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Avaliação da atividade da CYP1A2 com excreção de cafeína na urina de pacientes com esquizofrenia com prescrição de clozapinaMascarenhas, Rita de Cássia Gonçalves January 2010 (has links)
Introdução: A esquizofrenia é uma doença mental que evolui para a cronicidade em mais de 80 % dos casos, caracterizada por distorções do pensamento, delírios bizarros, alterações na senso-percepção e respostas emocionais inadequadas, que podem levar o paciente a algum grau de deterioração. É uma das formas mais importantes de doença psiquiátrica, porque afeta pessoas jovens, com evolução em geral para incapacitação funcional e prejuízo social. A farmacoterapia tem provado ser o ponto chave na terapêutica da esquizofrenia. Embora não curativas, as drogas antipsicóticas se estabeleceram como o tratamento primário para todos os estágios da doença, possuindo efeito clínico significativo em cerca de 80 % dos casos,os demais apresentam a chamada forma refratária, que responde em 60 % dos casos a medicação denominada Clozapina.A CYP1A2 é a principal enzima hepática de metabolização da clozapina, e o conhecimento prévio de sua atividade enzimática pode possibilitar a personalização da terapia medicamentosa, permitindo ao médico escolher o fármaco e a dose que melhor se adapte ao perfil de metabolização do paciente, aumentando desta forma a eficácia do tratamento e a redução do aparecimento dos efeitos adversos descritos para a clozapina. Objetivo: Avaliar a excreção de cafeína inalterada na urina, como um indicativo da atividade da CYP1A2, através da utilização de cafeína como fármaco de prova. Metodologia: Foram estudados 20 adultos portadores do diagnóstico DSM-IV e CID-10 de Esquizofrenia, com forma refratária, estabilizados, em uso continuado de clozapina há pelo menos 12 meses. Foi administrado 200mg de cafeína com coleta de urina 6 horas após, e dosagem através de uma técnica de cromatografia gasosa. Não foi evidenciada correlação entre a dose de clozapina administrada e a cafeína detectada, a qual deveria ser negativa, o que pode ser explicado pelo tamanho da amostra. Porém, a excreção de cafeína apresentou diferença (P=0,019) entre homens e mulheres, acompanhando o descrito na literatura para a atividade da CYP1A2.
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Avaliação da atividade da CYP1A2 com excreção de cafeína na urina de pacientes com esquizofrenia com prescrição de clozapinaMascarenhas, Rita de Cássia Gonçalves January 2010 (has links)
Introdução: A esquizofrenia é uma doença mental que evolui para a cronicidade em mais de 80 % dos casos, caracterizada por distorções do pensamento, delírios bizarros, alterações na senso-percepção e respostas emocionais inadequadas, que podem levar o paciente a algum grau de deterioração. É uma das formas mais importantes de doença psiquiátrica, porque afeta pessoas jovens, com evolução em geral para incapacitação funcional e prejuízo social. A farmacoterapia tem provado ser o ponto chave na terapêutica da esquizofrenia. Embora não curativas, as drogas antipsicóticas se estabeleceram como o tratamento primário para todos os estágios da doença, possuindo efeito clínico significativo em cerca de 80 % dos casos,os demais apresentam a chamada forma refratária, que responde em 60 % dos casos a medicação denominada Clozapina.A CYP1A2 é a principal enzima hepática de metabolização da clozapina, e o conhecimento prévio de sua atividade enzimática pode possibilitar a personalização da terapia medicamentosa, permitindo ao médico escolher o fármaco e a dose que melhor se adapte ao perfil de metabolização do paciente, aumentando desta forma a eficácia do tratamento e a redução do aparecimento dos efeitos adversos descritos para a clozapina. Objetivo: Avaliar a excreção de cafeína inalterada na urina, como um indicativo da atividade da CYP1A2, através da utilização de cafeína como fármaco de prova. Metodologia: Foram estudados 20 adultos portadores do diagnóstico DSM-IV e CID-10 de Esquizofrenia, com forma refratária, estabilizados, em uso continuado de clozapina há pelo menos 12 meses. Foi administrado 200mg de cafeína com coleta de urina 6 horas após, e dosagem através de uma técnica de cromatografia gasosa. Não foi evidenciada correlação entre a dose de clozapina administrada e a cafeína detectada, a qual deveria ser negativa, o que pode ser explicado pelo tamanho da amostra. Porém, a excreção de cafeína apresentou diferença (P=0,019) entre homens e mulheres, acompanhando o descrito na literatura para a atividade da CYP1A2.
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Posibles Mecanismos Involucrados en la Inactivación del Sistema Oxidativo del Citocromo P450 por Iones CobreJara Sandoval, José January 2007 (has links)
Memoria para optar al título de Químico Farmacéutico / La toxicidad celular del cobre se ha relacionado con la capacidad que los
iones de cobre libre tiene para catalizar, a través de las reacciones de Haber
Weiss y/o Fenton, la producción de radicales libres del oxígeno (O2
.- y HO.);
estos radicales inducen cambios en la estructura y/o función de las
biomoléculas. Recientes investigaciones del laboratorio demostraron que
diferentes enzimas tiólicas eran capaces de unir iones Cu2+ provocando pérdida
de su actividad biológica. La monooxigenasa citocromo P450, enzima
constituyente del sistema oxidativo citocromo P450, principal responsable de la
biotransformación de xenobióticos lipofílicos, entre ellos los fármacos, es una
proteína tiólica; ella une los sustratos a metabolizar en el primer paso del
mecanismo catalítico, por lo tanto, la unión de cobre a esta enzima podría
alterar la actividad catalítica del sistema oxidativo del citocromo P450.
En este trabajo probamos los efectos de Cu2+ y Cu2+/ascorbato (sistema
generador de radicales libres del oxígeno) sobre el espectro de absorbancia de
la monooxigenasa citocromo P450 y sobre la O-desmetilación de p-nitroanisol,
reacción catalizada por el sistema citocromo P450. Tanto el Cu2+ como el
Cu2+/ascorbato disminuyeron la absorbancia máxima a 450 ηm de esta
monooxigenasa. La extensión de esta disminución fue dependiente del tiempo
de incubación y de la concentración de Cu2+; más aún, la disminución de la
absorbancia fue prevenida por GSH, TTM y EDTA. Por otra parte, Cu2+ inhibió la O-desmetilación de p-nitroanisol; la extensión de esta inhibición fue
dependiente de la concentración de Cu2+. Estos resultados parecen indicar que
los mecanismos involucrados en esta inhibición están representados por la
unión de los iones cobre a la monooxigenasa citocromo P450 y por los cambios
redox provocados por la generación de radicales libres del oxígeno inducida por
el sistema Cu2+/ascorbato. La importancia farmacodinámica de estos resultados
es discutida en el texto / Cellular copper toxicity has been related to the capacity of free copper ions
to catalyze, through Haber-Weiss/Fenton reaction, the production of oxygen free
radicals species (O2
.- y HO.), so inducing oxidative changes to the structure
and/or function of biomolecules. Recently, we have demonstrated that several
thiol enzymes are capable to bind Cu2+, so altering their catalytic activities.
Cytochrome P450 monooxygenase, enzyme constituent of cytochrome P450
oxidative system is a thiol protein. This monooxygenase binds the substrates in
the first step of the catalytic mechanism; therefore, copper-binding to this
enzyme may occur, so altering the catalytic activity of this oxidative system.
In this work we assay the effects of Cu2+ and Cu2+/ascorbate on the
cytochrome P450 monooxygenase spectrum and on the p-nitroanisole Odemethylation,
enzymatic activity catalyzed by the cytochrome P450 system.
Our results showed that Cu2+ and Cu2+/ascorbate decrease the monooxygenase
absorbance to 450 nm as a copper concentration- and incubation-dependent
manner. GSH, TTM and EDTA prevented this phenomenon. Moreover, Cu2+
inhibited the p-nitroanisol O-demethylation; the extension of this inhibitory effect
was Cu2+ concentration-dependent. These results seem indicate that Cu2+ may
inhibit the cytochrome P450 system activities by two mechanisms: copperbinding
to the cytochrome P450 monooxygenase and oxidation induced by the
oxygen free radicals generated by Cu2+/ascorbate. The pharmacodynamic
importance of these phenomena is discussed in the text
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Conservation of Built Vernacular Heritage for Promoting Sustainable Rural Environments in Trabzon, Turkey / トルコ・トラブゾンにおける持続的地域環境構築のための風土建築保全Elif, Berna Var 25 March 2019 (has links)
付記する学位プログラム名: グローバル生存学大学院連携プログラム / 京都大学 / 0048 / 新制・課程博士 / 博士(地球環境学) / 甲第21934号 / 地環博第180号 / 新制||地環||36(附属図書館) / 京都大学大学院地球環境学舎地球環境学専攻 / (主査)教授 小林 広英, 教授 柴田 昌三, 准教授 深町 加津枝 / 学位規則第4条第1項該当 / Doctor of Global Environmental Studies / Kyoto University / DFAM
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The interaction of three local anaesthetic agents with hepatic microsomal cytochrome P-450Van den Honert, Leonard Howard January 1981 (has links)
The effect of inducing agents of cytochrome P-450 on the binding and metabolism of three local anaesthetic agents: lidocaine, mepivacaine and bupivacaine has been investigated. All three local anaesthetic agents bound to the type I binding site of cytochrome P-450, which is characteristic of substrate binding to cytochrome P-450, and stimulated the CO-inhibitable oxidation of NADPH. Lidocaine is shown to be metabolized by cytochrome P-450 to the products MEGX and acetaldehyde. The forms of cytochrome P-450 elevated with phenobarbital and/or pregnenolone-16α-carbonitrile were shown to play an important role in the binding of lidocaine to cytochrome P-450. Cytochrome P-448 did not appear to be involved in the binding of lidocaine to cytochrome P-450. These findings are supported by the ability of the inhibitors of cytochrome P-450 viz. metyrapone, SKF 525-A and CO:O₂ to inhibit binding of lidocaine to cytochrome P-450. No single form of cytochrome P-450 appears to preferentially metabolize lidocaine, but rather multiple forms of the enzyme appear to be involved in the metabolism of lidocaine. The phenobarbital inducible form of cytochrome P-450 appears to play a major role in the binding of mepivacaine to cytochrome P-450. Cytochrome P-450 in microsomes from rats pretreated with β-naphthoflavone and pregnenolone-16α-carbonitrile does not appear to have a significant role in the binding of mepivacaine to cytochrome P-450. All forms of cytochrome P-450 are involved in the metabolism of mepivacaine· to metabolic products as assessed by the oxidation of NADPH. However, the form of cytochrome P-450 induced by pretreatment of rats with phenobarbital may play a predominant role in the total metabolism of mepivacaine. Multiple forms of cytochrome P-450 appear to be involved in the binding and total metabolism of bupivacaine. As in the case of mepivacaine, the total metabolism of bupivacaine, as assessed by the oxidation of NADPH, may be predominantly catalyzed by the form of cytochrome P-450 found in microsomes from rats pretreated with phenobarbital. Partially purified cytochrome P-450 was found to bind lidocaine in a type I manner and, in the presence of the artificial electron donor H₂O₂, produce MEGX. This further supports the role of cytochrome P-450 in the in vitro metabolism of lidocaine. Hepatocytes were found to metabolize lidocaine to MEGX, indicating that lidocaine metabolism in vivo might well be mediated by cytochrome P-450.
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Challenges and Potentials of Retrofitting Masonry Non-Engineered Construction in Indonesia / インドネシアにおけるノンエンジニアド組積造建築の耐震補強の課題および展望に関する研究Teddy Boen 23 May 2014 (has links)
京都大学 / 0048 / 新制・論文博士 / 博士(地球環境学) / 乙第12836号 / 論地環博第9号 / 新制||地環||25(附属図書館) / 31374 / (主査)教授 ショウ ラジブ, 教授 岡﨑 健二, 准教授 古川 愛子 / 学位規則第4条第2項該当 / Doctor of Global Environmental Studies / Kyoto University / DFAM
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Indigenous alcoholic beverage production in rural villages of Tanzania and Cameroon / タンザニアおよびカメルーン農村部における地酒製造に関する研究Kubo, Ryousuke 25 May 2015 (has links)
京都大学 / 0048 / 新制・課程博士 / 博士(地球環境学) / 甲第19209号 / 地環博第136号 / 新制||地環||28(附属図書館) / 32201 / 京都大学大学院地球環境学舎地球環境学専攻 / (主査)教授 舟川 晋也, 教授 谷 史人, 准教授 真常 仁志 / 学位規則第4条第1項該当 / Doctor of Global Environmental Studies / Kyoto University / DFAM
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Characteristics of Home Garden and Its Improvement through Vanilla Introduction in Central Vietnam / 中部ベトナムにおけるホームガーデンの特性およびバニラ導入によるその改善に関する研究Vu, Tuan Minh 24 September 2015 (has links)
京都大学 / 0048 / 新制・課程博士 / 博士(地球環境学) / 甲第19346号 / 地環博第139号 / 新制||地環||28(附属図書館) / 32348 / 京都大学大学院地球環境学舎環境マネジメント専攻 / (主査)教授 舟川 晋也, 准教授 真常 仁志, 准教授 西前 出 / 学位規則第4条第1項該当 / Doctor of Global Environmental Studies / Kyoto University / DFAM
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Application of Remote Sensing and Geographic Information System Techniques to Monitoring of Protected Mangrove Forest Change in Sabah, Malaysia / マレーシア・サバにおけるマングローブ保護林の変化監視へのリモートセンシングおよび地理情報システムの適用Nurul, Aini Binti Kamaruddin 23 March 2016 (has links)
京都大学 / 0048 / 新制・課程博士 / 博士(地球環境学) / 甲第19878号 / 地環博第152号 / 新制||地環||30(附属図書館) / 32914 / 京都大学大学院地球環境学舎地球環境学専攻 / (主査)教授 藤井 滋穂, 教授 高岡 昌輝, 准教授 田中 周平 / 学位規則第4条第1項該当 / Doctor of Global Environmental Studies / Kyoto University / DFAM
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Synthèse sur support solide de dérivés aminostéroïdiens pour le développement d'agents anticancéreux et synthèse d'inhibiteurs stéroïdiens de la CYP1B1, une enzyme présentant un potentiel comme cible thérapeutiqueDutour, Raphaël 23 May 2018 (has links)
Tableau d'honneur de la Faculté des études supérieures et postdoctorales, 2017-2018 / Les stéroïdes et leurs dérivés constituent une classe biologique unique intervenant dans un grand nombre de processus physiologiques. Ces composés suscitent un fort intérêt thérapeutique, notamment parce qu'ils jouent un rôle crucial dans le développement des cancers hormono-dépendants tels que les cancers du sein et de la prostate. L'approche thérapeutique la plus utilisée consiste ainsi à développer des dérivés stéroïdiens qui vont agir en tant qu'inhibiteurs de certaines enzymes de la stéroïdogénèse, et ce, afin de bloquer la production des androgènes ou des estrogènes selon l'effet souhaité. Néanmoins, l'activité des dérivés stéroïdiens est versatile et ces composés peuvent aussi présenter d'autres intérêts thérapeutiques en agissant sur des cibles biologiques très distinctes. La première partie de ce mémoire est consacrée au développement d’une chimiothèque d’aminostéroïdes similaires au RM-581 (noyau C18-stéroïdien), un analogue du RM-133 (noyau C19-stéroïdien) qui a montré une activité cytotoxique sur une large variété de lignées cellulaires issues de différents cancers. La synthèse sur support solide a été utilisée pour le développement de ces analogues du RM-581. Quarante aminostéroïdes avec différentes chaînes latérales amino-substituées en position C2 du noyau estrane ont ainsi été obtenus. Une activité cytotoxique significative a été observée pour les mêmes composés indépendamment des lignées cancéreuses testées. Un composé a par ailleurs montré une activité anticancéreuse deux fois supérieure à celle du RM-581 et pourrait être un candidat prometteur pour le traitement de plusieurs cancers, dont le cancer du pancréas. La deuxième partie de ce mémoire porte sur le développement d'inhibiteurs de la CYP1B1, une enzyme ayant un rôle mutagène important dans le cadre de certains cancers. À partir d’inhibiteurs connus de cette enzyme, d’études de "docking" et basé sur un criblage de l'inhibition de la CYP1B1 par un large éventail de dérivés stéroïdiens; trois séries d'inhibiteurs C18-stéroïdiens ont été conceptualisées et synthétisés. Les résultats obtenus avec ces composés ont montré que l'introduction d'un groupe aromatique en position C2 d'un noyau 17β-estradiol favoriserait des interactions π-stacking avec la CYP1B1. L'activité inhibitrice de ces composés a été comparée avec l'α-naphthoflavone (ANF), un inhibiteur non stéroïdien connu de la CYP1B1. Certains de ces dérivés stéroïdiens ont montré une activité inhibitrice supérieure à celle de l'ANF et font actuellement l'objet de tests biologiques afin d'appuyer leur utilisation thérapeutique pour le traitement de certains cancers. / Steroids and their derivatives form a single biological class involved in a large number of physiological processes. These compounds have a great therapeutic interest, particularly because they play a crucial role in the development of hormone-dependent cancers such as prostate and breast cancers. The most widely used therapeutic approach consists to develop steroid derivatives that will act as inhibitors of certain steroidogenic enzymes to avoid the production of androgens and estrogens according to the desired effect. However, the activity of steroid derivatives is versatile and these compounds can have other therapeutic interests by acting on very distinct biological targets. The first part of this thesis is focused on the development of a library of aminosteroid similar to RM-581 (C18-steroidal nucleus), and analogue to RM-133 (C19-steroidal nucleus) that showed significant cytotoxic activities on a wide variety of cell lines from different cancers. Solid-phase synthesis was used for the development of these RM-581 analogues. Forty aminosteroids with different amino-substituted side chains at position C2 of an estrane nucleus (mestranol) were thus obtained. Significant cytotoxic activities were observed for the same compounds regardless of the cancer cell lines tested. Moreover, one of these aminosteroid derivatives was found to be twice more active than RM-581 and could be a promising candidate for the treatment of several cancers, including pancreatic cancer. The second part of this thesis is devoted to the development of steroidal inhibitors of CYP1B1, an enzyme playing an important mutagenic role in certain cancers. Based on known CYP1B1 inhibitors, docking studies and on a screening of the CYP1B1 inhibition by a broad range of steroid derivatives, three series of C18-steroidal inhibitors were designed and synthesized. The results obtained with these novel steroidal inhibitors showed that the introduction of an aromatic core at position C2 of the 17β-estradiol nucleus appears to be the best strategy for promoting pi-stacking interactions with CYP1B1. The inhibitory activity of these compounds was compared with α-naphthoflavone (ANF), a known nonsteroidal potent CYP1B1 inhibitor. Some of these steroidal inhibitors have shown a greater CYP1B1 inhibitory activity than ANF and are currently undergoing biological tests to support their therapeutic use for the treatment of certain cancers.
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