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Inflammation; Neuroprotection; Stroke Inflamació; Neuroprotecció; Ictus Inflamación; Neuroprotección; Ictus In the reperfusion era, a new paradigm of treating patients with endovascular treatment (EVT) and neuroprotective drugs is emerging as a promising therapeutic option for patients with acute ischemic stroke (AIS). In this context, ApTOLL, a Toll-like receptor 4 (TLR4) antagonist with proven neuroprotective effect in preclinical models of stroke and a very good pharmacokinetic and safety profile in healthy volunteers, is a promising first-in-class aptamer with the potential to address this huge unmet need. This protocol establishes the clinical trial procedures to conduct a Phase Ib/IIa clinical study (APRIL) to assess ApTOLL tolerability, safety, pharmacokinetics, and biological effect in patients with AIS who are eligible for EVT. This will be a multicenter, double-blind, randomized, placebo-controlled, Phase Ib/IIa clinical study to evaluate the administration of ApTOLL together with EVT in patients with AIS. The study population will be composed of men and non-pregnant women with confirmed AIS with a

Supplemental Material for In Silico Prediction of Eye Irritation Using Hansen Solubility Parameters and Predicted pKa Values by Martin Andersson, Ulf Norinder, Swapnil Chavan and Ian Cotgreave in Alternatives to Laboratory Animals

In the Swedish research programme Mistra TerraClean a tiered approach for life cycle based environmental and human health assessment early in process development was introduced. In the project smart filters for water and air purification are under development. Innovative materials and devices are applied and evaluated with a systems perspective. In our tiered approach life cycle assessment (LCA), chemical safety assessment and applied eco and human toxicity assessments are combined, with a particular focus on the inclusion of toxicity potential impacts in LCA. To this end, the consensus model USEtox has been applied, complemented with the method ProScale, that focusses on human direct exposure. The life cycle-based approach has so far been applied to material development and a pilot scale case study. The case study focuses on water purification of per- and polyfluoroalkyl substances (PFAS) for which we have a PFAS adapted life cycle impact assessment framework at hand. This tiered approach is relevant to process developers, people within the field of water and air treatment as well as the broader LCA community. This report produced within the Swedish research programme Mistra TerraClean describes the successful usage of a tiered LCA and chemical safety approach for environmental and (eco)toxicological assessment of new filter types for air and water purification that are tested and/or developed in the project.

ESAC, the EURL ECVAM Scientific Advisory Committee, advises EURL ECVAM on scientific issues. Its main role is to conduct independent peer review of validation studies of alternative test methods and to assess their scientific validity for a given purpose. The committee reviews the appropriateness of study design and management, the quality of results obtained and the plausibility of the conclusions drawn. ESAC peer reviews are formally initiated with a EURL ECVAM Request for ESAC Advice, which provides the necessary background for the peer-review and establishes its objectives, timelines and the questions to be addressed. The peer review is normally prepared by specialised ESAC Working Groups. ESAC's advice to EURL ECVAM is formally provided as 'ESAC Opinions' and 'Working Group Reports' at the end of the peer review. ESAC may also issue Opinions on other scientific issues of relevance to the work and mission of EURL ECVAM but not directly related to a specific alternative test method. The ESAC Opinion expressed in this report relates to the peer-review of the AR-CALUX in vitro test method., JRC.F.3-Chemicals Safety and Alternative Methods

ESAC, the EURL ECVAM Scientific Advisory Committee, advises EURL ECVAM on scientific issues. Its main role is to conduct independent peer review of validation studies of alternative test methods and to assess their scientific validity for a given purpose. The committee reviews the appropriateness of study design and management, the quality of results obtained and the plausibility of the conclusions drawn. ESAC peer reviews are formally initiated with a EURL ECVAM Request for ESAC Advice, which provides the necessary background for the peer-review and establishes its objectives, timelines and the questions to be addressed. The peer review is normally prepared by specialised ESAC Working Groups. ESAC's advice to EURL ECVAM is formally provided as 'ESAC Opinions' and 'Working Group Reports' at the end of the peer review. ESAC may also issue Opinions on other scientific issues of relevance to the work and mission of EURL ECVAM but not directly related to a specific alternative test method. The ESAC Opinion expressed in this report relates to the peer-review of the Bioelution in vitro test method., JRC.F.3-Chemicals Safety and Alternative Methods

Glutathione (GSH) deficiency may play a pivotal role in a variety of apparently unrelated clinical conditions and diseases. Orally administered N-acetylcysteine (NAC), which replenishes the cysteine required for GSH synthesis, has been tested in a large number of randomized placebo-controlled trials involving these diseases and conditions. This chapter focused on developing a base of evidence suggesting that NAC administration improves disease by increasing cysteine and/or GSH in a variety of diseases, thereby implying a significant role for GSH deficiency in the clinical basis of many diseases. To develop this base of evidence, we systematically selected studies which considered the hypothesis that the therapeutic efficacy for NAC is an indication that cysteine and/or GSH deficiency is a pathophysiological part of the diseases studied. In this manner we focus this chapter on explaining the biological mechanisms of NAC therapy in a wide variety of disorders and demonstrate its ubiquitous role in improving disease that involves disrupted GSH and/or cysteine metabolism. Electronic supplementary material The online version of this article (10.1007/978-981-10-5311-5_20) contains supplementary material, which is available to authorized users.

As part of the Swetox mission to react to emerging concerns in chemical health and environmental safety, a preliminary litterature investigation was undertaken to gather all readily available scientific information on PPF with respect to safety assessment, in order to better understand potential links between chemical exposure and the devopment of microcephaly in affected areas. Therefore the contents of the report do not constitute an attempt at either questioning the use of existing regulatory data in the manner prescribed by international regulatory proceedures, or as a new risk assessment, based on the scientific information and concepts discussed. Here we report our findings, with particular emphasis on exisiting regulatory information, potential for lack of translation of results from regulatory animal testing to humans, lack of human exposure data and suggestions on plausible mode(s) of action of PPF in human neurodevelopmental adversities such as microcephaly.

SEURAT-1 is a European public-private research consortium that is working towards animal-free testing of chemical compounds and the highest level of consumer protection. A research strategy was formulated around harnessing knowledge about toxicological modes-of-action and an organisational model was developed that combines crowd-sourcing with individual excellence. The proof of the initiative will be in demonstrating the applicability of the concepts on which SEURAT-1 is built. This is done on three levels: (i) Theoretical prototypes for adverse outcome pathways are formulated based on knowledge already available in the scientific literature on investigating the toxicological mode-of-actions leading to adverse outcomes; (ii) adverse outcome pathway descriptions are used as a guide for the formulation of case studies to further elucidate the theoretical model and to develop integrated testing strategies for the prediction of certain toxicological effects; (iii) further case studies target the application of knowledge gained within SEURAT-1 in the context of safety assessment. The ultimate goal would be to perform ab initio predictions based on a complete understanding of toxicological mechanisms. In the near-term it is more realistic that data from innovative testing methods will support read-across arguments. Both scenarios, the ab initio prediction and the read-across approach, are addressed with respective case studies for improved safety assessment. A conceptual framework for a rational integrated assessment strategy emerged from the efforts of designing the case studies and is discussed in the context of international developments focussing on alternative approaches for evaluating chemicals using the new 21st century tools for toxicity testing., JRC.I.5-Systems Toxicology

Background The issue of endocrine disrupting chemicals (EDCs) is receiving wide attention from both the scientific and regulatory communities. Recent analyses of the EDC literature have been criticized for failing to use transparent and objective approaches to draw conclusions about the strength of evidence linking EDC exposures to adverse health or environmental outcomes. Systematic review methodologies are ideal for addressing this issue as they provide transparent and consistent approaches to study selection and evaluation. Objective methods are needed for integrating the multiple streams of evidence (epidemiology, wildlife, laboratory animal, in vitro, and in silico data) that are relevant in assessing EDCs. Methods We have developed a framework for the systematic review and integrated assessment (SYRINA) of EDC studies. The framework was designed for use with the International Program on Chemical Safety (IPCS) and World Health Organization (WHO) definition of an EDC, which requires appraisal of evidence regarding 1) association between exposure and an adverse effect, 2) association between exposure and endocrine disrupting activity, and 3) a plausible link between the adverse effect and the endocrine disrupting activity. Results Building from existing methodologies for evaluating and synthesizing evidence, the SYRINA framework includes seven steps: 1) Formulate the problem; 2) Develop the review protocol; 3) Identify relevant evidence; 4) Evaluate evidence from individual studies; 5) Summarize and evaluate each stream of evidence; 6) Integrate evidence across all streams; 7) Draw conclusions, make recommendations, and evaluate uncertainties. The proposed method is tailored to the IPCS/WHO definition of an EDC but offers flexibility for use in the context of other definitions of EDCs. Conclusions When using the SYRINA framework, the overall objective is to provide the evidence base needed to support decision making, including any action to avoid/minimise potential adverse effects of exposures. This framework allows for the evaluation and synthesis of evidence from multiple evidence streams. Finally, a decision regarding regulatory action is not only dependent on the strength of evidence, but also the consequences of action/inaction, e.g. limited or weak evidence may be sufficient to justify action if consequences are serious or irreversible., Environmental Health, 15, ISSN:1476-069X

A proposed framework for the systematic review and integrated assessment (SYRINA) of endocrine disrupting chemicals. (DOCX 124Â kb)

A proposed framework for the systematic review and integrated assessment (SYRINA) of endocrine disrupting chemicals. (DOCX 124Â kb)