Ruthenium(II) phosphine/diimine/picolinate complexes: Inorganic compounds as agents against tuberculosis

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

Preparation of polymeric micelles for use as carriers of tuberculostatic drugs

Purpose: This paper focuses on the characterization of polymeric micelle-forming tuberculostatic prodrugs and the antimycobacterial activity of these prodrugs.Method: By the condensation of hydroxymethylpyrazinamide, isoniazid and rifampin with free carboxyl groups on the copolymer poly(ethyleneglycol)-poly(aspartic acid), micelle-forming carrier-drug conjugates were obtained. These micelles were characterized by dynamic light scattering, to measure the micelle diameter; by acid-base titration, to determine the percentage of carboxylic groups occupied by the tuberculostatic; by Sudan III solubility tests, to estimate the critical micelle concentration (CMC); and visual control and spectrophotometric measurement, to determine the stability of micelles. These micelles were tested in vitro against several Mycobacterium strains.Results: As expected, the size and distribution of the micelle-forming tuberculostatic prodrugs found to be small (78.2nm, 84.2nm and 98.9 nm) while the level of the drug conjugated was high (65.02-85.7%). Furthermore, the micelles were stable in vitro, exhibiting a low level of CMC and stronger antimycobacterial activity than the original drugs.Conclusion: the results demonstrate that polymeric micelles can be used as efficient carriers for drugs, which alone, exhibit undesired pharmacokinetics, poor solubility, and low stability. The synthesized micelle-forming tuberculostatic prodrugs opens a perspective of alternative prodrugs that prolong action and decrease the toxicity of the tuberculostatic drugs of choice.

Detection of mixed microbial biofilms on central venous catheters removed from Intensive care Unit Patients

Cateteres venosos centrais inseridos em pacientes internados em unidade de terapia intensiva foram avaliados por métodos microbiológicos (cultura semi-quantitativa) e microscopia eletrônica de varredura a fim de detectar adesão microbiana e correlacionar com a cultura de sangue. Durante o período de estudo, foram avaliados 59 pacientes com cateter venoso central. A idade dos pacientes, sexo, sítio de inserção e tempo de permanência do cateter foram anotados. O cateter era de poliuretano não tunelizado e de único lúmen. O sangue para cultura foi coletado no momento da remoção do cateter. de 63 pontas de cateteres, 30 (47,6%) foram colonizadas e a infecção encontrada em 5 (23,8%) cateteres. A infecção foi mais prevalente em 26 pacientes (41,3%) com cateteres inseridos em veia subclávia do que nos 3 (3,2%) inseridos em veia jugular. A infecção foi observada com mais freqüência em cateteres com tempo de permanência maior do que sete dias. Os microrganismos isolados incluíram 32 estafilococos coagulase-negativa (29,7%), 61 bactérias Gram-negativas (52,9%), 9 estafilcocos coagulase-positiva (8,3%) e 3 leveduras (2,7%). Como agentes causais de infecções em unidade de terapia intensiva foram isolados E. aerogenes, P. aeruginosa, A. baumannii. Os antimicrobianos com maior atividade in vitro contra as bactérias Gram-negativas foram o imipenem e contra as Gram-positivas vancomicina, cefepime, penicilina, rifampicina e tetraciclina. As análises por microscopia eletrônica de varredura revelaram biofilmes sobre a superfície de todos os cateteres examinados.

Stpahylococcus aureus biofilms on central venous haemodialysis catheters

As infecções devido a biofilmes bacterianos são comuns em pacientes sob tratamento em hemodiálise. Neste estudo, 16 pacientes (7 homens, 9 mulheres, de 22 a 81 anos, média 50 anos de idade), com um total de 25 cateteres de hemodiálise (3 de triplo-lúmen e 22 de duplo-lúmen) de poliuretano inseridos em veia subclávia foram estudados. Os cateteres permaneceram no local de 3 a 91 dias (média de 47 dias). Os cateteres foram removidos devido ao: mau funcionamento (44%), suspeita de infecção relacionada ao cateter (20%), viabilidade de um acesso permanente (16%), remoção acidental (12%), sinais e sintomas de infecção no local da inserção do cateter (4%) e contaminação exógena (4%). Culturas positivas de ponta foram observadas em sete cateteres (28%), concomitantemente com três culturas positivas de sangue. Das culturas de sangue foram identificados Staphylococcus aureus (12%) e de uma das conexões foi isolado S. aureus. Biofilmes foram observados sobre todas as pontas de cateteres. Os S. aureus isolados do sangue e cateter (ponta e conexão) eram resistentes a pencilina e sensíveis a azitromicina, ciprofloxacina, clindamicina, cloranfenicol, gentamicina, oxacilina, rifampicina, sulfametoxazole, tetraciclina e vancomicina. As cepas de S. aureus isoladas de sangue, ponta de cateter e conexão foram consideradas idênticas devido à coincidência do perfil de sensibilidade. E similaridade genética, avaliada por meio de ribotipagem.

Antimicrobial resistance of aerobes and facultative anaerobes isolated from the oral cavity

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Características clínico-demográficas de pacientes hospitalizados com tuberculose no Brasil, no período de 1994 a 2004

OBJETIVO: Descrever as características clínico-demográficas de pacientes com tuberculose internados no Hospital Nestor Goulart Reis, de Américo Brasiliense (SP). MÉTODOS: Investigação epidemiológica através de um estudo observacional, retrospectivo, descritivo, conforme as fichas de internações de pacientes com tuberculose, ocorridas no período de 1994 a 2004. RESULTADOS: O número de pacientes com tuberculose durante o período foi de 1787: 117 (7%) eram do sexo feminino; 1670 (93%) eram do sexo masculino; e 1215 (68%) eram separados, solteiros ou viúvos. O grau de escolaridade mais freqüente foi o de 1º grau incompleto (74%). A faixa etária mais atingida (de 30 a 50 anos) totalizou 63%. O alcoolismo esteve associado em 61%. A profissão mais freqüente foi a de lavrador (25%) e 70% dos pacientes estavam desempregados. A forma clínica mais freqüente foi a pulmonar (92%). O índice de alta por indicação médica foi de 60%. em 34% dos casos foi utilizado um esquema terapêutico diferente do usual (rifampicina, isoniazida e pirazinamida). CONCLUSÕES: O perfil dos internos para tratamento da tuberculose neste hospital indicou que estes tinham necessidades diferenciadas: dificuldades para cuidar de si mesmos (os casos sociais) e necessidade de terapia diferenciada do esquema usual, o que justificou as internações. O Hospital cumpriu importante papel social no tratamento e orientação destes pacientes.

Haematological and biochemical alterations in leprosy patients already treated with dapsone and MDT

Dapsone (DDS) is useful in the treatment of a number of inflammatory conditions which are characterized by neutrophil infiltration. It is the drug of choice for the treatment of leprosy and prophylaxis of malaria. Haematological side effects of methaemoglobinaemia and haemolysis have been long recognized. However, the frequency and severity of these side effects in patients already treated with DDS as a single drug or as part of a multidrug therapy (MDT) have not been well documented. We report herein an investigation of the effect of dapsone long-term treatment on the haematological and biochemical alterations in leprosy patients undergoing dapsone as a single drug (DDS group) or as part of a multidrug therapy in combination with rifampin and clofazimine (MDT group). Methaemoglobinaemia and haemolytic anaemia were the principal side effects observed. Reticulocytes were found to be elevated (> 1.5%) in 90% of the patients. Heinz bodies were also detected (6.6% of the patients). The osmotic fragility test showed a reduction in cell resistance and in the evaluation of white cells a severe eosinophilia was found. Hepatic, pancreatic and renal evaluation by the determination of biochemical parameters showed rare and occasional changes of no apparent clinical significance. We conclude that haematological side effects of dapsone are significant even at doses currently used to treat leprosy (100 mg/day) and that rifampin and clofazimine do not increase the incidence of these effects during long-term treatment.

Horseradish peroxidase-catalyzed oxidation of rifampicin: Reaction rate enhancement by co-oxidation with anti-inflammatory drugs

The tuberculostatic drug rifampicin has been described as a scavenger of reactive species. Additionally, the recent demonstration that oral therapy with a complex of rifampicin and horseradish peroxidase (HRP) was more effective than rifampicin alone, in an animal model of experimental leprosy, suggested the importance of redox reactions involving rifampicin and their relevance to the mechanism of action. Hence, we studied the oxidation of rifampicin catalyzed by HRP, since this enzyme may represent the prototype of peroxidation-mediated reactions. We found that the antibiotic is efficiently oxidized and that rifampicin-quinone is the product, in a reaction dependent on both HRP and hydrogen peroxide. The steady-state kinetic constants Km app (101±23 mmol/l), Vmax app (0.78±0.09 μmol/l·s-1) and kcat (5.1±0.6 s-1) were measured (n=4). The reaction rate was increased by the addition of co-substrates such as tetramethylbenzidine, salicylic acid, 5-aminosalicylic acid and paracetamol. This effect was explained by invoking an electron-transfer mechanism by which these drugs acted as mediators of rifampicin oxidation. We suggested that this drug interaction might be important at the inflammatory site. © 2005 Pharmaceutical Society of Japan.

Estudo terapêntico comparando a associação de rifampicina, ofloxacina e minociclina com a associação rifampicina, clofazimina e dapsona em pacientes multibacilar

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Virulência de linhagens de Rhodococcus equi isoladas de linfonodo de suínos e javalis (Sus scrofa) de abatedouros

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Rodococose equina: uma revisão com ênfase na fisiopatogenia e tratamento

The rhodococcosis affects humans and animals. Equine are the most important species for rhodococcosis, which is considered the most debilitating disease in the creation of foals, leading to a mortality rates greater than 50% in this category. The disease is caused by Rhodococcus equi, a bacteria considered as a soil-born opportunistic microorganism, intracellular and ubiquitous. The disease in horses is manifested mainly in the form of pyogranulomatous pneumonia and less often in the form of enteric disorders and / or joint disorders. Transmission occurs mainly by ingestion of contaminated food and water, and inhalation in contaminated environment. The organism has mechanisms of evasion of the immune system, maintain viable in inside phagocytic cells, and induces piogranulomatous infections, leading to lesions of difficult treatment using conventional antimicrobials. Lipophilic drugs with good intracellular activity are required to successful treatment. The conventional treatment for foals is based on the combination of erythromycin and rifampin. However, there is a growing concern about the emergence of resistant strains, which makes increasingly studies on the development of alternative antimicrobials for therapy