1,126 research outputs found

    Development and validation of a HPLC method for the determination of sertraline and three non-chiral related impurities

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    In this study, a screening on reversed-phase stationary phases (including C(8), C(18), CN, PEG and amide) was carried out in order to obtain an efficient HPLC method for the determination of sertraline and three of its more closely related synthetical and non-chiral impurities, without using ion-pair reagents. The best results in terms of both retention time and resolution of the target analytes were obtained with a Zorbax Bonus-RP column, which contains a polar amide group embedded in a C(14) alkyl chain. Once the most suitable stationary phase was chosen, the HPLC method was optimized by using a factorial design, evaluating three quantitative factors (column temperature, buffer pH and buffer concentration) in order to find the best conditions which maximize the resolution between impurities A and B (positional isomers) and minimize the total run time. The final HPLC conditions were set by means of a second experimental design, which allowed optimizing the effects of the buffer pH and the proportion of methanol in the mobile phase. The optimal conditions for simultaneously determining sertraline and its impurities, being baseline separated in less than 10min, were finally obtained with Zorbax Bonus-RP column (150mmx4.6mm, 5 um), under isocratic conditions with phosphate buffer (pH 2.8; 10mM)-methanol (63:37, v/v) at 50 degrees C, at the flow-rate of 1.0mL/min. UV detection was set at 220nm. This method was successfully validated following ICH guidelines and it proved to be reliable for the determination of sertraline and related impurities in tablets as pharmaceutical forms

    Simultaneous, phenotypic knockout of VEGF-R2 and Tie-2 with an intradiabody enhances antiangiogenic effects in vivo

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    Background: Intracellular antibodies (intrabodies) have been used for the generation of phenotypic knockouts in vivo by surface depletion of extracellular or transmembrane proteins. Intrabodies present an alternative to methods of gene inactivation that target genomic DNA or m-RNA, such as RNA interference. Several studies suggest that the VEGF receptor pathway and the Tie-2 pathway are independent and essential mediators of angiogenesis, leading to the hypothesis that simultaneous interference with both pathways should result in additive effects in tumor growth. Methods: In order to generate a precise tool for the simultaneous silencing of two independent signaling pathways essential for angiogenesis, we developed a bispecific, tetravalent endoplasmatic reticulum (ER)-targeted intradiabody, against Tie-2 and VEGF-R2. Results: Using an adenovirus mediated gene delivery system, we achieved the simultaneous downregulation of the two cell surface receptors and demonstrate that the intradiabody is significantly more powerful with respect to efficiency and duration of surface depletion of Tie-2 and VEGF-R2 when compared to scFv intrabodies. In a human melanoma xenograft mouse model, we could show that blockade of both VEGF-R2 and Tie-2 pathways or the VEGF receptor pathway alone resulted in a significant inhibition of tumor growth and tumor angiogenesis (92.2% and 74.4%). Conclusion: We demonstrate for the first time that simultaneous inhibition of the VEGF and the Tie-2 receptor pathways result in additive antiangiogenic effects in vitro and in vivo as compared to single VEGF receptor pathway blockade, strengthening the potential of simultaneous targeting of multiple pathways as a therapeutic strategy

    Humour, satire et absurde dans <i>Um homem de barbas</i> de Manuel de Lima

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    International audienceManuel de Lima (1915–1976), violinist, painter and music critic, began his writing career in 1944 with the long short-story Um homem de barbas [A man with a beard]. It was the middle of the Second World War and the Salazar dictatorship was well established in officially neutral Portugal. A few years before the belated emergence of Portuguese surrealism, to which he was linked, and in the midst of the development of neorealism, a protest movement followed mainly by the young writers of the time,Manuel de Lima asserted himself from the outset as a very singular writer. Um homem de barbas is a narrative of a love triangle that ends with the spectacular disappearance of the three protagonists. In this first work placed under the sign of the absurd, which mixes satire, marvelous, and burlesque and in which, according to Almada Negreiros' 1944 preface, the author uses realism to "undo realism", we will study the place and role of humor, as well as the various devices used.Manuel de Lima (1915–1976), violoniste, peintre et critique musical, initie sa carrière d’écrivain en 1944 avec la nouvelle Um homem de barbas [Un homme à barbe]. On est alors en pleine Seconde guerre mondiale et, au Portugal, officiellement neutre, la dictature salazariste est bien implantée. Quelques années avant l’apparition, tardive, du surréalisme portugais, auquel il sera rattaché, et en plein développement du néoréalisme, voie contestataire majoritairement suivie par les jeunes écrivains de l’époque, Manuel de Lima s’affirme dès ses débuts comme un écrivain très singulier. Um homem de barbas est le récit d’un triangle amoureux qui se termine par la disparition spectaculaire des trois protagonistes. Dans ce premier opus placé sous le signe de l’absurde, qui mêle satire, merveilleux et burlesque et où, selon le préfacier Almada Negreiros (1944), l’auteur se sert du réalisme pour "défaire le réalisme", nous étudierons la place et le rôle de l’humour ainsi que les divers procédés utilisés
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