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

Natural selection on cork oak: allele frequency reveals divergent selection in cork oak populations along a temperature cline

A recent study of population divergence at neutral markers and adaptive traits in cork oak has observed an association between genetic distances at locus QpZAG46 and genetic distances for leaf size and growth. In that study it was proposed that certain loci could be linked to genes encoding for adaptive traits in cork oak and, thus, could be used in adaptation studies. In order to investigate this hypothesis, here we (1) looked for associations between molecular markers and a set of adaptive traits in cork oak, and (2) explored the effects of the climate on among-population patterns in adaptive traits and molecular markers. For this purpose, we chose 9-year-old plants originating from thirteen populations spanning a broad range of climatic conditions. Plants established in a common garden site were genotyped at six nuclear microsatellites and phenotypically characterized for six functional traits potentially related to plant performance. Our results supported the proposed linkage between locus QpZAG46 and genes encoding for leaf size and growth. Temperature caused adaptive population divergence in leaf size and growth, which was expressed as differences in the frequencies of the alleles at locus QpZAG46

Estimating how inflated or obscured effects of climate affect forecasted species distribution

Climate is one of the main drivers of species distribution. However, as different environmental factors tend to co-vary, the effect of climate cannot be taken at face value, as it may be either inflated or obscured by other correlated factors. We used the favourability models of four species (Alytes dickhilleni, Vipera latasti, Aquila fasciata and Capra pyrenaica) inhabiting Spanish mountains as case studies to evaluate the relative contribution of climate in their forecasted favourability by using variation partitioning and weighting the effect of climate in relation to non-climatic factors. By calculating the pure effect of the climatic factor, the pure effects of non-climatic factors, the shared climatic effect and the proportion of the pure effect of the climatic factor in relation to its apparent effect (r), we assessed the apparent effect and the pure independent effect of climate. We then projected both types of effects when modelling the future favourability for each species and combination of AOGCM-SRES (two Atmosphere-Ocean General Circulation Models: CGCM2 and ECHAM4, and two Special Reports on Emission Scenarios (SRES): A2 and B2). The results show that the apparent effect of climate can be either inflated (overrated) or obscured (underrated) by other correlated factors. These differences were species-specific; the sum of favourable areas forecasted according to the pure climatic effect differed from that forecasted according to the apparent climatic effect by about 61% on average for one of the species analyzed, and by about 20% on average for each of the other species. The pure effect of future climate on species distributions can only be estimated by combining climate with other factors. Transferring the pure climatic effect and the apparent climatic effect to the future delimits the maximum and minimum favourable areas forecasted for each species in each climate change scenario.Ministerio de Ciencia e Innovación and FEDER (project CGL2009-11316/BOS). D. Romero is a PhD student at the University of Malaga with a grant of the Ministerio de Educacio´n y Ciencia (AP 2007-03633

Natural products as starting points for future anti-malarial therapies: going back to our roots?

Abstract Background The discovery and development of new anti-malarials are at a crossroads. Fixed dose artemisinin combination therapy is now being used to treat a hundred million children each year, with a cost as low as 30 cents per child, with cure rates of over 95%. However, as with all anti-infective strategies, this triumph brings with it the seeds of its own downfall, the emergence of resistance. It takes ten years to develop a new medicine. New classes of medicines to combat malaria, as a result of infection by Plasmodium falciparum and Plasmodium vivax are urgently needed. Results Natural product scaffolds have been the basis of the majority of current anti-malarial medicines. Molecules such as quinine, lapachol and artemisinin were originally isolated from herbal medicinal products. After improvement with medicinal chemistry and formulation technologies, and combination with other active ingredients, they now make up the current armamentarium of medicines. In recent years advances in screening technologies have allowed testing of millions of compounds from pharmaceutical diversity for anti-malarial activity in cellular assays. These initiatives have resulted in thousands of new sub-micromolar active compounds – starting points for new drug discovery programmes. Against this backdrop, the paucity of potent natural products identified has been disappointing. Now is a good time to reflect on the current approach to screening herbal medicinal products and suggest revisions. Nearly sixty years ago, the Chinese doctor Chen Guofu, suggested natural products should be approached by dao-xing-ni-shi or ‘acting in the reversed order’, starting with observational clinical studies. Natural products based on herbal remedies are in use in the community, and have the potential unique advantage that clinical observational data exist, or can be generated. The first step should be the confirmation and definition of the clinical activity of herbal medicinal products already used by the community. This first step forms a solid basis of observations, before moving to in vivo pharmacological characterization and ultimately identifying the active ingredient. A large part of the population uses herbal medicinal products despite limited numbers of well-controlled clinical studies. Increased awareness by the regulators and public health bodies of the need for safety information on herbal medicinal products also lends support to obtaining more clinical data on such products. Conclusions The relative paucity of new herbal medicinal product scaffolds active against malaria results discovered in recent years suggest it is time to re-evaluate the ‘smash and grab’ approach of randomly testing purified natural products and replace it with a patient-data led approach. This will require a change of perspective form many in the field. It will require an investment in standardisation in several areas, including: the ethnopharmacology and design and reporting of clinical observation studies, systems for characterizing anti-malarial activity of patient plasma samples ex vivo followed by chemical and pharmacological characterisation of extracts from promising sources. Such work falls outside of the core mandate of the product development partnerships, such as MMV, and so will require additional support. This call is timely, given the strong interest from researchers in disease endemic countries to support the research arm of a malaria eradication agenda. Para-national institutions such as the African Network for Drugs and Diagnostics Innovation (ANDi) will play a major role in facilitating the development of their natural products patrimony and possibly clinical best practice to bring forward new therapeutics. As in the past, with quinine, lapinone and artemisinin, once the activity of herbal medicinal products in humans is characterised, it can be used to identify new molecular scaffolds which will form the basis of the next generation of anti-malarial therapies.</p

A922 Sequential measurement of 1 hour creatinine clearance (1-CRCL) in critically ill patients at risk of acute kidney injury (AKI)

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