In this work electrochemical studies are broached as well the development of an analytical methodology to determinate ketoconazole in pharmaceuticals formulations with the help of electrode of carbon paste was modified with hemin. The tests were carried out in solution tampão Britton-Robinson (BR) in pH 2, with an electrode compounded by 50% of carbon past and 50% of hemin, for having the best analytical answer to the compound in question. Based on the electrochemical parameters that were taken of the technique cyclic voltammetry, differential pulse and of the square wave, it was possible diagnostic some information that was connected to the reaction mechanism such as: the reversibility of the process, the existence or not of adsorption process and the number of electrons that is involved in the electrochemical reactions. The resulted said that the reaction of ketoconazole reduction is irreversible, with one definite peaks at 1,44V device phenomenon of reduction do CTZ. The analytical methodology that was developed is fast, sensible and precise, to routine analysis on pills of CTZ. The analytic curve was linear in the concentration area between 1,8 and 5,5.10 6 mol/L, with detection limit 1,7.10 7 mol/L and quantification limit in 5,6.10 7 mol/L. / Neste trabalho são abordados os estudos eletroquímicos bem como o desenvolvimento de metodologia analítica para a determinação de cetoconazol em formulações farmacêuticas com auxílio de eletrodo de pasta de carbono modificado com hemina. Os experimentos foram realizados em solução tampão Britton-Robinson (BR) no pH 2, com uma composição do eletrodo de 50% de pasta de carbono e 50% de hemina, pois apresenta a melhor resposta analítica para o referido composto. Com base nos parâmetros eletroquímicos extraídos das técnicas de voltametria cíclica, de pulso diferencial e de onda quadrada, foi possível diagnosticar algumas informações relacionadas com o mecanismo da reação como: a reversibilidade do processo, a presença ou não de processos de adsorção e também o número de elétrons envolvidos nas reações eletroquímicas. Os resultados indicaram que a reação de redução do cetoconazol é irreversível com um pico a 1,44V devido ao fenômeno de redução de CTZ. A metodologia analítica desenvolvida é rápida, sensível e precisa para a análise de rotina de comprimidos de CTZ. A curva analítica foi linear na região de concentração entre 1,8 a 5,5.10 6 mol/L, com limite de detecção de 1,7.10 7mol/L e com limite de quantificação de 5,6.10 7 mol/L.

Made available in DSpace on 2018-06-27T18:56:37Z (GMT). No. of bitstreams: 3 Flabio da Rosa Pons Junior.pdf: 1999620 bytes, checksum: e5045f0611ac73ef991604e04484fbb8 (MD5) Flabio da Rosa Pons Junior.pdf.txt: 174053 bytes, checksum: 8140591651031d4c7b893b3bc3ce8675 (MD5) Flabio da Rosa Pons Junior.pdf.jpg: 3814 bytes, checksum: 8bd8fcbd7817488781e11c3f2a9361f5 (MD5) Previous issue date: 2011-08-30 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / The fungal infections in humans occur in several ways, can this is superficial and systemic mycoses mycoses. The use of new antifungal made important progress in the treatment of different types of fungal infections. Among the drugs used to treat, there is ketoconazole, azole derivative, a synthetic molecule that acts by inhibiting biosynthesis of ergosterol molecule, exerting fungicidal. Treatment with ketoconazole requires frequent applications of the product, which causes skin irritation, the adherence to treatment. Initial studies have shown that drugs have nanocarrier improvement in selectivity, reducing side effects by modifying the release and increasing the effectiveness of the asset. This study aimed to characterize, evaluate the physical and chemical stability and antimicrobial activity of systems composed of nanoparticles or microparticles incorporated into formulations containing ketoconazole shampoo. All studies were carried out comparing ketoconazole as nanostructured and microstructured with the free form. The samples were stored under conditions of 25 ± 2 ° C, 4 ± 2 ° C and 40 ± 2 ° C and 75 ± 5% RH and exposed to UV light for 90 days and analyzed at 0, 7, 15, 30, 60 and 90 days in relation to the determination of pH, particle diameter, polydispersity index, zeta potential, rate of association and the drug dosing, antimicrobial activity and viscosity for the samples of shampoo. The average particle size for the nanocapsules was less than 370 nm, for microparticles less than 52 micrometers. All samples consist of the nanocarrier showed negative zeta potential. The values for the rate of association were 92.10% for the nanocapsules and 97.69% for the microparticles. Regarding the content of the suspensions and tested for stability, the samples comprising nanocapsules showed the loss of a smaller amount of assets (17.9% and 19.7%) in conditions of 25 ± 2 ° C and ± 4 2 ° C respectively. For formulations of shampoo made by nanocarrier systems, the same place, but with losses (9.3% and 13.6%) for the same conditions of suspension. In the analysis of antimicrobial activity, suspensions of nanocapsules had power of 98.15% and 100.25% of microparticles. Samples of shampoo were analyzed by microbiological assay sensitivity, which analyzed both qualitatively and showed that the samples have antifungal activity. The validation of analytical methodologies for the suspensions showed satisfactory results for all parameters. The results obtained, it can be concluded that the suspensions have demonstrated good stability, even when incorporated into a topical pharmaceutical vehicle, thus representing a better technological feasibility for the pharmaceutical area. / As infecções fúngicas nos seres humanos ocorrem de formas variadas, podendo tratar-se de micoses superficiais ou micoses sistêmicas. O uso de novos antifúngicos permitiu importantes progressos na terapêutica dos diferentes tipos de infecções micóticas. Dentre os fármacos utilizados para o tratamento, destaca-se o cetoconazol, derivado dos azóis, uma molécula sintética que age inibindo na biossíntese da molécula do ergosterol, exercendo ação fungicida. O tratamento com cetoconazol exige aplicações freqüentes do produto, o que provoca irritação cutânea, dificultando a adesão ao tratamento. Estudos iniciais têm demonstrado que fármacos nanocarreados apresentam melhora na seletividade, reduzindo efeitos colaterais, modificando a liberação e aumentando a eficácia do ativo. Este trabalho teve como objetivo, caracterizar, avaliar a estabilidade físico química e a atividade antimicrobiana de sistemas compostos de nanopartículas ou micropartículas contendo cetoconazol incorporadas em formulações de xampu. Todos os estudos foram realizados comparando-se o cetoconazol na forma nanoestruturada e microestruturada com a forma livre. As amostras foram armazenadas nas condições de 25 ± 2 °C, 4 ± 2 °C e 40 ± 2 °C e 75 ± 5% UR e expostas à luz UV, durante 90 dias, sendo analisadas em períodos 0, 7, 15, 30, 60 e 90 dias, em relação à determinação do pH, diâmetro de partícula, índice de polidispersão, potencial zeta, taxa de associação e doseamento do fármaco, atividade antimicrobiana e viscosidade para as amostras de xampu. O tamanho médio das partículas para as nanocápsulas foi inferior a 370 nm, para as micropartículas inferior a 52 μm. Todas as amostras compostas pelos nanocarreadores apresentaram potencial zeta negativo. Os valores para a taxa de associação foram de 92,10 % para as nanocápsulas e 97,69 % para as micropartículas. Em relação ao teor das suspensões submetidas aos testes de estabilidade, as amostras compostas por nanocápsulas foram as que apresentaram uma menor perda de quantidade do ativo (17,9 % e 19,7 %) nas condições de 25 ± 2 °C e 4 ± 2 °C respectivamente. Para as formulações de xampu compostas pelos sistemas de nanocarreadores, o mesmo ocorreu, porém com perdas de (9,3 % e 13,6 %) para as mesmas condições das suspensões. Na análise da atividade antimicrobiana, as suspensões de nanocapsulas apresentaram potência de 98,15 % e as de micropartículas 100,25 %. As amostras de xampu foram analisadas pelo ensaio microbiológico de sensibilidade, o qual analisado de forma qualitativa e demonstrou que as amostras possuem atividade antifúngica. As validações das metodologias analíticas para as suspensões apresentaram resultados satisfatórios para todos os parâmetros analisados. Através dos resultados obtidos, pode-se concluir que as suspensões demonstraram ter boa estabilidade, mesmo quando incorporadas em um veículo farmacêutico de uso tópico, representando assim, uma melhor viabilidade tecnológica para a área farmacêutica.

Submitted by MARCIA ROVADOSCHI (marciar@unifra.br) on 2018-08-16T14:17:32Z No. of bitstreams: 2 license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Dissertacao_FlabioDaRosaPonsJunior.pdf: 2017674 bytes, checksum: ce2baac29e6f32b9170ceef6e8aa57e7 (MD5) / Made available in DSpace on 2018-08-16T14:17:32Z (GMT). No. of bitstreams: 2 license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Dissertacao_FlabioDaRosaPonsJunior.pdf: 2017674 bytes, checksum: ce2baac29e6f32b9170ceef6e8aa57e7 (MD5) Previous issue date: 2011-08-30 / The fungal infections in humans occur in several ways, can this is superficial and systemic mycoses mycoses. The use of new antifungal made important progress in the treatment of different types of fungal infections. Among the drugs used to treat, there is ketoconazole, azole derivative, a synthetic molecule that acts by inhibiting biosynthesis of ergosterol molecule, exerting fungicidal. Treatment with ketoconazole requires frequent applications of the product, which causes skin irritation, the adherence to treatment. Initial studies have shown that drugs have nanocarrier improvement in selectivity, reducing side effects by modifying the release and increasing the effectiveness of the asset. This study aimed to characterize, evaluate the physical and chemical stability and antimicrobial activity of systems composed of nanoparticles or microparticles incorporated into formulations containing ketoconazole shampoo. All studies were carried out comparing ketoconazole as nanostructured and microstructured with the free form. The samples were stored under conditions of 25 ± 2 ° C, 4 ± 2 ° C and 40 ± 2 ° C and 75 ± 5% RH and exposed to UV light for 90 days and analyzed at 0, 7, 15, 30, 60 and 90 days in relation to the determination of pH, particle diameter, polydispersity index, zeta potential, rate of association and the drug dosing, antimicrobial activity and viscosity for the samples of shampoo. The average particle size for the nanocapsules was less than 370 nm, for microparticles less than 52 micrometers. All samples consist of the nanocarrier showed negative zeta potential. The values for the rate of association were 92.10% for the nanocapsules and 97.69% for the microparticles. Regarding the content of the suspensions and tested for stability, the samples comprising nanocapsules showed the loss of a smaller amount of assets (17.9% and 19.7%) in conditions of 25 ± 2 ° C and ± 4 2 ° C respectively. For formulations of shampoo made by nanocarrier systems, the same place, but with losses (9.3% and 13.6%) for the same conditions of suspension. In the analysis of antimicrobial activity, suspensions of nanocapsules had power of 98.15% and 100.25% of microparticles. Samples of shampoo were analyzed by microbiological assay sensitivity, which analyzed both qualitatively and showed that the samples have antifungal activity. The validation of analytical methodologies for the suspensions showed satisfactory results for all parameters. The results obtained, it can be concluded that the suspensions have demonstrated good stability, even when incorporated into a topical pharmaceutical vehicle, thus representing a better technological feasibility for the pharmaceutical area. / As infecções fúngicas nos seres humanos ocorrem de formas variadas, podendo tratar-se de micoses superficiais ou micoses sistêmicas. O uso de novos antifúngicos permitiu importantes progressos na terapêutica dos diferentes tipos de infecções micóticas. Dentre os fármacos utilizados para o tratamento, destaca-se o cetoconazol, derivado dos azóis, uma molécula sintética que age inibindo na biossíntese da molécula do ergosterol, exercendo ação fungicida. O tratamento com cetoconazol exige aplicações freqüentes do produto, o que provoca irritação cutânea, dificultando a adesão ao tratamento. Estudos iniciais têm demonstrado que fármacos nanocarreados apresentam melhora na seletividade, reduzindo efeitos colaterais, modificando a liberação e aumentando a eficácia do ativo. Este trabalho teve como objetivo, caracterizar, avaliar a estabilidade físico–química e a atividade antimicrobiana de sistemas compostos de nanopartículas ou micropartículas contendo cetoconazol incorporadas em formulações de xampu. Todos os estudos foram realizados comparando-se o cetoconazol na forma nanoestruturada e microestruturada com a forma livre. As amostras foram armazenadas nas condições de 25 ± 2 °C, 4 ± 2 °C e 40 ± 2 °C e 75 ± 5% UR e expostas à luz UV, durante 90 dias, sendo analisadas em períodos 0, 7, 15, 30, 60 e 90 dias, em relação à determinação do pH, diâmetro de partícula, índice de polidispersão, potencial zeta, taxa de associação e doseamento do fármaco, atividade antimicrobiana e viscosidade para as amostras de xampu. O tamanho médio das partículas para as nanocápsulas foi inferior a 370 nm, para as micropartículas inferior a 52 μm. Todas as amostras compostas pelos nanocarreadores apresentaram potencial zeta negativo. Os valores para a taxa de associação foram de 92,10 % para as nanocápsulas e 97,69 % para as micropartículas. Em relação ao teor das suspensões submetidas aos testes de estabilidade, as amostras compostas por nanocápsulas foram as que apresentaram uma menor perda de quantidade do ativo (17,9 % e 19,7 %) nas condições de 25 ± 2 °C e 4 ± 2 °C respectivamente. Para as formulações de xampu compostas pelos sistemas de nanocarreadores, o mesmo ocorreu, porém com perdas de (9,3 % e 13,6 %) para as mesmas condições das suspensões. Na análise da atividade antimicrobiana, as suspensões de nanocapsulas apresentaram potência de 98,15 % e as de micropartículas 100,25 %. As amostras de xampu foram analisadas pelo ensaio microbiológico de sensibilidade, o qual analisado de forma qualitativa e demonstrou que as amostras possuem atividade antifúngica. As validações das metodologias analíticas para as suspensões apresentaram resultados satisfatórios para todos os parâmetros analisados. Através dos resultados obtidos, pode-se concluir que as suspensões demonstraram ter boa estabilidade, mesmo quando incorporadas em um veículo farmacêutico de uso tópico, representando assim, uma melhor viabilidade tecnológica para a área farmacêutica.

Drug discovery contains many strategies, one of which is the privileged scaffold strategy. This strategy incorporates a similar molecular framework within a collection of drug-like compounds in order to target various receptors. These scaffolds are useful to drug discovery scientists since they assist in developing libraries as well as demonstrating selectivity to a target. Oxazolidinones are 5-membered heterocyclic compound containing an oxygen, a nitrogen, and a carbonyl within the ring system. In this present study, the oxazolidinone structure was utilized as a privileged scaffold to target serotonin receptor 7 (5-HT7), mutated BRAF kinase (BRAFV6000E), Bruton’s tyrosine kinase (BTK), and Cyclin-dependent protein kinase 4 and 6 (CDK4/6). Aryl piperazines and piperidines were integrated as another privileged scaffold to support the selectivity towards 5-HT7, while aminopyrimidines were employed to increase binding against the kinases. The 5-HT7 oxazolidinone series was successfully synthesized and analyzed against 5-HT7; however, the three kinase oxazolidinone series were not successfully synthesized.Candidemia is the most common bloodstream infection in the U.S. and is associated with high patient mortality rates. Due to prolonged and/or repeated clinical use of current antifungal agents, drug-resistant fungi have become an emerging problem. There is a need for new antifungals to assist in overcoming drug resistant fungi. In the second project outlined in this work, a series of ketoconazole analogs were designed and successfully synthesized. The ketoconazole analogs exhibited antifungal activity; however, no clear trends were observed in this series. Overall, the series exhibited less CYP3A4 inhibition than the parent compound, ketoconazole. / Pharmaceutical Sciences

<p>In hyperparathyroidism (HPT) raised serum concentrations of ionized calcium is caused by increased secretion of parathyroid hormone (PTH) by parathyroid tumors. Active vitamin D, 1α,25-dihydroxyvitamin D₃, is known to suppress PTH secretion and to reduce proliferation of parathyroid tumor cells.</p><p>The aim of this thesis was to examine expression of vitamin D hydroxylating enzymes, regulating the activation and inactivation of vitamin D and to study effects of vitamin D analogues, in parathyroid tumors and breast cancer.</p><p>The vitamin D activating enzyme, CYP27B1/25-hydroxyvitamin D₃ 1α-hydroxylase (1α-hydroxylase) and the vitamin D inactivating enzyme CYP24A1/25-hydroxyvitamin D₃ 24-hydroxylase (24-hydroxylase) were expressed in parathyroid tumors and breast cancer. </p><p>The parathyroid tumors had raised expression levels of 1α-hydroxylase and reduced levels of 24-hydroxylase in comparison to normal parathyroid glands, indicating ability for endogenous activation of vitamin D. The expression of 1α-hydroxylase may be of therapeutic advantage for local activation of non-1α-hydroxylated vitamin D analogues in tumor cells, thereby reducing unwanted hypercalcemic effects. </p><p>Three of five selected low calcemic vitamin D analogues had as efficient PTH suppressing effect, in bovine parathyroid cells, as three vitamin D analogues used clinically for treatment of secondary HPT.</p><p>The non-1α-hydroxylated vitamin D analogue EB1285 showed antiproliferative and PTH suppressive effects as well as transcriptional activity in parathyroid and breast tumor cells, respectively.</p><p>Ketoconazole, an inhibitor of vitamin D hydroxylating enzymes, suppressed PTH secretion and potentiated the effect of vitamin D analogues. Combined treatment with vitamin D analogues and specific 24-hydroxylase inhibitors may be important for future therapy. </p>

In hyperparathyroidism (HPT) raised serum concentrations of ionized calcium is caused by increased secretion of parathyroid hormone (PTH) by parathyroid tumors. Active vitamin D, 1α,25-dihydroxyvitamin D3, is known to suppress PTH secretion and to reduce proliferation of parathyroid tumor cells. The aim of this thesis was to examine expression of vitamin D hydroxylating enzymes, regulating the activation and inactivation of vitamin D and to study effects of vitamin D analogues, in parathyroid tumors and breast cancer. The vitamin D activating enzyme, CYP27B1/25-hydroxyvitamin D3 1α-hydroxylase (1α-hydroxylase) and the vitamin D inactivating enzyme CYP24A1/25-hydroxyvitamin D3 24-hydroxylase (24-hydroxylase) were expressed in parathyroid tumors and breast cancer. The parathyroid tumors had raised expression levels of 1α-hydroxylase and reduced levels of 24-hydroxylase in comparison to normal parathyroid glands, indicating ability for endogenous activation of vitamin D. The expression of 1α-hydroxylase may be of therapeutic advantage for local activation of non-1α-hydroxylated vitamin D analogues in tumor cells, thereby reducing unwanted hypercalcemic effects. Three of five selected low calcemic vitamin D analogues had as efficient PTH suppressing effect, in bovine parathyroid cells, as three vitamin D analogues used clinically for treatment of secondary HPT. The non-1α-hydroxylated vitamin D analogue EB1285 showed antiproliferative and PTH suppressive effects as well as transcriptional activity in parathyroid and breast tumor cells, respectively. Ketoconazole, an inhibitor of vitamin D hydroxylating enzymes, suppressed PTH secretion and potentiated the effect of vitamin D analogues. Combined treatment with vitamin D analogues and specific 24-hydroxylase inhibitors may be important for future therapy.

Post-traumatic stress disorder (PTSD), an anxiety disorder, may develop after experiencing or witnessing a severe traumatic event. Characteristic symptoms include hyper arousal and amnesic symptoms, while volume reductions in the hippocampus of these patients appear correlated with illness severity and the degree of cognitive deficit. Stress-induced increases in plasma cortisol have been implicated in this apparent atrophy of the hippocampus, although, clinical studies have described a marked suppression of plasma cortisol in PTSD. Given this hypocortisolemia, the basis for hippocampal neuro degeneration and cognitive decline remains unclear. While stress-related hippocampal structural changes have been linked to the neurotoxic effects of glucocorticoids and glutamate. NMDA-NO pathways have been found to play a causal role in anxiety-related behaviours. Prior exposure to trauma is an important risk factor for PTSD. In most instances the disorder becomes progressively worse over time, possibly with a delayed onset, suggesting a role for sensitization. In this study a time-dependent sensitization (TDS) model was used to induce PTSD-like sequelae in male Spraque-Dawley rats. The TDS-model is based on exposure to acute stressors, with a reminder of the trauma, in the form of re-exposure to one of the acute stressor, seven days later. NOS-activity, NMDA receptor parameters (Bmax and Kd) and GABA levels in the hippocampus of rats, as well as plasma corticosterone levels were determined 21 days after exposure to the TDS-model. Increased levels of corticosterone were measured after exposure to acute stress, but these levels were found to decrease below basal levels 21 days after the re-exposure, thus mimicking glucocorticoid levels in patients with PTSD. These findings may also imply that the increase in glucocorticoid levels after stress exposure is only the initial step in a cascade of events leading to neuronal damage in the hippocampus. This study also found that stress-restress evoked a long-lasting increase in hippocampal NOS activity that was accompanied by a reactive down-regulation of hippocampal NMDA receptors and dysregulation of inhibitory GABA pathways. Subsequently, animals were chronically treated with certain pharmacological agents prior to exposure to the TDS-model to determine possible approaches for inhibiting the induction of PTSD. Pre-treatment with fluoxetine, currently indicated in the treatment of PTSD. and the nNOS inhibitor, 7-nitroindazole, had no effect on the increased NOS activity measured 21 days afler exposure to the TDS-model. Pre-treatment with the iNOS inhibitor, aminoguanidine, however, resulted in inhibition of the observed increase in hippocampal NOS-activity, implicating a possible role for the iNOS isoform in the etiology of PTSD. Treatment with ketoconazole, an inhibitor of glucoccfticoid synthesis, resulted in inhibition of the increase in NOS-activity observed after exposure to TDS-stress, thus indicating a possible link between stress glucocorticoid-release and NO synthesis. These perturbations may have importance in explaining the increasing evidence for stress-related hippocampal degenerative pathology and cognitive deficits seen in patients with PTSD. Uncovering and understanding the role of NO in PTSD will hopefully lead to the development of selective therapeutic agents in disorders like PTSD. as well as providing a better understanding of basic processes underlying normal and pathological neuronal functions in PTSD. / Thesis (Ph.D. (Pharmacology))--North-West University, Potchefstroom Campus, 2004.

Post-traumatic stress disorder (PTSD), an anxiety disorder, may develop after experiencing or witnessing a severe traumatic event. Characteristic symptoms include hyper arousal and amnesic symptoms, while volume reductions in the hippocampus of these patients appear correlated with illness severity and the degree of cognitive deficit. Stress-induced increases in plasma cortisol have been implicated in this apparent atrophy of the hippocampus, although, clinical studies have described a marked suppression of plasma cortisol in PTSD. Given this hypocortisolemia, the basis for hippocampal neuro degeneration and cognitive decline remains unclear. While stress-related hippocampal structural changes have been linked to the neurotoxic effects of glucocorticoids and glutamate. NMDA-NO pathways have been found to play a causal role in anxiety-related behaviours. Prior exposure to trauma is an important risk factor for PTSD. In most instances the disorder becomes progressively worse over time, possibly with a delayed onset, suggesting a role for sensitization. In this study a time-dependent sensitization (TDS) model was used to induce PTSD-like sequelae in male Spraque-Dawley rats. The TDS-model is based on exposure to acute stressors, with a reminder of the trauma, in the form of re-exposure to one of the acute stressor, seven days later. NOS-activity, NMDA receptor parameters (Bmax and Kd) and GABA levels in the hippocampus of rats, as well as plasma corticosterone levels were determined 21 days after exposure to the TDS-model. Increased levels of corticosterone were measured after exposure to acute stress, but these levels were found to decrease below basal levels 21 days after the re-exposure, thus mimicking glucocorticoid levels in patients with PTSD. These findings may also imply that the increase in glucocorticoid levels after stress exposure is only the initial step in a cascade of events leading to neuronal damage in the hippocampus. This study also found that stress-restress evoked a long-lasting increase in hippocampal NOS activity that was accompanied by a reactive down-regulation of hippocampal NMDA receptors and dysregulation of inhibitory GABA pathways. Subsequently, animals were chronically treated with certain pharmacological agents prior to exposure to the TDS-model to determine possible approaches for inhibiting the induction of PTSD. Pre-treatment with fluoxetine, currently indicated in the treatment of PTSD. and the nNOS inhibitor, 7-nitroindazole, had no effect on the increased NOS activity measured 21 days afler exposure to the TDS-model. Pre-treatment with the iNOS inhibitor, aminoguanidine, however, resulted in inhibition of the observed increase in hippocampal NOS-activity, implicating a possible role for the iNOS isoform in the etiology of PTSD. Treatment with ketoconazole, an inhibitor of glucoccfticoid synthesis, resulted in inhibition of the increase in NOS-activity observed after exposure to TDS-stress, thus indicating a possible link between stress glucocorticoid-release and NO synthesis. These perturbations may have importance in explaining the increasing evidence for stress-related hippocampal degenerative pathology and cognitive deficits seen in patients with PTSD. Uncovering and understanding the role of NO in PTSD will hopefully lead to the development of selective therapeutic agents in disorders like PTSD. as well as providing a better understanding of basic processes underlying normal and pathological neuronal functions in PTSD. / Thesis (Ph.D. (Pharmacology))--North-West University, Potchefstroom Campus, 2004.

Cetoconazol é um agente antifúngico que possui ação tópica e sistêmica, podendo ser incorporado em diferentes formas farmacêuticas. Como exemplo, pode-se citar o xampu de cetoconazol, que é efetivo no tratamento da dermatite seborréica e pitiríase versicolor. É reconhecido que o cetoconazol, nas formas farmacêuticas xampu e solução, rapidamente altera a coloração se tornando avermelhado. A exposição de fármacos à radiação pode influenciar a estabilidade da formulação, levando a modificações nas propriedades físico-químicas do produto. O objetivo deste trabalho foi avaliar a fotoestabilidade do cetoconazol em xampu e solução. As formulações foram expostas à radiação UV-A (352 nm), UV-C (254 nm) e luz diurna. Métodos foram desenvolvidos e validados para a determinação quantitativa do cetoconazol: cromatografia líquida de alta eficiência e ensaio microbiológico utilizando o método de cilindros em placa. Estudos comparativos entre xampu de cetoconazol e xampu de cetoconazol contendo produtos de degradação foram feitos para avaliar a atividade antifúngica e a segurança biológica in vivo (teste de Draize) e in vitro (teste de citotoxicidade). Os resultados demonstraram diminuição na atividade antifúngica, mas não demonstraram alteração na segurança biológica. Os métodos utilizados para análise do cetoconazol (ensaio microbiológico e CLAE) demonstraram ser lineares, precisos e exatos, sendo úteis no controle de qualidade do fármaco. Os resultados indicam alteração do cetoconazol em presença da luz. Dois produtos de degradação foram isolados e identificados: 1-acetil-4-{4-[2-(2-clorofenil)-2-(1H-imidazolil-1- metil)-1,3-dioxolanil-4-metoxi]fenil}piperazina e 1-acetil-4-{4-[2-(4-clorofenil)-2- (1H-imidazolil-1-metil)-1,3-dioxolanil-4-metoxi]fenil}piperazina. Conseqüentemente, adequada proteção da luz deve ser adotada durante armazenamento das duas formas farmacêuticas contendo o fármaco. / Ketoconazole is an antifungal agent with topic and systemic action and can be incorporated into several dosage forms. As an example, it could be mentioned ketoconazole shampoo, which is effective against seborrhoeic dermatitis and pityriasis versicolor. It is remarkable that ketoconazole is rapidly altered in shampoo and solution dosage forms, since its colour turns into red. Exposure of a drug to radiation can influence the stability of the formulation, leading to changes in the physicochemical properties of the product. The aim of this work was to assess the photostability of ketoconazole in shampoo and solution. The formulations were exposed to UV-A (352 nm) and UV-C (254 nm) radiations and daylight. Methods were developed and validated for the quantitative determination of ketoconazole: high performance liquid chromatography and microbiological assay using the cylinder-plate method. Comparative studies between ketoconazole shampoo and ketoconazole shampoo containing degradation products were conducted to evaluated the antifungal activity and biological reactivity in vivo (Draize test) and in vitro (cytotoxity test). The results showed a decrease in antifungal activity but not an alteration on the biological reactivity. The methods used for ketoconazole analysis (microbiological assay and HPLC) were linear, precise and accurate, providing valuable methods for the quality control of this drug. The results indicate alteration in ketoconazole in presence of light. Two photodegradation products were isolated and identified: 1-acetyl-4-{4-[2-(2-chlorophenyl)-2-(1H-imidazol- 1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}piperazine and 1-acetyl-4-{4-[2- (4-chlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl} piperazine. Consequently, adequate light protection should be adopted for storage of these two dosage forms containing the drug.

Cetoconazol é um agente antifúngico que possui ação tópica e sistêmica, podendo ser incorporado em diferentes formas farmacêuticas. Como exemplo, pode-se citar o xampu de cetoconazol, que é efetivo no tratamento da dermatite seborréica e pitiríase versicolor. É reconhecido que o cetoconazol, nas formas farmacêuticas xampu e solução, rapidamente altera a coloração se tornando avermelhado. A exposição de fármacos à radiação pode influenciar a estabilidade da formulação, levando a modificações nas propriedades físico-químicas do produto. O objetivo deste trabalho foi avaliar a fotoestabilidade do cetoconazol em xampu e solução. As formulações foram expostas à radiação UV-A (352 nm), UV-C (254 nm) e luz diurna. Métodos foram desenvolvidos e validados para a determinação quantitativa do cetoconazol: cromatografia líquida de alta eficiência e ensaio microbiológico utilizando o método de cilindros em placa. Estudos comparativos entre xampu de cetoconazol e xampu de cetoconazol contendo produtos de degradação foram feitos para avaliar a atividade antifúngica e a segurança biológica in vivo (teste de Draize) e in vitro (teste de citotoxicidade). Os resultados demonstraram diminuição na atividade antifúngica, mas não demonstraram alteração na segurança biológica. Os métodos utilizados para análise do cetoconazol (ensaio microbiológico e CLAE) demonstraram ser lineares, precisos e exatos, sendo úteis no controle de qualidade do fármaco. Os resultados indicam alteração do cetoconazol em presença da luz. Dois produtos de degradação foram isolados e identificados: 1-acetil-4-{4-[2-(2-clorofenil)-2-(1H-imidazolil-1- metil)-1,3-dioxolanil-4-metoxi]fenil}piperazina e 1-acetil-4-{4-[2-(4-clorofenil)-2- (1H-imidazolil-1-metil)-1,3-dioxolanil-4-metoxi]fenil}piperazina. Conseqüentemente, adequada proteção da luz deve ser adotada durante armazenamento das duas formas farmacêuticas contendo o fármaco. / Ketoconazole is an antifungal agent with topic and systemic action and can be incorporated into several dosage forms. As an example, it could be mentioned ketoconazole shampoo, which is effective against seborrhoeic dermatitis and pityriasis versicolor. It is remarkable that ketoconazole is rapidly altered in shampoo and solution dosage forms, since its colour turns into red. Exposure of a drug to radiation can influence the stability of the formulation, leading to changes in the physicochemical properties of the product. The aim of this work was to assess the photostability of ketoconazole in shampoo and solution. The formulations were exposed to UV-A (352 nm) and UV-C (254 nm) radiations and daylight. Methods were developed and validated for the quantitative determination of ketoconazole: high performance liquid chromatography and microbiological assay using the cylinder-plate method. Comparative studies between ketoconazole shampoo and ketoconazole shampoo containing degradation products were conducted to evaluated the antifungal activity and biological reactivity in vivo (Draize test) and in vitro (cytotoxity test). The results showed a decrease in antifungal activity but not an alteration on the biological reactivity. The methods used for ketoconazole analysis (microbiological assay and HPLC) were linear, precise and accurate, providing valuable methods for the quality control of this drug. The results indicate alteration in ketoconazole in presence of light. Two photodegradation products were isolated and identified: 1-acetyl-4-{4-[2-(2-chlorophenyl)-2-(1H-imidazol- 1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}piperazine and 1-acetyl-4-{4-[2- (4-chlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl} piperazine. Consequently, adequate light protection should be adopted for storage of these two dosage forms containing the drug.