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

Thesis (M.S.)--University of Kentucky, 2002. / Title from document title page. Document formatted into pages; contains. Includes abstract. Includes bibliographical references (p. 125-126).

A nanotecnologia tornou possível estruturar nanopartículas (NPs), utilizando-se polímeros biodegradáveis e atóxicos, como a quitosana (QS) - capaz de carrear e disponibilizar antígenos para a mucosa, devido sua propriedade mucoadesiva. Uma vacina liofilizada, em comparação a uma formulação líquida, possui inúmeras vantagens, tais como melhora na estabilidade do produto e melhor resistência às variações de temperatura, aumentando sua vida de prateleira e possibilitando melhor logística do produto aos locais onde o acesso à rede refrigerada é difícil; ademais, um produto liofilizado tem sua mucoadesividade aumentada, possibilitando maior tempo de permanência na mucosa. O presente trabalho teve como objetivo observar a resposta imune, em camundongos, de uma vacina desenvolvida por um mecanismo de entrega intranasal do HBsAg (Antígeno de superfície da Hepatite B) encapsulado pelo método de incorporação em nanopartículas de quitosana (NPs) liofilizadas. A formação das NPs foi realizada pela interação eletroestática da quitosana e do TPP (tripolifosfato de sódio), utilizando método de geleificação iônica. Formulações de NPs com glicina 5% apresentaram boas características após reconstituição, umidade residual inferior a 1% e processo de liofilização de 13 horas. Foi avaliada a imunogenicidade da inoculação do HBsAg em formulações de NPs de quitosana líquida e liofilizada, verificando-se que a forma líquida produziu anticorpos IgG contra HBsAg. / Nanotechnology has become possible to structure nanoparticles (NPs), using non-toxic and biodegradable polymers such as chitosan (CS), capable of carrying and deliver antigens to the mucosa, due to mucoadhesive property. A lyophilized vaccine compared to a liquid formulation, has several advantages, such as improved product stability as well as better resistance to temperature changes, increasing its shelf life allowing better logistics of the product to places where access to the chain cold is difficult and especially a lyophilized product increases muco-adhesiveness providing for longer staying in the mucosa. The work aims to observe the immune response in mice of vaccine developed by an intranasal delivery mechanism of HBsAg (hepatitis B surface antigen) encapsulated by incorporation method in chitosan nanoparticles (NPs) lyophilized. The formation of NPs was performed by electrostatic interaction between the chitosan and TPP (sodium tripolyphosphate) using the ionic gelation. Formulations showed good characteristics after reconstitution, residual humidity lower than 1% and the lyophilization process 15-hour. In this work, was evaluated the immunogenicity of inoculation of HBsAg in lyophilized and liquid formulations of chitosan nanoparticles, which liquid formulation produced anti-HBsAg antibodies.

A nanotecnologia tornou possível estruturar nanopartículas (NPs), utilizando-se polímeros biodegradáveis e atóxicos, como a quitosana (QS) - capaz de carrear e disponibilizar antígenos para a mucosa, devido sua propriedade mucoadesiva. Uma vacina liofilizada, em comparação a uma formulação líquida, possui inúmeras vantagens, tais como melhora na estabilidade do produto e melhor resistência às variações de temperatura, aumentando sua vida de prateleira e possibilitando melhor logística do produto aos locais onde o acesso à rede refrigerada é difícil; ademais, um produto liofilizado tem sua mucoadesividade aumentada, possibilitando maior tempo de permanência na mucosa. O presente trabalho teve como objetivo observar a resposta imune, em camundongos, de uma vacina desenvolvida por um mecanismo de entrega intranasal do HBsAg (Antígeno de superfície da Hepatite B) encapsulado pelo método de incorporação em nanopartículas de quitosana (NPs) liofilizadas. A formação das NPs foi realizada pela interação eletroestática da quitosana e do TPP (tripolifosfato de sódio), utilizando método de geleificação iônica. Formulações de NPs com glicina 5% apresentaram boas características após reconstituição, umidade residual inferior a 1% e processo de liofilização de 13 horas. Foi avaliada a imunogenicidade da inoculação do HBsAg em formulações de NPs de quitosana líquida e liofilizada, verificando-se que a forma líquida produziu anticorpos IgG contra HBsAg. / Nanotechnology has become possible to structure nanoparticles (NPs), using non-toxic and biodegradable polymers such as chitosan (CS), capable of carrying and deliver antigens to the mucosa, due to mucoadhesive property. A lyophilized vaccine compared to a liquid formulation, has several advantages, such as improved product stability as well as better resistance to temperature changes, increasing its shelf life allowing better logistics of the product to places where access to the chain cold is difficult and especially a lyophilized product increases muco-adhesiveness providing for longer staying in the mucosa. The work aims to observe the immune response in mice of vaccine developed by an intranasal delivery mechanism of HBsAg (hepatitis B surface antigen) encapsulated by incorporation method in chitosan nanoparticles (NPs) lyophilized. The formation of NPs was performed by electrostatic interaction between the chitosan and TPP (sodium tripolyphosphate) using the ionic gelation. Formulations showed good characteristics after reconstitution, residual humidity lower than 1% and the lyophilization process 15-hour. In this work, was evaluated the immunogenicity of inoculation of HBsAg in lyophilized and liquid formulations of chitosan nanoparticles, which liquid formulation produced anti-HBsAg antibodies.

<p>The aim of thie literature review was to study the advantages and disadventages of the intranasal medication, treating children with acute pain in  prehsopital settings and in emergency care. Searches were performed in databases PubMed and Cinahl. The intranasal method of administrating drugs could be a acceptable compliment to todays's traditional metods. Unnecessary pain is avoided as there is no need for skin penetration. Further studies are necessary in order to integrate this metod both in prehospital settings and in emeregncy care.</p>

The aim of thie literature review was to study the advantages and disadventages of the intranasal medication, treating children with acute pain in  prehsopital settings and in emergency care. Searches were performed in databases PubMed and Cinahl. The intranasal method of administrating drugs could be a acceptable compliment to todays's traditional metods. Unnecessary pain is avoided as there is no need for skin penetration. Further studies are necessary in order to integrate this metod both in prehospital settings and in emeregncy care.

Orientador: Maria Palmira Daflon Gremião / Banca: Raul Cesar Evangelista / Banca: Leila Aparecida Chiavacci / Banca: Célio Lopes Silva / Banca: Marco Vinícius Chaud / Resumo: A zidovudina (AZT) é um fármaco amplamente usado no tratamento da síndrome da imunodeficiência adquirida. O AZT apresenta baixa biodisponibilidade oral pois sofre rápido e extenso metabolismo de primeira passagem hepática, além de curto t1/2. Sendo assim, altas e freqüentes doses são requeridas para se manter concentrações plasmáticas efetivas e, dessa maneira, apresenta graves efeitos colaterais, dose-dependentes, que limitam o seu uso em determinados tipos de pacientes. As nanopartículas são eficientes sistemas poliméricos que contribuem para a redução da toxicidade de fármacos, pois são capazes de liberá-los de maneira prolongada, proporcionando maior tempo de contato do fármaco com o plasma e tecidos. A via de administração intranasal é uma rota interessante, quando se deseja evitar o metabolismo de primeira passagem e, também, pode oferecer um ótimo perfil de absorção para nanopartículas. Neste trabalho, estudouse a incorporação de AZT em nanopartículas de PLA e de blendas de PLA-PEG com diferentes razões molares. A caracterização físico-química demonstrou que a presença do PEG influenciou a forma, o diâmetro médio, a eficiência de encapsulação, assim como o potencial de superfície das partículas. O diâmetro médio e a eficiência de encapsulação das nanopartículas aumentaram com o aumento crescente da razão molar de PEG na blenda. A forma geral e a apresentação das partículas variaram em função da concentração de PEG, sendo que os melhores resultados foram obtidos com as menores razões molares deste na blenda. Os experimentos de liberação in vitro mostraram que a liberação do AZT a partir das nanopartículas foi mais lenta em relação ao AZT em solução. A presença do PEG nas nanopartículas alterou o perfil de liberação do AZT, tornando...(Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Zidovudine (AZT) is a drug widely used in the treatment of acquired immunodeficiency syndrome. AZT shows low bioavailability because it suffers fast and extensive by pass hepatic metabolism, besides of low t1/2. High and frequent doses are requested to achieve effective plasmatic concentrations, and thus, it shows serious and dosedependents side effects that limit its use in certain kind of patients. Nanoparticles are efficient polymeric systems that contributes to reduce the drug toxicity, because maintain prolonged drug release, making longer the contact between drug and plasma/tissues. The intranasal way is a very interesting route to avoid the by pass metabolism, and also offers a great absorption profile to nanoparticles. In the present work, the AZT encapsulation in PLA e PLA-PEG blends nanoparticles was studied. The physico-chemical characterization showed that the presence of PEG influences the nanoparticles shape, mean diameter, encapsulation efficiency and superficial charge. The mean diameter and encapsulation efficiency increase with increasing PEG proportion in the blend. The nanoparticles shape varied in function of PEG concentration, the better results being obtained with the lowest PEG concentration. In vitro experiments showed that AZT release from nanoparticles was slower than that of AZT solution. The presence of PEG in nanoparticles altered the AZT release profile, making it faster than that from PLA nanoparticles. The ex vivo phagocytosis experiments demonstrated that PLA-PEG blends nanoparticles were more efficient in avoiding the activation of phagocytic cells. The intranasal bioavailability in rats shows that blend PLA-PEG nanoparticles demonstrated longer plasmatic circulating times than that those make of PLA alone. These results demonstrate that PLA and PLA-PEG blends nanoparticles can be used as an efficient intranasal drug delivery system. / Doutor

Inom ambulanssjukvård är en av ambulanssjuksköterskans uppgifter att kunna ge patienten adekvat smärtlindring. Tidigare har det krävts en intravenös infart för detta, men sedan några år finns möjligheten att kunna ge smärtlindring intranasalt. Syftet med studien är att undersöka sjuksköterskors erfarenhet av att administrera intranasal smärtlindring i den prehospitala vårdmiljön. Studien är kvalitativ och baseras på åtta intervjuer med sjuksköterskor, vilka har erfarenhet av att ge smärtlindring intranasalt. Intervjuerna analyserades därefter enligt Lundman och Hällgren Graneheim (2012) för att kunna beskriva informanternas levda erfarenhet. Följande fem kategorier utkristalliserade sig: Förebyggande, Smidighet, Osäkerhet, Oerfarenhet och Biverkningar. Varje kategori hade även två till tre underkategorier. Resultatet belyser intranasal smärtlindring som ett bra alternativ till intravenös smärtlindring inom ambulanssjukvård. Det lyfts också fram att det känns skönt att kunna erbjuda smärtlindring utan att orsaka patienten mer smärta genom att behöva etablera en intravenös infart. Det framkommer även att den intranasala smärtlindringen hellre används på barn än på vuxna. Vid vård av vuxna patienter är tryggheten störst med intravenös smärtlindring. Det förefaller som att barn helst inte ska utsättas för nålstick. Det framkommer också att intranasal smärtlindring fungerar bättre på barn än på vuxna inom ambulanssjukvård.

Thesis (M.S.)--Worcester Polytechnic Institute. / Keywords: inhaled; nitric oxide; optical; sensor. Includes bibliographical references (p. 173-180).

A isquemia cerebral é uma das principais causas de morte no mundo, sendo decorrente de uma interrupção transitória ou permanente do fluxo sanguíneo, podendo levar à massiva morte neuronal. Um dos eventos neurotóxicos relacionados à isquemia é o aumento excessivo da concentração de glutamato extracelular, o que leva a hiperestimulação do sistema glutamatérgico (excitotoxicidade) podendo assim desencadear uma cascata de eventos intracelulares nos neurônios culminando em sua morte. Nos últimos anos, o nucleosídeo guanosina tem ganhado atenção dos pesquisadores devido ao seu potencial efeito neuroprotetor frente a insultos envolvendo excitotoxicidade. Na maioria dos experimentos in vivo no qual foram observados efeitos neuroprotetores, a guanosina foi administrada sistemicamente, apresentando considerável variabilidade na magnitude de seus efeitos entre os animais. Dado que a guanosina é uma molécula endógena, podendo ser rapidamente metabolizada via sistêmica até alcançar o cérebro, novas vias de administração devem ser exploradas a fim de maximizar seus efeitos neuroprotetores. A administração pela via intranasal tem se mostrado uma excelente alternativa visto que a boa perfusão da mucosa nasal fornece um excelente local para uma rápida absorção de drogas e transporte para o cérebro via líquido cefalorraquidiano (liquor). Neste sentido, nesta dissertação avaliamos o perfil farmacocinético da administração intranasal de guanosina e seu potencial neuroprotetor em um modelo de isquemia do córtex parietal cerebral por termocoagulação em ratos. Desta maneira, investigamos a concentração de guanosina e seus metabólitos em diferentes estruturas cerebrais, além do liquor e plasma após administração de diferentes doses, volumes de injeção e tempos após injeção intranasal de guanosina pelos métodos de CLAE e de quantificação de radioatividade. Houve diferenças significativas na concentração de purinas presentes nas estruturas analisadas (bulbo, córtex e hipocampo) além do liquor e do plasma. Observamos uma proporcionalidade entre o aumento significativo de radioatividade em relação ao aumento da concentração e do volume. Além disso, comparamos os parâmetros, acima citados, de animais que receberam administração de guanosina pela via intranasal ou intraperitoneal ou não receberam guanosina, apresentando diferenças significativas entre os grupos analisados. A indução isquêmica causou prejuízo sensoriomotor e lesão cerebral nos animais, os quais foram revertidos pelo tratamento com guanosina. Além disso, diferenças significativas na concentração das purinas foram observadas no plasma e no liquor desses animais as quais podem estar envolvidas tanto com o dano nos animais isquêmicos quanto com o efeito neuroprotetor da guanosina. Assim, este trabalho é o pioneiro mostrando a viabilidade da administração intranasal de guanosina, além de reforçar o efeito neuroprotetor da mesma frente a um modelo de isquemia. / Cerebral ischemia is a major cause of death worldwide is caused by a transient or permanent interruption of blood flow and can lead to massive neuronal death. One of neurotoxic events related to ischemia is the excessive increase in the extracellular concentration of glutamate, which leads to hyperstimulation of the glutamatergic system (excitotoxicity) thus triggering a cascade of intracellular events culminating in neurons death. In recent years, the guanosine nucleoside has claimed researchers attention because of its potential neuroprotective effect against insults involving excitotoxicity. In most in vivo experiments in which guanosine presented neuroprotective effects, it was administered systemically, resulting in considerable variability in the magnitude of their effects. Since guanosine is an endogenous molecule being rapidly metabolized systemically before to reach the brain, new routes of administration should be explored in order to maximize their neuroprotective effects. The intranasal route has proven to be an excellent alternative because the good perfusion of the nasal mucosa provides a great via for a quick absorption for drug transport to the brain via cerebrospinal fluid (CSF). In this sense, this thesis evaluated the pharmacokinetic profile of intranasal administration of guanosine and its potential neuroprotective in a model of cerebral ischemia in parietal cortex by thermocoagulation in rats. Thus, we investigated the concentration of guanosine and its metabolites in different brain structures, as well as CSF and plasma after administration of different doses, injection volumes and times after intranasal injection of guanosine by HPLC methods and quantification of radioactivity. There were significant differences in the concentration of purines present in the analyzed structures (cerebral bulb, cortex and hippocampus) plus CSF and plasma. We observed proportionality between the significant increase of radioactivity in relation to the increased concentration and volume. Furthermore, we analyzed these parameters in the plasma and CSF of rats which received intranasally or intraperitoneally injection of guanosine and with those that did not receive it, showing significant differences between these groups. The ischemic induction caused sensorimotor deficit and brain injury, which were reversed by guanosine treatment. Moreover, significant differences in the concentration of purines were observed in plasma and CSF of the animals which can be related with both the ischemic damage as well as with the neuroprotective effect of guanosine. In conclusion, this work is the pioneer showing the viability of intranasal administration of guanosine, in addition to reinforcing the potential neuroprotective effect of guanosine.