ASSESSMENT OF THE TABLETING CHARACTERISTICS OF A NOVEL SORBITOL AND CALCIUM DIPHOSPHATE COMPOSITES

Objective: To improve the tableting properties of sorbitol (SOR) via particle engineering through agglomeration with anhydrous calcium diphosphate (ACD) employing a house-made agglomerator.Methods: A novel SOR: ACD composites were produced by agglomeration at the 95:5; 80:20, 50:50, 20:80 and 6:94 SOR to ACD. The resulting tableting properties such as densification, compressibility, compactibility, ejection force, elastic recovery, sensitivity to lubricants, compression speed and disintegration time were then evaluated.Results: The new agglomerated excipient had better flow, compressibility and compactibility than the physical mixture of SOR and ACD being the 95:5 SOR: ACD ratio the composite that exhibited the best tableting properties.Conclusion: This novel excipient has a potential use as a pharmaceutical aid for direct compression applications.Â

Inhibition of granulomatous inflammation and prophylactic treatment of schistosomiasis with a combination of edelfosine and Praziquantel

This is an open access article distributed under the terms of the Creative Commons Attribution License.[Background]: Schistosomiasis is the third most devastating tropical disease worldwide caused by blood flukes of the genus Schistosoma. This parasitic disease is due to immunologic reactions to Schistosoma eggs trapped in tissues. Egg-released antigens stimulate tissue-destructive inflammatory and granulomatous reactions, involving different immune cell populations, including T cells and granulocytes. Granulomas lead to collagen fibers deposition and fibrosis, resulting in organ damage. Praziquantel (PZQ) is the drug of choice for treating all species of schistosomes. However, PZQ kills only adult Schistosoma worms, not immature stages. The inability of PZQ to abort early infection or prevent re-infection, and the lack of prophylactic effect prompt the need for novel drugs and strategies for the prevention of schistosomiasis. [Methodology/Principal Findings]: Using in vitro and in vivo approaches, we have found that the alkylphospholipid analog edelfosine kills schistosomula, and displays anti-inflammatory activity. The combined treatment of PZQ and edelfosine during a few days before and after cercariae infection in a schistosomiasis mouse model, simulating a prophylactic treatment, led to seven major effects: a) killing of Schistosoma parasites at early and late development stages; b) reduction of hepatomegaly; c) granuloma size reduction; d) down-regulation of Th1, Th2 and Th17 responses at late post-infection times, thus inhibiting granuloma formation; e) upregulation of IL-10 at early post-infection times, thus potentiating anti-inflammatory actions; f) down-regulation of IL-10 at late post-infection times, thus favoring resistance to re-infection; g) reduction in the number of blood granulocytes in late post-infection times as compared to infected untreated animals. [Conclusions/Significance]: Taken together, these data suggest that the combined treatment of PZQ and edelfosine promotes a high decrease in granuloma formation, as well as in the cellular immune response that underlies granuloma development, with changes in the cytokine patterns, and may provide a promising and effective strategy for a prophylactic treatment of schistosomiasis.This work was supported by grants from the Junta de Castilla y León (SA342U13, CSI052A11-2, and CSI221A12-2), Real Federación Española de Fútbol-Sociedad Española de Medicina Tropical y Salud Internacional (RFEF-SEMTSI 2013), Spanish Ministerio de Economía y Competitividad (SAF2011-30518, SAF2014-59716-R, and RD12/0036/0065 from Red Temática de Investigación Cooperativa en Cáncer, Instituto de Salud Carlos III, cofunded by the Fondo Europeo de Desarrollo Regional of the European Union), and European Community’s Seventh Framework Programme FP7-2007-2013 (grant HEALTH-F2-2011-256986, PANACREAS).Peer Reviewe

In vitro and in vivo anti-schistosomal activity of the alkylphospholipid analog edelfosine

This is an open-access article distributed under the terms of the Creative Commons Attribution License.[Background]: Schistosomiasis is a parasitic disease caused by trematodes of the genus Schistosoma. Five species of Schistosoma are known to infect humans, out of which S. haematobium is the most prevalent, causing the chronic parasitic disease schistosomiasis that still represents a major problem of public health in many regions of the world and especially in tropical areas, leading to serious manifestations and mortality in developing countries. Since the 1970s, praziquantel (PZQ) is the drug of choice for the treatment of schistosomiasis, but concerns about relying on a single drug to treat millions of people, and the potential appearance of drug resistance, make identification of alternative schistosomiasis chemotherapies a high priority. Alkylphospholipid analogs (APLs), together with their prototypic molecule edelfosine (EDLF), are a family of synthetic antineoplastic compounds that show additional pharmacological actions, including antiparasitic activities against several protozoan parasites. [Methodology/Principal Findings]: We found APLs ranked edelfosine> perifosine> erucylphosphocholine> miltefosine for their in vitro schistosomicidal activity against adult S. mansoni worms. Edelfosine accumulated mainly in the worm tegument, and led to tegumental alterations, membrane permeabilization, motility impairment, blockade of male-female pairing as well as induction of apoptosis-like processes in cells in the close vicinity to the tegument. Edelfosine oral treatment also showed in vivo schistosomicidal activity and decreased significantly the egg burden in the liver, a key event in schistosomiasis. [Conclusions/Significance]: Our data show that edelfosine is the most potent APL in killing S. mansoni adult worms in vitro. Edelfosine schistosomicidal activity seems to depend on its action on the tegumental structure, leading to tegumental damage, membrane permeabilization and apoptosis-like cell death. Oral administration of edelfosine diminished worm and egg burdens in S. mansoni -infected CD1 mice. Here we report that edelfosine showed promising antischistosomal properties in vitro and in vivo.This work was supported by the Spanish Ministerio de Ciencia e Innovación (SAF2011-30518, and RD12/0036/0065 from Red Temática de Investigación Cooperativa en Cáncer, Instituto de Salud Carlos III, cofunded by the Fondo Europeo de Desarrollo Regional of the European Union), European Community's Seventh Framework Programme FP7-2007-2013 (grant HEALTH-F2-2011-256986, PANACREAS), Junta de Castilla y León (CSI052A11-2and SA342U13), Sociedad Española de Medicina Tropical y Salud Internacional (RFEF-SEMTSI 2013) and the Universidad de Salamanca (USAL17008).Peer Reviewe

In Vitro and In Vivo Anti-Schistosomal Activity of the Alkylphospholipid Analog Edelfosine

BACKGROUND: Schistosomiasis is a parasitic disease caused by trematodes of the genus Schistosoma. Five species of Schistosoma are known to infect humans, out of which S. haematobium is the most prevalent, causing the chronic parasitic disease schistosomiasis that still represents a major problem of public health in many regions of the world and especially in tropical areas, leading to serious manifestations and mortality in developing countries. Since the 1970s, praziquantel (PZQ) is the drug of choice for the treatment of schistosomiasis, but concerns about relying on a single drug to treat millions of people, and the potential appearance of drug resistance, make identification of alternative schistosomiasis chemotherapies a high priority. Alkylphospholipid analogs (APLs), together with their prototypic molecule edelfosine (EDLF), are a family of synthetic antineoplastic compounds that show additional pharmacological actions, including antiparasitic activities against several protozoan parasites. METHODOLOGY/PRINCIPAL FINDINGS: We found APLs ranked edelfosine> perifosine> erucylphosphocholine> miltefosine for their in vitro schistosomicidal activity against adult S. mansoni worms. Edelfosine accumulated mainly in the worm tegument, and led to tegumental alterations, membrane permeabilization, motility impairment, blockade of male-female pairing as well as induction of apoptosis-like processes in cells in the close vicinity to the tegument. Edelfosine oral treatment also showed in vivo schistosomicidal activity and decreased significantly the egg burden in the liver, a key event in schistosomiasis. CONCLUSIONS/SIGNIFICANCE: Our data show that edelfosine is the most potent APL in killing S. mansoni adult worms in vitro. Edelfosine schistosomicidal activity seems to depend on its action on the tegumental structure, leading to tegumental damage, membrane permeabilization and apoptosis-like cell death. Oral administration of edelfosine diminished worm and egg burdens in S. mansoni-infected CD1 mice. Here we report that edelfosine showed promising antischistosomal properties in vitro and in vivo

Mejoramiento de la estructura de los recubrimientos de Al2o3-43% Tio2 elaborados mediante la técnica de proyección térmica por llama oxiacetilénica a partir de los parámetros de proyección

RESUMEN: Se evaluó el efecto de los parámetro de proyección tales como: relación del flujo de gases y dinámica del jet de aire sobre los defectos estructurales (porosidad) y la rugosidad superficial de recubrimientos de Al2O3- 43% en peso de TiO2 depositados mediante proyección térmica por combustión oxiacetilénica a partir de polvos de la casa comercial Saint- Gobain® referencia SG-109. Los resultados obtenidos indican que los recubrimientos elaborados presentan cambios en la estructura interna y superficial del recubrimiento según varíe los parámetros antes mencionados, encontrando que la más baja porosidad y rugosidad superficial se obtienen utilizando una llama oxidante recubierta por un jet de aire cilíndrico cuya presión fue de 30 psi.ABSTRACT: The effect of spraying parameters such as gas flow relaxation and air jet dynamic on structural defects (porosity) and surface roughness of Al2O3-43 wt. % TiO2 coatings manufactured by flame spraying from Saint Gobain 109TM powders was evaluated. The results indicate that the surface and internal structure of the coatings change according with the variations of the spraying parameters. The lowest porosity and surface roughness is obtained using an oxidative flame with a cylindrical air shield around the flame at 30 psi of pressure

Field and laboratory comparative evaluation of a LAMP assay for the diagnosis of urogenital schistosomiasis in Cubal, Central Angola

Objetive: To evaluate the performance of Rapid-Heat LAMPellet assay in field conditions for diagnosis of urogenital schistosomiasis in an endemic area in Cubal, Angola, and to assess the reproducibility in a reference laboratory. Methods: A total of 172 urine samples from school-age children were tested for microhaematuria, microscopic detection of Schistosoma haematobium eggs and LAMP for DNA detection. Urine samples were stored in a basic equipped laboratory. Field-LAMP tests were performed with and without prior DNA extraction from urine samples, and the results were read by turbidity and by colour change. When field procedures were finished, samples were sent to a reference laboratory to be reanalysed by LAMP. Results: A total of 83 of 172 (48.3%) were positive for microhaematuria, 87/172 (50.6%) were microscopy-positive for S. haematobium eggs detection, and 127/172 (73.8%) showed LAMP-positive results for detecting S. haematobium using purified DNA and 109/172 (63.4%) without prior DNA extraction. MacNemar's test showed a statistical significant relation between LAMP results and microscopy-detected S. haematobium infections and microhaematuria (P < 0.001 in both cases), respectively. When samples of purified DNA were reanalysed in a reference laboratory in Spain using the same LAMP methodology, the overall reproducibility achieved 72.1%. Conclusions: The ease of use, simplicity and feasibility demonstrated by LAMP assay in field conditions together with the acceptable level of reproducibility achieved in a reference laboratory support the use of LAMP assay as an effective test for molecular diagnosis of urogenital schistosomiasis in endemic remote areas.This study was supported by Mundo Sano Foundation (www.mundosano.org) and by the Institute of Health Carlos III, ISCIII, Spain (www.isciii.es), grants: RICET RD16/0027/0018, DTS16/00207, PI16/01784 European Union cofinancing by FEDER (Fondo Europeo de Desarrollo Regional) ‘Una manera de hacer Europa’.S

In Vitro and In Vivo Efficacy of Ether Lipid Edelfosine against Leishmania spp. and SbV-Resistant Parasites

Leishmaniasis represents a major international health problem, has a high morbidity and mortality rate, and is classified as an emerging and uncontrolled disease by the World Health Organization. The migration of population from endemic to nonendemic areas, and tourist activities in endemic regions are spreading the disease to new areas. Unfortunately, treatment of leishmaniasis is far from satisfactory, with only a few drugs available that show significant side-effects. Here, we show in vitro and in vivo evidence for the antileishmanial activity of the ether phospholipid edelfosine, being effective against a wide number of Leishmania spp. causing cutaneous, mucocutaneous and visceral leishmaniasis. Our experimental mouse and hamster models demonstrated not only a significant antileishmanial activity of edelfosine oral administration against different wild-type Leishmania spp., but also against parasites resistant to pentavalent antimonials, which constitute the first line of treatment worldwide. In addition, edelfosine exerted a higher antileishmanial activity and a lower proneness to generate drug resistance than miltefosine, the first drug against leishmaniasis that can be administered orally. These data, together with our previous findings, showing an anti-inflammatory action and a very low toxicity profile, suggest that edelfosine is a promising orally administered drug for leishmaniasis, thus warranting clinical evaluation

Efecto in vitro e in vivo de los análogos alquilfosfolípidos (APLs) en el desarollo de nuevos compuestos contra Schistosoma mansoni

329 p.-29 fig.-6 tab.-3 apéndices.-Tesis doctoral en formato compendio artículos/publicaciones.Los parásitos son organismos eucariotas (unicelulares o pluricelulares) que viven en el interior o sobre el tejido vivo de otro organismo más organizado denominado hospedador. El término parásito proviene del nombre dado a unos sacerdotes auxiliares que “sentados al lado del alimento” -sentido etimológico- del sacrificio, participaban más tarde de la ofrenda; de aquí el uso despectivo que se le da a dicha palabra que además, tiene el término, desde su origen griego (para, junto a y sitos, trigo, comida). La generalización biológica se debe a los médicos veterinarios romanos que denominaron así a aquellos animales que vivían y se alimentaban a expensas de otros. En las primeras definiciones de los parásitos se trataba de diferenciarlos de los depredadores, insistiendo en que, aunque la asociación era para la adquisición de alimentos, se tendía a conservar la vida del hospedador y a no proporcionarle beneficio alguno, sino al contrario, efectos dañinos o acciones patógenas.Todosestos conceptos se completaron al observar la naturaleza de la asociación; el carácter fisiológico de la misma; la interdependencia bioquímica con tendencia a la estabilidad por pérdida o adquisición mutua de información genética donde los parásitos han desarrollado mecanismos que son capaces de manipular el genoma de su hospedador compatible, orquestando cambios en los nucleos de sus células que alteran la expresión génica en favor del parásito [1, 2]. Recientemente los enfoques más informativos del Ácido Desoxirribonucleico (ADN) (secuencias de genes, polimorfismos de un solo nucleótido del inglés Single Nucleotide Polymorphism (SNP), y los microsatélites) [3], se han utilizado ampliamente para inferir la influencia de la genética en los diferentes aspectos de la biología del parásito.Por otra parte, de forma general, las acciones perjudiciales son mutuas o en ambas direcciones. La posible «bondad» de algunos parasitismos, o del parasitismo, en general, no existe. Algunos hospedadores van cambiando su metabolismo, ganando peso, o modificando su comportamiento. Por el contrario, los parásitos hallan ventajas adaptativas en conservar la expresión génica de la virulencia. Si los factores de virulencia son mantenidos por la selección natural, ocasionando una disminución del bienestar del hospedador, inevitablemente se producirá también la correspondiente selección para la resistencia del hospedador. Así, se mantiene el equilibrio inestable y dinámico de la comunidad antagónica de dos seres vivos de distinta especie en asociación definida como parasitismo [4, 5]. La gran mayoría de los parásitos pertenecen a uno de los siguientes Phylum: Apicomplexa, Microspora, Ciliophora, Plathelminthes, Nematoda y Arthropoda. Los helmintos se encuentran en dos de ellos Plathelminthes y Nematoda. Se han descrito cerca de 25.000 especies de nematodos. Muchos de ellos son parásitos de insectos, plantas o animales, pero también existen especies de vida libre como Caenorhabditis elegans. Sobre la base de las estimaciones mundiales, entre 75.000 y 300.000 especies de helminto nfectan a los vertebrados terrestres y acuáticos; entre estos, 287 son conocidos en los seres humanos, el 95% de los cuales son especies zoonóticas y aproximadamente el 25% de la población mundial está infectada con estos organismos [3]. La gran mayoría de los platelmintos parásitos pertenecen a las clases, Monogenea, Digenea (gr. dis, “doble” y genos, “raza”) y Cestoda (tenias) (figura I.1), y las dos primeras clases son comúnmente denominadas “trematodos”. Todos los trematodos que residen en los seres humanos son de la clase Digenea. Tienen complejos ciclos de vida indirectos, en los que incluyen uno o varios hospedadores intermediarios (Ej. caracoles terrestres), ejemplo de estos parásitos son los esquistosoma, objeto de esta Tesis Doctoral.Peer reviewe

Las lógicas de apropiación presentes en las músicas de banda pelayera

El presente trabajo de investigación se ha enfocado en la caracterización de las lógicas de apropiación a partir de los procesos de mediación- traducción presentes en las músicas de Banda Pelayera

Efecto in vitro e in vivo de los análogos alquilfosfolípidos (APLs) en el desarollo de nuevos compuestos contra Schistosoma mansoni

El cuerpo principal de esta Tesis Doctoral corresponde a un compendio de tres trabajos, uno previamente publicado, otro ya aceptado para su publicación y el tercer artículo lo conforma una patenteTesis por compendio de publicaciones[ES]El fármaco de elección para tratar la esquistosomosis es el praziquantel, aunque su falta de eficacia contra formas juveniles y la generación de resistencias sobre todo tras los tratamientos masivos que se realizan en áreas edémicas, nos sugiere, disponer de otros fármacos activos contra esta enfermedad. Los análogos Alquilfosfolípidos (APLs) son compuestos con acción antitumoral que han mostrado eficacia contra parasitosis, principalmente leishmaniosis y tripanosomosis. Por tanto, nuestra hipótesis de trabajo es que estos fármacos podrían constituir una nueva alternativa en la terapia de la esquistosomosis. Nuestro objetivo general fue estudiar el efecto in vitro e in vivo de los alquilfosfolípidos utilizando un modelo experimental de esquistosomosis marina. Los resultado obtenidos en esta Tesis Doctoral indican, primero que la edelfosina es el análogo alquilfosfolípido más potente de los probados en este estudio, ya que es capaz de inducir in vitro tanto la muerte de esquistosómulas como de vermes adultos de Schistosoma mansoni. Este efecto es consecuencia de la permeabilización de la membrana celular y del daño estructural del tegumento, a través de un proceso con características similares a la apoptosis. Segundo, que la combinación de praziquantel y edelfosina es útil para la profilaxis de la esquistosomosis ya que mata las formas inmaduras de Schistosoma mansoni, modula la respuesta inmune de ratones infectados y reduce significativamente tanto el número de parásitos adultos como el tamaño de los granulomas hepáticos. Y por ultimo, que la edelfosina es una alternativa terapéutica al tratamiento con praziquantel en la fase crónica de la esquistosomosis ya que disminuye significativamente tanto la carga parasitaria como la producción de huevos