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Distúrbios angioproliferativos bucais e cutâneos: correlações histopatológicas e expressão de mediadores angiogênicos / Oral and cutaneous angioproliferative diseases: histopathologic correlations and expression of angiogenic mediatorsCosta, Maria Renata Sales Nogueira 26 April 2006 (has links)
A mucosa bucal e a pele podem apresentar distúrbios vasculares proliferativos com comportamento biológico variado. Para classificar tais lesões foram adotados critérios etiopatogênicos e a avaliação desses critérios em grupos específicos de lesões angioproliferativas pode contribuir para o diagnóstico e tratamento das mesmas. O objetivo desse estudo retrospectivo foi caracterizar as principais lesões angioproliferativas da mucosa bucal, comparando-as com os mesmos tipos de lesões cutâneas, em relação aos achados histopatológicos e à expressão endotelial do fator de crescimento fibroblástico básico (FGFb) e do receptor p75 para neurotrofinas (p75NTR). Foram utilizados espécimes arquivados em blocos parafinados, divididos conforme o diagnóstico microscópico em seis grupos: (I) malformações venosas; (II) malformações linfáticas; (III) granulomas piogênicos; (IV) hemangiomas capilares; (V) hemangiomas arteriovenosos; (VI) sarcomas de Kaposi. Cada grupo foi subdividido em dois grupos quanto a sua localização bucal e cutânea. Os padrões microscópicos das lesões angioproliferativas bucais e cutâneas de nossa amostra são similares e podem ser classificadas sob os mesmos parâmetros. No entanto, alguns grupos apresentaram diferenças quanto ao estádio de maturação das lesões, em relação à incidência e principalmente em relação à expressão dos mediadores estudados. A diferença na expressão de FGFb e p75NTR, observada entre os grupos bucais e cutâneos dos mesmos tipos de lesões, permitiunos concluir que a evolução da angiogênese na mucosa bucal e na pele não é necessariamente mediado pelos mesmos fatores. Tais diferenças abrem perspectivas para pesquisas futuras e abordagens terapêuticas baseadas em tecnologias moleculares. / The oral mucosa and the skin may present proliferative vascular diseases with varied biological behavior. To classify such lesions, pathogenic criteria were adopted in specific groups of vascular lesions. The objective of this retrospective study was to characterize the main oral vascular lesions, comparing them with the same types of cutaneous lesions. The histopathologic findings were compared, as well as the endothelial expression of basic fibroblastic growth factor (FGFb) and p75 neurotrophin receptor (p75NTR). Paraffin embedded specimens were purchased and divided, according to microscopic diagnostic, into six groups: (I) venous malformations; (II) lymphatic malformations; (III) pyogenic granulomas; (IV) capillary hemangiomas; (V) arteriovenous hemangiomas; (VI) Kaposi sarcomas. Each group was divided in two subgroups of oral and cutaneous location. The microscopic data demonstrated that oral and cutaneous vascular lesions, in our sample, are similar and they can be classified under the same parameters. However, some groups presented differences related to maturation stage, incidence, and expression FGFb and p75NTR. These differences allowed us to conclude that the evolution of angiogenic process inside oral mucosa and in the skin, not necessarily is mediated by the same biological factors. Such differences open perspectives for future researches and therapeutic approaches, based on molecular technologies.
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Caracterização e relação de leveduras do gênero Candida isoladas das mucosas oral e vaginal de mulheres com lesões causadas por HPV de alto risco para câncer do colo do útero / Characterization and relation of yeasts of the genus Candida isolated from the oral and vaginal mucosa e of women with lesions caused by high risk HPV for cervical cancerSouza, Ana Clara de 17 March 2017 (has links)
Este estudo caracterizou e relacionou as leveduras do gênero Candida isoladas das mucosas oral e vaginal de mulheres com lesões causadas por HPV de alto risco para câncer do colo do útero. Foram examinadas 42 mulheres tratadas no ambulatório de Patologia do Trato Genital Inferior do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo sendo, 30 com lesões uterinas de alto grau (G1) com média de idade de 36,5 anos ± 11,1 e 12 com lesões uterinas de baixo grau (G2) com média de idade de 34,75 anos ± 15,5. Condições clínicas e dados laboratoriais sobre HPV foram coletados do prontuário médico das pacientes; os dados sócio-demográficos obtidos a partir de um questionário apropriado. Para o estudo de associação entre as variáveis foi utilizada a análise de razão de chance (Odds Ratio) a partir do programa STATA 13.1. Foram identificadas associação entre lesões uterinas de baixo grau com cultura positiva em mucosa oral (OR= 0,215) e com presença de doenças crônicas (OR = 0,167), sendo que pacientes com lesões uterinas de alto grau possuem maior prevalência para diabetes e os resultados indicaram 23% de prevalência de Candida spp. em mucosa oral e 27% em mucosa vaginal, em pacientes do G1,no G2 foi de 42% em mucosa oral e de 33% em mucosa vaginal. Entre as espécies encontradas em mucosa oral e vaginal das pacientes, Candida albicans foi a mais isolada com 88%, seguida de C. tropicalis (8%)e C. glabrata (4%). As cepas de C. albicans isoladas de ambas as mucosas apresentaram sensibilidade a todos os antifúngicos testados, ao contrário da cepa de C. tropicalis isolada no Grupo 2, em mucosa vaginal, que apresentou um perfil de resistência ao fluconazol. Assim, torna-se importante o acompanhamento e supervisão por meio de exames clínicos e laboratoriais das pacientes com HPV, reforçando a necessidade sobre cuidados, tratamento e prevenção de infecções relacionadas ao HPV e a Candida spp. / This study characterized and related yeasts of the genus Candida isolated from the oral and vaginal mucous membranes of women with lesions caused by high-risk HPV for cervical cancer. Forty-two women treated at the Lower Genital Tract Pathology Clinic of the University of São Paulo Medical School\'s Hospital of Clinics were examined, with 30 high-grade (G1) uterine lesions with a mean age of 36.5 years ± 11, 1 and 12 with low grade (G2) uterine lesions with a mean age of 34.75 years ± 15.5. Clinical conditions and laboratory data on HPV were collected from patients\' medical records; the socio-demographic data obtained from an appropriate questionnaire. For the study of association between the variables, Odds Ratio analysis was used from the STATA 13.1 program. An association between low grade uterine lesions with positive culture in oral mucosa (OR = 0.215) and presence of chronic diseases (OR = 0.167) was identified. Patients with high grade uterine lesions had a higher prevalence for diabetes and the results indicated 23% prevalence of Candida spp. In oral mucosa and 27% in vaginal mucosa, in G1 patients, in G2 it was 42% in oral mucosa and 33% in vaginal mucosa. Among the species found in oral and vaginal mucosa of patients, Candida albicans was the most isolated with 88%, followed by C. tropicalis (8%) and C. glabrata (4%). The strains of C. albicans isolated from both mucosa presented sensitivity to all tested antifungal agents, unlike the C. tropicalis strain isolated in Group 2, in vaginal mucosa, which presented a resistance profile to fluconazole. Thus, monitoring and supervision through clinical and laboratory testing of HPV patients is important, reinforcing the need for care, treatment and prevention of HPV-related infections and Candida spp.
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Transporte mucociliar em fumantes participantes de um programa de cessação do tabagismo /Xavier, Rafaella Fagundes. January 2011 (has links)
Orientador: Ercy Mara Cipulo Ramos / Banca: Dionei Doffinger Ramos / Banca: Mariangela Macchione / Resumo: Introdução: A exposição ao cigarro promove alterações que prejudicam a eficácia do transporte mucociliar. Contudo, a influência da intensidade de exposição, assim como os efeitos da abstinência ao tabagismo sobre essas alterações foram pouco elucidados. Objetivos: Avaliar a influência de diferentes intensidades de exposição ao cigarro sobre o transporte mucociliar e o efeito da cessação do tabagismo sobre o transporte mucociliar nasal em fumantes avaliados durante um período de 180 dias. Casuística e Métodos: Participantes de um programa de cessação ao tabagismo, foram avaliados quanto ao histórico tabagístico, ao nível de dependência à nicotina, à avaliação da função pulmonar (espirometria), a concentração de monóxido de carbono no ar exalado (COex), ao nível de carboxihemoglobina (COHb) e ao transporte mucociliar (tempo de trânsito de sacarina - TTS). Para comparação foi avaliado um grupo... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Introduction: Exposure to cigarette smoke promotes changes that harm the effectiveness of the mucociliary clearance. However, the influence of the intensity of exposure, as well as the effects of abstinence from smoking on these changes is poorly understood. Objectives: To assess the influence of different intensities of exposure to cigarette smoke on mucociliary clearance and the effect of cessation of smoking on nasal mucociliary clearance in smokers evaluated over a period of 180 days. Methods: Participants from a smoking cessation programme, were evaluated about smoking behavior, level of nicotine dependence, lung function (spirometry), the carbon monoxide in exhaled air (exhaled CO), the carboxyhemoglobin (COHb) and mucociliary clearance (saccharin transit time - STT). Was evaluated for comparison... (Complete abstract click electronic access below) / Mestre
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Tabagismo e mecanismos de defesa : resposta imune e transporte mucociliar /Rodrigues, Fernanda Maria Machado. January 2012 (has links)
Orientador: Ercy Mara Cipulo Ramos / Banca: Dionei Ramos / Banca: Renata Calciolari Rossi e Silva / Resumo: Introdução: O tabagismo é uma pandemia que causa inúmeros malefícios à saúde, dentre eles estão o aumento da inflamação sistêmica e o prejuízo do transporte mucociliar. Ambos colaboram para o aumento da frequência ou da severidade de infecções respiratórias em indivíduos com e sem doenças pulmonares crônicas tabaco relacionadas. A cessação tabagística é capaz de trazer benefícios, mas não se está bem estabelecido o comportamento dos marcadores inflamatórios nesta condição. Além disso, os efeitos da intensidade tabagística no prejuízo do transporte mucociliar também não foram completamente elucidados. Objetivo: Avaliar o comportamento sistêmico e local de marcadores inflamatórios em 30 dias de abstinência tabagística além dos efeitos das intensidades de consumo tabagístico no transporte mucociliar de tabagistas ativos. Métodos: Foram avaliados tabagistas participantes de um Programa de cessação... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Introduction: Smoking is a pandemic that causes numerous health hazards, including increased systemic inflammation, impaired mucociliary clearance and increased frequency or severity of respiratory infections in individuals with and without chronic lung diseases related to tobacco. Smoking cessation can bring benefits, but is not well established the inflammatory markers' behavior at such condition. Besides that, the effects of the cigarette consumption intensity on impairment of mucociliary clearance have not been fully investigated. Aim: To evaluate the systemic and local behavior of the inflammatory markers at 30 days of smoking abstinence besides the effects of tobacco consumption intensities on mucociliary clearance of active smokers. Methods: We evaluated smokers participating in a smoking cessation program, who were... (Complete abstract click electronic access below) / Mestre
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Characterization of CNS pharmacokinetics and pharmacodynamics of intranasally delivered selected antipsychotic. / CUHK electronic theses & dissertations collectionJanuary 2013 (has links)
目的:抗精神病藥物是多功能的藥物。鼻腔給藥可提供高效的藥物遞送,但關於鼻腔遞送抗精神病藥物的研究仍十分有限。此外,有關鼻腔給藥後生成的活性代謝物於全身及中樞神經系統的分佈的報導亦很少。本研究的主要目的在於:1)篩選出適合鼻腔給藥的抗精神病藥物,以及2)研究被選定抗精神病藥物在鼻腔給藥後於中樞神經系統的藥代動力學和藥效學特徵,尤其關注藥物代謝在藥代動力學和藥效學中的作用。 / 方法:本研究系統地採用了in silico 評估及體外透過模型,篩選出具有較高鼻腔給藥發展潛力的抗精神病藥物。通過不同的鼻腔給藥動物體內模型,研究所選藥物全身及中樞神經系統的藥代動力學和藥效學特徵,並與口服和靜脈注射進行比較。 / 結果:第一階段的in silico篩選包括了二十二種抗精神病藥物。其中氯丙嗪、氟奮乃靜、丙氯拉嗪及洛沙平具有鼻腔給藥所需的良好的理化性質和臨床特點,因此被挑選到第二階段篩選。第二階段篩選採用體外Calu-3單層細胞模型研究藥物經鼻腔吸收的能力。Calu-3細胞模型的實驗結果表明,抗精神病藥物的表觀滲透係數與藥物的親脂性和總回收率呈負相關,其中洛沙平具有最高的透過性,並被選擇作進一步的體內研究。 / 我們建立了一種全新的可以同時測定大鼠腦內和血漿中洛沙平及其體內代謝產物(包括7-羥基-洛沙平)的液質聯用方法,並比較了在大鼠清醒及麻醉狀態下洛沙平鼻腔給藥後的藥代動力學。結果表明無論在大鼠清醒還是麻醉狀態下,鼻腔給藥均具有較高的絶對生物利用度(清醒狀態:~50%;麻醉狀態:~100%)。另外,研究發現麻醉和鼻腔手術對洛沙平及其代謝產物的體內處置具有很大影響,且這些影響依賴於給藥途徑。 / 本研究亦考察了洛沙平在鼻腔及口服給藥後,於大鼠中樞神經系統的藥代動力學和藥效學特徵。鼻腔給藥後,洛沙平迅速被吸收入血,隨即進入腦部,且15分鐘內在所有腦部區域達至最高藥物濃度。與之相反,口服給藥後僅有極少量的洛沙平吸收入血及腦部。但是,在鼻腔與口服給藥後,主要代謝產物7-羥基-洛沙平在腦內的濃度水平相當,且兩種給藥途徑對腦部紋狀體中多巴胺、5-羥色胺、和它們的代謝物水平的影響亦無差異。由於錐體外系癥狀乃抗精神病藥物常見的運動障礙性副作用,我們採用了大鼠僵直模型對大鼠在服用洛沙平後的運動障礙反應進行了評價。研究表明相比鼻腔給藥而言,口服洛沙平後誘發了大鼠更強的僵直反應。另外,當分別靜脈注射洛沙平及7-羥基-洛沙平後,7-羥基-洛沙平誘發的僵直反應比洛沙平更強;但同時注射洛沙平及7-羥基-洛沙平則降低了由7-羥基-洛沙平誘發的僵直反應。 / 結論:洛沙平有望進一步開發成為一種鼻腔遞藥,用於治療精神分裂症及其他中樞神經系統疾病。服用洛沙平後,錐體外系癥狀副作用很大程度上是由體內代謝產物7-羥基-洛沙平引起,而非洛沙平本身。藥物代謝對抗精神病藥物及鼻腔遞藥的臨床作用能產生很大的影響。 / Purpose: Antipsychotics are versatile drugs. Intranasal route could provide efficient delivery for certain therapeutic agents; however, studies on intranasal antipsychotics are limited. Moreover, the systemic and central nervous system (CNS) dispositions of active metabolites after intranasal drug administration are seldom investigated. The current project aims to 1) identify the antipsychotics that are more suitable to be developed into intranasal medications; and 2) characterize the CNS pharmacokinetic (PK) and pharmacodynamic (PD) profiles of the selected antipsychotic delivered by intranasal route, with a special attention to the role of drug metabolism in PK and PD outcomes. / Methods: To select an antipsychotic with greater potential for intranasal delivery, a systematic approach was adopted to screen antipsychotic candidates with in silico evaluations and then in vitro permeability assays. The systemic and CNS PK and PD profiles of the selected antipsychotic would be investigated in different intranasal delivery models and compared to that after oral and intravenous (IV) administrations. / Results: Twenty two antipsychotics were included in the primary in silico screening. Chlorpromazine, fluphenazine, prochlorperazine, and loxapine, which possessed more favorable physicochemical and clinical properties required for intranasal delivery, were selected. Secondary screening in the Calu-3 cell monolayer model demonstrated that the apparent permeability coefficients (P[subscript app]) correlated inversely to the antipsychoitc’s lipophilicity and total recovery. Loxapine, which demonstrated the highest permeability, was selected for further in vivo investigations. / A novel LCMS/MS assay method was first developed for quantification of loxapine and its metabolites including 7-hydroxy-loxapine (7-OH-loxapine) in rat brain and plasma. The systemic PKs of loxapine in conscious and anesthetized rat models of intranasal delivery were then studied and compared. While intranasal loxapine achieved satisfactory absolute bioavailabilities in both conscious (~50%) and anesthetized (~100%) models, anesthesia and nasal surgery were found to exert profound effects on the systemic disposition of loxapine and its metabolites, and such effects were dependent on the administration route. / The CNS PK and PD outcomes after intranasal and oral loxapine administrations were characterized. Intranasally administered loxapine was efficiently absorbed into systemic circulation followed by entering brain, with a t[subscript max] less than 15 min in all the studied brain regions. In contrast, oral route delivered minimal amounts of loxapine to plasma and brain. Intranasal and oral loxapine achieved similar brain levels of 7-OH-loxapine, the major metabolite, and these two routes induced similar changes in the striatal levels of dopamine, serotonin, and their metabolites. Extrapyramidal symptoms (EPS), the motor side effects frequently associated with antipsychotics, were evaluated by the catalepsy models. The severity and incidence of catalepsy were consistently higher after oral than after intranasal loxapine administration. Individual IV injections of loxapine and 7-OH-loxapine to rats revealed that 7-OH-loxapine was even more cataleptogenic than the loxapine, while co-injection of loxapine tended to lower the catalepsy induced by 7-OH-loxapine. / Conclusion: Loxapine seems to be a promising antipsychotic for further development into intranasal medication. 7-OH-loxapine, rather than the parent loxapine, could be the culprit in EPS associated with loxapine treatment. Drug metabolism could have considerable contribution to the clinical effects of antipsychotics and intranasal drugs. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Wong, Yin Cheong. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2013. / Includes bibliographical references (leaves 259-296). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstracts also in Chinese. / Table of contents --- p.I / Acknowledgements --- p.VII / Publications --- p.IX / Abstract --- p.XI / 摘要 --- p.XIII / List of Tables --- p.XV / List of Figures --- p.XVII / List of Abbreviations --- p.XX / Chapter Chapter One. --- Introduction --- p.1 / Chapter 1.1 --- Overview of antipsychotics --- p.1 / Chapter 1.1.1 --- Pharmacology --- p.1 / Chapter 1.1.2 --- Therapeutic applications --- p.7 / Chapter 1.1.2.1 --- Schizophrenic and other mental disorders --- p.7 / Chapter 1.1.2.2 --- Pain management --- p.9 / Chapter 1.1.3 --- Antipsychotic-induced extrapyramidal symptoms (EPS) --- p.11 / Chapter 1.1.3.1 --- Clinical manifestations --- p.11 / Chapter 1.1.3.2 --- Preclinical evaluation of EPS by catalepsy tests --- p.13 / Chapter 1.1.3.3 --- Role of active metabolites in EPS --- p.16 / Chapter 1.2 --- Overview of intranasal drug delivery --- p.20 / Chapter 1.2.1 --- Absorption of drug in nasal cavity --- p.21 / Chapter 1.2.1.1 --- Nasal anatomy --- p.21 / Chapter 1.2.1.2 --- Pathways from the nasal passages to the central nervous system --- p.25 / Chapter 1.2.2 --- Metabolite formation after intranasal drug application --- p.26 / Chapter 1.2.2.1 --- Nasal metabolisms --- p.27 / Chapter 1.2.2.2 --- Contribution of gastrointestinal absorption and metabolism --- p.27 / Chapter 1.3 --- Potentials of delivering antipsychotics via intranasal route --- p.33 / Chapter 1.3.1 --- Advantages and limitations of intranasal drug delivery --- p.33 / Chapter 1.3.2 --- Advantages of intranasal antipsychotics --- p.37 / Chapter 1.4 --- Research questions and hypotheses of current study --- p.40 / Chapter 1.5 --- Objectives and thesis outline --- p.42 / Chapter 1.6 --- Significance of the current study --- p.46 / Chapter Chapter Two. --- In silico screening of antipsychotic candidates for their intranasal delivery potential --- p.47 / Chapter 2.1 --- Introduction --- p.47 / Chapter 2.2 --- Methods --- p.49 / Chapter 2.2.1 --- Antipsychotic candidates included in the in silico screening --- p.49 / Chapter 2.2.2 --- Evaluation of physicochemical properties of the candidates --- p.49 / Chapter 2.2.3 --- Clinical development potential of the candidates --- p.51 / Chapter 2.2.3.1 --- Therapeutic uses in conditions other than chronic schizophrenia --- p.51 / Chapter 2.2.3.2 --- Previous reports on intranasal delivery of antipsychotics --- p.52 / Chapter 2.2.4 --- Set up of selection criteria for further in vitro investigations --- p.53 / Chapter 2.3 --- Results and discussions --- p.54 / Chapter 2.3.1 --- Selection based on physicochemical characteristics --- p.54 / Chapter 2.3.2 --- Selection based on therapeutic usage --- p.58 / Chapter 2.3.3 --- Antipsychotic candidates selected for further in vitro investigations --- p.61 / Chapter 2.4 --- Conclusion --- p.66 / Chapter Chapter Three. --- In vitro permeation studies of selected antipsychotic candidates using Calu-3 cell line model --- p.67 / Chapter 3.1 --- Introduction --- p.67 / Chapter 3.2 --- Materials --- p.70 / Chapter 3.2.1 --- Chemicals --- p.70 / Chapter 3.2.2 --- Materials for cell culture --- p.70 / Chapter 3.2.3 --- Instruments --- p.71 / Chapter 3.3 --- Methods --- p.71 / Chapter 3.3.1 --- Cell culture --- p.71 / Chapter 3.3.2 --- Cytotoxicities of the drug candidates on Calu-3 cells by MTS/PES assay --- p.72 / Chapter 3.3.3 --- Stabilities of the drug candidates in loading solutions --- p.74 / Chapter 3.3.4 --- Permeation studies of drug candidates using Calu-3 cell line model --- p.75 / Chapter 3.3.5 --- HPLC/UV assay development and validation for the drug candidates --- p.77 / Chapter 3.3.6 --- Data analysis --- p.79 / Chapter 3.4 --- Results and discussions --- p.80 / Chapter 3.4.1 --- HPLC/UV methods for the drug candidates --- p.80 / Chapter 3.4.2 --- Cytotoxicities of the drug candidates on Calu-3 cells by MTS/PES assay --- p.82 / Chapter 3.4.3 --- Stabilities of the drug candidates in loading solutions --- p.85 / Chapter 3.4.4 --- Permeation studies of drug candidates using Calu-3 cell line model . --- p.86 / Chapter 3.4.4.1 --- Permeability across Calu-3 cell monolayer --- p.86 / Chapter 3.4.4.2 --- Relationship between lipophilicity and permeability and cellular uptake of the antipsychotic candidates --- p.89 / Chapter 3.5 --- Conclusion --- p.93 / Chapter Chapter Four. --- LCMS/MS assay development for quantification of loxapine, amoxapine and their hydroxylated metabolites in rat brain tissues, plasma and CSF --- p.94 / Chapter 4.1 --- Introduction --- p.94 / Chapter 4.2 --- Materials and chemicals --- p.100 / Chapter 4.3 --- Methods --- p.100 / Chapter 4.3.1 --- Preparation of stock solutions, calibration standards and quality control (QC) samples --- p.100 / Chapter 4.3.2 --- Sample extraction procedure --- p.102 / Chapter 4.3.2.1 --- Plasma --- p.102 / Chapter 4.3.2.2 --- Brain tissue --- p.103 / Chapter 4.3.2.3 --- CSF --- p.103 / Chapter 4.3.3 --- LCMS/MS conditions --- p.104 / Chapter 4.3.4 --- Method validation --- p.106 / Chapter 4.3.4.1 --- Linearity and range --- p.106 / Chapter 4.3.4.2 --- Accuracy and precision --- p.106 / Chapter 4.3.4.3 --- Recovery and stability --- p.107 / Chapter 4.3.4.4 --- Assay selectivity and matrix effects --- p.107 / Chapter 4.3.5 --- Application to pharmacokinetic study of orally administered loxapine in rats --- p.108 / Chapter 4.4 --- Results and discussions --- p.110 / Chapter 4.4.1 --- Optimization of LC and MS conditions --- p.110 / Chapter 4.4.2 --- Extraction of loxapine and metabolites from biological matrices --- p.114 / Chapter 4.4.2.1 --- Plasma --- p.114 / Chapter 4.4.2.2 --- Brain tissue --- p.115 / Chapter 4.4.2.3 --- Sample cleanup by SPE --- p.115 / Chapter 4.4.3 --- Method validation --- p.119 / Chapter 4.4.3.1 --- Linearity and range --- p.119 / Chapter 4.4.3.2 --- Accuracy and precision --- p.120 / Chapter 4.4.3.3 --- Recovery and stability --- p.120 / Chapter 4.4.3.4 --- Assay selectivity and matrix effects --- p.121 / Chapter 4.4.4 --- Application to pharmacokinetic study of orally administered loxapine in rats --- p.124 / Chapter 4.4.4.1 --- Plasma pharmacokinetic profiles --- p.124 / Chapter 4.4.4.2 --- Brain distribution study --- p.126 / Chapter 4.4.4.3 --- CSF disposition --- p.128 / Chapter 4.4.5 --- Implications on the further investigations of low-dose loxapine --- p.128 / Chapter 4.5 --- Conclusion --- p.131 / Chapter Chapter Five. --- Pharmacokinetic profiles of loxapine and its metabolites after intranasal loxapine administration: comparison of conscious and anesthetized rat models --- p.132 / Chapter 5.1 --- Introduction --- p.132 / Chapter 5.2 --- Materials and chemicals --- p.135 / Chapter 5.3 --- Methods --- p.135 / Chapter 5.3.1 --- Animal surgery --- p.135 / Chapter 5.3.1.1 --- Conscious rat model --- p.135 / Chapter 5.3.1.2 --- Anesthetized rat model --- p.136 / Chapter 5.3.2 --- Loxapine administration through intranasal, oral and IV routes --- p.138 / Chapter 5.3.2.1 --- Preparation of drug solutions --- p.138 / Chapter 5.3.2.2 --- Drug administration in conscious rat model --- p.138 / Chapter 5.3.2.3 --- Drug administration in anesthetized rat model --- p.139 / Chapter 5.3.3 --- Blood and brain samplings --- p.139 / Chapter 5.3.4 --- Pharmacokinetic and statistical analyses --- p.142 / Chapter 5.4 --- Results and discussions --- p.143 / Chapter 5.4.1 --- Pharmacokinetics of loxapine and its metabolites in conscious model --- p.149 / Chapter 5.4.1.1 --- Plasma concentration versus time profiles --- p.149 / Chapter 5.4.1.2 --- Brain dispositions of loxapine and its metabolites --- p.150 / Chapter 5.4.2 --- Pharmacokinetics of loxapine and its metabolites in anesthetized model --- p.151 / Chapter 5.4.2.1 --- Plasma concentration versus time profiles --- p.151 / Chapter 5.4.2.2 --- Brain dispositions of loxapine and its metabolites --- p.153 / Chapter 5.4.3 --- Effects of anesthesia and nasal surgery on the pharmacokinetics of loxapine and its metabolites --- p.155 / Chapter 5.4.3.1 --- Effects of anesthesia and nasal surgery on loxapine absorption --- p.158 / Chapter 5.4.3.2 --- Effects of anesthesia and nasal surgery on distribution of loxapine and its metabolites --- p.161 / Chapter 5.4.3.3 --- Effects of anesthesia and nasal surgery on loxapine metabolism --- p.164 / Chapter 5.4.3.4 --- Effects of anesthesia and nasal surgery on elimination of loxapine and its metabolites --- p.167 / Chapter 5.4.3.5 --- Overall effects of anesthesia and nasal surgery on the pharmacokinetics of loxapine and its metabolites --- p.168 / Chapter 5.5 --- Conclusion --- p.172 / Chapter Chapter Six. --- CNS pharmacokinetics of loxapine and its metabolites and pharmacodynamic effects on catalepsy and neurotransmission after intranasal loxapine administration --- p.173 / Chapter 6.1 --- Introduction --- p.173 / Chapter 6.2 --- Materials and chemicals --- p.178 / Chapter 6.3 --- Methods --- p.178 / Chapter 6.3.1 --- LCMS/MS assay development for quantification of neurotransmitters and their metabolites in rat brain tissue --- p.178 / Chapter 6.3.1.1 --- Preparation of stock solutions, calibration standards and quality control samples --- p.178 / Chapter 6.3.1.2 --- Sample extraction procedure --- p.179 / Chapter 6.3.1.3 --- LCMS/MS conditions --- p.180 / Chapter 6.3.1.4 --- Method validation --- p.180 / Chapter 6.3.2 --- Experimental procedures --- p.182 / Chapter 6.3.2.1 --- Drug administration through nasal and oral routes --- p.183 / Chapter 6.3.2.2 --- Catalepsy tests --- p.184 / Chapter 6.3.2.3 --- Drug and neurotransmitter analyses --- p.185 / Chapter 6.3.3 --- Data analysis --- p.185 / Chapter 6.4 --- Results and discussions --- p.187 / Chapter 6.4.1 --- LCMS/MS assay for quantification of neurotransmitters and their metabolites in rat brain tissue --- p.187 / Chapter 6.4.2 --- Pharmacokinetics of loxapine and its metabolites --- p.192 / Chapter 6.4.2.1 --- Pharmacokinetic profiles of loxapine and its metabolites in brain --- p.192 / Chapter 6.4.2.2 --- Pharmacokinetic profiles of loxapine and its metabolites in plasma --- p.197 / Chapter 6.4.3 --- Effects of nasal and oral loxapine administrations on catalepsy --- p.202 / Chapter 6.4.4 --- Effects of nasal and oral loxapine administrations on neurotransmitter levels --- p.208 / Chapter 6.4.5 --- Comparison of the present study on intranasal loxapine with previous studies on intranasal delivery of CNS drugs --- p.215 / Chapter 6.4.5.1 --- Intranasal delivery of antipsychotic --- p.215 / Chapter 6.4.5.2 --- Metabolite disposition in brain after intranasal administration of CNS drugs --- p.218 / Chapter 6.4.6 --- Clinical significance of the present study --- p.221 / Chapter 6.5 --- Conclusion --- p.225 / Chapter Chapter Seven. --- Cataleptogenic effects of loxapine and its metabolites --- p..226 / Chapter 7.1 --- Introduction --- p.226 / Chapter 7.2 --- Methods --- p.229 / Chapter 7.2.1 --- Literature study on the cataleptogenicity of loxapine and its metabolites --- p.229 / Chapter 7.2.2 --- Cataleptogenic effects of loxapine and its metabolites given by IV route --- p.229 / Chapter 7.2.2.1 --- Cataleptogenic effect of individual compounds --- p.229 / Chapter 7.2.2.2 --- Effect of addition of loxapine on the cataleptogenic effect of 7-OH-loxapine --- p.230 / Chapter 7.2.3 --- Data analysis --- p.230 / Chapter 7.3 --- Results and discussions --- p.231 / Chapter 7.3.1 --- Literature study on the cataleptogenicity of loxapine and its metabolites --- p.231 / Chapter 7.3.2 --- Cataleptogenic effects of loxapine and its metabolites given by IV route --- p.236 / Chapter 7.3.2.1 --- Cataleptogenic effect of individual compounds --- p.236 / Chapter 7.3.2.2 --- Effect of addition of loxapine on the cataleptogenic effect of 7-OH-loxapine --- p.240 / Chapter 7.3.3 --- Clinical significance of the present study --- p.245 / Chapter 7.4 --- Conclusion --- p.252 / Chapter Chapter Eight. --- Overall Conclusion --- p.253 / References --- p.259
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Distúrbios angioproliferativos bucais e cutâneos: correlações histopatológicas e expressão de mediadores angiogênicos / Oral and cutaneous angioproliferative diseases: histopathologic correlations and expression of angiogenic mediatorsMaria Renata Sales Nogueira Costa 26 April 2006 (has links)
A mucosa bucal e a pele podem apresentar distúrbios vasculares proliferativos com comportamento biológico variado. Para classificar tais lesões foram adotados critérios etiopatogênicos e a avaliação desses critérios em grupos específicos de lesões angioproliferativas pode contribuir para o diagnóstico e tratamento das mesmas. O objetivo desse estudo retrospectivo foi caracterizar as principais lesões angioproliferativas da mucosa bucal, comparando-as com os mesmos tipos de lesões cutâneas, em relação aos achados histopatológicos e à expressão endotelial do fator de crescimento fibroblástico básico (FGFb) e do receptor p75 para neurotrofinas (p75NTR). Foram utilizados espécimes arquivados em blocos parafinados, divididos conforme o diagnóstico microscópico em seis grupos: (I) malformações venosas; (II) malformações linfáticas; (III) granulomas piogênicos; (IV) hemangiomas capilares; (V) hemangiomas arteriovenosos; (VI) sarcomas de Kaposi. Cada grupo foi subdividido em dois grupos quanto a sua localização bucal e cutânea. Os padrões microscópicos das lesões angioproliferativas bucais e cutâneas de nossa amostra são similares e podem ser classificadas sob os mesmos parâmetros. No entanto, alguns grupos apresentaram diferenças quanto ao estádio de maturação das lesões, em relação à incidência e principalmente em relação à expressão dos mediadores estudados. A diferença na expressão de FGFb e p75NTR, observada entre os grupos bucais e cutâneos dos mesmos tipos de lesões, permitiunos concluir que a evolução da angiogênese na mucosa bucal e na pele não é necessariamente mediado pelos mesmos fatores. Tais diferenças abrem perspectivas para pesquisas futuras e abordagens terapêuticas baseadas em tecnologias moleculares. / The oral mucosa and the skin may present proliferative vascular diseases with varied biological behavior. To classify such lesions, pathogenic criteria were adopted in specific groups of vascular lesions. The objective of this retrospective study was to characterize the main oral vascular lesions, comparing them with the same types of cutaneous lesions. The histopathologic findings were compared, as well as the endothelial expression of basic fibroblastic growth factor (FGFb) and p75 neurotrophin receptor (p75NTR). Paraffin embedded specimens were purchased and divided, according to microscopic diagnostic, into six groups: (I) venous malformations; (II) lymphatic malformations; (III) pyogenic granulomas; (IV) capillary hemangiomas; (V) arteriovenous hemangiomas; (VI) Kaposi sarcomas. Each group was divided in two subgroups of oral and cutaneous location. The microscopic data demonstrated that oral and cutaneous vascular lesions, in our sample, are similar and they can be classified under the same parameters. However, some groups presented differences related to maturation stage, incidence, and expression FGFb and p75NTR. These differences allowed us to conclude that the evolution of angiogenic process inside oral mucosa and in the skin, not necessarily is mediated by the same biological factors. Such differences open perspectives for future researches and therapeutic approaches, based on molecular technologies.
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Oral physiological pigmentation in a Western Cape sampleGovender, Shogan January 2018 (has links)
Magister Chirurgiae Dentium - MChD / Oral physiological pigmentation presents with great variability with respect to sites, forms,
patterns and contrasts in colour. Knowledge of the existence of pigmented lesions and their
significance remained unclear for both the general public and oral clinicians alike. The
possibility of malignant transformation of some pigmented lesions makes them important to
monitor and biopsy. The prevalence of physiological pigmentation is unknown for the defined
population group in this study. The results will be beneficial as part of a larger multicentre
study with South Africa (Feller et al, 2015).
Methodology: A cross sectional analytical study of patients that attended the University of the
Western Cape Oral Health centres for routine treatment was conducted. After obtaining
informed consent, patients were screened and asked a series of questions using a standardized
questionnaire. From these completed questionnaires a prevalence relating to oral physiological
pigmentation was determined.
Oral physiological pigmentation did not have a male or female predominance in this study
population group, but was associated with increased age. Oral pigmentation seemed to be well
represented after 18 years of age. Patients were not usually aware of the pigmented gingiva
unless being made aware off it.
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Chemotherapy - induced intestinal mucositis : the role of apoptosis regulatorsBowen, Joanne M January 2006 (has links)
Mucositis is the damage that occurs to the alimentary canal from anti - cancer therapies. It is caused by chemotherapy, radiotherapy and combination therapy and affects a large proportion of patients. Despite its prevalence, an effective anti - mucositis agent has yet to be developed that protects the whole tube, although the use of keratinocyte growth factor ( Amgen ' s Palifermin ) has recently been approved for the prevention of oral mucositis. It is important to understand mechanisms controlling mucositis so that treatment can be targeted appropriately. This thesis has investigated some of the key components identified as being involved in mucositis as well as identifying new genes which contribute to chemotherapy - induced intestinal injury. The research chapters investigated : 1 ) Gene expression of the apoptosis - regulating Bcl - 2 family, p53 and caspase - 3, and the changes which occur in the intestine following chemotherapy treatment for cancer. 2 ) The effect of different chemotherapeutic agents on intestinal cells in vitro and the role p53 plays. 3 ) The mucositis caused by single dose irinotecan in the rat with breast cancer and the role of p53 in induction of intestinal damage. 4 ) The early gene changes that occur in the small intestine of the rat with breast cancer following irinotecan treatment. Firstly, to investigate the difference in susceptibility to damage between the small and large intestine, the protein expression of 8 members of the Bcl - 2 family ( 4 pro - apoptotic ; Bax, Bak, Bid, Bim and 4 anti - apoptotic ; Bcl - 2, Bcl - xL, Bcl - w, Mcl - 1 ) was quantified in jejunal and colonic sections taken from rats inoculated with breast cancer. It was found that there was significantly higher expression of the pro - apoptotic proteins, Bax, Bak, Bim and Bid, in the crypts of the jejunum compared to the colon. Furthermore, expression of the anti - apoptotic proteins, Bcl - 2, Bcl - xL and Bcl - w, was significantly lower in jejunal crypts compared to colonic crypts. Mcl - 1 expression was similar in both regions. Thus, the small intestine is an environment balanced to favour apoptosis through specific Bcl - 2 family protein expression profiles. The Bcl - 2 family regulates apoptosis in response to a variety of chemotherapy agents. However, it is unknown how Bcl - 2 family gene expression changes along with other apoptogenic factors following cytotoxic therapy in the normal intestine. To investigate this, sections of rat jejunum treated with methotrexate and duodenal biopsies from chemotherapy patients treated with various regimens for cancer were subjected to quantitative immunohistochemistry to detect Bcl - 2 family proteins, p53 and caspase - 3. Treatment caused expression of p53 and caspase - 3 to increase within the crypts and follow a similar pattern to apoptosis levels. Pro - apoptotic Bcl - 2 family members, Bax and Bak, were increased, while the anti - apoptotic protein, Mcl - 1, was significantly reduced. A significant increase in mRNA expression for Bax and Bak was noticed at 6 h, without a concurrent decrease in Mcl - 1. Thus, Bcl - 2 family genes were altered in the small intestine in both humans and rats, and this was irrespective of chemotherapy agent or regimen used. The best characterised changes which occur during chemotherapy - induced damage in the intestine are in the epithelial layer, although it is thought that pan #45 mucosal alterations are involved. Two intestinal cell lines were chosen to investigate changes in apoptosis, proliferation and protein expression following cytotoxic treatment with various chemotherapeutic agents. These were the rat IEC - 6 and human FHs 74 cell lines, which represent untransformed epithelial cells. The human breast carcinoma cell line, MCF - 7, was also used as a positive control. Intestinal cells were resistant to the occurrence of methotrexate toxicities within 24 h of treatment, modestly affected by irinotecan and extremely sensitive to doxorubicin. Doxorubicin caused a marked increase in p53 and p21 expression, which for irinotecan was less pronounced. The effect of cytotoxic treatment on Bcl - 2 family expression in intestinal cells varied, however the pro - apoptotic proteins, Bax and Bak, were generally upregulated following doxorubicin. Temporary inhibition of p53 using pifithrin alpha resulted in a significant improvement in cell survival in cancerous cell only and did not alter Bcl - 2 family expression. It was concluded that cultured epithelial cells exhibit varying sensitivities to different chemotherapeutic agents which is dependent on induction of p53 gene expression. The topoisomerase I inhibitor, irinotecan, is a chemotherapeutic agent commonly used in the treatment of colorectal cancer. It often induces severe mucositis with the most common symptom being diarrhoea. Previous research has shown that irinotecan damages the small and large bowel equally, which is unusual. This is characterised by an increase in apoptosis and a reduction in proliferation within epithelial crypts, an increase in inflammatory cell infiltrate in the lamina propria and excess mucin production. These investigations used two sequential doses of irinotecan. The early effect of a single dose of irinotecan on the intestine have yet to be studied. Thus the primary aim of this experiment was to examine in detail the changes caused by irinotecan at 6 and 48 h in the rat. A secondary aim was to investigate the role of p53 on induction of apoptosis and cell cycle arrest within intestinal crypts and the effect of temporary inhibition of the protein. Single dose irinotecan caused a decrease in body and small intestinal weight by 48 h after treatment. This was accompanied by crypt and villous degeneration, increased apoptosis and reduced proliferation within crypt epithelium as well as inflammatory infiltrate throughout lamina propria. An increase in Bax expression was seen at 6 h, however p53 protein levels remained relatively low until 48 h. Rats also treated with pifithrin alpha to inhibit p53 and had a significantly lower peak in apoptosis in the colon at 6 h, however did not show improvements in any other parameters tested. It was concluded that irinotecaninduced damage in the rat intestine is primarily p53 - independent, and that pifithrin alpha acts to inhibit apoptosis in the large intestine via a p53 - independent pathway. A study was designed to investigate the early genome - wide changes which occur following irinotecan treatment in the rat small intestine. Microarray analysis found that regulation of many genes was altered at 6 h following dual dose irinotecan. These genes were involved in apoptosis, cell cycle regulation, immune function, calcium homeostasis and protein turnover. Multiple genes from the MAP kinase pathway were also activated by irinotecan. The cystine protease, caspase - 1 was upregulated and was chosen for further investigations due to its role in apoptosis and inflammation. Real time PCR analysis confirmed the increase in gene expression at 6 h and also showed a return to baseline levels by 24 h which was followed by another modest increase at 48 h. It was concluded that irinotecan induces a wide range of gene changes within the intestine and that apoptosis and inflammatory damage pathways are activated during treatment. This thesis described key molecules in apoptosis and their role in induction of chemotherapy - induced intestinal mucositis. It has provided evidence of the importance of apoptosis in mucosal injury and also highlighted areas requiring further research. Results presented herein show that the Bcl - 2 family is involved in intestinal damage following many chemotherapy agents, whereas p53 is agent - specific. It has also shown that irinotecan causes intestinal damage via a mainly p53 - independent manner in the rat. It can be concluded that gastrointestinal mucositis is complex and activates multiple pathways to induce damage. Findings from this thesis will aid targeting of new anti - mucotoxic agents. / Thesis (Ph.D.) -- University of Adelaide, School of Medicine, 2006.
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The effect of cytotoxic chemotherapy on the mucosa of the small intestine / by Dorothy Mary Kate Keefe.Keefe, Dorothy Mary Kate January 1998 (has links)
Copy of author's previously published article inserted. / Bibliography: leaves 210-234. / xiii, 235 leaves : / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Investigates the effect of chemotherapy on the mucosa of the small intestine and the prevalence, duration and severity of mucositis, both in humans and in rats. / Thesis (M.D.)--University of Adelaide, Depts. of Gastroenterology and Haematology/Oncology, 1998
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The effect of cytotoxic chemotherapy on the mucosa of the small intestine / by Dorothy Mary Kate Keefe.Keefe, Dorothy Mary Kate January 1998 (has links)
Copy of author's previously published article inserted. / Bibliography: leaves 210-234. / xiii, 235 leaves : ill. ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Investigates the effect of chemotherapy on the mucosa of the small intestine and the prevalence, duration and severity of mucositis, both in humans and in rats. / Thesis (M.D.)--University of Adelaide, Depts. of Gastroenterology and Haematology/Oncology, 1998
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