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

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

Introdução: As cavidades nasais constituem a via de acesso à hipófise na cirurgia transesfenoidal endoscópica. Deste modo, alterações naturais ou adquiridas da anatomia nasal podem prejudicar a cirurgia. Objetivos: Estudar as variações anatômicas das cavidades nasais, principalmente desvio do septo, correlacionando-as com a visibilidade no acesso transesfenoidal endoscópico, para subsidiar a decisão do tipo de acesso ou necessidade de correção do desvio. Material e Método: Estudo seccional em 38 pacientes submetidos ao acesso transesfenoidal endoscópico entre fevereiro de 2009 e janeiro de 2011 em centro de referência. No intraoperatório foram registradas as variações anatômicas, localização do desvio de septo no plano axial e coronal, largura do corredor cirúrgico, profundidade do acesso até o esfenoide e a sela, exposição do esfenoide e da sela após abertura dos mesmos. A dificuldade de visibilidade do acesso foi avaliada por escala ordinal: 0- sem dificuldade, 1- dificuldade leve a moderada, 2- dificuldade acentuada. Os testes empregados para correlação entre as variáveis foram qui-quadrado e razão de verossimilhança. A comparação entre duas médias foi pelo teste t de Student e três ou mais médias pela análise de variância (ANOVA), com teste complementar de Turkey. Resultados: Foram estudadas 76 cavidades nasais e foram observados 50 desvios septais (66%). A largura do corredor cirúrgico no local do desvio menor ou igual a 9 mm associou-se em 72% à dificuldade acentuada (p<0,001). Desvios de septo no andar médio (p=0,005) ou terço posterior (p<0,001) associaram-se à dificuldade acentuada. A largura da cavidade na região do desvio também foi menor no desvio do andar médio (8,41 mm, p=0,012) ou no desvio do terço posterior (6,9 mm, p<0,0001). No corredor cirúrgico, apenas a largura do meato médio se associou à dificuldade (5-13 mm, 73% dificuldade acentuada, p=0,001). Variações anatômicas das conchas foram observadas em 17%, sem impacto na visibilidade. O comprimento médio do septo nasal foi 64 mm (IC95%: 61,8-66,8 mm), a profundidade até o rostro do esfenoide 69 mm (IC95%: 67-71 mm) e até a sela 82 mm (IC 95%: 80,2- 83,8 mm). A exposição média do esfenoide foi de 20 mm (laterolateral) e 20,8mm (anteroposterior), enquanto da sela foi de 12,8 mm e 11,7 mm respectivamente. Conclusões: A largura da cavidade nasal na região do desvio e a presença de desvio de septo localizado em terço posterior ou no andar médio da cavidade nasal associaram-se à maior dificuldade na visibilidade do acesso transesfenoidal / Background: Nasal anatomical variations can impair the visibility on endoscopic transsphenoidal approach for pituitary tumors. Objective: To evaluate anatomical variations, mainly nasal septum deviation, and their impact on the visibility of transsphenoidal endoscopic approach. To support the decision of access type or need to correct the deviated septum. Methods: Cross-sectional study with 38 patients who underwent transsphenoidal endoscopic surgery using the two nostrils - four hands between February 2009 and January 2011 in a referral center. They were submitted to the intraoperative register of anatomical variations, septal deviations, surgical corridor width and location of the deviated septum (height and depth), depth of the access to sphenoid and sella, exposure of sphenoid and sella after opening. Visibility was assessed using an ordinal scale: 0- no difficulty, 1- low to moderate difficulty, 2- severe difficulty. Comparisons of two means were performed using Students t test, and three or more means using analysis of variance (ANOVA) with Turkeys complementary test. Correlations between scores were analyzed using the non-parametric chi-square test and the likelihood ratio. Results: Seventy-six nasal cavities were studied, and 50 septal deviations were found (66%). Among the patients with severe difficulty, 73% had a surgical corridor width in the location of the deviated septum of up to 9 mm (p < 0.001). Septal deviations in the middle level (p = 0.005) or posterior third (p < 0.001) were associated with severe difficulty. The width of the nasal cavity at the deviation was also smaller in the middle level (8.41 mm, p = 0,012) or posterior third (6.9 mm, p<0.001). In the surgical corridor, only the middle meatus was associated with difficulty (5 to 13 mm, 73% severe difficulty, p = 0.001). Anatomical variations of the nasal conchae were observed in 17% of cases with no impact on visibility. The average length of the nasal septum was 64 mm (95% CI 61.8 -66.8 mm); the mean depth to the sphenoid was 69 mm (95% CI 67-71 mm) and to the sella 82 mm (95% CI 80.2 - 83.8 mm). The average lateral exposure of the sphenoid was 20 mm and anteroposterior 20.8 mm and to the sella 12.8 mm and 11.7 mm respectively. Conclusions: The width of nasal cavity at deviation and site of septal deviation were associated with difficulty in visibility of the access. Septal deviations located at posterior third and at middle level in nasal cavities were strongly associated with difficulty

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

Objetivo: Analisar os efeitos da rinosseptoplatia sobre as áreas seccionais e volumes nasais e a nasalância da fala de indivíduos com fissura de lábio e palato unilateral reparada, utilizando rinometria acústica e nasometria. Modelo: Análise prospectiva. Local de Execução: Centro Cirúrgico e Laboratório de Fisiologia, HRAC-USP. Participantes: Indivíduos com fissura de lábio e palato unilateral reparada (n=21, idade=15-46 anos) foram avaliados antes da cirurgia (PRE) e 6-9 meses (POS1) e 12-23 meses (POS2) após. Variáveis: Na rinometria acústica foram aferidas as áreas de secção transversa dos segmentos correspondentes à válvula nasal (AST1), porção anterior (AST2) e porção posterior da concha nasal inferior (AST3), e, os volumes da região da válvula (V1) e conchas (V2) nasais, de ambas os lados, antes e após a descongestão nasal com vasoconstrictor tópico. Na nasometria, avaliou-se a nasalância na leitura de um texto contendo predominantemente sons nasais, e, outro, exclusivamente sons orais. Resultados: No lado fissurado, antes da descongestão nasal, observou-se um aumento significante (p<0.05) nos valores médios de AST1 e V1 em POS1 e POS2, relativamente ao PRE. Após a descongestão, observou-se aumento também para AST2 e V2 em POS2. No lado não-fissurado, não foram observadas variações significativas. Os valores médios de nasalância em PRE, POS1 e POS2 não diferiram entre si, nos textos oral e nasal. Conclusão: A medida das áreas seccionais e volumes mostraram que a rinosseptoplastia levou, na maioria dos casos analisados, a um aumento significativo da permeabilidade nasal, sem modificações concomitantes na ressonância da fala, estimada pela medida da nasalância. / Objective: To analyze the effects of rhinoseptoplasty on the nasal cross-sectional areas and volumes, and the speech nasalance of individuals with repaired unilateral cleft lip and palate, assessed by acoustic rhinometry and nasometry. Design: Prospective analysis. Setting: Surgery Service and Laboratory of Physiology at the Hospital for Rehabilitation of Craniofacial Anomalies (HRAC-USP). Participants: Individuals with previously repaired unilateral cleft lip and palate (n=21, age=15-46 years) were evaluated before surgery (PRE) after 6-9 months (POST1) and after 12-18 months (POST2). Variables: Acoustic rhinometry was used to measure the cross-sectional areas of segments corresponding to the nasal valve (CSA1), anterior portion (CSA2) and posterior portion (CSA3) of the lower turbinate, and the nasal volumes at the regions of the nasal valve (V1) and nasal turbinates (V2) at both sides, before and after nasal decongestion with a topical vasoconstrictor. Nasometry was employed to evaluate the speech nasalance during the reading of a text predominantly containing nasal sounds and other containing only oral sounds. Results: At the cleft side, before nasal decongestion, there was a significant increase (p<0.05) in mean CSA1 and CSA2 values at POST1 and POST2 compared to PRE. After decongestion, increased values were also observed for CSA2 and V2 at POST2. No significant changes were observed at the non-cleft side. The mean nasalance values at PRE, POST1 and POST2 were not different from each other in both oral and nasal texts. Conclusion: The measurement of cross-sectional areas and volumes by acoustic rhinometry revealed that rhinoseptoplasty provided, in most cases analyzed, a significant increase in nasal patency, without concomitant changes in speech resonance, as estimated by nasalance assessment.

Objectives: To investigate whether any changes in nasal cavity dimensions or subjective report of nasal symptoms exist after rapid maxillary expansion using two types of expansion appliances, comparing results with an untreated control group. Methods: Subjects were randomly assigned into one of three groups: tooth-borne or bone-anchored expander or untreated control. Acoustic rhinometry was used to measure minimal cross-sectional area and volume of the nasal cavity over three timepionts for treatment subjects and two timepoints for control subjects, taken along with the NOSE Instrument survey. Results: No significant changes in nasal cavity dimension or subjective reports were found in subjects treated with tooth- or bone-anchored appliances compared to control subjects over three timepoints. In addition, non-significant correlation was observed between nasal airway dimensional change and subject symptoms. Conclusions: Rapid maxillary expansion does not result in change of i) nasal airway dimensions or ii) the sensation of nasal symptoms. / Orthodontics

Aims: To evaluate and compare the wound healing process following osteotomies performed with either conventional rotary burs or piezoelectric surgery in a rabbit model mimicking access to the maxillary sinus cavity for sinus floor augmentation. Materials and methods: On the nasal bone of 16 adult New Zealand white rabbits, two types of osteotomy window defects of nasal cavities were marked to critical size with a Trephine drill (ø 5 mm) and then prepared with either a conventional rotary bur or piezo-surgery (PIEZOSURGERY® Insert OT5 of PIEZOSURGERY® 3 unit, Mectron s.p.a., Genova, Italy). The defects were covered with a resorbable membrane (Bio-Gide®, Geistlich Pharma AG, Wohusen LU, Switzerland). Four animals were sacrificed at one, two, three and five weeks after surgical procedure, respectively. Histological and morphometric evaluations were performed to assess the volumetric density of various tissue components: the blood clot (BC), vascularized structures (VS), provisional matrix (PM), osteoid, mineralized bone (MB), bone debris (BD), residual tissue, old bone (OB). Results: at the 1 week, more BC detected after piezo- surgical preparation. However, the difference did not reach statistical significance. A tendency of higher proportions of osteoid in the conventional bur defects was noted, but not statistically significant. Significantly more BD was found in the conventionally compared to the piezo-surgically prepared defects. At two weeks, new bone formation was noted, and the process of modeling of the newly formed bone had started. More MB was detected in the defect prepared by piezo-surgery than by conventional bur, but without any statistically significant difference. In the marginal areas of defect, slightly more osteoblasts (Obl) were present in piezo-surgically prepared defect than in conventional prepared defect, although there is no significant difference. At 3 week, a newly formed hard tissue bridge mainly composed of woven bone was seen. A high volumetric density of mineralized bone (MB) presented in all the specimens, At the 5 week, the defects were completely filled with newly formed bone. Conclusion: the defect prepared by piezo-surgery showed a significantly decreased proportion of bone debris at one week compared to conventional rotary bur defect. Increased volumetric densities of mineralized bone were observed in the piezo-surgical compared to the conventional bur defect after two weeks, although not statistically significant. Irrespective of the preparation modality of the defect performed, the defect was almost filled with newly formed bone at three weeks. At five weeks, complete regeneration of the calvaria defects was achieved. / published_or_final_version / Dental Surgery / Master / Master of Dental Surgery

published_or_final_version / Pathology / Doctoral / Doctor of Philosophy

No description available.

A rinite do desuso (RD) foi inicialmente observada em pacientes laringectomizados. Nestes pacientes encontravam-se cornetos nasais edemaciados e, por vezes, violáceos sem a presença de história de rinopatias ou mesmo de outras situações que justificassem tais alterações1. O fator desencadeante seria a mudança da respiração nasal pela respiração via traqueostoma. A restrição da mucosa nasal às variações cíclicas de temperatura e umidade e o comprometimento do clearance mucoso pela ausência de fluxo aéreo nasal (FAN) desencadeariam uma reação vasomotora com perda do tônus vascular acarretando engurgitamento dos cornetos nasais. Em 1970, Frank N. Ritter foi o primeiro a sugerir a ocorrência do mesmo fenômeno em crianças com obstrução importante por hiperplasia de adenóides2. Porém, nesta época não havia recursos confiáveis o suficiente para a confirmação desta hipótese. A avaliação da patência nasal é conhecida por sua complexidade. A história clínica e exame das fossas nasais não são suficientes para objetivar satisfatoriamente modificações da congestão nasal. Nas últimas duas décadas, a rinometria acústica (RA) foi validada e vem sendo empregada no estudo de doenças e tratamentos nasais, principalmente da congestão da mucosa em diferentes situações 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14. Trata-se de um exame rápido, não invasivo e que necessita pouca colaboração do examinado15. O exame calcula áreas de secção transversal (AST) em diferentes pontos da cavidade nasal, providencia uma curva áreadistância, localizando os sítios de maior estreitamento, chamados de área de secção transversal mínima (ASTM). Outro dado fornecido pela RA é o volume nasal. 7, 8, 16, 17. OBJETIVO: Este estudo propôs demonstrar o efeito sobre o tecido erétil nasal acarretado pela recuperação do fluxo nasal em pacientes submetidos à adenoidectomia. Recorreu-se a RA por ser um exame complementar prático para execução em crianças e por aumentar a objetividade na avaliação da permeabilidade nasal, principalmente, nas mudanças da congestão da mucosa nasal. MATERIAL E MÉTODOS: Foram selecionadas 21 crianças com diagnóstico de obstrução nasal importante e indicação exclusiva de adenoidectomia. Rinometria acústica foi coletada antes e 90 dias após o procedimento cirúrgico. Utilizaram-seos valores do volume da região limitada aos cornetos nasais. RESULTADOS: O volume nasal correspondente à região dos cornetos passou de 6,03cm³ no pré-operatório para 6,99cm³ no pós-operatório, representando um aumento de 16% nesta área (P< 0,05). Nos modelos de regressão linear e logística múltipla, nenhum fator testado interferiu significativamente na associação principal. CONCLUSÃO: Estudos anteriores utilizaram a RA no seguimento de crianças submetidas a cirurgias nasais e tiveram resultados variados, provavelmente devido às diferenças amostrais, às variações na técnica e na aparelhagem empregadas e a diferentes escolhas de dados a serem analisados no rinograma. Uma vez que a proposta do estudo foi observar o comportamento do tecido erétil da mucosa nasal com a recuperação do FAN, diferente de outros estudos, analisamos apenas o volume da região localizada entre 2,20cm e 5,40cm de profundidade nasal antes da vasoconstrição. Em crianças da faixa etária estudada, a cabeça do corneto nasal inferior localiza-se após os 2 cm de profundidade nasal, e as adenóides, após 6,5cm. 6,21-22 Como o único estímulo para a mudança do tecido erétil foi a recuperação do fluxo nasal, os autores concluem que a adenoidectomia influenciou favoravelmente no comportamento dos cornetos.