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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
71

Properties of a Genetically Unique Mycobacteriophage

Staples, Amanda K. 01 April 2019 (has links)
Bacteriophage MooMoo is a temperate phage that was isolated and propagated on Mycobacterium smegmatis (M. smeg). It typically produces turbid plaques, however spontaneous clear plaque mutants can be readily isolated. Both turbid (MooMoo-T) and clear plaque (MooMoo-C) formers can establish stable lysogens, but the parental turbid plaque forming phage has a higher lysogenic frequency. The phage repressor protein typically plays the central role in regulating the lysis/lysogeny decision. Therefore, we expected that the mutation responsible for the clear plaque phenotype would be located in the repressor gene. Remarkably, whole genome sequencing detected a single base pair mutation in the minor tail protein gene (gp19). The regulatory role of the repressor protein could not be excluded considering it was unclear how the mutation in gp19 was leading to the altered plaque phenotype. To locate the phage repressor, we used bioinformatics to identify several candidate genes with helix-turn-helix and DNA binding motifs (gp42, gp43 and gp44). We also cloned the parental and mutant gp19 genes. Each candidate gene was cloned into a shuttle vector. The clones of gp43, gp44 and both derivatives of gp19 did not prevent MooMoo growth, whereas the clones of gp42 inhibited phage growth. Based on these results, we concluded that gp42 is the phage repressor for MooMoo. To determine if the presence of gp19 alters lysogenic frequency, lysogeny assays of wild-type (WT) and mutant gp19 clones were evaluated. Compared to the MooMoo-C lysate, the cloned copy of the mutant gp19 showed a slight increase in lysogeny efficiency. The lysogeny frequencies on strains that carry cloned copies of gp19 (WT or mutant) were similar to those obtained on strains that lacked the plasmids. From these results, we concluded, the presence of either parental or mutant gp19 clones does not affect the lysogeny frequency. To determine if host cell physiology was affected by lysogeny, carbon, nitrogen, phosphorus and sulfur utilization resources were screened using high-throughput phenotypic microarrays. From these results, we concluded the presence of the WT or mutant prophage had no significant effect on the utilization of the resources tested.
72

Consumo materno de dois compostos bioativos da semente da linhaça sobre parâmetros bioquímicos e hormonais das mães e proles durante a lactação / Maternal intake of two bioactive compounds from flax seed on biochemical and hormonal parameters of mothers and offspring during lactation

Aline Andrade Troina 30 March 2011 (has links)
Conselho Nacional de Desenvolvimento Científico e Tecnológico / Avaliamos o efeito do consumo materno de SDG (Diglicosídeo Secoisolariciresinol) e de óleo de Linhaça+SDG sobre parâmetros bioquímicos e hormonais das ratas e das proles machos e fêmeas na lactação. As ratas lactantes foram separadas em: controle (C), ração controle cuja proteína foi caseína; (SDG): ração C com 400mg de SDG/Kg de ração; OLSDG: ração C com 400mg de SDG/Kg de ração e 7% de óleo de linhaça. No 14 e 20 dias de lactação as ratas foram ordenhadas e no 21 dia foram sacrificadas por punção cardíaca. Leite e soro foram coletados para avaliação bioquímica e hormonal. Hormônios foram quantificados por radioimunoensaio. As proles machos e fêmeas foram sacrificadas aos 14 e 21 dias de idade. Os animais foram eviscerados para análise da composição corporal. Monitoramos a ingestão alimentar e a massa corporal (MC) durante o período experimental. As ratas SDG apresentaram maior gordura corporal (GC; +39%), enquanto as OLSDG menor conteúdo mineral (-20%) e trigliceridemia (TG) (-39%). As ratas SDG e OLSDG apresentaram hiperprolactinemia (+389% e 153%, respectivamente) sem alteração na concentração de estradiol. No 14 dia de lactação, o leite das ratas OLSDG apresentou menores teores de lactose(-17%) e de proteínas (-20%) e o das ratas SDG apenas menor teor de proteína (-21%). A partir do 13 dia de lactação tanto os machos quanto as fêmeas OLSDG apresentaram menor MC (-14%, -16%, respectivamente). No 14 dia de lactação os machos SDG e OLSDG apresentaram menor gordura corporal (-24%, -55%, respectivamente ) e a prole SDG maior massa de gordura visceral (+39%). Os machos SDG apresentaram maiores concentrações de TG (+105%) e hipoprolactinemia (-41%). Os machos OLSDG também apresentaram hipoprolactinemia (-41%). As fêmeas SDG e OLSDG apresentaram maior estradiol aos 14 dias (+86% e +176%) que se normalizou aos 21 dias, maior colesterolemia (+16%) e as SDG apresentaram maior trigliceridemia (+74%). Aos 21 dias os machos e as fêmeas SDG e OLSDG apresentaram menor trigliceridemia (-48%, -54%,42% e -59%, respectivamente). Os dois componentes principais da semente de linhaça produzem alterações bioquímicas e hormonais tanto nas mães, quanto nas proles, independente do sexo. Entretanto, as alterações observadas diferem entre mães e prole e de acordo com o gênero. Entre as alterações mais importantes ressaltamos a hiperprolactinemia materna que pode ser um dos motivos para a hipoprolactinemia da prole e a hipertrigliceridemia causada pela ingestão de SDG pelas mães. / We evaluated the mothers intake of SDG (Diglicoside secoisolariciresinol) and flaxseed oil + SDG upon biochemical and hormonal parameters of lactating female rats and the male and female offspring during lactation. The female lactating rats were divided into: Control (C): feeding a diet with casein; (SDG): feeding diet C added 400mg of SDG/Kg diet; (OLSDG): diet C added 400mg of SDG/Kg diet and 7% of flaxseed oil. Milk samples were obtained on the 14th and 20th days of lactation and the mothers were sacrificed and blood collected by cardiac puncture on the 21st day. Milk and serum were collected for biochemical and hormonal analysis. The male and female offsprings were sacrified on the 14th and 21st day. The hormonal dosages were measured by radioimunassay. The animals were completely eviscerated to analyze body composition. Body mass (BM) and food intake were monitored during all experimental period. The SDG rats showed higher fat mass (+39%) while the OLSDG rats showed lower mineral content (-20%) and triglycerides (TG) serum levels (-39%). The SDG and OLSDG rats showed higher prolactin levels (+339% and +153% respectively) without changes in serum estradiol. On the 14th day of lactation we observed lower lactose (-17%) and protein (-20%) content in the OLSDG rats milk while in the SDG only lower protein (-21%). From the 13th day of lactation both the males and females OLSDG showed lower BM ( - 14%, - 16%, respectively). On the 14th day the male SDG and OLSDG showed lower fat mass (-24%, -55%, respectively), and the SDG offspring showed higher visceral fat mass (+39%). The SDG male also showed higher TG levels (+105%) and lower prolactin levels (-41%). The OLSDG males also showed lower prolactin serum levels (-41%). The OLSDG female showed higher serum estradiol at 14 days (+86% e +176%), which normalized at 21 days and higher cholesterolemia (+16%) and the SDG female presented higher TG levels (+74%). On day 21th day the male and female SDG and OLSDG showed lower TG levels (-48%,-54%, -42% and 59% respectively). Thus, the two main component of flaxseed showed biochemical and hormonal changes in the mothers and offspring, independent of gender. However, the changes observed in mothers differ from the offspring, and differ accordingly with the sex of offspring. The most impressive changes were the maternal hyperprolactinemia that can be one of the cause for the observed hypoprolactinemia in the offspring and the other main finding was the hypertriglyceridemia in the SDG group.
73

Efeito do cádmio sobre a enzima d-aminolevulinato desidratase de pulmão de ratos in vitro: interação com agentes quelantes e antioxidantes / Effects of cadmium on d-aminolevulinate dehydratase from rat lung in vitro: interaction with chelating and antioxidant agents

Luchese, Cristiane 01 June 2007 (has links)
Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / The exposure of human populations to a variety of heavy metals has been a public health concern. Cadmium is a non-essential elements due to its immense usage in various industrial applications, is an environmental contaminant with food and tobacco smoking. This toxic metal is more efficiently absorbed through the lungs than through the gastrointestinal tract. Therefore, the use of lung as a target tissue of cadmium exposure is of great importance because this heavy metal can be absorbed on suspended particles, entering the lung through the respiration. Thus, a possible therapy for metal intoxication is to remove the toxic metals from the bound functional bioligands. The present study was designed to evaluate the effect of cadmium on d-minolevulinate dehydratase (d-ALA-D) activity from rat lung in vitro. d-ALA-D activity, a toxicological parameter, has been reported as a target of cadmium in different tissues. The protective effect of monotherapies with dithiol chelating (meso-2,3-dimercaptosuccinic acid (DMSA) and 2,3-dimercaptopropane-1- sulfonic acid (DMPS)) or antioxidant agent (ascorbic acid, diphenyl diselenide, (PhSe)2, and Nacetylcysteine (NAC)) were also evaluated; as well as, the effect of a combined therapy (dithiol chelating x antioxidant agent) was studied. Moreover, to investigate the possible mechanism involved, we determined the effect of zinc chloride (ZnCl2) and dithiothreitol (DTT). The rat lung d-ALA-D activity was inhibited by low concentrations of cadmium, this inhibition occurred due the oxidation of SH groups of enzyme, and not by displacing zinc from the enzyme structure. The chelating agents were not effective in restoring enzyme activity inhibited by cadmium, and it presented an inhibitory effect per se. The possible mechanism involved in this inhibition was demonstrated. DTT restored the inhibition caused by both chelating agents, but ZnCl2 restored only the inhibitory effect of DMSA. This indicated that DMPS did not remove the zinc ions of the enzyme structure. This study also demonstrated that these chelating agents potentialized the d-ALA-D inhibition caused by cadmium. In this way, the study of possible mechanism verified that DTT restore the enzyme inhibition caused by cadmium/DMSA complex, but not by cadmium/DMPS complex. In contrast to DTT, ZnCl2 did not restore the enzyme activity inhibited by both complexes. In relation to antioxidants compounds, we can verify that none antioxidant utilized in this work was efficient in restoring the enzyme activity inhibited by cadmium. Some authors had demonstrated that the association of chelating and antioxidant agents is a good alternative in treatment of metal intoxication. In this way, we observed a combined effect of cadmium x DMPS x (PhSe)2 and cadmium x DMPS x NAC. However, this combined effect of cadmium x antioxidant x chelating did not observe when we utilized DMSA as chelating agent. In general, the results of this study indicate that cadmium inhibited the pulmonary d-ALA-D activity; and, the use oh chelating and antioxidant agents, alone or combined, 6 did not restore the enzyme activity, in some cases, potentialized the inhibition induced by cadmium. The principal mechanism involved in enzyme inhibition was the oxidation of SH groups. / A exposição das populações humanas a uma variedade de metais pesados é um problema de saúde pública. O cádmio é um elemento não essencial e devido ao seu imenso uso em diversas aplicações industriais, é um contaminante ambiental através da comida e da fumaça do cigarro. Este metal tóxico é mais eficientemente absorvido através dos pulmões do que do trato gastrointestinal. Portanto, o uso dos pulmões como um tecido alvo do cádmio é de grande importância porque este metal pesado pode ser absorvido, entrando nos pulmões através da respiração. Uma terapia possível para a intoxicação por metais é remover os metais tóxicos ligados a bioligantes funcionais. O presente estudo foi delineado para avaliar o efeito in vitro do cádmio na atividade da d-aminolevulinato desidratase (d-ALA-D) em pulmão de rato. A atividade da d-ALA-D, um parâmetro toxicológico, tem sido reportada como alvo do cádmio em diferentes tecidos. Foram avaliados também o possível efeito protetor dos agentes quelantes ditiólicos (ácido 2,3-dimercapto-1-propanosulfônico (DMPS) e o ácido meso 2,3- dimercaptosuccínico (DMSA)) ou agentes antioxidantes (ácido ascórbico, N-acetilcisteína (NAC) e o disseleneto de difenila (PhSe)2) isolados ou em combinação (agentes quelantes x antioxidantes). Além disso, para investigar o possível mecanismo envolvido, nós determinamos o efeito restaurador do cloreto de zinco (ZnCl2) e do ditiotreitol (DTT) na d-ALA-D. A atividade da d-ALA-D de pulmão de rato foi inibida por baixas concentrações de cádmio, e esta inibição ocorreu devido a oxidação dos grupos -SH da enzima, e não por remover os íons zinco da estrutura enzimática. Os agentes quelantes não foram efetivos em proteger a atividade da enzima inibida por cádmio, e apresentaram um efeito inibitório per se. O possível mecanismo envolvido nesta inibição foi demonstrado. O DTT restaurou a inibição causada por ambos agentes quelantes, mas o ZnCl2 restaurou somente o efeito inibitório do DMSA. Isto indica que o DMPS não remove os íons zinco da estrutura da enzima. Este estudo demonstrou também que estes agentes quelantes potencializam a inibição da d-ALA-D causada por cádmio. Neste sentido, o estudo do possível mecanismo verificou que o DTT restaura a inibição da enzima causada pelo complexo cádmio/DMSA, mas não pelo complexo cádmio/DMPS. Ao contrário do DTT, o ZnCl2 não restaura a atividade da enzima inibida por ambos complexos. Em relação aos compostos antioxidantes, nós podemos verificar que nenhum antioxidante utilizado neste trabalho foi eficiente em restaurar a atividade da enzima inibida por cádmio. Alguns autores têm demonstrado que a associação de agentes quelantes e antioxidantes é uma boa alternativa no tratamento das intoxicações por metais. Neste sentido, observou-se um efeito combinado de cádmio x DMPS x (PhSe)2 e cádmio x DMPS x NAC. Porém esse efeito combinado de cádmio x antioxidantes x quelantes não foi observado quando se utilizou o DMSA como 4 agente quelante. De uma maneira geral, os resultados deste estudo indicam que o cádmio inibiu a atividade da d-ALA-D do tecido pulmonar; e ainda, o uso de agentes quelantes e antioxidantes, sozinhos ou combinados, não restauraram a atividade da enzima, sendo que em alguns casos, potencializaram a inibição induzida por cádmio. O mecanismo principal envolvido na inibição da enzima foi à oxidação dos grupos sulfidrílicos.
74

Consumo materno de dois compostos bioativos da semente da linhaça sobre parâmetros bioquímicos e hormonais das mães e proles durante a lactação / Maternal intake of two bioactive compounds from flax seed on biochemical and hormonal parameters of mothers and offspring during lactation

Aline Andrade Troina 30 March 2011 (has links)
Conselho Nacional de Desenvolvimento Científico e Tecnológico / Avaliamos o efeito do consumo materno de SDG (Diglicosídeo Secoisolariciresinol) e de óleo de Linhaça+SDG sobre parâmetros bioquímicos e hormonais das ratas e das proles machos e fêmeas na lactação. As ratas lactantes foram separadas em: controle (C), ração controle cuja proteína foi caseína; (SDG): ração C com 400mg de SDG/Kg de ração; OLSDG: ração C com 400mg de SDG/Kg de ração e 7% de óleo de linhaça. No 14 e 20 dias de lactação as ratas foram ordenhadas e no 21 dia foram sacrificadas por punção cardíaca. Leite e soro foram coletados para avaliação bioquímica e hormonal. Hormônios foram quantificados por radioimunoensaio. As proles machos e fêmeas foram sacrificadas aos 14 e 21 dias de idade. Os animais foram eviscerados para análise da composição corporal. Monitoramos a ingestão alimentar e a massa corporal (MC) durante o período experimental. As ratas SDG apresentaram maior gordura corporal (GC; +39%), enquanto as OLSDG menor conteúdo mineral (-20%) e trigliceridemia (TG) (-39%). As ratas SDG e OLSDG apresentaram hiperprolactinemia (+389% e 153%, respectivamente) sem alteração na concentração de estradiol. No 14 dia de lactação, o leite das ratas OLSDG apresentou menores teores de lactose(-17%) e de proteínas (-20%) e o das ratas SDG apenas menor teor de proteína (-21%). A partir do 13 dia de lactação tanto os machos quanto as fêmeas OLSDG apresentaram menor MC (-14%, -16%, respectivamente). No 14 dia de lactação os machos SDG e OLSDG apresentaram menor gordura corporal (-24%, -55%, respectivamente ) e a prole SDG maior massa de gordura visceral (+39%). Os machos SDG apresentaram maiores concentrações de TG (+105%) e hipoprolactinemia (-41%). Os machos OLSDG também apresentaram hipoprolactinemia (-41%). As fêmeas SDG e OLSDG apresentaram maior estradiol aos 14 dias (+86% e +176%) que se normalizou aos 21 dias, maior colesterolemia (+16%) e as SDG apresentaram maior trigliceridemia (+74%). Aos 21 dias os machos e as fêmeas SDG e OLSDG apresentaram menor trigliceridemia (-48%, -54%,42% e -59%, respectivamente). Os dois componentes principais da semente de linhaça produzem alterações bioquímicas e hormonais tanto nas mães, quanto nas proles, independente do sexo. Entretanto, as alterações observadas diferem entre mães e prole e de acordo com o gênero. Entre as alterações mais importantes ressaltamos a hiperprolactinemia materna que pode ser um dos motivos para a hipoprolactinemia da prole e a hipertrigliceridemia causada pela ingestão de SDG pelas mães. / We evaluated the mothers intake of SDG (Diglicoside secoisolariciresinol) and flaxseed oil + SDG upon biochemical and hormonal parameters of lactating female rats and the male and female offspring during lactation. The female lactating rats were divided into: Control (C): feeding a diet with casein; (SDG): feeding diet C added 400mg of SDG/Kg diet; (OLSDG): diet C added 400mg of SDG/Kg diet and 7% of flaxseed oil. Milk samples were obtained on the 14th and 20th days of lactation and the mothers were sacrificed and blood collected by cardiac puncture on the 21st day. Milk and serum were collected for biochemical and hormonal analysis. The male and female offsprings were sacrified on the 14th and 21st day. The hormonal dosages were measured by radioimunassay. The animals were completely eviscerated to analyze body composition. Body mass (BM) and food intake were monitored during all experimental period. The SDG rats showed higher fat mass (+39%) while the OLSDG rats showed lower mineral content (-20%) and triglycerides (TG) serum levels (-39%). The SDG and OLSDG rats showed higher prolactin levels (+339% and +153% respectively) without changes in serum estradiol. On the 14th day of lactation we observed lower lactose (-17%) and protein (-20%) content in the OLSDG rats milk while in the SDG only lower protein (-21%). From the 13th day of lactation both the males and females OLSDG showed lower BM ( - 14%, - 16%, respectively). On the 14th day the male SDG and OLSDG showed lower fat mass (-24%, -55%, respectively), and the SDG offspring showed higher visceral fat mass (+39%). The SDG male also showed higher TG levels (+105%) and lower prolactin levels (-41%). The OLSDG males also showed lower prolactin serum levels (-41%). The OLSDG female showed higher serum estradiol at 14 days (+86% e +176%), which normalized at 21 days and higher cholesterolemia (+16%) and the SDG female presented higher TG levels (+74%). On day 21th day the male and female SDG and OLSDG showed lower TG levels (-48%,-54%, -42% and 59% respectively). Thus, the two main component of flaxseed showed biochemical and hormonal changes in the mothers and offspring, independent of gender. However, the changes observed in mothers differ from the offspring, and differ accordingly with the sex of offspring. The most impressive changes were the maternal hyperprolactinemia that can be one of the cause for the observed hypoprolactinemia in the offspring and the other main finding was the hypertriglyceridemia in the SDG group.
75

Módulo fotônico para terapia fotodinâmica (PDT) em cápsulas endoscópicas / Photonic module for photodynamic therapy (PDT) in endoscopic capsules

Rodrigo Henrique Gounella 28 June 2018 (has links)
A cápsula endoscópica é um instrumento revolucionário, que permite a realização de um exame livre de desconfortos para o paciente e possibilitou a técnica de endoscopia chegar a partes do sistema gastrointestinal que antes não era possível, como grande parte do intestino delgado. Este trabalho apresenta um módulo fotônico para realizar Terapia Fotodinâmica (PDT, Photodynamic Therapy) em cápsulas endoscópicas. A PDT é uma forma de tratamento para lesões que envolve a administração prévia de um medicamento fotossensível (PS, Photosensitizer) e posterior ativação com irradiação de luz em um comprimento de onda (λ) específico. Geralmente para a ativação do PS utiliza-se λ na região vermelha do espectro visível, pois a penetração nos tecidos é elevada. Células de adenocarcinoma gástrico humano (AGS, Adenocarcinoma Gastric of Stomach) foram preparadas com ácido 5-aminolevulínico (5-ALA) que é um Pró-fármaco precursor do agente fotossensível Protoporfirina IX (PpIX) com máximo de absorção nos 635 nm. Para realizar a irradiação com luz vermelha nas células, 16 LEDs do modelo LRQ396-P1Q2-1 da Osram Opto Semiconductors com dimensões muito reduzidas foram selecionados, caracterizados, montados em uma PCB (Printed Circuit Board) e alimentados por um Arduino Mega 2560. Este sistema de iluminação foi eficaz em seu propósito e causou morte celular nas células submetidas ao tratamento com o ALA em uma concentração de 2 milimol por litro e dose de luz em 5 Joules por centímetro quadrado que resulta em uma exposição de 49 minutos. Com o objetivo de se construir um módulo para controle de iluminação em cápsulas endoscópicas, foi desenvolvido em tecnologia CMOS 0.7 μm da ON Semiconductor um dispositivo capaz de controlar a intensidade dos LEDs utilizando PWM (Pulse Width Modulation). Unindo este componente com os LEDs selecionados é perfeitamente possível construir o módulo e inseri-lo CEs para realizar PDT em locais do trato gastrointestinal (GI) não acessíveis pela endoscopia convencional. / The endoscopic capsule is a revolutionary instrument that gives a free examination of discomforts for patient and allows the endoscopic technique to reach parts of the gastrointestinal system that were previously not possible, such as a large part of the small intestine. This work presents a photonic module to perform Photodynamic Therapy (PDT) in endoscopic capsules. PDT is a form of treatment for injuries involving prior administration of a photosensitive drug (PS, Photosensitizer) and subsequent activation with light irradiation at a specific wavelength (λ). Usually for PS activation, λ is used in the red region of the visible spectrum, because the tissue penetration is high. Human gastric adenocarcinoma cells (AGS) were prepared with 5-aminolevulinic Acid (5-ALA) which is a Pro-drug precursor of the photosensitive agent Protoporphyrin IX (PpIX) with maximum absorption at 635 nm. To perform red light irradiation on the cells, 16 LEDs, model LRQ396-P1Q2-1 of the Osram Opto Semiconductors with very small dimensions were selected, characterized, mounted on a PCB (Printed Circuit Board) and powered by an Arduino Mega 2560. This system was effective in its purpose and caused cell death in cells treated with ALA at a concentration of 2 mMol/L and dose of light at 5 J/cm² resulting in a 49 minutes exposure. With the objective of build a module for control of lighting in endoscopic capsules, a device able to controlling the intensity of the LEDs using PWM (Pulse Width Modulation) was developed in CMOS technology 0.7 μm of the ON Semiconductor. Combining this component with the selected LEDs, it is perfectly possible to construct the module and insert in CEs to perform PDT at sites of the gastrointestinal tract (GI) not accessible by conventional endoscopy.
76

Vietinio poveikio vaisto formų ir jontoforezės poveikio 5-aminolevulino rūgšties ir jos provaisto skvarbai į (pro) odą įvertinimas / Evaluation of the effect of topical formulations and iontophoresis on the penetration of 5-aminolevulinic acid and its prodrug into (through) skin

Armoškaitė, Vilma 30 September 2014 (has links)
Siekiant pagreitinti 5-aminolevulino rūgšties (5-ALA) skvarbą į (pro) odą ir sudaryti terapines fotodinaminiam gydymui tinkamas jos koncentracijas, įvertinta 5-ALA ir naujo provaisto skvarba į (pro) odą iš įvairių vietinio poveikio vaisto formų. Atlikta naujo provaisto 2-(dimetilamino)-etil-5-amino-4-oksopentanoato (DMAE-ALA) sintezė, ištirtos jo charakteristikos. Nustatytas susintetinto provaisto stabilumas įvairių pH verčių buferiniuose vandeniniuose tirpaluose ir odos esterazių poveikyje, įrodytas provaisto tinkamumas pernašai į (pro) odą. Atlikti 5-ALA ir du teigiamus krūvius vaisto formoje įgaunančio provaisto jontoforetinės ir pasyvios pernašos iš buferinių tirpalų ir celiuliozinės bei polivinilkarboksilinės kilmės polimerinių gelių į (pro) odą tyrimai in vitro. Patvirtintas reikšmingas skatinamas jontoforezės poveikis krūvinių molekulių pernašai į (pro) odą ir krūvio dydžio reikšmė elektros srovės skatinamos pernašos greičiui. Ištirta vaisto formų, pagamintų iš polivilinkarboksilinės kilmės ir celiuliozės polimerų, kokybė ir jų pasyvioji bei jontoforetinė pernaša. Įrodyta, kad provaisto įterpimui naudojant celiuliozės polimerų pagrindu pagamintus gelius, pasiekiama didžiausia 5-ALA pernaša. Nustatyta, kad du krūvius turintis 5-ALA provaistas į (pro) odą skverbėsi geriau negu vieną krūvį įgaunantys arba elektriškai neutralūs 5-ALA dariniai. Sudarytos rekomendacijos, skirtos pasiekti didžiausiai 5-ALA pernašai į (pro) odą. / Passive and iontophoretic delivery of 5-aminolevulinic acid and newly synthesized prodrug into (through) skin from various topical formulations was evaluated, while trying to accelerate the penetration of 5-ALA and its derivative into (through) skin and to generate the therapeutic concentration suitable for photodynamic therapy. A new prodrug 2-(dimethylamino)-ethyl-5-amino-4-oxopentanoate (DMAE-ALA) was synthesized, its characteristics have been evaluated. Stability of the prodrug in aqueous solutions of various pH values and at exposure with skin esterases (dermal and epidermal stability) has been evaluated. Suitability of the prodrug for topical delivery was confirmed. Studies for the evaluation of 5-ALA and DMAE-ALA passive and active delivery from cutaneous solutions, cellulose and polyvinyl carboxy polymer gels into (through) skin in vitro have been performed. Significant effect of iontophoresis on delivery of charged molecules into (through) skin as well as the significance of the charge of the molecule on the delivery rate has been confirmed. It has been shown that the insertion of the prodrug into cellulose-based polymer gels produces the highest amount of 5-ALA delivered into (through) skin. It was determined that the two-charged prodrug DMAE-ALA penetrated into (through) the skin more efficiently than single-charged or electrically neutral 5-ALA derivatives. Recommendations for achieving most efficient 5-ALA delivery into (through) the skin have been composed.
77

Avaliação do efeito fotodinâmico a partir da associação dos precursores da PPIX (ALA e MAL) em epitélio suíno / Photodynamic effect evaluation from the association of the precursors of PPIX (ALA and MAL) in swine epithelium

Fujita, Alessandra Keiko Lima 23 May 2016 (has links)
A terapia fotodinâmica (TFD) utilizando ácido 5-aminolevulinico (ALA) e derivados em aplicação tópica e, como precursor da protoporfirina IX (PPIX) apresenta alguns limitantes relativos a baixa permeação das substâncias na pele. Comportamento este que afeta a produção e homogeneidade da distribuição da PPIX na superfície e camadas mais profundas da pele. Para resolver essa limitação muitos autores propõem alternativas modificando a molécula do ALA e derivados, bem como modificando as propriedades químicas da fase externa da emulsão (mais hidrofílica ou hidrofóbica) ou então o sistema de entrega para a emulsão. O objetivo desse estudo é avaliar qual a proporção de ALA e metil-5-aminolevulinato (MAL) que quando misturados levam ao aumento da quantidade e uniformidade da formação da PPIX na superfície e em profundidade na pele. Para esse estudo foi realizada análises de fluorescência e histologia. O estudo foi conduzido in vivo e ex vivo usando biópsias de pele de porco cultivadas in vitro. A produção de PPIX foi monitorada utilizando espectroscopia de fluorescência, imagem de fluorescência de campo amplo e microscopia confocal de fluorescência. E para a aplicação da TFD os parâmetros usados foram de 125 mW/cm2 de intensidade e 150 J/cm2 de dose. A análise do dano causado pela irradiação foi realizada por meio de histologia da pele após 24 e 48 horas da aplicação da TFD. O ALA e MAL na concentração de 20% foram misturados nas seguintes proporções: ALA ou M, M2 (80% ALA - 20% MAL), M3 (60% ALA 40% MAL), M4 (50% ALA MAL), M5 (40% ALA 60% MAL), M6 (20% ALA 80% MAL) e MAL como M7. As diferentes proporções foram incorporadas em emulsões óleo em água (O/A) e água em óleo (A/O). De acordo com os resultados, as misturas M3, M4 e M5 mostraram maior produção de PPIX na superfície da pele segundo as medidas de fluorescência em 3h de incubação e, no estudo da cinética mostraram produzir PPIX em menor tempo. No estudo de permeação do creme in vitro em pele ex vivo, por microscopia confocal de fluorescência, observou-se que as misturas M3, M4 e M5 produziram mais PPIX nas camadas da pele do que ALA e MAL. As análises histológicas das misturas apresentaram maior dano fotodinâmico na superfície e profundidade das camadas da pele após a TFD, independente da emulsão. A análise em até 48h observou-se predominantemente a fase do processo de reparo referente à fase inflamatória, mas existem indícios ao longo das análises tanto macroscópicas e histológicas que o processo de reparo referente as fases subsequentes de proliferação e remodelamento estão iniciando-se em paralelo. A mistura M4 em ambas as emulsões apresentou elevada quantidade de formação de PPIX em menor tempo de incubação. M4 em emulsão O/A apresentou menor dano fotodinâmico já que a evolução do processo reparo foi mais rápida sugerindo-se potencial de aplicação em TFD voltado para área cosmética-estética. Já M4 em emulsão A/O levou a um maior dano fotodinâmico já que a evolução do processo de reparo foi mais lenta sugerindo-se potencial de aplicação em TFD voltado para área oncológica e de doenças de pele. De modo geral o estudo proposto apresentou impacto positivo para a otimização da terapia fotodinâmica em aplicação tópica. / Photodynamic therapy (PDT) using 5-aminolevulinic acid and derivatives on topical application and as a precursor of protoporphyrin (PPIX) has some limitations for low permeation of substances into the skin. This behavior affects PPIX production and homogeneous distribution on the surface and deeper layers of the skin. To resolve this limitation, many authors propose alternatives such as modifying the molecule of ALA and its derivatives, as well as changing the chemical properties of the external phase of the emulsion (more hydrophilic or hydrophobic) or the delivery system to the emulsion. The aim of this study is to assess the proportion of ALA and methyl-5-aminolevulinate (MAL) that when mixed leads to an increase in the amount and uniformity of the PPIX formation on surface and deep skin. For this study we performed fluorescence analysis and histology. The studies were conducted in vivo and also using pig skin biopsies (ex vivo) cultured in vitro. The PPIX production was monitored using fluorescence spectroscopy, widefield fluorescence imaging, and fluorescence confocal microscopy. For the application of PDT an intensity of 125 mW/cm2 and a dose 150 J/cm2 were used. Analysis of the damage caused by irradiation was performed through skin histology after 24 and 48 hours after PDT application. ALA and MAL in concentration of 20% were mixed in the following proportions: ALA or M, M2 (80% ALA - 20% MAL), M3 (60% ALA - 40% MAL), M4 (50% ALA - MAL) M5 (40% ALA - 60% MAL), M6 (20% ALA - 80% MAL) MAL and as M7. Different proportions were incorporated in oil-in-water emulsions (O/W) and water-in-oil (W/O). The fluorescence measurements for 3h of incubation showed better PPIX production in the skin surface for mixtures M3, M4 and M5. Moreover, the kinetics study showed PPIX production in less time for these mixtures. In the study of cream permeation of ex vivo skin in vitro by confocal fluorescence microscopy, we observed that the mixtures M3, M4 and M5 produced more PPIX in the skin layers than ALA and MAL. The histological analyses of the mixtures showed higher photodynamic damage on the surface and deeper layers of the skin after PDT, independent of the emulsion. The analysis in 48 hours predominantly observed the phase of the healing process regarding the inflammatory phase but there are signs along both macroscopic and histological analysis that the healing process concerning the subsequent stages of proliferation and remodeling are initiating in parallel. The mixture M4 in both emulsions had high amounts of PPIX formation in shorter incubation time. M4 emulsion O/A showed a lower photodynamic damage since the evolution of the healing process was faster suggesting to potential application in PDT facing cosmetic-aesthetic area. M4 already in W/O emulsion led to a greater photodynamic damage since the evolution of the healing process was slower suggesting to potential application in PDT facing oncology and skin diseases. Overall the proposed study had a positive impact on the optimization of photodynamic therapy for topical application.
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Electrochemical Methods for Drug Characterisation and Transdermal Delivery : Capillary Zone Electrophoresis, Conductometry, and Iontophoresis

Merclin, Nadia January 2003 (has links)
<p>This thesis concerns the development and utilisation of techniques for characterisation and transdermal delivery of various systems for pharmaceutical applications.</p><p>The degree of dissociation of drug molecules and the mobilities of the different species formed are essential factors affecting the rate of drug delivery by iontophoresis. Hence, determination of drug mobility parameters and equilibrium constants are important for the development of iontophoretic systems. With capillary zone electrophoresis using a partial filling technique and methyl-β-cyclodextrin as chiral selector, the enantiomers of orciprenaline were separated. The association constants between the enantiomers of the drug and the selector were also evaluated. Precision conductometry studies were performed for the hydrochloride salts of lidocaine and 5-aminolevulinic acid in aqueous propylene glycol and water as media, respectively.</p><p>Iontophoresis is a technique for drug delivery where charged molecules are transported into and through skin by application of a weak direct electrical current. The drugs 5-aminolevulinic acid and its methyl ester were used as model compounds and incorporated in two different drug delivery vehicles, a sponge phase and carbopol gel. The bicontinuous structure of the sponge phase, constituted of monoolein and a mixture of propylene glycol and water, makes it interesting for use in iontophoretic delivery, since ions can move more or less freely in the aqueous as well as in the lipid domains. Furthermore, all three components are known for their penetration enhancing abilities. Hydrogels like carbopol gels are interesting media with respect to iontophoretic studies, since devices for iontophoresis often utilize hydrogels as contact interfaces between the skin and the electrodes. The results indicate that the transport achieved iontophoretically using the gel (1 % active substance) was comparable with the passive delivery of clinically used formulations (16 % - 20 % active substance).</p>
79

Electrochemical Methods for Drug Characterisation and Transdermal Delivery : Capillary Zone Electrophoresis, Conductometry, and Iontophoresis

Merclin, Nadia January 2003 (has links)
This thesis concerns the development and utilisation of techniques for characterisation and transdermal delivery of various systems for pharmaceutical applications. The degree of dissociation of drug molecules and the mobilities of the different species formed are essential factors affecting the rate of drug delivery by iontophoresis. Hence, determination of drug mobility parameters and equilibrium constants are important for the development of iontophoretic systems. With capillary zone electrophoresis using a partial filling technique and methyl-β-cyclodextrin as chiral selector, the enantiomers of orciprenaline were separated. The association constants between the enantiomers of the drug and the selector were also evaluated. Precision conductometry studies were performed for the hydrochloride salts of lidocaine and 5-aminolevulinic acid in aqueous propylene glycol and water as media, respectively. Iontophoresis is a technique for drug delivery where charged molecules are transported into and through skin by application of a weak direct electrical current. The drugs 5-aminolevulinic acid and its methyl ester were used as model compounds and incorporated in two different drug delivery vehicles, a sponge phase and carbopol gel. The bicontinuous structure of the sponge phase, constituted of monoolein and a mixture of propylene glycol and water, makes it interesting for use in iontophoretic delivery, since ions can move more or less freely in the aqueous as well as in the lipid domains. Furthermore, all three components are known for their penetration enhancing abilities. Hydrogels like carbopol gels are interesting media with respect to iontophoretic studies, since devices for iontophoresis often utilize hydrogels as contact interfaces between the skin and the electrodes. The results indicate that the transport achieved iontophoretically using the gel (1 % active substance) was comparable with the passive delivery of clinically used formulations (16 % - 20 % active substance).
80

The past on trial : the Sixteenth Street Baptist Church bombing, civil rights memory and the remaking of Birmingham /

Anderson, Susan Willoughby. Hall, Jacquelyn Dowd. January 2008 (has links)
Thesis (Ph. D.)--University of North Carolina at Chapel Hill, 2008. / "... in partial fulfillment of the requirements for a degree of doctor of philosophy in the Department of History." Discipline: History; Department/School: History.

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