Prediction of disease progression, treatment response and dropout in chronic obstructive pulmonary disease (COPD).

Drug development in chronic obstructive pulmonary disease (COPD) has been characterised by unacceptably high failure rates. In addition to the poor sensitivity in forced expiratory volume in one second (FEV1), numerous causes are known to contribute to this phenomenon, which can be clustered into drug-, disease- and design-related factors. Here we present a model-based approach to describe disease progression, treatment response and dropout in clinical trials with COPD patients

Characterising QT interval prolongation in early clinical development: a case study with methadone

Recently, we have shown how pharmacokinetic-pharmacodynamic (PKPD) modelling can be used to assess the probability of QTc interval prolongation both in dogs and humans. A correlation between species has been identified for a drug-specific parameter, making it possible to prospectively evaluate non-clinical signals. Here, we illustrate how nonclinical data on methadone can be used to support the evaluation of prodromic drug effects in humans. ECG and drug concentration data from safety pharmacology study in dogs were analysed using nonlinear mixed effects modelling. The slope of the PKPD model describing the probability of QT interval prolongation was extrapolated from dogs to humans and subsequently combined with methadone pharmacokinetic data as input for clinical trial simulations. Concentration vs. time profiles were simulated for doses between 5 and 500 mg. Predicted peak concentrations in humans were then used as reference value to assess the probability of an increase in QTc interval of ≥ 5 and ≥10 ms. Point estimates for the slope in dogs suggested low probability of ≥10 ms prolongation in humans. However, an effect of approximately 5 ms increase is predicted when accounting for the 90% credible intervals the drug-specific parameter in dogs. In addition, our analysis show that understanding of interspecies differences in drug disposition is required to accurately predict the QT prolonging effects in humans. Extrapolation of the effects of parent compound may not be sufficient to describe the increase in QT interval observed after administration of methadone in humans. Assessment of the contribution of enantioselective metabolism and active metabolites is critical

Quasi-residual quasi-symmetric designs

AbstractIt is shown that for each λ ⩾ 3, there are only finitely many quasi-residual quasi-symmetric (QRQS) designs and that for each pair of intersection numbers (x, y) not equal to (0, 1) or (1, 2), there are only finitely many QRQS designs.A design is shown to be affine if and only if it is QRQS with x = 0. A projective design is defined as a symmetric design which has an affine residual. For a projective design, the block-derived design and the dual of the point-derivate of the residual are multiples of symmetric designs

Bespiegelingen over Farmacologie = Reflections on Pharmacology

Ter gelegenheid van zijn afscheid als hoogleraar in de Farmacologie aan de Universiteit Leiden op vrijdag 31 maart 2017Pharmacolog

Digitale Video Digitale Universiteit

The article is an evaluation of a pilot project focussing on a new webtool for teacher training courses based on using (streaming)digital video & internet for (peer to peer) reflection and evaluation of classroom interaction, named Digital Video for the Digital University

Characterization of the ATO Gene Family in Alternative Carbon Metabolism

As a commensal colonizer and opportunistic pathogen, Candida albicans is the most clinically important human associated fungus. Systemic infection carries an unacceptably high mortality rate of ~40% in the growing population of immunocompromised individuals. Macrophages are important innate immune cells that limit the niches in the human body in which C. albicans can persist through phagocytic removal. However, following phagocytosis C. albicans readily escapes from the immune cell by differentiating into filamentous hyphae, a process that should be inhibited in the normally acidic phagolysosome. We have shown that C. albicans induces germination by neutralizing the phagolysosome. To better understand this process we compared transcript profiles of cells in conditions that promote alkalinization in vitro to macrophage phagocytosed cells, which revealing an overlapping set of up-regulated genes, including several members of the poorly understood ATO family. This family is greatly expanded in C. albicans relative to other fungi and has been implicated in both ammonia release (Ammonia Transport Outward) and acetate metabolism. I hypothesized that the Ato proteins are important effectors of the pH change in vitro and in macrophages. Deletion of one of the 10 homologs, ATO5, or the over-expression of a dominant negative ATO1G53D allele results in a delay in environmental alkalinization in vitro, a defect in hyphal formation. Further, these strains form fewer hyphae after phagocytosis, have a reduced ability to escape macrophages, and reside in more acidic phagolysosomal compartments than wild-type cells. Analysis of an ato5Δ ATO1G53D double mutant strain revealed additive in vitro defects, similar in magnitude to the stp2∆ mutant. Additionally, over-expression of many ATO genes in a wild-type background significantly increases alkalinization and ammonia release, strongly suggesting functional overlap between them. In a complementary approach we examined Ato function in S. cerevisiae Ato proteins as important to weak acid stress tolerance and cytosolic pH homeostasis; revealing that ato mutants are sensitive to weak acid stress and are unable to maintain cytosolic pH homeostasis. This defect was largely dependent upon ScAto1. Taken together, we conclude that Ato proteins are important mediators of the host-pathogen interaction by regulating pH in some host niches

Just-in-Time Retail Distribution:A Systems Perspective on Cross-Docking

Cross-docking is a just-in-time strategy for distribution logistics. It is aimed at reducing inventory levels and distribution lead times by creating a seamless flow of products from suppliers to customers. Prior supply chain literature has argued that creating such a seamless product flows requires a holistic view on cross-docking management, aimed at synchronizing cross-docking operations at the distribution center with its inbound and outbound network logistics. This paper provides an in-depth case study illustrating how cross-docking operations can be managed more holistically in a retail distribution context. A discrete event simulation model has been developed to understand and improve the cross-docking operations of a large grocery retailer in The Netherlands. The model is used to quantitatively evaluate two proposed changes that exploit opportunities in the design and control of the retailer’s distribution network. An extensive real-world data set is used as input to the model. Overall, the case and simulation results show that a holistic cross-docking management approach can indeed improve system-wide performance, which further stresses the importance of making cross-dock operational decisions making and network decisions together

Pharmacotherapy in paediatric epilepsy: from trial and error to rational drug and dose selection – a long way to go

Whereas ongoing efforts in epilepsy research focus on the underlying disease processes, the lack of a physiologically-based rationale for drug and dose selection contributes to inadequate treatment response in children. In fact, limited information on the interindividual variation in pharmacokinetics and pharmacodynamics of anti-epileptic drugs (AEDs) in children drive prescription practice, which relies primarily on dose regimens according to a mg/kg basis. Such practice has evolved despite advancements in paediatric pharmacology showing that growth and maturation processes do not correlate linearly with changes in body size. Areas covered: In this review we aim to provide 1) a comprehensive overview of the sources of variability in the response to AEDs, 2) insight into novel methodologies to characterise such variation and 3) recommendations for treatment personalisation. Expert Opinion: The use of pharmacokinetic-pharmacodynamic principles in clinical practice is hindered by the lack of biomarkers and by practical constraints in the evaluation of polytherapy. The identification of biomarkers and their validation as tools for drug development and therapeutics will require some time. Meanwhile, one should not miss the opportunity to integrate the available pharmacokinetic data with modelling and simulation concepts to prevent further delays in the development of personalised treatments for paediatric patients