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      New delivery systems for amphotericin B applied to the improvement of leishmaniasis treatment

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          Abstract

          Leishmaniasis is one of the six major tropical diseases targeted by the World Health Organization. It is a life-threatening disease of medical, social and economic importance in endemic areas. No vaccine is yet available for human use, and chemotherapy presents several problems. Pentavalent antimonials have been the drugs of choice to treat the disease for more than six decades; however, they exhibit high toxicity and are not indicated for children, for pregnant or breastfeeding women or for chronically ill patients. Amphotericin B (AmpB) is a second-line drug, and although it has been increasingly used to treat visceral leishmaniasis (VL), its clinical use has been hampered due to its high toxicity. This review focuses on the development and in vivo usage of new delivery systems for AmpB that aim to decrease its toxicity without altering its therapeutic efficacy. These new formulations, when adjusted with regard to their production costs, may be considered new drug delivery systems that promise to improve the treatment of leishmaniasis, by reducing the side effects and the number of doses while permitting a satisfactory cost-benefit ratio.

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          Principles of early drug discovery.

          Developing a new drug from original idea to the launch of a finished product is a complex process which can take 12-15 years and cost in excess of $1 billion. The idea for a target can come from a variety of sources including academic and clinical research and from the commercial sector. It may take many years to build up a body of supporting evidence before selecting a target for a costly drug discovery programme. Once a target has been chosen, the pharmaceutical industry and more recently some academic centres have streamlined a number of early processes to identify molecules which possess suitable characteristics to make acceptable drugs. This review will look at key preclinical stages of the drug discovery process, from initial target identification and validation, through assay development, high throughput screening, hit identification, lead optimization and finally the selection of a candidate molecule for clinical development. © 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.
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            Leishmaniasis--current chemotherapy and recent advances in the search for novel drugs.

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              Chitosan nanoparticles as delivery systems for doxorubicin.

              The aim of this paper was to evaluate the potential of chitosan nanoparticles as carriers for the anthracycline drug, doxorubicin (DOX). The challenge was to entrap a cationic, hydrophilic molecule into nanoparticles formed by ionic gelation of the positively charged polysaccharide chitosan. To achieve this objective, we attempted to mask the positive charge of DOX by complexing it with the polyanion, dextran sulfate. This modification doubled DOX encapsulation efficiency relative to controls and enabled real loadings up to 4.0 wt.% DOX. Separately, we investigated the possibility of forming a complex between chitosan and DOX prior to the formation of the particles. Despite the low complexation efficiency, no dissociation of the complex was observed upon formation of the nanoparticles. Fluorimetric analysis of the drug released in vitro showed an initial release phase, the intensity of which was dependent on the association mode, followed by a very slow release. The evaluation of the activity of DOX-loaded nanoparticles in cell cultures indicated that those containing dextran sulfate were able to maintain cytostatic activity relative to free DOX, while DOX complexed to chitosan before nanoparticle formation showed slightly decreased activity. Additionally, confocal studies showed that DOX was not released in the cell culture medium but entered the cells while remaining associated to the nanoparticles. In conclusion, these preliminary studies showed the feasibility of chitosan nanoparticles to entrap the basic drug DOX and to deliver it into the cells in its active form.
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                Author and article information

                Contributors
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                Journal
                rsbmt
                Revista da Sociedade Brasileira de Medicina Tropical
                Rev. Soc. Bras. Med. Trop.
                Sociedade Brasileira de Medicina Tropical - SBMT (Uberaba )
                1678-9849
                June 2015
                : 48
                : 3
                : 235-242
                Affiliations
                [1 ] Universidade Federal de Minas Gerais Brazil
                [2 ] Universidade Federal de Minas Gerais Brazil
                [3 ] Universidade Federal de Minas Gerais Brazil
                [4 ] Universidade Federal de Minas Gerais Brazil
                [5 ] Bioprospection Ltda Brazil
                [6 ] Universidade Federal de Minas Gerais Brazil
                [7 ] Universidad Autónoma de Madrid Spain
                [8 ] Universidade Federal de Minas Gerais Brazil
                Article
                S0037-86822015000300235
                10.1590/0037-8682-0138-2015
                e3d67bf9-61fb-4477-94de-7d2febf59e86

                http://creativecommons.org/licenses/by/4.0/

                History
                Product

                SciELO Brazil

                Self URI (journal page): http://www.scielo.br/scielo.php?script=sci_serial&pid=0037-8682&lng=en
                Categories
                TROPICAL MEDICINE

                Infectious disease & Microbiology
                Amphotericin B,Leishmaniasis,Nanoparticles,Toxicity,Treatment,Lipid-based formulations

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