Search

Lemborexant is a novel dual orexin receptor antagonist being developed to treat insomnia. Its potential to cause QT prolongation was evaluated using plasma concentration-response (CR) modeling applied to data from 2 multiple ascending-dose (MAD) studies. In the primary MAD study, placebo or lemborexant (2.5 to 75 mg) was administered for 14 consecutive nights. In another MAD study designed to "bridge" pharmacokinetic and safety data between Japanese and non-Japanese subjects (J-MAD), placebo or lemborexant (2.5, 10, or 25 mg) was administered for 14 consecutive nights. QT intervals were estimated using a high-precision measurement technique and evaluated using a linear mixed-effects CR model, for each study separately and for the pooled data set. When each study was analyzed separately, the slopes of the CR relationship were shallow and not statistically significant. In the pooled analysis, the slope of the CR relationship was -0.00002 milliseconds per ng/mL (90%CI, -0.01019 to 0.01014 milliseconds). The highest observed Cmax was 400 ng/mL, representing a margin 8-fold above exposures expected for the highest planned clinical dose. The model-predicted QTc effect at 400 ng/mL was 1.1 milliseconds (90%CI, -3.49 to 5.78 milliseconds). In neither the J-MAD study nor the pooled analysis was an effect of race identified. CR modeling of data from early-phase clinical studies, including plasma levels far exceeding those anticipated clinically, indicated that a QT effect >10 milliseconds could be excluded. Regulatory agreement with this methodology demonstrates the effectiveness of a CR modeling approach as an alternative to thorough QT studies.

The article 1 discusses selected findings of a narrative review, funded by the Institute of Physics,2 in response to the continuing decline in the number of girls studying physics post-16 in England; 177 selected sources, of national and international research literature about girls' participation in physics, were reviewed. In the article, we argue that gender and science are mutually constitutive and girls' participation in physics education, historically and currently, needs to be understood in relation to this. Prior achievement and perceptions of the difficulty of physics are determinants of students' decisions about whether to continue to study physics. These influences may be heightened for girls by gendered associations about who is, and is not, competent in mathematics and physics. Interest and enjoyment in physics also influence students' course choices, particularly those of girls, and these decline relative to other sciences through schooling, more so for girls than boys. This decline is not di...

The changes in the statutory science curriculum specification for all students aged 14–15 in England and Wales in 2006 herald a shift in how curriculum content is organized, and the purposes for science learning. In a curriculum for scientific literacy the selection of social situations and scientific controversies determines the knowledge that is required. The goal for students' learning is to enable them to participate competently in a world permeated by science and technology. Such changes involve recognition of the situated nature of science and the situated nature of learning; hence authenticity is at the core of students' curriculum experiences. To support students as they learn about the nature of science and the communities and situations where science is created and used requires a wide range of primary and secondary sources. Energy Foresight 1 is a set of multimedia resources to support the teaching and learning of ‘Radioactive materials’ in the new curriculum. The article describes and discusse...

Much of the research into examinations and assessment has tended to ignore their social role and impact. Research in testing and examinations, in particular, has predominantly been concerned with the development and refinement of different approaches to educational measurement and technical critiques of the assessment models and associated procedures used to assess students (Broadfoot, 1996). Such a focus has tended to divert research related to examinations and testing away from the effects of the assessment procedures used in the performance of students and the social impact on learning and teaching that assessment techniques generate. However, as part of the shift in the models of learning and achievement that underpin assessment and examination systems (Murphy, 1998), informed by a wider debate about how best to assess students to fully understand their learning, educational assessors now recognise that assessment practices are not technical devices which are socially neutral; they are social techniques that have social consequences (Connell, Johnston & White, 1992). Assessors' choices of assessment techniques are not value free nor value neutral. The choices of what to assess, how to assess it and how it is evaluated all involve subjective judgements about what is valued knowledge and how this is assessed. This then involves choices about the language used, the contexts deemed appropriate, the selection of

The production of nitric oxide by the inflammatory isoform of nitric oxide synthase (NOS2) in brain glial cells is thought to contribute to the causes and development of neurological diseases and trauma. We previously demonstrated that activation of a heat shock response (HSR) by hyperthermia reduced NOS2 expression in vitro, and in vivo attenuated the clinical and histological symptoms of the demyelinating disease experimental autoimmune encephalomyelitis (EAE; Heneka et al. [2001] J. Neurochem. 77:568–579). Benzoquinoid ansamycins are fungal-derived antibiotics with tyrosine kinase inhibitory properties, and which also induce a HSR by allowing activation of HS transcription factor HSF1. We now show that two members of this class of drugs (geldanamycin and 17-allylamino-17-demethoxygeldanamycin) also induce a HSR in primary rat astrocytes and rat C6 glioma cells. Both drugs dose-dependently reduced nitrite accumulation, NOS2 steady-state mRNA levels, and the cytokine-dependent activation of a rat 2.2-kB NOS2 promoter construct stably expressed in C6 cells. These inhibitory effects were partially reversed by quercetin, a bioflavonoid which prevents HSF1 binding to DNA and thus attenuates the HSR. Ansamycins increased mRNA levels of the inhibitory IκBα protein, suggesting that inhibition of NFκB activation could contribute to their suppressive effects. Finally, in C57BL/6 mice actively immunized to develop EAE, a single injection of geldanamycin at 3 days after immunization reduced disease onset by over 50%. These results indicate that ansamycins can exert potent anti-inflammatory effects on brain glial cells which may provide therapeutic benefit in neuroinflammatory diseases. © 2002 Wiley-Liss, Inc.

The stress response (SR) can block inflammatory gene expression by preventing activation of transcription factor nuclear factor-kappa B (NF-kB). As inflammatory gene expression contributes to the pathogenesis of demyelinating diseases, we tested the effects of the SR on the progression of the demyelinating disease experimental autoimmune encephalomyelitis (EAE). EAE was actively induced in C57BL/6 mice using an encephalitogenic myelin oligodendrocyte glycoprotein (MOG35255) peptide. Whole body hyperthermia was used to induce a heat shock response (HSR) in immunized mice 2 days after the booster MOG35255 peptide injection. The HSR reduced the incidence of EAE by 70%, delayed disease onset by 6 days, and attenuated disease severity. The HSR attenuated leukocyte infiltration into CNS assessed by quantitation of perivascular infiltrates, and by reduced staining for CD4 and CD25 immunopositive T-cells. T-cell activation, assessed by the production of interferon g (IFNg) in response to MOG35255, was also decreased by the HSR. The HSR reduced inflammatory gene expression in the brain that normally occurs during EAE, including the early increase in RANTES (regulated on activation of normal T-cell expressed and secreted) expression, and the later expression of the inducible form of nitric oxide synthase. The early activation of transcription factor NF-kB was also blocked by the HSR. The finding that the SR reduces inflammation in the brain and the clinical severity of EAE opens a novel therapeutic approach for prevention of autoimmune diseases.