Spelling suggestions: "subject:"toxicological."" "subject:"toxicology.""
111 |
Exposição dérmica de trabalhadores a resíduos de deltametrina presentes nas plantas, na reentrada na lavoura de algodão após pulverizaçãoRotundo, Maurício [UNESP] 28 February 2007 (has links) (PDF)
Made available in DSpace on 2014-06-11T19:29:44Z (GMT). No. of bitstreams: 0
Previous issue date: 2007-02-28Bitstream added on 2014-06-13T19:59:38Z : No. of bitstreams: 1
rotundo_m_me_ilha.pdf: 850611 bytes, checksum: 1909101afb4dae7d59c34fa46384f158 (MD5) / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / A exposição dérmica de amostradores foi avaliada na reentrada em lavoura de algodão após pulverização com o inseticida deltametrina. Aos 3 minutos após a aplicação quatro pessoas vestiram um conjunto de roupas (calça, camisa e luvas), entrando e permanecendo na área tratada por 30 minutos, simulando uma amostragem de pragas. O procedimento foi repetido aos 60 e 300 minutos e aos 1, 3, e 7 dias após a aplicação. Partes do tecido, correspondentes ao local de contato com várias partes do corpo, foram recortadas e analisadas quanto à quantidade de resíduos presentes. O inseticida foi extraído das roupas com acetato de etila e a determinação quantitativa foi feita por cromatografia gasosa. As exposições foram extrapoladas para uma jornada de trabalho de oito horas. Para classificar a segurança das condições de trabalho foram estimadas a margem de segurança (MS), dose tóxica (%DT/dia), dose tolerável dérmica e o tempo de trabalho seguro. O conjunto correspondente aos antebraços/braços/mãos concentrou 61,27% dos resíduos presentes na roupa. Partes correspondentes ao peitoral, pernas, coxas e costas alcançaram 13,40; 9,33; 9,32; e 6,65% dos resíduos totais encontrados nas roupas, respectivamente. Pela análise dos dados constatou-se que o intervalo de reentrada estabelecido para o produto comercial Decis 25 CE (deltametrina) que é de 24 h está superestimado. / The objective of this work was to study the dermal exposure of workers to residues of the deltamethrin, applied in cotton. After 3 minutes of application four people dressed a group with cotton clothes (pant, shirt and gloves), entered and stayed in the treated area by 30 minutes, simulating a sampling. The procedure was repeated after 60 and 300 minutes and 1, 3, and 7 days of the application. The clothes were cut and put in plastic bags, and stored cold at -18º until analyses was performed. The analytical method consisted on the extraction of deltamethrin residues with a ethyl acetate and the quantitative determination was done by gas chromatograph. Exposure was extrapolated to a work day of 8 hours. To evaluate safety's conditions at work was estimated the Working Condition Unsafe (margin of safety - MOS <1), Poisonous Dose (%PD/day), Dermal Dose Tolerable and the estimate of Safe Work Duration (SWD). The corresponding group for the forearms/arms/hands concentrated 61.27% of present residues in the clothes. The residues found on the clothes, chest, legs, lame and back, were 13.40, 9.33, 9.32, and 6.65%, respectively. Results of deltamethrins amounts trapped on cotton clothes showed that 24h as a reentry interval for Decis 25 EC is overestimated.
|
112 |
Exposição dérmica de trabalhadores a resíduos de deltametrina presentes nas plantas, na reentrada na lavoura de algodão após pulverização /Rotundo, Maurício. January 2007 (has links)
Orientador: Geraldo Papa / Banca: Sérgio Luis de Carvalho / Banca: Luiz Roberto Pimentel Trevizan / Resumo: A exposição dérmica de amostradores foi avaliada na reentrada em lavoura de algodão após pulverização com o inseticida deltametrina. Aos 3 minutos após a aplicação quatro pessoas vestiram um conjunto de roupas (calça, camisa e luvas), entrando e permanecendo na área tratada por 30 minutos, simulando uma amostragem de pragas. O procedimento foi repetido aos 60 e 300 minutos e aos 1, 3, e 7 dias após a aplicação. Partes do tecido, correspondentes ao local de contato com várias partes do corpo, foram recortadas e analisadas quanto à quantidade de resíduos presentes. O inseticida foi extraído das roupas com acetato de etila e a determinação quantitativa foi feita por cromatografia gasosa. As exposições foram extrapoladas para uma jornada de trabalho de oito horas. Para classificar a segurança das condições de trabalho foram estimadas a margem de segurança (MS), dose tóxica (%DT/dia), dose tolerável dérmica e o tempo de trabalho seguro. O conjunto correspondente aos antebraços/braços/mãos concentrou 61,27% dos resíduos presentes na roupa. Partes correspondentes ao peitoral, pernas, coxas e costas alcançaram 13,40; 9,33; 9,32; e 6,65% dos resíduos totais encontrados nas roupas, respectivamente. Pela análise dos dados constatou-se que o intervalo de reentrada estabelecido para o produto comercial Decis 25 CE (deltametrina) que é de 24 h está superestimado. / Abstract: The objective of this work was to study the dermal exposure of workers to residues of the deltamethrin, applied in cotton. After 3 minutes of application four people dressed a group with cotton clothes (pant, shirt and gloves), entered and stayed in the treated area by 30 minutes, simulating a sampling. The procedure was repeated after 60 and 300 minutes and 1, 3, and 7 days of the application. The clothes were cut and put in plastic bags, and stored cold at -18º until analyses was performed. The analytical method consisted on the extraction of deltamethrin residues with a ethyl acetate and the quantitative determination was done by gas chromatograph. Exposure was extrapolated to a work day of 8 hours. To evaluate safety's conditions at work was estimated the Working Condition Unsafe (margin of safety - MOS <1), Poisonous Dose (%PD/day), Dermal Dose Tolerable and the estimate of Safe Work Duration (SWD). The corresponding group for the forearms/arms/hands concentrated 61.27% of present residues in the clothes. The residues found on the clothes, chest, legs, lame and back, were 13.40, 9.33, 9.32, and 6.65%, respectively. Results of deltamethrins amounts trapped on cotton clothes showed that 24h as a reentry interval for Decis 25 EC is overestimated. / Mestre
|
113 |
Avaliação de biomarcadores bioquímicos em tilápias (Oreochromis niloticus) expostos a óleo diesel e biodieselBedin, Bruno Henrique [UNESP] 22 May 2013 (has links) (PDF)
Made available in DSpace on 2014-06-11T19:29:07Z (GMT). No. of bitstreams: 0
Previous issue date: 2013-05-22Bitstream added on 2014-06-13T20:38:22Z : No. of bitstreams: 1
bedin_bh_me_sjrp.pdf: 519842 bytes, checksum: e719795aab77f431ee35d7bdf1177bfa (MD5) / Dentre os contaminantes ambientais mais produzidos no mundo estão os derivados do petróleo, que atingem e contaminam os ambientes aquáticos. Sendo o petróleo uma forma de energia não renovável, alternativas renováveis e menos poluentes como o biodiesel vêm sendo pesquisadas. Entretanto, apesar de ser considerado menos poluente, mais biodegradável e produzir menos gases de efeito estufa durante a queima, pouco se sabe ainda sobre os potenciais efeitos tóxicos do biodiesel para a biota aquática. Estes efeitos podem ser avaliados por meio da análise de biomarcadores de contaminação, tais como alterações metabólicas na atividade de enzimas de biotransformação e em parâmetros de estresse. Neste trabalho foram analisados os efeitos de duas concentrações (0,1 e 0,01 mL/L, com manutenção do tratamento a cada 5 dias) do biodiesel puro (B100) e da mistura de 20% de biodiesel com diesel de petróleo (B20), em comparação com os efeitos do diesel de petróleo contendo 5% de biodiesel (B5) e animais não expostos a nenhum dos combustíveis, em fígado e brânquias de tilápias do Nilo (Oreochromis niloticus) expostas por 15 e 30 dias. Foram avaliadas as atividades das enzimas de biotransformação etóxiresorufina-O-deetilase (EROD) e glutationa S-transferase (GST), das enzimas antioxidantes superóxido dismutase (SOD), catalase (CAT) glutationa peroxidase (GPx) e níveis de peroxidação lipídica por meio da quantificação do produto malondialdeído. Testes de toxicidade foram também realizados para se estabelecer valores de LC50 para cada contaminante, de forma a melhor compararmos os efeitos dos contaminantes, os quais mostraram que o B5 foi o composto mais tóxico, seguido do B20 e em seguida o B100. Animais expostos ao B5 e ao B20 por 15 dias tiveram a atividade da EROD aumentada e suas enzimas... / Among the environmental contaminants most produced in the world are derived from petroleum, which reach and contaminate aquatic environments. Because oil is a form of non-renewable energy, renewable and less polluting alternatives such as biodiesel have been researched. However, despite being considered less polluting, more biodegradable and produce less greenhouse gases during the burning, little is known about the potential toxic effects of biodiesel on aquatic biota. These effects can be evaluated through the analysis of biomarkers of contamination, such as changes in metabolic activity of biotransformation enzymes and stress parameters. In this study, we analyzed the effects of two concentrations (0.1 and 0.01 mL / L, with maintenance treatment every 5 days) of pure biodiesel (B100) and the mixture of 20% biodiesel with petroleum diesel (B20), compared with the effects of diesel oil containing 5% biodiesel (B5) and animals not exposed to any fuel in liver and gills of tilapia (Oreochromis niloticus) exposed for 15 and 30 days. We evaluated the activities of biotransformation enzymes etóxiresorufina-O-deetilase-(EROD) and glutathione S-transferase (GST), of antioxidant enzymes superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and lipid peroxidation levels through quantifying the product malondialdehyde. Toxicity tests were also conducted to establish LC50 values for each contaminant in order to better compare the effects of contaminants, which showed that B5 was the most toxic compound, followed by B20 and then B100. Animals exposed to B5 and B20 for 15 days had increased EROD activity of and their antioxidant enzymes significantly inhibited, which was not observed in animals exposed to B100. Nevertheless, despite the inhibition observed in the antioxidant defenses, the... (Complete abstract click electronic access below)
|
114 |
Avaliação de biomarcadores bioquímicos em tilápias (Oreochromis niloticus) expostos a óleo diesel e biodiesel /Bedin, Bruno Henrique. January 2013 (has links)
Orientador: Eduardo Alves de Almeida / Banca: Carlos Roberto Ceron / Banca: Lilian Castiglioni / Resumo: Dentre os contaminantes ambientais mais produzidos no mundo estão os derivados do petróleo, que atingem e contaminam os ambientes aquáticos. Sendo o petróleo uma forma de energia não renovável, alternativas renováveis e menos poluentes como o biodiesel vêm sendo pesquisadas. Entretanto, apesar de ser considerado menos poluente, mais biodegradável e produzir menos gases de efeito estufa durante a queima, pouco se sabe ainda sobre os potenciais efeitos tóxicos do biodiesel para a biota aquática. Estes efeitos podem ser avaliados por meio da análise de biomarcadores de contaminação, tais como alterações metabólicas na atividade de enzimas de biotransformação e em parâmetros de estresse. Neste trabalho foram analisados os efeitos de duas concentrações (0,1 e 0,01 mL/L, com manutenção do tratamento a cada 5 dias) do biodiesel puro (B100) e da mistura de 20% de biodiesel com diesel de petróleo (B20), em comparação com os efeitos do diesel de petróleo contendo 5% de biodiesel (B5) e animais não expostos a nenhum dos combustíveis, em fígado e brânquias de tilápias do Nilo (Oreochromis niloticus) expostas por 15 e 30 dias. Foram avaliadas as atividades das enzimas de biotransformação etóxiresorufina-O-deetilase (EROD) e glutationa S-transferase (GST), das enzimas antioxidantes superóxido dismutase (SOD), catalase (CAT) glutationa peroxidase (GPx) e níveis de peroxidação lipídica por meio da quantificação do produto malondialdeído. Testes de toxicidade foram também realizados para se estabelecer valores de LC50 para cada contaminante, de forma a melhor compararmos os efeitos dos contaminantes, os quais mostraram que o B5 foi o composto mais tóxico, seguido do B20 e em seguida o B100. Animais expostos ao B5 e ao B20 por 15 dias tiveram a atividade da EROD aumentada e suas enzimas... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Among the environmental contaminants most produced in the world are derived from petroleum, which reach and contaminate aquatic environments. Because oil is a form of non-renewable energy, renewable and less polluting alternatives such as biodiesel have been researched. However, despite being considered less polluting, more biodegradable and produce less greenhouse gases during the burning, little is known about the potential toxic effects of biodiesel on aquatic biota. These effects can be evaluated through the analysis of biomarkers of contamination, such as changes in metabolic activity of biotransformation enzymes and stress parameters. In this study, we analyzed the effects of two concentrations (0.1 and 0.01 mL / L, with maintenance treatment every 5 days) of pure biodiesel (B100) and the mixture of 20% biodiesel with petroleum diesel (B20), compared with the effects of diesel oil containing 5% biodiesel (B5) and animals not exposed to any fuel in liver and gills of tilapia (Oreochromis niloticus) exposed for 15 and 30 days. We evaluated the activities of biotransformation enzymes etóxiresorufina-O-deetilase-(EROD) and glutathione S-transferase (GST), of antioxidant enzymes superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and lipid peroxidation levels through quantifying the product malondialdehyde. Toxicity tests were also conducted to establish LC50 values for each contaminant in order to better compare the effects of contaminants, which showed that B5 was the most toxic compound, followed by B20 and then B100. Animals exposed to B5 and B20 for 15 days had increased EROD activity of and their antioxidant enzymes significantly inhibited, which was not observed in animals exposed to B100. Nevertheless, despite the inhibition observed in the antioxidant defenses, the... (Complete abstract click electronic access below) / Mestre
|
115 |
Development of polyvalent erythrocyte- and parasitized erythrocyte-targeted nanovectors as novel site-specific drug delivery approaches for Plasmodium falciparum malaria chemotherapyMoles Meler, Ernest 09 December 2015 (has links)
Tesi realitzada al Grup de Nanomalària (IBEC-ISGlobal) / Bearing in mind the absence of an effective preventive vaccine against malaria (WHO, 2015) and its severe clinical manifestations that are principally associated with red blood cell (RBC) destruction and parasitized-RBC (pRBC) cytoadherence to host cells causing in turn nearly half a million deaths every year, this disease represents nowadays a major threat to life and consequently its control and ultimate global eradication must be undertaken without preconceptions.
Additionally, the basic rationale followed by most of the currently marketed antimalarial approaches is based on the administration of single/multiple drugs on their own, strategy that promotes the emergence of drug-resistant parasites owing to the limitation in delivering drug payloads into the pRBC high enough to kill the intracellular parasite while at the same time minimizing the risk of causing toxic side effects to the patient. Such dichotomy has been successfully addressed through the preparation of RBC- and pRBC-targeted drug delivery systems in the form of antibody-vectorized liposomes (iLPs), among other types of nanovectors, improving in this way the activity of antimalarials (Chandra, 1991; Owais, 1995; Urbán, 2011).
Nevertheless, the aforesaid iLP models have been poorly characterized with a minimal knowledge regarding: their mechanism of interaction with the target cell, release kinetics of encapsulated material or antibody coupling yield; and their recognized antigens have not been reported or are still unknown. Besides, the improvement in drug activity they have provided has been rather modest when evaluated against the human-infecting Plasmodium falciparum species. The main scope of this PhD thesis has been in this regard the characterization and development of more effective immunoliposomal nanovectors against P. falciparum with special attention given to the obtainment of chemotherapeutic approaches displaying multiple mechanisms of action.
Antibody coupling yields of >40% were obtained by means of their derivatization with the SATA crosslinker and the incorporation of maleimide-containing, PEGylated phospholipids into LPs, which results in the highly stable thioether linkage. SATA/antibody molar ratios of up to 10× provided adequate antigen recognition and minimal iLP aggregation. Furthermore, the pH- driven active encapsulation of chloroquine (CQ) and primaquine antimalarials into DSPC-based LPs together with their conjugation with a monoclonal antibody specific for the glycophorin A antigen of RBCs (GPA-iLPs) enabled these iLPs (i) to completely recognize and become retained into both RBCs/pRBCs, as well as (ii) a total and stable drug encapsulation along with its effective intracellular release under parasite culture conditions. The improved antimalarial efficacy of CQ-loaded, GPA-iLPs was demonstrated in vivo in P. falciparum-infected, humanized mice through the reduction of their parasite densities to undetectable levels (<0.01% parasitemia) and following a 4 × 0.5 mg CQ/kg dosage schedule. Free CQ at a dosage 3.5 times higher was at least 40-fold less effective.
Moreover, lumefantrine-laden iLPs targeted against rosette-forming variants of PfEMP1 exhibited a great potential for severe malaria therapeutics by means of mechanically disrupting already generated rosettes while at the same time eliminating those parasites forming them. An increased activity of lumefantrine in reducing the number of rosette-forming pRBCs was obtained when delivered by homologous PfEMP1-targeted-iLPs with a ~5.5-fold decreased IC50 compared to either free drug or non-targeted LPs. The rosette-disrupting activity of anti- PfEMP1 antibodies was importantly preserved after their conjugation to LPs. Finally, based on a recent study in Toxoplasma gondii (Nagamune, 2008), the biosynthesis of ABA by P. falciparum was explored as a new target route for the design of antimalarials. However, ABA could not be found in late form-pRBC extracts even though the sensitivity for its detection had been extraordinarily improved (LOD of 0.03 ng/ml).
|
116 |
Antioxidantes y nanoestructuras lipídicas para prevenir el daño solar en tejidos lipoqueratínicosFernández Pinto, Estibalitz 04 December 2015 (has links)
Tesi realitzada a l'Institut de Química Avançada de Catalunya (IQAC-CSIC) / La formación de radicales libres en el cabello y la piel debido a una excesiva radiación solar, se asocia principalmente a la presencia de los rayos ultravioleta (UV) aunque la radiación infrarroja (IR) también puede desencadenar reacciones celulares que forman radicales libres y dañan proteínas como el colágeno.
La aplicación de antioxidantes sobre la piel y el cabello podría reforzar el sistema antioxidante natural de estos dos tejidos reduciendo el daño causado por la radiación solar. Sin embargo, es necesaria la penetración de los antioxidantes en el tejido para poder esperar un efecto protector. En el caso de la piel, la penetración del tejido supone un reto debido a la función barrera que desempeña el estrato corneo, la capa más superficial de la piel. Además, la eficacia de los antioxidantes se pierde rápidamente debido a su inestabilidad. El uso de vehículos promueve la penetración de activos en la piel y retrasa la degradación de los antioxidantes.
Las bicelas son nanoestructuras discoidales de 15- 25 nm de diámetro formadas por fosfolípidos de cadena larga y fosfolípidos de cadena corta. Los bicosomas surgen como una estrategia para proteger las bicelas en entornos de alta dilución acuosa. Para ello, las bicelas son encapsuladas en vesículas formando los sistemas de bicosoma de diámetro alrededor de 200 nm. En trabajos anteriores se ha demostrado la efectividad de las bicelas como vehículos tópicos. En el caso de los bicosomas, las ventajas de su uso tópico no se habían demostrado hasta esta tesis.
Los objetivos de esta tesis han sido, por una parte, la optimización de las metodologías para evaluar la oxidación del cabello y la piel provocada por la radiación ultravioleta-visible (UV-VIS) e IR, y por otro lado, el estudio de la interacción de las bicelas y los bicosomas con la piel. Se ha evaluado la capacidad anti-radicalaria de ambos sistemas con y sin antioxidante, y se ha determinado la penetración de los bicosomas en piel normal y expuesta a radiación UV-VIS. Finalmente, se ha estudiado la estabilidad de los vehículos lipídicos frente a radiación UV-VIS, y con el fin de prolongar la eficacia de antioxidantes, se ha evaluado la capacidad de ambos sistemas lipídicos conservando estas moléculas.
Las fibras de cabello mostraron un incremento de radicales frente a radiación UV-VIS. Además se observó una notable oxidación de la fracción proteica y lipídica del cabello. Las propiedades como el brillo y el color del cabello también se vieron afectadas bajo radiación UV-VIS. Estas propiedades físico-químicas del cabello se conservaron mediante la aplicación de diferentes formulaciones de antioxidantes provenientes de la alcachofa y del arroz.
La aplicación en la piel de bicelas y bicosomas con y sin el antioxidante β-caroteno mostró una capacidad anti-radicalaria frente a radiación UV-VIS, siendo el sistema más efectivo el bicosoma con β-caroteno. La degradación del β-caroteno bajo radiación UV- VIS también disminuye al incluir este antioxidante en las bicelas y los bicosomas. Se demostró una significativa penetración de los bicosomas en piel normal, mientras que la penetración en piel expuesta a radiación UV-VIS fue menor. Se pudo comprobar que el alcance de penetración en la piel era también dependiente de las propiedades físico-químicas de la molécula incorporada en el bicosoma.
Se evaluó la capacidad de la radiación IR de formar radicales libres en el cabello y la piel a temperaturas fisiológicas, y se observó un deterioro del colágeno cutáneo en piel expuesta a radiación IR, aunque en este último caso fue necesario elevar la temperatura de la piel hasta los 65ºC. Ambos daños causados por la radiación IR fueron reducidos con un previo tratamiento de la piel con bicosomas incorporando β- caroteno. / Ultraviolet (UV) and infrared radiation (IR) can damage human hair and skin. Antioxidants could avoid the harmful effects of sunlight, but the incorporation of these molecules especially into the skin is difficult due to the barrier function of the superficial layer of this tissue, the stratum corneum (SC). The lipid vehicles are used to facilitate the incorporation of different active compounds in the skin.
Bicelles are described as discoidal nanostructures with diameters of approximately 15¬25 nm and a thickness of 5.4 nm formed by long and short alkyl chain phospholipid molecules dispersed in aqueous solution. Bicosomes emerge as strategy to stabilize and protect bicelles encapsulating these nanostructures in liposomes.
The aims of this work were the optimization of the techniques in order to quantify the oxidation of hair and skin caused by UV, VIS and IR radiation. Additionally, the evaluation of two antioxidants formulations, coming from artichoke and rice, to reduce the oxidation of the hair, and the incorporation of 13-carotene in bicelles and bicosomes to reduce the oxidation of the skin was evaluated.
The results showed the preservation of physical and chemical properties of hair fibers treated with the two antioxidant formulations under UV-VIS radiation.
The skin treatment with bicelles and bicosomes incorporating 13-carotene reduced the free radical formation in the skin subjected to UV, VIS and IR radiation. The skin treatment with bicosomes incorporating 13-carotene also preserved the structure of collagen under IR radiation. Moreover, bicelles and bicosomes were useful vehicles stabilizing the 13-carotene under UV-VIS radiation.
Bicosome systems were able to penetrate into the skin, and the physical-chemical properties of the actives incorporated in bicosome systems had influence in its penetration into this tissue. In addition, previous irradiation of the skin made skin more impermeable to bicosomes (in vitro experiments).
|
117 |
Role of the sigma-1 receptor in the sensory-discriminative and affective-motivational components of acute and chronic painde la Puente Robles, Beatriz 18 December 2015 (has links)
Tesi realitzada als Laboratoris Farmacèutics Esteve / The present Doctoral Thesis focuses on the study of the sigma-1 receptor (σ1R) in the field of pain. This research has been a part of the preclinical σ1R project focusing on drug discovery of σ1R ligands for the treatment of pain at the pharmaceutical company ESTEVE. The overall purpose of this Doctoral Thesis was to explore the role of σ1R in the sensory-discriminative and affective-motivational components of pain. To this end, acetic acid-induced visceral pain and partial sciatic nerve ligation in mice were used to model an acute and chronic pain state, respectively. The sensory discriminative and affective-motivational components of pain in these models were infered by changes in reflexive and non-reflexive behavioural outcomes, respectively. Abdominal contractions (writhing) and paw behavioural hypersensitivity to mechanical and thermal stimuli were analysed as reflexive outcomes. On the other hand, pain-related changes of sweet preference, locomotor activity and reward-seeking behaviour were analysed as non reflexive outcomes. These models and behavioural outcomes were used to evaluate the effect of pharmacological and genetic blockade of σ1R and also the effects of some reference compounds. Furthermore, electrophysiological and molecular studies in knock-out (σ1R /-) mice were used to understand the role of σ1R in the sensory discriminative component of chronic pain.
Taken together, the results of this Doctoral Thesis provide new knowledge about σ1R and support the clinical development of selective σ1R antagonists as a suitable therapeutic intervention to treat neuropathic pain and its mood-related comorbidities. / El dolor es una experiencia sensorial y emocional desagradable. Es un mecanismo muy complejo determinado por dos componentes: el componente sensorial discriminativo, que corresponde a los mecanismos neurofisiológicos de la nocicepción y que informa de las características del dolor (naturaleza, duración, intensidad,…) y el componente afectivo-motivacional, que expresa la connotación desagradable relacionada con la percepción del dolor y que conlleva consecuencias emocionales que afectan al estado de ánimo y al bienestar del individuo. En la presente Tesis Doctoral se estudian estos dos componentes que conforman el dolor, evaluando respuestas de comportamiento en dos modelos animales de dolor, un modelo de dolor agudo visceral y un modelo de dolor crónico de origen neuropático. Además, se estudia el papel del receptor sigma-1 (σ1R) en cada modelo animal de dolor, evaluando su posible implicación tanto en el componente sensorial como en el afectivo. Para ello, se pusieron en práctica dos estrategias experimentales. Por un lado, se utilizaron ratones modificados genéticamente a los que se les ha eliminado el gen del receptor del sigma-1 (ratones knock-out σ1R) y por otro lado, se realizó un tratamiento farmacológico sistémico en ratones salvajes (wild-type) con el E-52862 (S1RA), un antagonista del receptor sigma-1 altamente selectivo. El E-52862 es un compuesto que ha sido desarrollado por ESTEVE y que tras su primera evaluación en seres humanos ha demostrado un buen perfil de seguridad y tolerabilidad (estudios clínicos de Fase I). Actualmente continúa siendo evaluado en subsecuentes estudios clínicos como indicación para el dolor neuropático de diferentes etiologías (estudios de Fase II).
Los resultados de esta Tesis Doctoral proporcionan nuevos conocimientos sobre el receptor sigma-1 que apoyan el desarrollo clínico del antagonista selectivo para este receptor, el E-52862, como una opción terapéutica adecuada para el tratamiento del dolor neuropático y las comorbilidades afectivas asociadas a esta patología.
|
118 |
Desarrollo y caracterización de liposomas para aplicación tópica de fármacosVázquez González, Martha Leticia 21 December 2015 (has links)
La piel es el órgano más extenso y accesible del cuerpo, debido a ello la administración de fármacos por vía tópica para efectos locales o sistémicos ha sido ampliamente documentada. A pesar de todas las ventajas que la administración tópica de fármacos ofrece, la piel y su compleja estructura formada de múltiples capas, la cual le proporciona excelentes propiedades de barrera, hacen que la administración de medicamentos a través de esta vía sea un proceso complicado.
En las últimas décadas, con la finalidad de evadir la extraordinaria función de barrera del estrato córneo, se han empleado diversas estructuras nanoscópicas que han aumentado el espectro de fármacos susceptibles de ser administrados por vía tópica.
Estos hechos alientan la investigación en el desarrollo de formulaciones para mejorar la administración tópica de fármacos.
En la presente investigación, diseñamos formulaciones de liposomas para la administración tópica de fármacos, teniendo como hipótesis que la adición extemporánea de un activador de membrana en los liposomas, desestabiliza parcialmente las vesículas para que al contacto con la superficie de la piel humana promueva la liberación del principio activo y con ello aumente su biodisponibilidad.
Se estudiaron dos fármacos, el ibuprofeno y el ácido hialurónico (AH), y la eficacia de las formulaciones fue evaluada mediante ensayos in vitro y ex vivo con piel humana.
Posteriormente, para tener un conocimiento más profundo acerca de cómo las formulaciones desarrolladas aumentan la liberación de los fármacos, se utilizó el microscopio de fuerza atómica (AFM) y se observaron las estructuras que forman las formulaciones desarrolladas al ser aplicadas en la superficie de la piel humana.
Inicialmente, se utilizó fosfatidilcolina (PC) para producir los liposomas y en una segunda etapa de la investigación, se diseñó una composición biomimética con los principales componentes del estrato córneo. En base a esta composición se siguió la estrategia de incorporar los fármacos previamente estudiados, en combinación con los surfactantes seleccionados. La eficacia de las formulaciones fue evaluada y se verificó que la adición de potenciadores de la permeación (PEs) a liposomas, mejora la permeación de AH e ibuprofeno a través de la piel humana.
En relación a las imágenes obtenidas mediante el AFM, se observó que la adición de PEs promueve claramente la formación de las estructuras planas, debido a las regiones, parecidas a bicapas o multicapas de lípidos, en coexistencia con liposomas no fusionados y/o intactos observadas.
Se estudiaron también las modificaciones de las propiedades elásticas que se producen en las formulaciones desarrolladas al ser aplicadas, lo que permitió correlacionar estas propiedades con la permeación del fármaco incorporado en los liposomas. Por lo tanto, la técnica empleada en el desarrollo del presente trabajo de investigación puede utilizarse como herramienta auxiliar en el desarrollo de sistemas nano vesiculares para administración transdérmica de fármacos. / Skin is the extensive and most accessible organ of the body because of that, topical and systemic delivery of drugs are widely documented.
Even though all the advantages that topical drug delivery offers, the skin and their multilayered complex structure, provide excellent barrier properties which imply a complicated process to delivery of drugs through this administration via.
From the last decades, in order to avoid the SC barrier, several nanocarrier structures have been developed to accomplish the administration of drugs by topical via.
All of these facts encourage to investigating in the development of formulations to enhance drug delivery through the skin.
In the present study, we design liposomal formulations for topical delivery according the thermodynamic stability of the components.
Once obtained the adequate components, we started to develop liposomal formulations taking into account a preliminary hypothesis: the enhancement of the permeation of the drugs encapsulated in liposomes are relating with the ability to form planar bilayers.
We studied the permeation through artificial membranes and human skin of two molecules, ibuprofen and hyaluronic acid, when they were entrapped in liposomes.
To have a deeper knowledge about how the formulations developed are enhancing the liberation of drugs from the liposomes when applied to the human skin, the atomic force microscopy (AFM) was used.
Initially, phosphatidylcholine (PC) was used to produce the liposomes. In a second stage of the investigation, a biomimetic composition with the main components of the stratum corneum was designed. The efficacy of the formulations was evaluated and we confirmed that the addition of permeation enhancers (PEs) to liposomes improves the permeation of AH and ibuprofen through human skin.
Regarding the images obtained by the AFM, it was observed that the addition of PEs clearly promotes the formation of planar structures due to the regions like bilayers or multilayers lipids, in coexistence with liposomes fused and /or intact observed.
Changes in the elastic properties that occur in the formulations developed to be applied is also studied, allowing to correlate these properties with the permeation of drug incorporated into liposomes. Therefore, the technique used in the development of this research can be used as an auxiliary tool in the development of nanovesicular systems for transdermal drug delivery.
|
119 |
Optimización en la fabricación de medicamentos según ICH Q8, Q9 y Q10: aplicación a comprimidos recubiertos mediante diseño experimental de datos retrospectivosGalí Serra, Albert 11 December 2015 (has links)
El proyecto de esta tesis doctoral se basa en las metódicas de trabajo descritas en las guías ICH Q8, Q9 y Q10, que permiten establecer una estrategia de pruebas para optimizar los recursos existentes y acortar los tiempos de las etapas del desarrollo y mejora de proceso de fabricación de un producto, minimizando el número de pruebas y mejorando el conocimiento obtenido.
El trabajo llevado a cabo en esta tesis doctoral se centra en los procesos de recubrimiento pelicular y en la aplicación de las herramientas estadísticas para la optimización del proceso de fabricación de un producto ya comercializado que presenta problemas de calidad, ya que ha sido desarrollado siguiendo la metodología tradicional de ensayo-error. Se pretende plantear una optimización del proceso de recubrimiento que permitirá abaratar costes de producción y mejorar ciertos atributos de calidad, así como aportar una sistemática de estudio apta para aplicar en la mejora de procesos de producción de medicamentos.
Con la optimización de los tiempos de proceso se pueden reducir los costes de producción, debido a una menor ocupación de la maquinaria de producción, estando por tanto disponibles para la fabricación de otros lotes comerciales u otros productos que se recubran en el mismo equipo. A su vez, también hay una disminución de horas necesarias (horas de máquina y de mano de obra directa) para la elaboración de un lote comercial, es decir, una optimización de tiempos. También hay que tener en cuenta que al mejorar la calidad de producto final se reducen las horas destinadas a reprocesar el lote para eliminar los comprimidos que presentan defectos de calidad.
En general, la optimización de los procesos de recubrimiento requiere trabajos experimentales exhaustivos, no obstante la hipótesis del trabajo es comprobar si se pueden alcanzar mejoras sin necesidad de invertir mucho tiempo en recursos ni pruebas adicionales a nivel galénico para mejorar los procesos y que esto se traduzca en una mayor eficiencia en la fabricación de campañas comerciales. Es decir, para optimizar procesos comerciales no es necesario volver a la fase de desarrollo galénico, ya que con la información de los propios lotes comerciales anteriores se podrían plantear las mejoras. Se pretende en este caso aplicar la metodología a un proceso más complejo como es el recubrimiento de comprimidos.
Este proyecto ha permitido identificar los parámetros críticos de proceso de la fase de recubrimiento de un producto comercial mediante un estudio retrospectivo de lotes comerciales. Por tanto, se demuestra que se pueden mejorar los procesos existentes mediante una evaluación de un histórico de datos sin necesidad de realizar pruebas de desarrollo del producto de nuevo.
Mediante el análisis estadístico retrospectivo se han establecido los parámetros de proceso para mejorar los defectos de calidad estudiados, sin necesidad de llevar a cabo un diseño experimental con una batería de pruebas asociada. Se han aportado técnicas de mejora del proceso actual, desde un punto de vista tecnológico, que han permitido optimizar el proceso de recubrimiento sin implementar cambios en el proceso de fabricación y reducir los defectos de calidad estéticos. Mediante los datos evaluados retrospectivamente se ha podido llevar a cabo un diseño de experimentos que ha permitido seleccionar el mínimo número de factores que influyen para optimizar el proceso. Gracias al diseño factorial y a la posterior validación, se ha establecido un espacio de diseño que permite tener un proceso de recubrimiento que garantiza un medicamento producible, seguro, eficaz y de calidad. En la posterior validación industrial se ha demostrado que estos parámetros son los óptimos para obtener un producto con la calidad adecuada.
También se ha alcanzado una reducción de costes, directos e indirectos, en el proceso de recubrimiento de comprimidos, mejorando simultáneamente los atributos de calidad del medicamento, ya que un espacio de diseño se puede establecer mediante una inversión mínima en experimentos, porque los datos retrospectivos de los lotes comerciales pueden ser evaluados y tratados estadísticamente.
Mediante la validación comercial, los resultados demuestran que una evaluación retrospectiva de datos es una herramienta muy útil para mejorar los procesos de recubrimiento de productos comerciales. Por consiguiente, se ha establecido una sistemática de investigación apta para la mejora de procesos de producción de medicamentos, que da cumplimiento a las normativas ICH Q8, Q9 y Q10. / Although tablet coating processes are widely used in the pharmaceutical industry, they
often lack adequate robustness. Up-scaling can be challenging as minor changes in parameters can lead to varying quality results.
The aim of this study is to improve the current coating process of a commercial product, from a technological point of view, in order to optimize the coating process and decrease coating aesthetic defects. Then, to establish a design space, which would allow to obtain reproducible between-batch results. We describe the manufacturing process of the selected product and compile the process parameters of several commercial batches and analyze them retrospectively to establish the design space, based on the previously identified quality ranges. Without implementing changes to the process, the aim of this study is to identify the most adequate working ranges in order to reduce the number of aesthetic defects and avoid variations that are not within the registered product specifications.
The main objective is to select critical process parameters (CPP) using retrospective data of a commercial product and to establish a design of experiments (DoE) that would improve the robustness of the coating process. A retrospective analysis of data from 36 commercial batches was carried out. Batches were selected based on the quality results generated during batch release, some of which revealed quality deviations concerning the appearance of the coated tablets. The product is already marketed and belongs to the portfolio of a multinational pharmaceutical company. The data were statistically processed to determine critical process parameters in order to propose new working ranges.
This study confirms that it is possible to determine the critical process parameters and create design spaces based on retrospective data of commercial batches. This type of analysis is thus converted into a tool to optimize the robustness of existing processes. Our results show that a design space can be established with minimum investment in experiments, since current commercial batch data are processed statistically.
|
120 |
Estudis exploratoris en la síntesi dels alcaloides indòlics pericina (subincanadina E) i quebrachamina emprant una estratègia unificadaValldosera Juárez, Magdalena 18 December 2015 (has links)
Diversos alcaloides indòlics que pertanyen a famílies biogenètiques diferents es caracteritzen per presentar estructures tetracícliques amb pont constituïdes per un anell mitjà fusionat amb l'indole i una piperidina 3-substituïda. En aquest sentit, el nostre grup de recerca ha realitzat amb éxit la construcció dels sistemes tetracíclics de l'ervitsina i la 5-nor cleavamina, i la síntesi total de l'aparicina i les cleavamines utilitzant una estratègia unificada que combina dues reaccions d'eficàcia reconeguda en la formació d'enllaços C-C: una reacció de metàtesi intramolecular d'alquens (ring-closing metathesis, RCM) i una ciclació de Heck d'un halur vinílic.
En la present Tesi Doctoral ens proposàrem avaluar les possibilitats sintètiques de l'estratègia de doble anulació RCM-Heck per la síntesi dels alcaloides indòlics pericina (subincanadina E) i quebrachamina.
En el Capítol 2 es detallen els nostres esforços per establir una nova aproximació sintètica a l'alcaloide pericina basada en aquests conceptes. Després d'haver desenvolupat una ruta basada en reaccions de RCM de diens indòlics per accedir a estructures tricícliques que incorporen l'anell central de 9 baules característic de l'alcaloide, s'ha perseguit sense èxit la ciclació de Heck que hauria completat l'esquelet de la pericina.
Al Capítol 3 es descriu la construcció d'estructures tricícliques d'azonino[5,4-b]indole substituïdes a la posició 5, com a intermedis potencials en la síntesi de l'alcaloide quebrachamina. Aquest estudi sintètic ha implicat avaluar l'ús de reaccions de RCM, tant de diens com d'enins indòlics. En concret, cal destacar la utilització d'halurs alquinílics com a substrats en la reacció de metàtesis d'enins (RCEYM) ja que, fins al present, no havien estat mai explorats per aquesta finalitat. / Several indole alkaloids belonging to different biogenetic families are characterized by a bridged tetracyclic structure formed by a medium ring fused with the indole system and a 3-substituted piperidine. In this regard, our group has successfully completed the construction of the tetracyclic systems ervitsine and 5-nor cleavamine and the total synthesis of aparicine and cleavamines using a unified strategy that combines two highly recognized reactions in C-C bond formation: the ring-closing metathesis reaction (RCM) and the Heck reaction.
In the present work we wanted to evaluate the synthetic possibilities of the double annulation strategy RCM-Heck for the synthesis of indole alkaloids pericine (subincanadine E) and quebrachamine.
Chapter 2 details our efforts to establish a new synthetic approach to pericine alkaloid based on these concepts. Having developed an indole templated diene RCM-based route to access to the tricylic structures that incorporate the characteristic central 9-membered ring of the alkaloid, we have pursued the Heck cyclization for the completion of the pericine skeleton unsuccessfully.
Chapter 3 describes the construction of tricyclic azonino[5,4-b]indole structures substituted at position 5 as potential intermediates for the synthesis of quebrachamine alkaloid. This synthetic study involved evaluating the use of RCM reactions (indole templated dienes and enynes). In particular, it is noteworthy the use of alkynyl halides as substrates for enyne metathesis reaction (RCEYM) because, up to now, they had never been explored for this purpose.
|
Page generated in 0.0605 seconds