luz (LED) não apresentaram toxicidade em nível celular, vindo mesmo a estimular a proliferação dos fibroblastos cultivados sob déficit nutricional, sobretudo no grupo irradiado com o laser infravermelho (780nm, 50mW). A incidência e a severidade da mucosite bucal, assim como a dor associada, foram muito baixas nos grupos irradiados com laser vermelho (660nm, 40mW) e LED (637 ± 15nm, 40mW). Não houve diferença estatisticamente significativa entre os grupos; A coerência da luz não interferiu no resultado da fototerapia in vitro e in vivo. / The use of low-intensity laser and Light-Emitting Diode (LED) on the behavior of fibroblasts and in reducing the incidence of oral mucositis in children under chemotherapy were evaluated. The study was performed in two separate experiments. In the first moment, the viability of fibroblasts Balb/c 3T3 cultured under nutritional stress irradiated with red laser (660nm, 40mW), infrared laser (780nm, 50mW) and red LED (637 ± 15nm, 40mW) for 4 and 8 seconds was analyzed through the MTT and neutral red assays. The second experiment carried out was a double-blind randomized clinical trial aiming to assess the effectiveness of red laser (660nm, 40mW) and red LED (637 ± 15nm, 40mW) in reducing the incidence and severity of oral mucositis and related pain in children with cancer undergoing chemotherapy using the World Health Organization oral mucositis grading system and the Faces Pain Scale - Revised associated with a visual analogue scale. Statistical analysis was performed using the Kruskal-Wallis nonparametric test and ANOVA with a significance level of 5% (p = 0.05). It was observed with the MTT assay a trend of cell proliferation increase directly related to the irradiation time, however, not statistically significant. After 72 hours, the groups that showed higher cell proliferation were: infrared laser irradiated group, LED irradiated group, red laser irradiated group, positive control group and negative control group. By the neutral red assay, though, after 72 hours the group that showed higher cell proliferation was the positive control (grown under ideal nutritional conditions) followed by the group irradiated with infrared laser, the negative control group and groups irradiated with red laser and LED. By analyzing the results and considering the used parameters and phototherapy protocol, it is plausible to conclude that phototherapy with lowintensity laser and light emitting diode (LED) showed no toxicity at cellular level, even stimulating the proliferation of fibroblasts cultured under nutritional stress, especially in the group irradiated with infrared laser (780nm, 50mW). The incidence and severity of oral mucositis and associated pain, were very low in the groups irradiated with red laser (660nm, 40mW) and LED (637 ± 15nm, 40mW). There was no statistically significant difference between these groups, the coherence of light did not affect the outcome of phototherapy in vitro and in vivo.

Objetivos: O objetivo deste estudo foi o de identificar compostos seletivamente tóxicos ao carcinoma espinocelular de boca in vitro por meio do reposicionamento de fármacos. Material e Métodos: Por meio de um escaneamento baseado na viabilidade celular de 1.280 fármacos, nós selecionamos três princípios ativos (luteolin, metixene hydrochloride e nitazoxanide) letais às células de câncer de boca SCC-25 e pouco tóxicos às células de queratinócitos cutâneos imortalizados HaCaT. Os fármacos candidatos foram investigados quanto à sua dose- e tempo-resposta bem como comparados e combinados à agentes quimioterápicos padrão por meio do ensaio por colorimetria com brometo de tiazolil azul de tetrazolio (MTT). O impacto dos fármacos na motilidade do SCC-25 e do HaCaT foi verificado pelo ensaio de migração celular e seus mecanismos de ação também foram explorados por meio da verificação dos níveis das proteínas fosforiladas pelo western blotting. Todos os experimentos foram realizados em triplicata e, pelo menos, três vezes independentes. O teste t de student foi utilizado para confrontar as variáveis e nível de significância de 5% foi estabelecido para todos os testes. Resultados: O flavonoide natural luteolin exerceu citotoxicidade potente contra as células de câncer de boca in vitro, apresentando baixa toxicidade ao HaCaT e alta eficiência quando comparado a quimioterápicos como a cisplatina e o AG1478. Do ponto de vista molecular, a luteolin ativou a via de sinalização do dano do DNA e, combinada com um inibidor do Chk, apresentou efeitos potencializados. Além disso, nós demonstramos que a nitazoxanide e o metixene hydrochloride são capazes de destruir células SCC-25 porém não as HaCaT de maneira proporcional à dose e ao tempo de tratamento. As combinações entre os três fármacos hit e com a cisplatina ou o AG1478 potencializaram seus efeitos contra as células malignas. Conclusões: O presente estudo traz a luteolin, o metixene hydrochloride e a nitazoxanide como fortes candidatos a agentes terapêuticos contra o câncer de boca uma vez que estes compostos apresentam maior eficácia contra células de câncer de boca e menor toxicidade contra células não tumorais in vitro do que agentes quimioterápicos convencionais. / Objectives: Here we aimed at identifying and reposition approved drugs that could be selectively toxic towards oral squamous cell carcinoma cells. Materials and Methods: Through a cell-based drug screening of 1,280 chemical molecules, we selected 3 compounds (luteolin, metixene hydrochloride, and nitazoxanide) lethal to oral cancer SCC-25 cells, while sparing immortalized keratinocyte HaCaT cells. The drugs were then further challenged for their time- and dose-responses, as well as their comparison and combination to standard chemotherapeutic agents by colorimetric assay 1-(4,5-Dimethylthiazol-2-yl)-3,5-diphenylformazan, Thiazolyl blue formazan (MTT). The impact on SCC-25 and HaCaT motility as well as the mode of action of the drugs was then further explored by scratching assay and western blotting, respectively. All the experiments were performed in triplicated and, at least, three independent times. Students t test was performed to verify the differences among the variables and the level of significance was set at 5%. Results: The natural flavonoid luteolin was a potent cytotoxic agent against oral cancer cells in vitro, presenting low toxicity against HaCaT cells and high efficiency as compared to standard-of-care, such as cisplatin and AG1478. From a molecular standpoint, luteolin coopted the DNA-damage pathway and could be efficiently combined with Chk pharmacological inhibitor. Moreover, we demonstrated that nitazoxanide and metixene hydrochloride kill the SCC-25 but not the HaCaT cells in a dose- and time-dependent. The combinations among the three drugs hit and with cisplatin and AG1478 improved their effect against the malignant cells. Conclusions: Luteolin, metixene hydrochloride, and nitazoxanide emerge as strong cytotoxic and/or adjuvant therapy in oral cancer, as these compounds present higher efficiency and lower toxicity against oral cancer cells in vitro than conventional chemotherapeutic agents.

Conclusion 1. The results of the research partly supported hypothesis 1a. There was a significant reduction in both endothelium-dependent arterial relaxation following a surgical menopause. The results of the research partly supported hypothesis 1b. There was a significant reduction in endothelium-dependent arterial relaxation but no significant effect on endothelium-independent arterial relaxation. / Conclusion 2. The results of the research partly supported hypothesis 2a. The addition of unopposed oestrogen significantly improved endothelium-dependent but not endothelium-independent arterial relaxation. The results of the research supported hypothesis 2b. The addition of oestradiol combined with progestogen (norethisterone acetate) reversed the reduction in arterial relaxation caused by a surgical menopause. The results of the research partly supported hypothesis 2c. The addition of tibolone reversed the reduction endothelium-dependent but not endothelium-independent arterial relaxation. The results of the research partly supported hypothesis 2d. The addition of oestradiol combined with a progestogen (norethisterone acetate) reversed the reduction in endothelium-dependent but not endothelium-independent arterial relaxation. / Conclusion 3. The results of the research partly supported hypothesis 3a. Endothelium-dependent arterial relaxation but no endothelium-independent arterial relaxation was improved after the addition of menopausal hormone therapy using oestrogen combined with a progestogen in a continuous manner. The results of the research did not support hypothesis 3b. Neither endothelium-dependent arterial relaxation nor the endothelium-independent arterial relaxation was improved by cyclical menopausal HT. / Conclusion 4. The results of the research did not support hypothesis 4. The addition of menopausal hormone therapy using combined oestrogen with progestogen did not improve arterial relaxation in postmenopausal women with established coronary heart disease. / Hypothesis 2. This hypothesis examined three different types of commonly used menopausal HT. That unopposed oestrogen (2a), oestrogen combined with a progestogen (2b and 2d) or a synthetic steriod that has oestrogenic, progestogenic as well as androgenic activity (tibolone, 2c), reverse the reduction in arterial relaxation following menopause in Hong Kong Chinese women. / Hypothesis 3. That menopausal hormone therapy using oestrogen combined with progestogen given in either continuous (3a) or cyclical (3b) regimens improves arterial relaxation in postmenopausal Hong Kong Chinese women. / Hypothesis 4. That menopausal hormone therapy using combined oestrogen with progestogen improves arterial relaxation in postmenopausal Hong Kong Chinese women with established coronary heart disease. / Menopausal HT can in general at least partially reverse changes in arterial relaxation in postmenopausal women. Different types of menopausal HT exhibit different effects on arterial relaxation. In healthy vessels, menopause HT mainly reverses the endothelium-dependent vascular effect, but it remains unclear how menopausal HT affects the endothelium-independent vascular effect. However, with established coronary heart disease, menopausal HT cannot reverse the changes in vascular reactivity. / Summary. Menopause results in a reduction in arterial relaxation. However, GnRHa temporarily induced menopause in young women, the endothelium-independent vasodilatation was not impaired. This difference can be partly explained by the difference in age as vascular reactivity is age dependent. Secondly, GnRHa works with an initial phase of increase in oestrogen production resulting in a shorter duration of hypo-oestrogenism resulting in the lack of impairment on endothelium-independent vasodilatation. / This thesis tested the following hypotheses: Hypothesis 1. That vascular reactivity decreases after the menopause as shown in premenopausal Hong Kong Chinese women with either a surgical (1a) or a medically induced (1b) menopause. / This thesis will examine the effects of menopause and menopausal HT on arterial reactivity which is an indirect measurement of vascular function. Previous studies have shown that oestrogen is a potent coronary artery vasodilator, and this effect may be mediated via both endothelium-dependent and endothelium-independent mechanisms. One method of assessing vascular reactivity is to use ultrasound measurement of changes in brachial artery diameter in response to certain stimuli. Using this technique, changes in both endothelium-dependent and endothelium-independent vasodilatation can be measured. Increased rather than decreased arterial relaxation after stimulus can be viewed as a favourable response. / Yim, So-fan. / Adviser: C. J. Haines. / Source: Dissertation Abstracts International, Volume: 68-09, Section: B, page: 5873. / Thesis (M.D.)--Chinese University of Hong Kong, 2006. / Includes bibliographical references (p. 159-194). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / School code: 1307.

In conclusion, the present study successfully demonstrate BJ as a potent anti-pancreatic cancer herb; BD is the main ingredient for its cytotoxic and apoptotic effects on the pancreatic cancer cells through activation of the redox-sensitive p38-MAPK signaling pathway and reduction of anti-apoptotic activity by inhibition of NF-kappaB activation in pancreatic cancer cells. The in vivo efficacy and low toxicity of BD render this chemical compound to be a potential for its further development into an anti-pancreatic cancer agent. / In recent decades, the application of Chinese herbal medicine has become an increasingly popular approach and alternative to treating cancer. Moreover, Chinese herbal medicine is the source for the discovery of novel anti-cancer drugs. For example, irinotecan and topotecan, the analogues of camptothecin which is isolated from the bark and stem of Camptotheca acuminate are found to be effective in ovarian, lung and colon cancers. Given that Chinese medicine is commonly used in the treatment of cancers, we postulate that Chinese herbs are a valuable source to possess anti-pancreatic cancer compounds. Accordingly, the aims of the present project are: (1) to screen Chinese medicinal herbs which has the most potent cytotoxic activity in pancreatic cancer cells in vitro; (2) to isolate and identify the effective compound in Brucea javanica (BJ) which mediates apoptosis in pancreatic cancer cell lines; (3) to study the mechanistic pathways involved in brucein D - (BD, a quassinoid found in abundance in BJ) mediated apoptosis in pancreatic cancer in vitro; and (4) to evaluate the efficacy of BD in pancreatic cancer using an xenograft animal model of pancreatic cancer. / In vivo study demonstrated that daily administration of BD through intravenous injection for ten days in nude mice bearing pancreatic cancer cells effectively reduced tumor growth in terms of tumor weight and size, while showing no significant toxicity in heart, liver and kidney tissues of the mice. / Nine Chinese medicinal herbs were selected for the screening experiment and, among them, BJ exhibited the most potent cytotoxic action on the three pancreatic adenocarcinoma cell lines, namely PANC-1, SW-1990 and CAPAN-1, with IC50 values of 2.5mug/ml, 5.1mug/ml and 1.5mug/ml, respectively. BD, one of the main chemical compounds found in BJ was found to possess strong apoptogenic effect in PANC-1 cells, as evidenced by DNA condensation and fragmentation, sub-G1 phase formation, proteolytic activation of caspase 3, 8 and 9, and attenuation of bcl-2 activity. Further mechanistic studies revealed that the apoptotic signals generated by BD were transduced from the cell membrane to nucleus via the mediation of p38-MAPK signaling pathway while the reactive oxygen species (ROS) was found to accumulate in BD-treated PANC-1 cells. The activation p38-MAPK phosphorylation was inhibited by pretreatment with an antioxidant. However, the inhibition of NF-kappaB activity and downregulation of anitapoptotic genes in BD-treated cells was independent of the ROS changes. / Pancreatic cancer is the forth and sixth leading cause of cancer deaths in the United States and Hong Kong, respectively. The morbidity of pancreatic cancer is almost equal to its mortality rate. Poor diagnosis and intrinsic resistance to chemotherapy are the major characteristics for pancreatic cancer. Therefore, new therapeutic strategy is urgently warranted to overcome the drug-resistance challenge in the management of pancreatic cancer. / Lau Sin Ting Cynthia. / Source: Dissertation Abstracts International, Volume: 73-03, Section: B, page: . / Thesis (Ph.D.)--Chinese University of Hong Kong, 2009. / Includes bibliographical references (leaves 228-271). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [201-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese.