Bioavailability of repeated oral administration of MDL 100,240, a dual inhibitor of angiotensin-converting enzyme and neutral endopeptidase in healthy volunteers.

BACKGROUND: MDL 100,240 (pyrido[2,1-a] [2]benzazepine-4-carboxylic acid,7-[[2-(acetylthio)-1-oxo-3-phenylpropyl]amino]-1,2,3,4,6,7,8, 12b-octahydro-6-oxo, [4S-[4alpha,7alpha(R(*)),12bbeta]]-) is a molecule possessing an inhibiting ability on both angiotensin converting enzyme (ACE) and neutral endopeptidase, the enzyme responsible for atrial natriuretic peptide (ANP) degradation. Such a dual mechanism of action presents a potential clinical interest for the treatment of hypertension and congestive heart failure. OBJECTIVES: To evaluate the bioavailability of MDL 100,240 and its accumulation over repeated oral administration, using ACE inhibition as a surrogate for plasma drug level and determining its profile after oral and i.v. administration. METHODS: First, in an open, one-period, single-dose study, the ACE inhibition profile was characterised following a 12.5 mg MDL 100,240 i.v. infusion. Second, in a three-group, parallel, randomised, double-blind study, each group of four subjects received q.d., over 8 days, 2.5, 10 or 20 mg of MDL 100,240 orally. The ACE inhibition profile was determined on day 1 and day 8. Trough plasma ACE was measured on days 2, 3 and 4. The recovery of ACE activity was monitored up to 72 h after the last dose of MDL 100,240. RESULTS: ACE inhibition profile was similar on day 1 and day 8, and trough inhibition remained unchanged after the 8 days of treatment with 10 mg or 20 mg. Following repeated 2.5-mg ingestion, trough inhibition increased from 33% to 44% after the eighth dose. The oral bioavailability of MDL 100,240 was estimated at 85%, not statistically different from 100%. The accumulation ratio at steady state was estimated at 112%. Expressing the accumulation ratio in terms of half-life, a t(1/2) of 0.31 days or 7. 5 h was estimated. CONCLUSION: MDL 100,240 (oral solution) has a good bioavailability, as estimated by ACE inhibition, and no drug accumulation seems to occur over 8 days with the 10-mg and 20-mg doses, but a slight rise in the trough level is observed with the 2. 5-mg dose.

Differentiation of heroin and cocaine using dual-energy CT-an experimental study.

OBJECTIVE: To evaluate if heroin and cocaine can be distinguished using dual-energy CT. MATERIALS AND METHODS: Twenty samples of heroin and cocaine at different concentrations and standardized compression (SC) were scanned in dual-energy mode on a newest generation Dual Energy 64-row MDCT scanner. CT number, spectral graphs, and dual-energy index (DEI) were evaluated. Results were prospectively tested on six original samples from a body packer. Wilcoxon's test was used for statistical evaluation. RESULTS: Values are given as median and range. Under SC, the CT number of cocaine samples (-29.87 Hounsfield unit (HU) [-125.85; 16.16 HU]) was higher than the CT number of heroin samples (-184.37 HU [-199.81; -159.25 HU]; p < 0.01). Slope of spectral curves for cocaine was -2.36 HU/keV [-7.15; -0.67 HU/keV], and for heroin, 1.75 HU/keV [1.28; 2.5 HU/keV] (p < 0.01). DEI was 0.0352 [0.0081; 0.0528] for cocaine and significantly higher than for heroin samples (-0.0127 [-0.0097; -0.0159]; p < 0.001). While CT number was inconclusive, all six original packs were correctly classified after evaluation of the spectral curve and DEI. In contrast to the CT number, slope of the spectral curve and DEI were independent of concentration and compression. CONCLUSION: The slope of the spectral curve and the DEI from dual-energy CT data can be used to distinguish heroin and cocaine in vitro; these results are independent of compression and concentration in the measured range.

A dual functional origin of transfer in the ICEclc genomic island of Pseudomonas knackmussii B13.

Genomic islands (GEIs) are large DNA segments, present in most bacterial genomes, that are most likely acquired via horizontal gene transfer. Here, we study the self-transfer system of the integrative and conjugative element ICEclc of Pseudomonas knackmussii B13, which stands model for a larger group of ICE/GEI with syntenic core gene organization. Functional screening revealed that unlike conjugative plasmids and other ICEs ICEclc carries two separate origins of transfer, with different sequence context but containing a similar repeat motif. Conjugation experiments with GFP-labelled ICEclc variants showed that both oriTs are used for transfer and with indistinguishable efficiencies, but that having two oriTs results in an estimated fourfold increase of ICEclc transfer rates in a population compared with having a single oriT. A gene for a relaxase essential for ICEclc transfer was also identified, but in vivo strand exchange assays suggested that the relaxase processes both oriTs in a different manner. This unique dual origin of transfer system might have provided an evolutionary advantage for distribution of ICE, a hypothesis that is supported by the fact that both oriT regions are conserved in several GEIs related to ICEclc.

O uso do campo MARC 9XX para controle bibliográfico institucional

Utilização do conceito de controle bibliográfico definido pela IFLA e do formato MARC 21 bibliográfico para gerenciar a produção científica, técnica, artística e administrativa de uma instituição de ensino superior. Definição de campo MARC 9XX e de campos associados para registro das informações bibliográficas dos documentos de produção intelectual institucional. Contribuição da IES para o controle bibliográfico nacional.

Biomechanical concept and clinical outcome of dual mobility cups.

Dual mobility cup systems in total hip arthroplasty consist of a metal back with a non-constrained liner, in which a constrained standard head articulates. While superior stability of such implants in comparison with standard total hip replacements is assumed, it is the purpose of this study to outline the biomechanical concept of dual mobility cups and to describe implant survival and dislocation rate based on the series published in the English-speaking and Francophone literature. A growing body of evidence indicates reduced dislocation rates in primary and revision total hip arthroplasty and in selected tumour cases. The limited availability of studies evaluating long-term implant survival and existing concerns with regard to increased wear rates and aseptic loosening, leads to the conclusion that such implants have to be used with prudence, particularly in standard primary hip arthroplasty and in young patients.

How can a dual oriT system contribute to efficient transfer of an integrative and conjugative element?

Integrative and conjugative elements (ICEs) are particularly interesting model systems for horizontal gene transfer, because they normally reside in an integrated state in the host chromosome but can excise and self-transfer under particular conditions, typically requiring exquisite regulatory cascades. Despite important advances in our understanding of the transfer mechanisms of a number of ICE, many essential details are lacking. Recently we reported that ICEclc, a 103 kb ICE of Pseudomonas knackmussii B13, has two active origins of transfer (oriTs), which is very much unlike conjugative plasmids that usually employ a single oriT. We discuss here how this dual oriT system could function and how it actually could have presented an evolutionary advantage for ICEclc distribution.

Phase-sensitive dual-inversion recovery for accelerated carotid vessel wall imaging.

OBJECTIVES: Dual-inversion recovery (DIR) is widely used for magnetic resonance vessel wall imaging. However, optimal contrast may be difficult to obtain and is subject to RR variability. Furthermore, DIR imaging is time-inefficient and multislice acquisitions may lead to prolonged scanning times. Therefore, an extension of phase-sensitive (PS) DIR is proposed for carotid vessel wall imaging. METHODS: The statistical distribution of the phase signal after DIR is probed to segment carotid lumens and suppress their residual blood signal. The proposed PS-DIR technique was characterized over a broad range of inversion times. Multislice imaging was then implemented by interleaving the acquisition of 3 slices after DIR. Quantitative evaluation was then performed in healthy adult subjects and compared with conventional DIR imaging. RESULTS: Single-slice PS-DIR provided effective blood-signal suppression over a wide range of inversion times, enhancing wall-lumen contrast and vessel wall conspicuity for carotid arteries. Multislice PS-DIR imaging with effective blood-signal suppression is enabled. CONCLUSIONS: A variant of the PS-DIR method has successfully been implemented and tested for carotid vessel wall imaging. This technique removes timing constraints related to inversion recovery, enhances wall-lumen contrast, and enables a 3-fold increase in volumetric coverage at no extra cost in scanning time.

Thrombin-sensitive dual fluorescence imaging and therapeutic agent for detection and treatment of synovial inflammation in murine rheumatoid arthritis.

We have developed a thrombin-sensitive polymeric photosensitizer prodrug (T-PS) to selectively image and eradicate inflammatory lesions in rheumatoid arthritis (RA). Thrombin is a serine protease up-regulated in synovial tissues of rheumatoid arthritis (RA) patients. T-PS consists of a polymeric backbone, to which multiple photosensitizer (PS) units are tethered via short thrombin-cleavable peptide linkers. Fluorescence emission and phototoxicity of the prodrug are efficiently quenched due to the interaction of neighboring photosensitizer units. The prodrug is passively delivered to the inflammation site via the enhanced permeability and retention (EPR) effect. Subsequent site-selective proteolytic cleavage of the peptide linkers restores its photoactivity by increasing the mutual distance between PS. Whole animal imaging in murine collagen-induced arthritis, an experimental model of RA revealed a dose-dependent fluorescence increase in arthritic paws after systemic prodrug injection. In addition, administration of T-PS resulted in much higher fluorescence selectivity for arthritic joints as compared to the free PS. Irradiation of the arthritic joints induced light dose dependent phototoxic effects such as apoptosis, vascular damage and local hemorrhage. Long-term observations showed complete regression of the latter. Irradiated non-arthritic tissues or non-irradiated arthritic tissues showed no histological effects after photodynamic therapy with T-PS. This illustrates that T-PS can localize inflammatory lesions with excellent selectivity and induce apoptosis and vascular shut down after irradiation.

Aplicação de fungicidas via água de irrigação por aspersão para o controle da ferrugem-do-feijoeiro-comum

Este trabalho objetivou avaliar os fungicidas bitertanol, mancozeb, benomyl e iprodione nas doses de 175, 1.600, 350 e 750 g i.a./ha, respectivamente, aplicados via irrigação, no controle da ferrugem (Uromyces appendiculatus) do feijoeiro (Phaseolus vulgaris L.). Em parcelas de 12 x 12 m, foram realizadas quatro aplicações de cada fungicida, por meio de aplicador portátil de produtos químicos, a intervalos de seis a dez dias, lâmina de água de 3,4 mm, e seis minutos de aplicação. A produção de grãos (kg/ha) e a porcentagem de infecção foram de 1.550,0 e 6,6; 1.238,0 e 20,5; 1.358,0 e 26,9; 1.014,0 e 42,0; e 1.088,0 e 52,2 com bitertanol, mancozeb, benomyl, iprodione e testemunha, respectivamente. Os resultados mostraram a viabilidade da fungigação e a eficácia do bitertanol no controle da ferrugem-do- feijoeiro.

Controle químico da ferrugem (Hemileia vastatrix Berk & Br.) do cafeeiro através de diferentes esquemas de aplicação

O presente trabalho foi desenvolvido com o objetivo de testar os diferentes esquemas de controle químico da ferrugem do cafeeiro disponíveis, durante o período de 1994 a 1996 em São Sebastião do Paraíso, MG. Os tratamentos foram constituídos por esquemas preventivos, baseados em fungicidas cúpricos (oxicloreto de cobre e óxido cuproso), curativos, baseados em fungicidas sistêmicos (grupo dos triazois) e mistos (associação de esquemas curativos e preventivos). As datas de aplicação foram previamente fixadas. Os resultados obtidos demonstraram que: a) a aplicação de esquemas de controle por meio de datas pré-fixadas tem permitido a elevação da ferrugem ao final do seu ciclo; b) o fungicida triadimenol 1,5%, associado ao inseticida dissulfoton 7,5%, granulado, aplicado ao solo no mês de dezembro, na dosagem de 40 kg/ha do produto comercial, foi o único tratamento que manteve baixos índices de ferrugem durante o ciclo da doença; c) os tratamentos aplicados por meio do sistema radicular, triadimenol e cyproconazole, foram beneficiados pela associação com o inseticida dissulfoton.

Efeito de roçadas no controle do alho-macho (Sisyrinchium platense johnst.)

O alho-macho (Sisyrinchium platense Johnst.) é uma planta que ocorre especialmente em campos de boa qualidade localizados ao sul do Rio Grande do Sul, em solos negros de textura argilosa, imperfeitamente drenados, que foram alterados por algum cultivo, e onde a pecuária, sozinha ou associada à agricultura, tem uma expressão econômica relevante. Por não ser consumida pelos animais, a planta é favorecida na competição com as espécies forrageiras nativas, podendo restringir o potencial de ganhos da pecuária regional. Visando avaliar o efeito de uma, duas e quatro roçadas no controle desta espécie, foi realizado, em uma área de campo natural, um experimento de blocos completos casualizados, distribuídos em duas situações topográficas, por um período de três anos. Verificou-se que uma, duas ou quatro roçadas, em áreas úmidas, reduziram, em média, 55% da cobertura da folhagem do alho-macho, ao passo que em áreas mais secas, uma ou duas roçadas reduziram, em média, 30,7% da cobertura desta espécie.

Produtividade, estabilidade e adaptabilidade de cultivares de amendoim em três níveis de controle de doenças foliares

O objetivo deste trabalho foi avaliar o desempenho produtivo, a estabilidade da produção e a adaptabilidade de três cultivares de amendoim em diversos ambientes típicos de cultivo e severidade das doenças foliares que podem ocorrer no Estado de São Paulo. Foram avaliadas as cultivares Tatu, Florunner e IAC-Caiapó sob três níveis de controle de doenças foliares, em experimentos onde as doenças predominantes foram a mancha-preta (Cercosporidium personatum) e a ferrugem (Puccinia arachidis). Os experimentos utilizaram delineamento em parcelas subdivididas com quatro repetições, em subparcelas de quatro linhas de 5 m de comprimento. As parcelas principais consistiram de controle químico com duas ou quatro pulverizações, e um tratamento sem controle das doenças. Estimaram-se, também, a estabilidade e adaptabilidade entre os ambientes, dentro de cada nível de controle das doenças. A cultivar Florunner mostrou as maiores respostas ao controle químico, em relação à produtividade e adaptabilidade aos ambientes onde as doenças foram bem controladas. As cultivares Tatu e IAC-Caiapó apresentaram comportamentos semelhantes em resposta ao controle das doenças e superaram a cultivar Florunner em produtividade, na qual a pressão das doenças foi maior. A cultivar IAC-Caiapó mostrou produtividade, maior que a da cultivar Tatu e desempenho produtivo mais estável (previsível) do que as outras cultivares, nos três níveis de controle das doenças.

Fitomassa de adubos verdes e controle de plantas daninhas em diferentes densidades populacionias de leguminosas

O objetivo deste trabalho foi avaliar a fitomassa de calopogônio, mucuna-preta, mucuna-rajada, feijão-de-porco, guandu de porte alto, Crotalaria spectabilis e C. breviflora sob diferentes densidades de semeadura (10, 20, 40, 80 e 160 sementes viáveis m-2), e o crescimento de plantas daninhas nessas densidades, em área de tabuleiros costeiros. O experimento foi desenvolvido de maio a agosto de 1996, no Campo Experimental "Antônio Martins" (EMDAGRO/Embrapa-CPATC), em Lagarto, SE. O número de plantas vivas na floração (NPVF) e a matéria seca da parte aérea das leguminosas (MSPA) foram determinados quando, em cada espécie, cerca de 50% das plantas floresceram. Maiores incrementos de MSPA, em resposta ao adensamento populacional, foram observados em C. spectabilis e C. breviflora, seguidas pelo calopogônio, mucuna-preta e mucuna-rajada. Em relação ao feijão-de-porco, a resposta foi negativa, enquanto com o guandu não houve influência. Quanto ao NPVF, as respostas ao adensamento foram lineares e positivas em C. spectabilis, C. breviflora e calopogônio, e quadráticas com ponto de máxima em feijão-de-porco, guandu e mucuna-rajada. Embora nenhum modelo tenha sido ajustado para expressar a relação entre NPVF e adensamento na semeadura de mucuna-preta, a sobrevivência dessa espécie foi reduzida em todas as densidades. Maiores inibições de plantas daninhas ocorreram nas parcelas de mucuna-preta e feijão-de-porco.