Levamisole (Lms) is an anthelminthic drug with immunomodulatory activity. Chagas disease (CD) is caused by Trypanosoma cruzi and there is very low access to the drugs available, benznidazole (Bz) and ...nifurtimox, both far from ideal. In a drug-repurposing strategy to test potential activity as antiparasitic and immunomodulatory agent for CD, Lms was assayed on acute T. cruzi murine infection, alone and in co-administration with Bz. During protocol standardization, 100 and 10 mpk of Bz given for five consecutive days resulted in parasitaemia suppression and 100% animal survival only with the highest dose. Flow cytometry showed that both optimal (100 mpk) and suboptimal (10 mpk) doses of Bz equally decreased the plasma levels of cytokines commonly elevated in this acute infection model. Lms alone (10-0.5 mpk) did not decrease parasitaemia nor mortality rates. Co-administration was investigated using the suboptimal dose of Bz and different doses of Lms. While Bz 10 mpk did not alter parasitaemia, the combo partially reduced it but only slightly promoted animal survival. This effect could be related to Th1-response modulation since interleukin-6 and interferon-γ were higher after treatment with the combo.
Prior investigations showed that increased levels of cyclic AMP down-regulate lung inflammatory changes, stimulating the interest in phosphodiesterase (PDE)4 as therapeutic target. Here, we described ...the synthesis, pharmacological profile and docking properties of a novel sulfonamide series (5 and 6a-k) designed as PDE4 inhibitors. Compounds were screened for their selectivity against the four isoforms of human PDE4 using an IMAP fluorescence polarized protocol. The effect on allergen- or LPS-induced lung inflammation and airway hyper-reactivity (AHR) was studied in A/J mice, while the xylazine/ketamine-induced anesthesia test was employed as a behavioral correlate of emesis in rodents. As compared to rolipram, the most promising screened compound, 6a (LASSBio-448) presented a better inhibitory index concerning PDE4D/PDE4A or PDE4D/PDE4B. Accordingly, docking analyses of the putative interactions of LASSBio-448 revealed similar poses in the active site of PDE4A and PDE4C, but slight unlike orientations in PDE4B and PDE4D. LASSBio-448 (100 mg/kg, oral), 1 h before provocation, inhibited allergen-induced eosinophil accumulation in BAL fluid and lung tissue samples. Under an interventional approach, LASSBio-448 reversed ongoing lung eosinophilic infiltration, mucus exacerbation, peribronchiolar fibrosis and AHR by allergen provocation, in a mechanism clearly associated with blockade of pro-inflammatory mediators such as IL-4, IL-5, IL-13 and eotaxin-2. LASSBio-448 (2.5 and 10 mg/kg) also prevented inflammation and AHR induced by LPS. Finally, the sulfonamide derivative was shown to be less pro-emetic than rolipram and cilomilast in the assay employed. These findings suggest that LASSBio-448 is a new PDE4 inhibitor with marked potential to prevent and reverse pivotal pathological features of diseases characterized by lung inflammation, such as asthma.
RESUMO Este artigo analisa os projetos de arquitetura contemporânea referentes a novos museus e sua relação com a demanda pela repatriação de acervos museológicos. A metodologia baseia-se no estudo ...do projeto arquitetônico do Grande Museu Egípcio (GME) - ainda em fase de consolidação - em diálogo com as experiências do Museu da Acrópole, em Atenas, e do Museu Real do Benim. Localizado a cerca de dois quilômetros das Pirâmides de Gizé, o GME está sendo construído com padrões de excelência para acondicionar e expor suas coleções egiptológicas. Seu desenvolvimento foi fruto de uma competição internacional de arquitetura promovida pelo governo egípcio, que selecionou três projetos finalistas: Rizzi, Himmelblau e Peng. Entendemos que essas propostas podem ser interpretadas a partir de três figuras importantes que nortearam o desenvolvimento de formas arquitetônicas contemporâneas: a tumba, o templo e a pirâmide. Consideramos que o projeto do GME está vinculado ao processo de consolidação da estruturação museal egípcia, que pode se relacionar aos pedidos de repatriação (ou mesmo empréstimo) de acervos museológicos, empreendidos desde 2002 no país pelo arqueólogo egípcio Zahi Hawass. Acreditamos que o caso do GME, assim como os outros exemplos citados, contribui para desarticular o argumento da falta de condições para armazenamento e pesquisa dos acervos museológicos.
ABSTRACT This article analyzes contemporary architecture projects for new museums and their relationship with the demand for the repatriation of museum collections. The methodology is based on the study of the architectural design of the Great Egyptian Museum (GEM) - still under development - in dialogue with the experiences of the Acropolis Museum, in Athens, and the Royal Museum of Benin. Located about two kilometers away from the Pyramids of Giza, the GEM is being built according to the international excellence standards to store and display its Egyptological collections. Its development was the result of an international architecture competition promoted by the Egyptian government, which selected three finalist projects: Rizzi, Himmelblau, and Peng. We understand that these proposals can be interpreted from three important figures that guided the development of contemporary architectural forms: the tomb, the temple, and the pyramid. We consider that the GEM project is linked to the consolidation process of the Egyptian museal structure, which may be related to the requests for repatriation (or even loan) of museum collections undertaken since 2002 in the country by the Egyptian archaeologist Zahi Hawass. We believe that the GEM project, like the other examples cited, contributes to dismantle the argument of the lack of conditions for storage and research of museum collections.
Neuropathy is a serious complication of diabetes that has a significant socioeconomic impact, since it frequently demands high levels of health care consumption and compromises labor productivity. ...Recently, LASSBio-1471 (3) was demonstrated to improve oral glucose tolerance, reduce blood glucose levels, and display an anti-neuropathy effect in a murine streptozotocin-induced diabetes model. In the present work, we describe the design, synthesis, solubility, plasma stability, and pharmacological evaluation of novel sulfonylhydrazone derivatives (referred to herein as compounds 4-9), which were designed by molecular modification based on the structure of the prototype LASSBio-1471 (3). Among the compounds tested, better plasma stability was observed with 4, 5, and 9 in comparison to compounds 6, 7, and 8. LASSBio-1773 (7), promoted not only hypoglycemic activity but also the reduction of thermal hyperalgesia and mechanical allodynia in a murine model of streptozotocin-induced diabetic neuropathic pain.
Purpose
The aim of this study was to identify in vivo phase I metabolites of five psychoactive substances:
N
-ethylpentylone, ethylone, methylone, α-PVP and 4-CDC, using the in house developed ...experimental set-up zebrafish (
Danio rerio
) water tank (ZWT). High-resolution mass spectrometry allowed for metabolite identification. A pilot study of reference standard collection of
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-ethylpentylone from the water tank was conducted.
Methods
ZWT consisted in 8 fish placed in a 200 mL recipient-containing water for a single cathinone. Experiments were performed in triplicate. Water tank samples were collected after 8 h and pretreated through solid-phase extraction. Separation and accurate-mass spectra of metabolites were obtained using liquid chromatography–high resolution tandem mass spectrometry.
Results
Phase I metabolites of α-PVP were identified, which were formed involving ketone reduction, hydroxylation, and 2″-oxo-pyrrolidine formation. The lactam derivative was the major metabolite observed for α-PVP in ZWT.
N
-Ethylpentylone and ethylone were transformed into phase I metabolites involving reduction, hydroxylation, and dealkylation. 4-CDC was transformed into phase I metabolites, reported for the first time, involving
N
-dealkylation,
N
,
N
-bis-dealkylation and reduction of the ketone group, the last one being the most intense after 8 h of the experiment.
Conclusions
ZWT model indicated to be very useful to study the metabolism of the synthetic cathinones, such as
N
-ethylpentylone, ethylone, α-PVP and 4-CDC. Methylone seems to be a potent CYP450 inhibitor in zebrafish. More experiments are needed to better evaluate this issue. Finally, this approach was quite simple, straightforward, extremely low cost, and fast for “human-like” metabolic studies of synthetic cathinones.
Asthma is a disease characterized by chronic inflammation and hyper responsiveness of airways. We aimed to assess the relaxant potential of phosphodiesterase-4 (PDE4) inhibitors N-sulfonilhidrazonic ...derivatives on non-asthmatic and asthmatic guinea pig trachea. Firstly, guinea pigs were sensitized and challenged with ovalbumin, and then morphological, and contractile changes were evaluated resulting from asthma, followed by evaluation of relaxant effect of derivatives on guinea pig trachea and the cAMP levels measurement by ELISA. It has been evidenced hypertrophy of airway smooth muscle, inflammatory infiltrate, and vascular abnormalities. Moreover, only sensitized tracheal rings were responsive to OVA. Contractile response to histamine, but not to carbachol, was greater in sensitized animals, however the relaxant response to aminophylline and isoprenaline were the same in non-asthmatics and asthmatics. N-sulfonilhidrazonic derivatives presented equipotent relaxant action independent of epithelium, with exception of LASSBio-1850 that presented a low efficacy (< 50%) and LASSBio-1847 with a 4-fold higher potency on asthmatics. LASSBio-1847 relaxant curve was impaired in the presence of propranolol and potentiated by isoprenaline in both groups. Furthermore, relaxation was potentiated 54- and 4-fold by forskolin in non-asthmatics and asthmatics, respectively. Likewise, LASSBio-1847 potentiated relaxant curve of aminophylline 147- and 4-fold in both groups. The PKA inhibitor H-89 impaired the relaxant potency of the derivative. Finally, LASSBio-1847 increased tracheal intracellular cAMP levels similarly to rolipram, selective PDE4 inhibitor, in both animals. LASSBio-1847 showed to be promising to relax guinea pig trachea from non-sensitized and sensitized guinea pigs by activation of β
2
-adrenergic receptors/AC/cAMP pathway.
A revisão apresenta um panorama da literatura nacional que trata da vivência espiritual/religiosa de graduandos no contexto da formação científico-acadêmica do psicólogo. O objetivo foi delinear e ...analisar pesquisas empíricas sobre a relação entre estudantes, espiritualidade, religião e formação nos cursos de psicologia do país. Realizou-se uma busca nas bases de dados virtuais: Biblioteca Virtual em Saúde, Scientific Eletronic Library Online, Periódicos Eletrônicos em Psicologia, e no Banco de Teses e Dissertações da CAPES, sendo selecionados e analisados 11 estudos, no período de 2002 a 2017. Observou-se um número reduzido de publicações, especialmente no formato de artigo. A maioria das pesquisas é oriunda de instituições de ensino confessionais e de Programas de Pós-graduação em Psicologia. Verificou-se que estudantes de psicologia tendem a apresentar índices menores de bem-estar espiritual quando comparados a outros estudantes universitários. Formandos de diferentes regiões do país mencionam sentir dificuldade e insegurança quando o assunto se apresenta na clínica. Questionam sobre a postura ética adequada; sentem medo de influenciar o paciente, de revelar a religião pessoal e não saber lidar com suas próprias crenças. Admitem falta de conhecimento e manejo teórico-clínico; e a dificuldade ou impedimento de abordar tais questões com professores e supervisores de estágio. A revisão apresenta um panorama da literatura nacional que trata da vivência espiritual/religiosa de graduandos no contexto da formação científico-acadêmica do psicólogo. O objetivo foi delinear e analisar pesquisas empíricas sobre a relação entre estudantes, espiritualidade, religião e formação nos cursos de psicologia do país. Realizou-se uma busca nas bases de dados virtuais: Biblioteca Virtual em Saúde, Scientific Eletronic Library Online, Periódicos Eletrônicos em Psicologia, e no Banco de Teses e Dissertações da CAPES, sendo selecionados e analisados 11 estudos, no período de 2002 a 2017. Observou-se um número reduzido de publicações, especialmente no formato de artigo. A maioria das pesquisas é oriunda de instituições de ensino confessionais e de Programas de Pós-graduação em Psicologia. Verificou-se que estudantes de psicologia tendem a apresentar índices menores de bem-estar espiritual quando comparados a outros estudantes universitários. Formandos de diferentes regiões do país mencionam sentir dificuldade e insegurança quando o assunto se apresenta na clínica. Questionam sobre a postura ética adequada; sentem medo de influenciar o paciente, de revelar a religião pessoal e não saber lidar com suas próprias crenças. Admitem falta de conhecimento e manejo teórico-clínico; e a dificuldade ou impedimento de abordar tais questões com professores e supervisores de estágio.
Phosphodiesterase 4 (PDE4) inhibitors have emerged as a new strategy to treat asthma and other lung inflammatory diseases. Searching for new PDE4 inhibitors, we previously reported the discover of ...LASSBio-448, a sulfonamide with potential to prevent and reverse pivotal pathological features of asthma. In this paper, two novel series of sulfonamide (6a-6m) and sulfonyl hydrazone (7a-7j) analogues of LASSBio-448 have been synthetized and evaluated for selective inhibitory activity toward cAMP-specific PDE4 isoforms. From these studies, we have identified 7j (LASSBio-1632) as a new anti-asthmatic lead-candidate associated with selective inhibition of PDE4A and PDE4D isoenzymes and blockade of airway hyper-reactivity (AHR) and TNF-α production in the lung tissue. In addition, it was able to relax guinea pig trachea on non-sensitized and sensitized animals and showed great TGI permeability.
Display omitted
•A new selective PDE4A and PDE4D inhibitor.•Good drug-like properties.•Blockade of airway hyper-reactivity (AHR) and TNF-α production in the lung tissue.•relaxant effects on guinea pig trachea.
Resumo Objetivo Analisar o conteúdo e usabilidade de um protótipo de aplicativo móvel para apoiar a educação do paciente no pré-operatório de revascularização miocárdica. Métodos Estudo metodológico, ...quantitativo, baseado no referencial design instrucional contextualizado. Na etapa de análise realizou-se revisão de escopo e um estudo qualitativo com 13 pacientes com a finalidade de identificar o conteúdo para compor o aplicativo. Na etapa de design e desenvolvimento estruturou-se o conteúdo. Durante a implementação, procedeu-se a configuração dos recursos e, na avaliação, utilizou-se a técnica Delphi, com a avaliação do conteúdo a partir dos critérios de Pasquali e a usabilidade do aplicativo por meio do ERGOLIST por 20 juízes na primeira rodada e 16 na segunda. Usou-se, para análise, o coeficiente de validade de conteúdo, considerado válido acima de 0,8 e o percentual de concordância igual ou superior a 80%. Realizou-se o teste binomial em cada item para determinar o nível de significância (p<0,05). Resultados A análise do conteúdo resultou em um coeficiente de validade de conteúdo superior a 0,8 e percentual de concordância superior a 80% em todos os critérios analisados. Já a usabilidade, apresentou percentual superior a 90% em todos os itens. Todos os itens analisados apresentaram significância estatística. O aplicativo OrientaRVM foi composto por 90 telas que formam o menu inicial e nove seções: entenda mais sobre o coração; entenda a sua doença; entenda a cirurgia de ponte de safena ou ponte mamária; cuidados antes da cirurgia; cuidados após a cirurgia; reabilitação e mudanças no estilo de vida; registros do paciente; agenda; quiz. Conclusão O OrientaRVM apresenta conteúdo confiável, funcionalidade adequada e foi recomendado para ser utilizado como recurso auxiliar na educação do paciente antes da revascularização miocárdica.
In this study, we examined the effects of LASSBio-965 (N-2-(3,4-dimethoxyphenyl) ethyl-benzenesulfonamide), a compound designed as a simplified structure of a non-selective phosphodiesterase 4 ...inhibitor, on vascular smooth muscle in vitro as well as in a rat model of monocrotaline (MCT)-induced pulmonary arterial hypertension. LASSBio-965 (50mg/kg) treatment caused a significant decrease in right systolic ventricular pressure (32.47±3.09mmHg) compared to the MCT-vehicle group (51.88±3.23mmHg; P<0.05) and in the ratio of right ventricular weight to left ventricular weight plus septum (0.42±0.03g compared to 0.59±0.06g, respectively; MCT-vehicle group; P<0.05). LASSBio-965 induced a concentration-dependent relaxation of rat aortic rings, which was decreased by mechanical removal of the endothelium. Milrinone, rolipram, and sildenafil reduced the maximum relaxation (100%) to 22.4±5.8, 69.5±5.6 and 80.1±10.7%, respectively (P<0.05). Maximum relaxation responses of aortic and pulmonary artery rings were decreased in the MCT-vehicle group (54.80±5.69 and 35.87±4.78, respectively) compared to the control (91.51±4.79 and 54.32±2.39, respectively) but improved with LASSBio-965 treatment (50mg/kg; 88.43±4.54 and 59.36±4.83, respectively). These results indicate that LASSBio-965 can attenuate the pulmonary arterial hypertension in an animal model most likely through the nonselective inhibition of phosphodiesterases 3, 4, and 5.
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