Reseña de Escotorín, Roche y Delvalle (Eds.) (2014) Relaciones Prosociales en Comunidades Educativas

Obra ressenyada: Pilar ESCOTORÍN; Ignasi ROCHE y Rosaura DELVALLE (Eds.), Relaciones Prosociales en Comunidades Educativas. Algunas conclusiones del proyecto europeo MOST. Barcelona: Fundació Universitària Martí l'Humà, 2014

Linking murine and human Plasmodium falciparum challenge models in a translational path for antimalarial drug development

Effective progression of candidate antimalarials is dependent on optimal dosing in clinical studies, which is determined by a sound understanding of pharmacokinetics and pharmacodynamics (PK/PD). Recently, two important translational models for antimalarials have been developed: the NOD/SCID/IL2Rgamma−/− (NSG) model, whereby mice are engrafted with noninfected and Plasmodium falciparum-infected human erythrocytes, and the induced blood-stage malaria (IBSM) model in human volunteers. The antimalarial mefloquine was used to directly measure the PK/PD in both models, which were compared to previously published trial data for malaria patients. The clinical part was a single-center, controlled study using a blood-stage Plasmodium falciparum challenge inoculum in volunteers to characterize the effectiveness of mefloquine against early malaria. The study was conducted in three cohorts (n = 8 each) using different doses of mefloquine. The characteristic delay in onset of action of about 24 h was seen in both NSG and IBSM systems. In vivo 50% inhibitory concentrations (IC50s) were estimated at 2.0 mug/ml and 1.8 mug/ml in the NSG and IBSM models, respectively, aligning with 1.8 mug/ml reported previously for patients. In the IBSM model, the parasite reduction ratios were 157 and 195 for the 10- and 15-mg/kg doses, within the range of previously reported clinical data for patients but significantly lower than observed in the mouse model. Linking mouse and human challenge models to clinical trial data can accelerate the accrual of critical data on antimalarial drug activity. Such data can guide large clinical trials required for development of urgently needed novel antimalarial combinations.This work, including the efforts of James S. McCarthy, was funded by Australian National Health and Medical Research Council. This work, including the efforts of Timothy Wells, was funded by Wellcome Trust (095909/Z/11/Z)

Characterization of Novel Antimalarial Compound ACT-451840: Preclinical Assessment of Activity and Dose-Efficacy Modeling

Background Artemisinin resistance observed in Southeast Asia threatens the continued use of artemisinin- based combination therapy in endemic countries. Additionally, the diversity of chemical mode of action in the global portfolio of marketed antimalarials is extremely limited. Addressing the urgent need for the development of new antimalarials, a chemical class of potent antimalarial compounds with a novel mode of action was recently identified. Herein, the preclinical characterization of one of these compounds, ACT-451840, conducted in partnership with academic and industrial groups is presented Method and Findings The properties of ACT-451840 are described, including its spectrum of activities against multiple life cycle stages of the human malaria parasite Plasmodium falciparum (asexual and sexual) and Plasmodium vivax (asexual) as well as oral in vivo efficacies in two murine malaria models that permit infection with the human and the rodent parasites P. falciparum and Plasmodium berghei, respectively. In vitro, ACT-451840 showed a 50% inhibition concentration of 0.4 nM (standard deviation [SD]: ± 0.0 nM) against the drug-sensitive P. falciparum NF54 strain. The 90% effective doses in the in vivo efficacy models were 3.7 mg/kg against P. falciparum (95% confidence interval: 3.3±4.9 mg/kg) and 13 mg/kg against P. berghei (95% confidence interval: 11±16 mg/kg). ACT-451840 potently prevented male gamete formation from the gametocyte stage with a 50% inhibition concentration of 5.89 nM (SD: ± 1.80 nM) and dose-dependently blocked oocyst development in the mosquito with a 50% inhibitory concentration of 30 nM (range: 23±39). The compound's preclinical safety profile is presented and is in line with the published results of the first-in-man study in healthy male participants, in whom ACT-451840 was well tolerated. Pharmacokinetic/pharmacodynamic (PK/PD) modeling was applied using efficacy in the murine models (defined either as antimalarial activity or as survival) in relation to area under the concentration versus time curve (AUC), maximum observed plasma concentration (Cmax), and time above a threshold concentration. The determination of the dose±efficacy relationship of ACT- 451840 under curative conditions in rodent malaria models allowed prediction of the human efficacious exposure. Conclusion The dual activity of ACT-451840 against asexual and sexual stages of P. falciparum and the activity on P. vivax have the potential to meet the specific profile of a target compound that could replace the fast-acting artemisinin component and harbor additional gametocytocidal activity and, thereby, transmission-blocking properties. The fast parasite reduction ratio (PRR) and gametocytocidal effect of ACT-451840 were recently also confirmed in a clinical proof-of-concept (POC) study.This work was funded by Actelion Pharmaceuticals Ltd and Medicines for Malaria Venture

Risk Attitude and Wage Growth: Replication and Reconstruction

We replicate Shaw (1996) who found that individual wage growth is higher for individuals with greater preference for risk taking. Expanding her dataset with more American observations and data for Germany, Spain and Italy, we find mixed support for the earlier results. We present and estimate a new model and find that in particular the wage level is sensitive to attitudes towards risk taking.wage growth, risk, post-school investment

Trisubstituted Pyrimidines as Efficacious and Fast-Acting Antimalarials

Documento escrito por un elevado número de autores/as, solo se referencia el/la que aparece en primer lugar y los/as autores/as pertenecientes a la UC3M.In this paper we describe the optimization of a phenotypic hit against Plasmodium falciparum, based on a trisubstituted pyrimidine scaffold. This led to compounds with good pharmacokinetics and oral activity in a P. berghei mouse model of malaria. The most promising compound (13) showed a reduction in parasitemia of 96% when dosed at 30 mg/kg orally once a day for 4 days in the P. berghei mouse model of malaria. It also demonstrated a rapid rate of clearance of the erythrocytic stage of P. falciparum in the SCID mouse model with an ED90 of 11.7 mg/kg when dosed orally. Unfortunately, the compound is a potent inhibitor of cytochrome P450 enzymes, probably due to a 4-pyridyl substituent. Nevertheless, this is a lead molecule with a potentially useful antimalarial profile, which could either be further optimized or be used for target hunting.We acknowledge Medicines for Malaria for financial support. The University of Dundee also acknowledges support from the Wellcome Trust (Grant 100476 and a Principal Research Fellowship to A.H.F.). This work is partially funded by the MSD Scottish Life Sciences Fund. As part of an ongoing contribution to Scottish life sciences, Merck Sharp & Dohme (MSD) Ltd. (known as Merck & Co., Inc., Kenilworth, NJ, U.S., in the United States and Canada) has given substantial monetary funding to the Scottish Funding Council (SFC) for distribution via the Scottish Universities Life Sciences Alliance (SULSA) to develop and deliver a high quality drug discovery research and training program

A tetraoxane-based antimalarial drug candidate that overcomes PfK13-C580Y dependent artemisinin resistance

Documento escrito por un elevado número de autores/as, solo se referencia el/la que aparece en primer lugar y los/as autores/as pertenecientes a la UC3M.K13 gene mutations are a primary marker of artemisinin resistance in Plasmodium falciparum malaria that threatens the long-term clinical utility of artemisinin-based combination therapies, the cornerstone of modern day malaria treatment. Here we describe a multinational drug discovery programme that has delivered a synthetic tetraoxane-based molecule, E209, which meets key requirements of the Medicines for Malaria Venture drug candidate profiles. E209 has potent nanomolar inhibitory activity against multiple strains of P. falciparum and P. vivax in vitro, is efficacious against P. falciparum in in vivo rodent models, produces parasite reduction ratios equivalent to dihydroartemisinin and has pharmacokinetic and pharmacodynamic characteristics compatible with a single-dose cure. In vitro studies with transgenic parasites expressing variant forms of K13 show no cross-resistance with the C580Y mutation, the primary variant observed in Southeast Asia. E209 is a superior next generation endoperoxide with combined pharmacokinetic and pharmacodynamic features that overcome the liabilities of artemisinin derivatives.This work was supported by grants from the European Union (Antimal, FP6, S.A.W., P.M.O’N.), the Medicines for Malaria Venture (S.A.W., P.M.O’N., G.A.B., G.L.N., R.K.A.), the NIH (R01 AI109023 to D.A.F.), the Global Health and Innovative Technology (GHIT) Fund (G2015-120, S.A.W., P.M.O’N., G.A.B, G.L.N.) and Medical Research Council, United Kingdom (G0700654, M.H.-L.W., A.E.M., I.M.C.)

Hα kinematics of S^(4)G spiral galaxies – I. NGC 864

We present a study of the kinematics of the isolated spiral galaxy NGC 864, using Hα Fabry–Perot data obtained with the Galaxy Hα Fabry–Perot System (GHαFaS) instrument at the William Herschel Telescope in La Palma, complemented with images at 3.6 μm, in the R band and in Hα filter, and integral-field spectroscopic data. The resulting data cubes and velocity maps allow the study of the kinematics of the galaxy, including in-depth investigations of the rotation curve, velocity moment maps, velocity residual maps, gradient maps and position–velocity diagrams. We find asymmetries in the velocity field in the bar zone, caused by non-circular motions, probably in response to the potential of the bar. We also find a flat-profile bar, in agreement with the strong bar, with the grand design spiral pattern, and with the gap between the ends of the bar and the start of the spiral arms. We quantify the rate of massive star formation, which is concentrated in the two spiral arms