Made available in DSpace on 2014-06-11T19:22:21Z (GMT). No. of bitstreams: 0 Previous issue date: 2006-07-17Bitstream added on 2014-06-13T19:27:32Z : No. of bitstreams: 1 derosa_hj_me_arafcf.pdf: 478559 bytes, checksum: f1d5bcb78f493bd18ca8a97c083e3088 (MD5) / Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) / Universidade Estadual Paulista (UNESP) / Propp / Este trabalho teve como objetivo estudar os efeitos da rifampicina (RMP) sobre os parâmetros farmacocinéticos da isoniazida (INH), sobre a produção de seus metabólitos e sobre a sua hepatotoxicidade. Foram utilizados 140 ratos (Wistar, machos, peso médio 250g) que receberam, por gavagem, durante 21 dias: Grupo I - água estéril (n = 20); Grupo II - INH (100mg/Kg) (n = 50); Grupo III - RMP (100mg/Kg) (n = 20) e Grupo IV- INH (100mg/Kg) + RMP (100mg/Kg) ( n= 50). Anteriormente ao início do experimento, o sangue de todos os animais foi coletado pela cauda para determinação da atividade sérica de AST e ALT, cujos valores foram considerados como basais. No 21o do experimento os animais foram sacrificados por decapitação e o material biológico obtido foi utilizado para a determinação da atividade de AST e ALT e para a análise dos parâmetros farmacocinéticos da INH nos grupos II e IV. A cinética da isoniazida e de seus metabólitos foi investigada com base na relação concentração plasmática x tempo a partir de amostras seriadas de sangue em 10 tempos diferentes (0; 15þ; 30þ; 45þ; 60þ; 1,5h; 3h; 6h; 12h; e 24h); para cada tempo de coleta foram empregados 5 ratos (5 replicatas). As amostras de soro foram desproteinizadas com ácido tricloroacético 10%, derivatizeda com cinamaldeído 1% e analisada por HPLC.... / The aim of the present study was to evaluate the hepatotoxicity, pharmacokinetic parameters and biotransformation of isoniazid when rats were treated with isoniazid (INH); rifampicin (RMP); and INH + RMP. Daily doses of the tuberculostatic drugs were administrated intragastrically to the animals (Wistar rats) for one period of 21 days as follow: sterile water (group I, control); INH (100mg/Kg) (group II), RMP (100mg/Kg) (group III); INH (100mg/Kg) + RMP (100mg/Kg) (group IV). The serum levels of the biomarkers aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were determined before the administration of the drugs (basal) and after the 21 days treatments. On day 21, blood samples were obtained before and 15þ; 30þ; 45þ; 60þ; 1,5; 3h; 6h; 12h and 24 hours after the dose. (five animals for each point). The blood samples were deproteinized with 10% trichloroacetic acid, derivatized by 1% cinnamaldehyde and analyzed by liquid chromatograph. For the determination of the acetylated metabolites acetylisoniazid (AcINH) and acetylhydrazine (AcHz) a previous hydrolysis with 6 M hydrochloride acid was performed. The results are presented as mean and SEM. The pharmacokinetic parameter of the INH and its metabolites AcINH and hydrazine (Hz) were compared between the groups (p < 0.05, Student t-test)...(Complete abstract, click electronic address below).

[pt] Nas últimas décadas, o câncer ganhou uma dimensão maior, convertendo-se em um evidente problema de saúde pública mundial. Nesse sentido, o presente trabalho visou desenvolver compostos de coordenação que sejam menos tóxicos e mais eficazes, do que os atualmente usados no tratamento clinico, e que causem o mínimo de efeitos colaterais ao paciente no tratamento quimioterápico contra o câncer. Para isso foram sintetizados dois ligantes binucleantes um simétrico, já anteriormente sintetizado por outro grupo de pesquisa, e outro não-simétrico, este inédito. Ambos os ligantes contém como átomos doadores N, O, advindos de braços pendentes contendo grupos, tais como, amida, amina, piridina e fenol. A partir deles foram sintetizados quatro complexos homonucleares e dois heteronucleares. A escolha dos metais visou minimizar a citotóxicidade ao organismo e por isso foram usados metais fisiológicos, encontrados em diversas metaloenzimas do corpo humano. Todos os compostos sintetizados foram caracterizados por diversas técnicas instrumentais de análise. Além disso, os compostos sintetizados neste trabalho e em um trabalho anterior foram testados em linhagens celulares de câncer de pulmão (A549) e de próstata (PC3) e de mama (MCF-7). Dentre os compostos testados, um deles, a saber 10 apresentou ser bastante citotóxico. Os valores de IC50 encontrados foram aproximadamente 1,3 micrômetros , 1,4 micrômetros e 1,8 micrômetros na linhagem A549, MCF-7 e PC3 , respectivamente, É importante destacar que o complexo 10 se mostrou aproximadamente cem vezes mais ativos que a própria cisplatina frente às linhagens A549 e MCF-7, tornando este estudo extremamente promissor. Nesse estudo foi possível comprovar o potencial terapêutico de compostos de coordenação na terapia do câncer destacando o caráter promissor deste ramo da ciência. Este trabalho realizou ainda um estudo a respeito da aplicação das hidrazonas na fabricação de OLEDs, utilizando o ligante H3L1 como componente emissor. / [en] In the last few decades, cancer has reached a new level, becoming an evident global public health issue. In that direction, the present work aims at developing less toxic and more effective coordination compounds, compared to the ones that are currently being used in clinical treatment, which could lead to minimal side effects to patients in chemotherapy. Therefore, two binucleating ligands were synthesized. A symmetrical one, which was previously created by other research group and a unique nonsymmetrical one. Both ligands contain N and O as donor atoms, deriving from pending arms containing groups such as amide, amine, pyridine and phenol. From them, four homonuclear and two heteronuclear complexes were synthesized. The purpose of chosen metals was to minimize the cytotoxicity to the body. Therefore, physiological metals were used, that are found in numerous metalloenzymes in human body. All synthesized compounds were characterized by several instrumental analysis techniques. Also, the compounds synthesized in this work and in a previous one have been tested in cell lines of lung cancer (A549), prostate cancer (PC3) and breast cancer (MCF-7). Among tested compounds, one compound, 10 showed a high cytotoxicity. The found IC50 values were about 1,3 micrometers, 1,4 micrometers and 1,8 micrometers in the A549, MCF-7 and PC3 line, respectively. It is important to note that the complex 10 proved almost one hundred times more active than the very front of cisplatin and A549 lines MCF-7, making this extremely promising study. In this study, it was possible to confirm the therapeutic potential of coordination compounds in cancer therapy, highlighting the promising nature of this branch of science. This study also conducted a study on the application of hydrazones in the manufacture of OLEDs using the H3L1 binder as emitting component.

Conselho Nacional de Desenvolvimento CientÃfico e TecnolÃgico / FundaÃÃo de Amparo a CiÃncia e Tecnologia / Coccidioidomicose à uma micose sistÃmica que acomete o homem e outros animais domÃsticos e silvestres, causada pelo fungo dimÃrfico geofÃlico Coccidioides posadasii. Nos Ãltimos anos, a melhoria dos mÃtodos de diagnÃstico micolÃgico e o aumento da ocorrÃncia de doenÃas imunossupressoras causaram grande impacto na incidÃncia das micoses profundas e oportunistas no mundo. Apesar da existÃncia de terapias antifÃngicas eficazes contra a coccidioidomicose, a busca por novas drogas para o tratamento desta doenÃa se faz necessÃria. O objetivo desse estudo foi determinar o efeito inibitÃrio, in vitro, e o mecanismo de aÃÃo dos anÃlogos quÃmicos da isoniazida, isolados e em combinaÃÃo com os antifÃngicos anfotericina B (AMB) e itraconazol (ITC), frente a cepas de Coccidioides posadasii (n=12). Para isso 12 cepas de C.posadasii, foram repicadas em Ãgar dextrose batata e utilizadas na realizaÃÃo dos testes de sensibilidade frente ao agente antituberculose isoniazida (INH) e seus anÃlogos quÃmicos. Os ensaios foram conduzidos por meio do teste de macrodiluiÃÃo em caldo ou definiÃÃo da concentraÃÃo inibitÃria mÃnima (CIM) e o sinergismo foi avaliado pelo mÃtodo do tabuleiro. Os anÃlogos quÃmicos inibiram o crescimento de todas as cepas de C. posadasii testadas isoladamente, com valores de CIM para cada composto que variaram de 100 a 400 Âg/mL, para os anÃlogos P3-[Nâ-(1- (4-methoxifeniletilideno) isonicotinohidrazida] P5- [Nâ- (1-m-tolileilidene) isonicotinohidrazida] e P6- [Nâ-(1-(4-metilfenil) etilideno) isonicotinohidrazida], de 25 a 100 Âg/mL para a PACT- Nâ- (1-feniletilideno) isonicotinohidrazida e de 0,0625 a 0,125 Âg/mL para AMB e 0,125 a 0,5 Âg/mL para ITC. Quanto a combinaÃÃo entre as drogas antifÃngicas e os anÃlogos quÃmicos da droga isoniazida, todos foram capazes de inibir o crescimento in vitro das cepas de C. posadasii. Sinergismo foi detectado em 8 combinaÃÃes nÃo sendo observado nenhum antagonismo em nenhuma delas. Os anÃlogos da isoniazida apresentaram valores de CIM de 2, 4, 8, 16, 32 vezes superior à atividade da droga antituberculose padrÃo. A extraÃÃo dos esterÃis e a permeabilidade da membrana fÃngica foram averiguadas, respectivamente, por saponificaÃÃo com aquecimento e por meio da leitura do sobrenadante da suspensÃo fÃngica em comprimento de onda de 260 e 280 nm. Todos os compostos inibiram o crescimento in vitro das cepas de C. posadasii. Foi observado que os anÃlogos da isoniazida isolados e em combinaÃÃo com antifÃngicos foram capazes de causar reduÃÃo do teor de ergosterol celular; apenas os anÃlogos P3 e P6 foram capazes de alterar a permeabilidade da membrana plasmÃtica nas condiÃÃes testadas. Em conclusÃo, os resultados mostram que os anÃlogos derivados da isoniazida possuem atividade inibitÃria frente a C. posadasii

Submitted by Fabio Sobreira Campos da Costa (fabio.sobreira@ufpe.br) on 2016-08-18T14:46:04Z No. of bitstreams: 2 license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) PRISCILA ROCHA. DISSERTAÇÃO.DIGITAL.pdf: 900577 bytes, checksum: 21461faf83aca3f0a9ae61d40c9c66e3 (MD5) / Made available in DSpace on 2016-08-18T14:46:04Z (GMT). No. of bitstreams: 2 license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) PRISCILA ROCHA. DISSERTAÇÃO.DIGITAL.pdf: 900577 bytes, checksum: 21461faf83aca3f0a9ae61d40c9c66e3 (MD5) Previous issue date: 2015-08-26 / Objetivo: Descrever as reações adversas decorrentes do uso dos fármacos antituberculose do novo esquema preconizado pelo Ministério da Saúde (rifampicina, isoniazida, pirazinamida e etambutol) utilizando comprimidos em dose fixa combinada. Métodos: Estudo descritivo utilizando dados coletados em prontuários médicos de pacientes com tuberculose pulmonar tratados com esquema básico no serviço de referência para tuberculose da Paraíba no período de 2010-2014. Resultados: A amostra foi composta por 257 pacientes com tuberculose pulmonar e houve reação adversa em 71 pacientes (27,63%) totalizando 118 eventos. Esses eventos dividiram-se em reações menores e maiores respectivamente 47,9% e 43,7%, e em 8,5% dos casos, ocorreram ambas as reações. O sistema mais comprometido foi o gastrointestinal em 68,4%, seguido pelo osteoarticular em 13,56%. A hepatotoxicidade foi isoladamente a reação adversa mais comum (30,5%). A toxicidade visual ocorreu em apenas um paciente (0,38%). Houve necessidade de suspender o tratamento em 7,39% e de troca de esquema terapêutico em 1,95%. A frequência de reações adversas observada com o novo esquema foi inferior a de outros estudos nacionais e semelhante aos estudos que utilizaram o esquema antigo. Conclusão: As reações adversas foram principalmente alterações gastrointestinais, sendo a mais comum a hepatotoxicidade. Houve apenas um caso de alteração visual. Na maioria dos casos, não houve necessidade de suspensão nem troca do tratamento. / Objective: To describe the adverse reactions due to the use of antituberculosis drugs under the new regimen recommended by the Health Ministry (rifampicin, isoniazid, pyrazinamide and ethambutol) using tablets in fixed doses combination. Methods: A descriptive study using data collected from medical records of patients with pulmonary tuberculosis treated with basic outline reference service of tuberculosis in Paraíba during the period from 2010 to 2014. Results: The sample consisted of 257 patients with pulmonary tuberculosis, and adverse effects occurred in 71 patients (27.63%) totalizing 118 events. These events were divided into smaller and bigger reactions respectively 47.9% and 43.7%, and in 8.5% of the cases both reactions occurred. The most compromised system was the gastrointestinal at 68.4%, followed by osteoarticular at 13.56%. The hepatotoxicity alone was the most common adverse reaction (30.5%). The visual toxicity occurred in only one patient (0.38%). It was necessary to discontinue the treatment in 7.39% and change the regimen for 1.95%. The frequency of adverse reactions observed with the new scheme was lower than other national studies and similar to studies that used the old scheme. Conclusion: The adverse reactions were mainly gastrointestinal disorders, being hepatotoxicity the most common one, there was only one case of visual change. In most cases there was no need to suspend neither to change the treatment.

The World Health Organization (WHO) estimated that eight million new cases of tuberculosis (TB) occur every year and that one-third of the world’s population is infected with Mycobacterium tuberculosis (M. tuberculosis). With the increase in HIV/AIDS in the 1980’s, an increase in transmission of TB led to an increase in TB incidence. A study showed that South African adults (ages 15 to 49) will suffer 278 154 deaths between 2008 and 2017 if current control measures are continued. A M. tuberculosis strain that is resistant to isoniazid (INH) and rifampicin (RIF) used in the treatment of TB is known as a multi-drug resistant (MDR-TB) strain. In extensively drugresistant tuberculosis (XDR-TB) the M. tuberculosis strains are not only resistant to INH, RIF and any one of the fluoroquinolones but to at least one of the three injectable second-line drugs such as amikacin or kanamycin. Unfortunately, many people with XDR-TB will die because it is virtually impossible to formulate an effective treatment before the resistance pattern of the M. tuberculosis strain has been identified. Bacteriological culture is considered the diagnostic gold standard and can identify mycobacteria in over 80% of TB cases, with a specificity of over 98%. However, culturing the mycobacteria takes 4 to 6 weeks and makes diagnosis and treatment a prolonged process. In this study 60 patients suspected of TB disease, from the Anti-retroviral (ARV) clinic at the Tshwane District Hospital (TDH) were collected from October 2008 to April 2009. This study evaluated the use of the QuantiFERON-TB GOLD ELISA assay in a high burden setting. Tshwane District Hospital, South Africa. The sensitivity and specificity of the QFT assay in the clinic were 30% (9/30) and 63% (19/30) respectively when compared to the gold standard culture results. Analysis suggested that the sensitivity of the QuantiFERON assay is determined by a limiting patient CD4 value of between 150 and 200. Real-time PCR assays were used for rapid identification of Mycobacterium spp and to determine the presence of isoniazid and rifampicin resistant genes of M. tuberculosis strains. The real-time PCR assay identified 28% (17/60) M. tuberculosis, 2% (1/60) M. kansasii and 70% (42/60) of the isolates Mycobacterium spp negative. No M. avium were detected. The 17 M. tuberculosis positive specimens were further analysed for the presence of INH and RIF resistance genes. All 17 specimens had either no mutation or one or more mutations at the specific gene targets (rpo1, rpo2, katG and inhA). This study showed several possibilities for the use of both an immunological assay as well as molecular methods for the diagnosis of TB. This study suggested that in terms of routine diagnosis of TB in high HIV prevalence settings the QFT test should be used with caution. Realtime PCR for both detection and identification showed useful results and can be used together with culture results to improve turnaround times for TB diagnosis. Copyright / Dissertation (MSc)--University of Pretoria, 2010. / Medical Microbiology / unrestricted

This study compare immunological and virological outcomes in antiretroviral therapy naïve patients exposed to Isoniazid prevention treatment.Medical records of antiretroviral naïve patients managed in the public sector from 1st January 2006 to 31st December 2006 were analysed.Multivariate analysis of variance showed that each treatment group achieved statistically significant increases in CD4+ cell count and viral load decay at each follow-up time point. Pairwise post hoc contrast tests showed patients in NVPipt-past group and EFVipt-past group to have superior immunological and virological outcomes respectively. / Health Studies / M.A. (Public health)

This study compare immunological and virological outcomes in antiretroviral therapy naïve patients exposed to Isoniazid prevention treatment.Medical records of antiretroviral naïve patients managed in the public sector from 1st January 2006 to 31st December 2006 were analysed.Multivariate analysis of variance showed that each treatment group achieved statistically significant increases in CD4+ cell count and viral load decay at each follow-up time point. Pairwise post hoc contrast tests showed patients in NVPipt-past group and EFVipt-past group to have superior immunological and virological outcomes respectively. / Health Studies / M.A. (Public health)

Collaborative TB/HIV management is essential to prevent and treat TB among HIV-positive TB patients, and to ensure that HIV-positive TB patients are detected and treated appropriately. This quantitative, descriptive, contextual study identified problems encountered during the implementation of TB case detection among HIV-positive individuals in one Ethiopian hospital. During December 2012, 300 checklists were completed about HIV-positive patients’ TB/HIV collaborative management, as reflected in their files. Only 60.2% of HIV-positive patients, who should have received Isoniazid preventive treatment (IPT), were placed on this treatment. X-rays and laboratory examinations of sputum samples were not done according to the Ethiopian guidelines. Most TB patients’ initial screening was done by nurses, not doctors, and included only symptom screening without CD4 count considerations. Managers and healthcare personnel should improve IPT, especially for those with early HIV infection and timely effective treatment for those suffering from TB, before complications arise / Health Studies / Health Studies / M.A. (Public Health)

Collaborative TB/HIV management is essential to prevent and treat TB among HIV-positive TB patients, and to ensure that HIV-positive TB patients are detected and treated appropriately. This quantitative, descriptive, contextual study identified problems encountered during the implementation of TB case detection among HIV-positive individuals in one Ethiopian hospital. During December 2012, 300 checklists were completed about HIV-positive patients’ TB/HIV collaborative management, as reflected in their files. Only 60.2% of HIV-positive patients, who should have received Isoniazid preventive treatment (IPT), were placed on this treatment. X-rays and laboratory examinations of sputum samples were not done according to the Ethiopian guidelines. Most TB patients’ initial screening was done by nurses, not doctors, and included only symptom screening without CD4 count considerations. Managers and healthcare personnel should improve IPT, especially for those with early HIV infection and timely effective treatment for those suffering from TB, before complications arise / Health Studies / Health Studies / M.A. (Public Health)

Thesis (MScMed (Biomedical Sciences. Molecular Biology and Human Genetics))--University of Stellenbosch, 2005. / Tuberculosis (TB) is one of the most serious infectious diseases known to mankind, with devastating outcomes in the poorest countries in the world. Isoniazid is the cornerstone of all first-line anti-TB regimens. Forty-eight percent of all drug resistant TB isolates in the Western Cape are Isoniazid mono-resistant, and the majority of these isolates belong to the Beijing/W strain family. Currently, the known molecular mechanisms which confer Isoniazid resistance in these isolates are attributed to mutations within the katG gene and account for up to 70% of all drug resistant TB isolates. Risk factors for the development of Isoniazid resistance can be attributed to either pathogen or host related factors and may partially account for the other 30% of Isoniazid resistant isolates. In this study, three aspects which may contribute to Isoniazid resistance were investigated: DNA repair in the bacterium, host response to anti-TB treatment and socioeconomic factors. A PCR based dot-blot strategy was used to screen for previously reported missense mutations in the mutT2, Rv3908 and ogt DNA repair genes of different strains of M. tuberculosis. All the Beijing isolates (drug resistant and susceptible), in contrast to the Atypical Beijing strains and other dominant strain families, exhibited missense mutations in all three base excision repair genes. It is therefore speculated that defects in the DNA repair genes (mutator phenotypes) of the Beijing isolates may contribute to the development of drug resistance and hence, may account for the large proportion of isolates that are Isoniazid mono-resistant. A novel method, based on primer extension, was initially developed to screen the NAT2 gene and then used to type individuals into fast, intermediate and slow acetylators of Isoniazid. The newly develop method, which is sensitive and accurate, improves the detection of Single Nucleotide Polymorphisms within the NAT2 gene, in contrast to the traditionally used methods. Utilising this method, it was found that the combination of fast and intermediate acetylators was significantly associated with Isoniazid resistance in the study community. This finding may have an important impact on TB control programmes, since it may allow for the administration of higher dosages of Isoniazid to fast/intermediate acetylators and a lower dose for slow acetylators. Clinical factors (compliance and retreatment after cure) and socio-economic factors (education, employment and income) were found to be significantly associated with the development of INH resistance. Diagnostic delay was also found to be a risk factor, since it may allow for transmission of TB during this period. The HIV prevalence in the study population is low and subsequently HIV status was not associated with the development of INH resistance. This study indicates that a combination of risk factors, both pathogen and host related, are involved in the development of Isoniazid resistance.