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

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

Preparation of scientific texts from first year of degree: experience in the subject " Información y Metodología Científica”

La asignatura “Información y Metodología Científica” tiene asignadas en el Grado en Farmacia, entre otras, las competencias genéricas de saber obtener información científica, conocer las partes de un trabajo científico, el lenguaje métrico y la forma de citar la bibliografía, y saber utilizar las tecnologías de la información y la comunicación. Se pretende que el estudiante adquiera una forma de trabajar que vaya poniendo en práctica en otras asignaturas de la titulación y se facilite la elaboración del Trabajo de Fin de Grado. Para trabajar y adquirir estas competencias, en esta asignatura se han diseñado unas actividades cuyo objetivo principal es la elaboración de un trabajo tutelado. Siguiendo unas instrucciones precisas, en la primera fase del trabajo cada pareja de estudiantes realiza dos documentos: un texto científico y una presentación de diapositivas. En una segunda fase, tres parejas de estudiantes con el mismo tema ponen en común su experiencia y realizan un único trabajo final. Cada uno de estos trabajos finales es subido a la plataforma de apoyo a la docencia y valorado por sus compañeros del grupo de seminarios (8 grupos de 6 estudiantes que presentan 8 trabajos finales). A esta valoración, se le suma la calificación otorgada por el profesorado en base al trabajo entregado en ambas fases. El profesorado está muy satisfecho con los objetivos de aprendizaje conseguidos con esta actividad que supone entre el 40 y el 60 % de la evaluación de la asignatura.The main aims of the subject “Información y Metodología Científica” in the Degree in Pharmacy are, among others, to teach students how to obtain scientific information, to familiarize them with the parts of a scientific paper, the language metric and the literature citation format, and show them how to use information and communication technologies. It is expected to help students acquire a way of working to be implemented in other subjects of the Degree and it facilitates the preparation of the Final Degree Project. To work on these skills, this subject is designed around some activities whose primary objective is the development of a guided piece of work. Following precise instructions in the first phase of the assignment, each pair of students prepares two documents: a scientific text and a slide presentation. In a second phase, three pairs of students with the same subject pool their experience and they prepare one final document. Each of these final documents is uploaded to a teaching support platform and evaluated by their classmates (eight teams of six students who submit eight projects). The mark given by teachers in previous phases is added to that of this assessment. Teachers are very pleased with the learning objectives achieved with this activity, which constitutes between 40 and 60 % of the assessment of the subject. In the academic year 2009/10, 290 students were enrolled in this subject

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

Uso de edelfosina para la prevención y/o tratamiento de helmintiasis

La presente invención se refiere al uso de un compuesto de fórmula general (1) donde preferiblemente el compuesto es edelfosina (1- O-octadecil-2-0-metil-rac-glicero-3-fosfocolina), para la fabricación de un medicamento para la prevención y/o el tratamiento de helmintiasis, es decir, para su uso como antihelmíntico, preferiblemente para la prevención y/o el tratamiento de esquistosomiasis y/o estrong iloidiasis.Peer reviewedUniversidad de Salamanca, Consejo Superior de Investigaciones Científicas (España)A1 Solicitud de patente con informe sobre el estado de la técnic

The alkylphospholipid edelfosine shows activity against Strongyloides venezuelensis and induces apoptosis-like cell death

33 p.-6 fig.-1 tab.Strongyloidiasis is widely distributed in the tropical and subtropical areas. Ivermectin is the drug of choice for the treatment. However, the concerns about relying treatment on a single drug make identification of new molecules a priority. Alkylphospholipid analogues, including edelfosine, are a group of synthetic compounds that have shown activity against some parasites. The objective was to assess the in vitro and in vivo activity of edelfosine, miltefosine, perifosine against Strongyloides venezuelensis. Moreover, apoptosis-like mechanism in larvae after treatment was studied. Edelfosine displayed the highest activity and the best selectivity index (LD50 = 49.6 ± 5.4 μM, SI = 1.1) compared to miltefosine or perifosine. Third stage larvae after culture with edelfosine were not able to develop an infection in mice. Treatment of mice with edelfosine showed reduction of 47% in parasitic females allocated in the gut. Moreover, DNA fragmentation was observed by TUNEL staining in larvae treated with edelfosine. These results suggest that edelfosine could be an effective drug against strongyloidiasis, probably through induction of apoptosis-like cell death.This work has been supported by Proyectos Integrados IBSAL (IBY15/00003; Salamanca, Spain; 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-Fondo Europeo de Desarrollo Regional of the European Union), and the European Union’s Seventh Framework Programme FP7-2007-2013 (grant HEALTH-F2-2011-256986, PANACREAS).Peer reviewe

Time-course investigation of the gene expression profile during Fasciola hepatica infection: A microarray-based study

Fasciolosis is listed as one of the most important neglected tropical diseases according with the World Health Organization and is also considered as a reemerging disease in the human beings. Despite there are several studies describing the immune response induced by Fasciola hepatica in the mammalian host, investigations aimed at identifying the expression profile of genes involved in inducing hepatic injury are currently scarce. Data presented here belong to a time-course investigation of the gene expression profile in the liver of BALB/c mice infected with F. hepatica metacercariae at 7 and 21. days after experimental infection. The data published here have been deposited in NCBI's Gene Expression Omnibus and are accessible through GEO Series accession number GSE69588, previously published by Rojas-Caraballo et al. © [email protected]

Systematic Review and Meta-Analysis of Artemisinin Based Therapies for the Treatment and Prevention of Schistosomiasis

<div><h3>Background</h3><p>Chemotherapy based on repeated doses of praziquantel is still the most effective control strategy against Schistosomiasis, however artemisinin derivatives emerged as a family of compounds with schistomicide activity. The aim of the present work is to compare the efficacy of artemisinin-based therapies in the treatment and prophylaxis of human schistosomiasis. The design of this work involved a quantitative systematic review and meta-analysis.</p> <h3>Methodology/Principal Findings</h3><p>Retrieval of published studies was carried out through an electronic search of the PubMed (MEDLINE), EMBASE, Cochrane Library and CINAHL databases. This included reports comparing the therapeutic efficacy of artesunate alone, artesunate <em>plus</em> sulfadoxine-pyrimethamine and a combination of artemisinin derivatives <em>plus</em> praziquantel against praziquantel alone on different types of schistosomiasis. Moreover, studies on artesunate and artemether used as preventive drugs were also analyzed against placebo. The primary outcome measure for schistosomiasis treatment was “parasitological cure”, whereas for the prophylaxis the outcome evaluated was “infection rate”. Our results show that patients treated with artesunate alone have significantly lower cure rates than those treated with praziquantel (OR = 0.27 (95% C.I. 0.13–0.53; p<0.001)) and that the combined therapy of artesunate <em>plus</em> sulfadoxine-pyrimethamine is also significantly less effective than praziquantel treatment (OR = 0.14 (95% C.I. 0.02–0.92; p = 0.04)). However, the combination of an artemisinin derivatives <em>plus</em> praziquantel showed a higher cure rate than praziquantel monotherapy with OR = 2.07 (95% C.I. 1.27–3.36; p = 0.003). Finally, chemoprophylaxis with either artesunate (RR = 0.11 (95% C.I. 0.06–0.22; p<0.001)) or artemether (RR = 0.25 (95% C.I. 0.16–0.40; p<0.001)) was significantly better than a placebo in both cases.</p> <h3>Conclusions/Significance</h3><p>This meta-analysis confirms that artemisinin derivatives used in combination with praziquantel have the potential to increase the cure rates in schistosomiasis treatment, but not artesunate alone. It is also confirmed that repeated doses of artemisinin derivatives play a prophylactic role, significantly reducing the incidence of <em>Schistosoma japonicum</em> infections compared with placebo.</p> </div